Brazilian Journal of Cardiovascular Surgery 29.2

29.2 APRIL/JUNE 2014

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR | BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY

VOL. 29 Nยบ 2 APRIL/JUNE 2014

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RBCCV REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

EDITOR/EDITOR Prof. Dr. Domingo M. Braile - PhD São José do Rio Preto - SP - Brasil domingo@braile.com.br

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY

EDITORES ANTERIORES/FORMER EDITORS • Prof. Dr. Adib D. Jatene PhD - São Paulo (BRA) [1986-1996] • Prof. Dr. Fábio B. Jatene PhD - São Paulo (BRA) [1996-2002]

EDITOR EXECUTIVO EXECUTIVE EDITOR Ricardo Brandau Pós-graduado em Jornalismo Científico - S. José do Rio Preto (BRA) brandau@sbccv.org.br

ASSESSORA EDITORIAL/EDITORIAL ASSISTANT Rosangela Monteiro Camila Safadi PhD - São Paulo (BRA) S. José do Rio Preto (BRA) rosangela.monteiro@incor.usp.br camila@sbccv.org.br

EDITORES ASSOCIADOS/ASSOCIATE EDITORS • Antônio Sérgio Martins • Gilberto Venossi Barbosa • José Dario Frota Filho • José Teles de Mendonça • Luciano Cabral Albuquerque • Luis Alberto Oliveira Dallan • Luiz Felipe Pinho Moreira

Botucatu (BRA) Porto Alegre (BRA) Porto Alegre (BRA) Aracaju (BRA) Porto Alegre (BRA) São Paulo (BRA) São Paulo (BRA)

• Manuel Antunes • Mario Osvaldo P. Vrandecic • Michel Pompeu B. Oliveira Sá • Paulo Roberto Slud Brofman • Ricardo C. Lima • Ulisses A. Croti • Walter José Gomes

Coimbra (POR) Belo Horizonte (BRA) Recife (BRA) Curitiba (BRA) Recife (BRA) S.J. Rio Preto (BRA) São Paulo (BRA)

EDITOR DE ESTATÍSTICA/STATISTICS EDITOR • Orlando Petrucci Jr.

Campinas (BRA)

CONSELHO EDITORIAL/EDITORIAL BOARD • Adib D. Jatene • Adolfo Leirner • Adolfo Saadia • Alan Menkis • Alexandre V. Brick • Antônio Carlos G. Penna Jr. • Bayard Gontijo Filho • Borut Gersak • Carlos Roberto Moraes • Christian Schreiber • Cláudio Azevedo Salles • Djair Brindeiro Filho • Eduardo Keller Saadi • Eduardo Sérgio Bastos • Enio Buffolo • Fábio B. Jatene • Fernando Antônio Lucchese • Gianni D. Angelini • Gilles D. Dreyfus • Ivo A. Nesralla • Jarbas J. Dinkhuysen • José Antônio F. Ramires • José Ernesto Succi • José Pedro da Silva • Joseph A. Dearani

São Paulo (BRA) São Paulo (BRA) Buenos Aires (ARG) Winnipeg (CAN) Brasília (BRA) Marília (BRA) Belo Horizonte (BRA) Ljubljana (SLO) Recife (BRA) Munique (GER) Belo Horizonte (BRA) Recife (BRA) Porto Alegre (BRA) Rio de Janeiro (BRA) São Paulo (BRA) São Paulo (BRA) Porto Alegre (BRA) Bristol (UK) Harefield (UK) Porto Alegre (BRA) São Paulo (BRA) São Paulo (BRA) São Paulo (BRA) São Paulo (BRA) Rochester (USA)

VERSÃO PARA O INGLÊS/ENGLISH VERSION • Carolina Zuppardi • Fernando Pires Buosi • Marcelo Almeida

• Joseph S. Coselli • Luiz Carlos Bento de Souza • Luiz Fernando Kubrusly • Mauro Paes Leme de Sá • Miguel Barbero Marcial • Milton Ary Meier • Nilzo A. Mendes Ribeiro • Noedir A. G. Stolf • Olivio Souza Neto • Otoni Moreira Gomes • Pablo M. A. Pomerantzeff • Paulo Manuel Pêgo Fernandes • Paulo P. Paulista • Paulo Roberto B. Évora • Pirooz Eghtesady • Protásio Lemos da Luz • Reinaldo Wilson Vieira • Renato Abdala Karam Kalil • Renato Samy Assad • Roberto Costa • Rodolfo Neirotti • Rui M. S. Almeida • Sérgio Almeida de Oliveira • Tomas A. Salerno

Houston (USA) São Paulo (BRA) Curitiba (BRA) Rio de Janeiro (BRA) São Paulo (BRA) Rio de Janeiro (BRA) Salvador (BRA) São Paulo (BRA) Rio de Janeiro (BRA) Belo Horizonte (BRA) São Paulo (BRA) São Paulo (BRA) São Paulo (BRA) Ribeirão Preto (BRA) Cincinatti (USA) São Paulo (BRA) Campinas (BRA) Porto Alegre (BRA) São Paulo (BRA) São Paulo (BRA) Cambridge (USA) Cascavel (BRA) São Paulo (BRA) Miami (USA)

ÓRGÃO OFICIAL DA SOCIEDADE BRASILEIRA DE CIRURGIA CARDIOVASCULAR DESDE 1986 OFFICIAL ORGAN OF THE BRAZILIAN SOCIETY OF CARDIOVASCULAR SURGERY SINCE 1986

ENDEREÇO/ADDRESS

Sociedade Brasileira de Cirurgia Cardiovascular

Rua Beira Rio, 45 • 7º andar - Cj. 72 • Vila Olímpia • Fone: 11 3849-0341. Fax: 11 5096-0079. Cep: 04548-050 • São Paulo, SP, Brasil E-mail RBCCV: revista@sbccv.org.br • E-mail SBCCV: sbccv@sbccv.org.br • Site SBCCV: www.sbccv.org.br • Sites RBCCV: www.scielo.br/rbccv / www.rbccv.org.br (também para submissão de artigos)

Publicação trimestral/Quarterly publication Edição Impressa - Tiragem: 250 exemplares

(*)

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR (Sociedade Brasileira de Cirurgia Cardiovascular) São Paulo, SP - Brasil. v. 119861986, 1: 1,2 1987, 2: 1,2,3 1988, 3: 1,2,3 1989, 4: 1,2,3 1990, 5: 1,2,3 1991, 6: 1,2,3 1992, 7: 1,2,3,4 1993, 8: 1,2,3,4 1994, 9: 1,2,3,4 1995, 10: 1,2,3,4

1996, 11: 1,2,3,4 1997, 12: 1,2,3,4 1998, 13: 1,2,3,4 1999, 14: 1,2,3,4 2000, 15: 1,2,3,4 2001, 16: 1,2,3,4 2002, 17: 1,2,3,4 2003, 18: 1,2,3,4 2004, 19: 1,2,3,4 2005, 20: 1,2,3,4

2006, 21: 1 [supl] 2006, 21: 1,2,3,4 2007, 22: 1 [supl] 2007, 22: 1,2,3,4 2008, 23: 1 [supl] 2008, 23: 1,2,3,4 2009, 24: 1 [supl] 2009, 24: 1,2,3,4 2009, 24: 2 [supl] 2010, 25: 1,2,3,4

2010, 25: 1 [supl] 2011, 26: 1,2,3,4 2011, 26: 1 [supl] 2012, 27: 1,2,3,4 2012, 27: 1 [supl] 2013, 28: 1,2,3,4 2013, 28: 1 [supl] 2014, 29: 1,2

ISSN 1678-9741 - Publicação on-line ISSN 0102-7638 - Publicação impressa RBCCV 44205

CDD 617.4105 NLM18 WG 168

(*) ASSOCIAÇÃO PAULISTA DE BIBLIOTECÁRIOS. Grupo de Bibliotecários Biomédicos. Normas para catalogação de publicações seriadas nas bibliotecas especializadas. São Paulo, Ed. Polígono, 1972

INDEXADA EM • Thomson Scientific (ISI) http://science.thomsonreuters.com • PubMed/Medline www.ncbi.nlm.nih.gov/sites/entrez • SciELO - Scientific Library Online www.scielo.br • Scopus www.info.scopus.com • LILACS - Literatura Latino-Americana e do Caribe em Ciências da Saúde. www.bireme.org • LATINDEX -Sistema Regional de Información en Línea para Revistas Cientificas de America Latina, el Caribe, España y Portugal www.latindex.uam.mx

• ADSAUDE - Sistema Especializado de Informação em Administração de Saúde www.bibcir.fsp.usp.br/html/p/pesquisa_em_ bases_de_dados/programa_rede_adsaude • Index Copernicus www.indexcopernicus.com • Google scholar http://scholar.google.com.br/scholar • EBSCO www2.ebsco.com/pt-br

SOCIEDADE BRASILEIRA DE CIRURGIA CARDIOVASCULAR

BRAZILIAN SOCIETY OF CARDIOVASCULAR SURGERY DEPARTAMENTO DE CIRURGIA DA SOCIEDADE BRASILEIRA DE CARDIOLOGIA DEPARTMENT OF SURGERY OF THE BRAZILIAN SOCIETY OF CARDIOLOGY

“Valorizando o profissional em prol do paciente” DIRETORIA 2014 - 2015 Presidente: Vice-Presidente: Secretário Geral: Tesoureiro: Diretor Científico:

Marcelo Matos Cascudo (RN) Fábio Biscegli Jatene (SP) Henrique Murad (RJ) Eduardo Augusto Victor Rocha (MG) Rui M.S. Almeida (PR)

Conselho Deliberativo:

Bruno Botelho Pinheiro (GO) Henrique Barsanulfo Furtado (TO) José Pedro da Silva (SP) Luciano Cabral Albuquerque (RS) Ricardo de Carvalho Lima (PE)

Editor da Revista: Editor do Site: Editores do Boletim:

Domingo Marcolino Braile (SP) João Carlos Ferreira Leal (SP) Walter José Gomes (SP) Domingo Marcolino Braile (SP) Orlando Petrucci (SP) Luciano Cabral Albuquerque (RS) Fernando Moraes Neto (PE)

Presidentes das Regionais Afiliadas Norte-Nordeste: Rio de Janeiro: São Paulo: Minas Gerais: Centro-Oeste: Rio Grande do Sul: Paraná: Santa Catarina:

Vinícius José da Silva Nina (MA) Marcelo Sávio da Silva Martins Rubens Tofano de Barros Rodrigo de Castro Bernardes Jorge Luiz França de Vasconcelos (MS) Marcela da Cunha Sales Luiz César Guarita Souza Milton de Miranda Santoro

Departamentos DCCVPED: DECAM: DECA: DECEN: DEPEX: DECARDIO: DBLACCV: ABRECCV:

Luiz Fernando Canêo (SP) Juan Alberto Cosquillo Mejia (CE) Cláudio José Fuganti (PR) Eduardo Keller Saadi (RS) Alexandre Ciappina Hueb (SP) José Carlos Dorsa V. Pontes (MS) Gabriel Liguori (SP) Francisco Siosney Almeida Pinto (AL)

SOCIEDADE BRASILEIRA DE CIRURGIA CARDIOVASCULAR BRAZILIAN SOCIETY OF CARDIOVASCULAR SURGERY E-mail: revista@sbccv.org.br Sites: www.scielo.br/rbccv www.rbccv.org.br

SOCIEDADE BRASILEIRA DE CIRURGIA CARDIOVASCULAR BRAZILIAN SOCIETY OF CARDIOVASCULAR SURGERY E-mail: revista@sbccv.org.br Sites: www.scielo.br/rbccv www.rbccv.org.br

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

ISSN 1678-9741 - On-line version ISSN 0102-7638 - Printed version RBCCV 44205

Impact Factor: 0.809

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY Rev Bras Cir Cardiovasc, (São José do Rio Preto, SP - Brazil) apr/jun 2014;29(2) 123-298

CONTENTS/SUMÁRIO EDITORIALS/EDITORIAIS Condemnation to plagiarism Repúdio ao plágio Domingo M. Braile.................................................................................................................................................................................. I Brazilian Registry of Cardiovascular Surgery in Adults. From design to reality Registro Brasileiro de Cirurgias Cardiovasculares em Adultos. Do projeto à realidade Walter José Gomes.................................................................................................................................................................................III Increasing isolated right heart chambers in second trimester ultrasound: always a warning sign? Aumento isolado das câmaras cardíacas no ultrassom de segundo trimestre de gestação: sempre um sinal de alerta? Milena Carvalho Carrilho, Fernanda Silveira Bello de Barros, Edward Araujo Júnior........................................................................ IV ORIGINAL ARTICLES/ARTIGOS ORIGINAIS 1531 Horizontal right axillary minithoracotomy: aesthetic and effective option for atrial and ventricular septal defect repair in infants and toddlers Minitoracotomia axilar direita horizontal: opção estética e eficaz para correção de comunicação interventricular e interatrial em lactentes e crianças Luciana da Fonseca da Silva, José Pedro da Silva, Aida L R Turquetto, Sonia Meiken Franchi, Cybelle M Cascudo, Rodrigo Moreira Castro, Walter José Gomes, Christian Schreiber..................................................................................................................................123 1532 Impact of type of procedure and surgeon on EuroSCORE operative risk validation Impacto do tipo de procedimento e do fator cirurgião na validação do EuroSCORE Fernando A. Atik, Claudio Ribeiro da Cunha......................................................................................................................................131 1533 Predictors of stroke in patients undergoing cardiac surgery Preditores de acidente vascular cerebral em pacientes submetidos à cirurgia cardíaca Handerson Nunes dos Santos, Ellen Hettwer Magedanz, João Carlos Vieira da Costa Guaragna, Natalia Nunes dos Santos, Luciano Cabral Albuquerque, Marco Antonio Goldani, João Batista Petracco, Luiz Carlos Bodanese............................................................140 1534 Analysis of transit time flow of the right internal thoracic artery anastomosed to the left anterior descending artery compared to the left internal thoracic artery Análise da medida de fluxo por tempo de trânsito da artéria torácica interna direita anastomosada para a artéria interventricular anterior comparada com a artéria torácica interna esquerda Rodrigo Milani, Daniela de Moraes, Aline Sanches, Rodrigo Jardim, Thais Lumikoski, Gabriela Miotto, Vitor Hugo Santana, Paulo Roberto Brofman..................................................................................................................................................................................148 1535 Comparison of fractal dimension and Shannon entropy in myocytes from rats treated with histidine-tryptophan-glutamate and histidine-tryptophan cetoglutarate Comparação da dimensão fractal e entropia de Shannon em miócitos de ratos submetidos à cardioplegia utilizando solução histidinatriptofano-cetoglutarato e histidina-triptofano com glutamato Marcos Aurélio Barboza de Oliveira, Antônio Carlos Brandi, Carlos Alberto dos Santos, Paulo Henrique Husseni Botelho, José Luís Lasso Cortez, Moacir Fernandes de Godoy, Domingo Marcolino Braile............................................................................................156

1536 Pain and cardiorespiratory responses of children during physiotherapy after heart surgery Dor e respostas cardiorrespiratórias durante a fisioterapia de crianças no pós-operatório de cirurgia cardíaca Adriana Sanches Garcia, Jyrson Guilherme Klamt, Walter Villela de Andrade Vicente, Luis Vicente Garcia...................................163 1537 Impact of hospital infections on patients outcomes undergoing cardiac surgery at Santa Casa de Misericórdia de Marília Impacto das infecções hospitalares na evolução de pacientes submetidos à cirurgia cardíaca na Santa Casa de Misericórdia de Marília Lucieni Oliveira Conterno, Silvana Martins Dias Toni, Rubiana Gonçalves Konkiewitz, Elaine Salla Guedes, Rubens Tofano de Barros, Marcos Gradim Tiveron.......................................................................................................................................................................167 1538 Management of multivessel coronary disease after primary angioplasty: staged reintervention versus optimized clinical treatment and two-year follow-up Manejo da doença coronária multiarterial após angioplastia primária: reintervenção estadiada versus tratamento clínico otimizado e seguimento de 2 anos José Guilherme Rodrigues de Paula, Moacir Fernandes de Godoy, Márcio Antônio dos Santos, Flávio Corrêa Pivatelli, Alan Vinicius Gamero Osti, Luciano Folchine Trindade, Diego Novelli, Marcelo Arruda Nakazone.......................................................................177 1539 High postoperative serum levels of surfactant type B as novel prognostic markers for congenital heart surgery Níveis séricos pós-operatórios tipo surfactante B elevados como novos marcadores prognósticos para cirurgia cardíaca congênita Onur Isık, Olcay Murat Disli, Tolga Bas, Hakan Aydın, Murat Koç, Ali Kutsal.................................................................................186 1540 Comparative analysis of the patency of the internal thoracic artery in the CABG of left anterior descending artery: 6-month postoperative coronary CT angiography evaluation Análise comparativa da perviedade das artérias torácicas internas na revascularização da região anterior do coração. Avaliação por angiotomografia no 6º mês de pós-operatório Maurilio Onofre Deininger, Luiz Felipe Pinho Moreira, Luiz Alberto Oliveira Dallan, Orlando Gomes de Oliveira, Daniel Marcelo Silva Magalhães, José Reinaldo de Moura Coelho, Eugênia di Giuseppe Deininger, Norland de Souza Lopes, Ricardo Wanderley Queiroga, Elizabeth Ferreira Belmont.................................................................................................................................................192 1541 Myocardial regeneration after implantation of porcine small intestinal submucosa in the left ventricle Regeneração miocárdica após implante de submucosa intestinal suína no ventrículo esquerdo Cassiana Maria Garcez Ramos, Julio César Francisco, Marcia Olandoski, Katherine Athayde Teixeira de Carvalho, Ricardo Cunha, Bruna Olandoski Erbano, Lianna Ferrari Jorge, Cristina Pellegrino Baena, Vivian Ferreira do Amaral, Lucia Noronha, Rafael Michel de Macedo, José Rocha Faria-Neto, Luiz César Guarita-Souza..........................................................................................................202 1542 Morphologic expression of the left coronary artery in pigs. An approach in relation to human heart Expressão morfológica da artéria coronária esquerda em porcos. Abordagem em relação ao coração humano Fabian Alejandro Gómez, Luis Ernesto Ballesteros.............................................................................................................................214 1543 Preoperative therapy restores ventilatory parameters and reduces length of stay in patients undergoing myocardium revascularization Fisioterapia pré-operatória restabelece parâmetros ventilatórios e reduz tempo de internação após revascularização do miocárdio Moises Teixeira Sobrinho, Gabriel Negretti Guirado, Marcos Augusto de Moraes Silva...................................................................221 1544 Improvement in cardioplegic perfusion technique in single aortic clamping - initial results Aperfeiçoamento em técnica de perfusão cardioplégica no pinçamento único de aorta - resultados iniciais Marcelo Luiz Peixoto Sobral, Sérgio Francisco dos Santos Júnior, Juliano Cavalcante de Sá, Anderson da Silva Terrazas, Daniel Francisco de Mendonça Trompieri, Thierry Araújo Nunes de Sousa, Gilmar Geraldo dos Santos, Noedir Antonio Groppo Stolf.........................229 1545 Left subclavian artery stenting: an option for the treatment of the coronary-subclavian steal syndrome Angioplastia com stent de artéria subclávia esquerda: uma opção no tratamento da Síndrome do Roubo Coronário-subclávio Bruno Lorenção de Almeida, Antonio Massamitsu Kambara, Fabio Henrique Rossi, Samuel Martins Moreira, Eduardo Silva Jordao de Oliveira, Frederico Augusto de Carvalho Linhares Filho, Patrick Bastos Metzger, Aldo Zampieri Passalacqua...........................236 1546 Evolution of weight and height of children with congenital heart disease undergoing surgical treatment Evolução pondero-estatural de crianças com cardiopatias congênitas submetidas a tratamento cirúrgico Murilo Bertazzo Peres, Ulisses Alexandre Croti, Moacir Fernandes de Godoy, Carlos Henrique De Marchi, Sírio Hassem Sobrinho, Lilian Beani, Airton Camacho Moscardini, Domingo Marcolino Braile.............................................................................................241

SPECIAL ARTICLES/ARTIGOS ESPECIAIS 1547 The calcium paradox - What should we have to fear? Paradoxo do cálcio - o que temos a temer? Marcos Aurélio Barboza de Oliveira, Antônio Carlos Brandi, Carlos Alberto dos Santos, Paulo Henrique Husseni Botelho, José Luís Lasso Cortez, Gilberto Goissis, Domingo Marcolino Braile...............................................................................................................249 1548 Cardiac risk stratification in cardiac rehabilitation programs: a review of protocols Estratificação de risco cardíaco em programas de reabilitação cardíaca: revisão de protocolos Anne Kastelianne França da Silva, Marianne Penachini da Costa de Rezende Barbosa, Aline Fernanda Barbosa Bernardo, Franciele Marques Vanderlei, Francis Lopes Pacagnelli, Luiz Carlos Marques Vanderlei.................................................................................255 REVIEW ARTICLE/ARTIGO DE REVISÃO 1549 Vacuum-assisted drainage in cardiopulmonary bypass: advantages and disadvantages Sistema a vácuo na circulação extracorpórea: vantagens e desvantagens Élio Barreto de Carvalho Filho, Fernando Augusto de Lima Marson, Loredana Nilkenes Gomes da Costa, Nilson Antunes...........266 EXPERIMENTAL STUDY/TRABALHO EXPERIMENTAL 1550 Biocompatibility of Ricinus communis polymer with addition of calcium carbonate compared to titanium. Experimental study in guinea pigs. Biocompatibilidade do polímero de óleo de mamona com acréscimo de carbonato de cálcio comparado ao titânio. Estudo experimental em cobaias. Yorgos Luiz Santos de Salles Graça, Ana Cristina Opolski, Barbara Evelin Gonçalves Barboza, Bruna Olandoski Erbano, Caroline Cantalejo Mazzaro, Flávia Caroline Klostermann, Enéas Eduardo Sucharski, Luiz Fernando Kubrusly...........................................272 BRIEF COMMUNICATION/COMUNICAÇÃO BREVE 1551 The use of virtual resources in preoperative preparation of infrarenal aneurysms: exploring the OsiriX's potential O uso de recursos virtuais na preparação pré-operatória de aneurismas infrarrenais: explorando o potencial do OsiriX Giovani Jose Dal Poggetto Molinari, Andréia Marques de Oliveira Dalbem, Ana Terezinha Guillaumon.........................................279 CLINICAL-SURGICAL CORRELATION/CORRELAÇÃO CLÍNICO-CIRÚRGICA 1552 Intracardiac embolization of inferior vena cava filter associated with right atrium perforation and cardiac tamponade Embolização de filtro de veia cava associado à perfuração de átrio direito e tamponamento cardíaco Alexandre de Matos Soeiro, Felipe Lourenço Fernandes, Rafael Plens Teixeira, Pedro Felipe Gomez Nicz, Maria Carolina Feres de Almeida Soeiro, Carlos V. Serrano Jr., Múcio Tavares de Oliveira Jr..................................................................................................285 LETTERS TO THE EDITOR/CARTAS AO EDITOR 1553 Comment on " Depression after CABG: a prospective study" Umit Cintosun, Umut Safer..................................................................................................................................................................289 Reviewers BJCVS 29.2/Revisores RBCCV 29.2.................................................................................................................................291 ERRATUM/ERRATA...........................................................................................................................................................................292

Impresso no Brasil Printed in Brazil

Graphic design and layout: Heber Janes Ferreira

Editorial

Condemnation to plagiarism Repúdio ao plágio

Domingo M. Braile1 DOI: 10.5935/1678-9741.20140089

O

cited article. The citation network currently covers more than 67 million journal articles, in addition to book chapters, data, theses and technical reports[2]. This is a very valuable tool for authors and publishers, which will be paid with funds from the Brazilian Society of Cardiovascular Surgery. A major achievement implanted in our journal was to make it available as APP (application), both for iOS (iPhone, iPad) and Android system (Samsung, Motorola, Sony, and others). Thus, once downloaded the app, the reader can simply access it to find BJCVS articles. The application is available for download on the App Store for iOS, or GOOGLE PLAY for Android.

ne of the biggest spots of science communication is plagiarism. This despicable practice, although it is practiced by a small percentage of scientists has created many hitches and put under suspicion the serious studies of those engaged in science as a form of knowledge to improve the condition of life on our planet. Plagiarism was one of the dominant themes of the XXI Scientific Publishing Course of the Brazilian Association of Medical Editors (ABEC), held 15-17 May in São José dos Campos, SP, in which the Brazilian Journal of Cardiovascular Surgery (BJCVS) was represented by its Executive Editor, Ricardo Brandau. In his presentation, Marcelo Krokscz, Professor of Scientific Methodology at Fundação Escola de Comércio Álvares Penteado (FECAP) and experts in the field, drew a picture on ethics in science and consequences of plagiarism, as the growing number of articles portrayed. He showed a study published in 2011 in Nature, revealing that the number of retractions has risen 10 times in the previous decade, while in the same period the number of articles published has increased by only 44% in journals indexed in PubMed and Web of Science (http://www.nature.com/news/2011/111005/ full/478026a/box/2.html)[1]. Krokscz and other speakers emphasized the need for scientific publications to be vigilant in curbing the practice, which involves not only plagiarism, but also the self-plagiarism, an issue ignored by many. Among the suggestions are carefully reading of submitted manuscripts by the Editors and Reviewers, and explicit instructions in Guidelines for Authors and use of plagiarism detection software. BJCVS always vehemently repudiated plagiarism and already uses detection software (eTBLAST®) and will leave clear its position in Instructions to Authors. Also, the Journal will include in the submission process of manuscripts a letter that must be signed by the authors, warning of the risks and consequences of plagiarism and self-plagiarism. I ask the Editorial Board of BJCVS to remain vigilant in order to avoid that our journal suffers with this problem. Another point I wish to emphasize is the adoption of CrossRef by BJCVS. The CrossRef is an association of publishers that aims to make the most effective scientific communication. With just a click on a reference duly identified by the DOI in a publication, the researcher has access to the

DOI articles in “ahead of print” Fortunately, the flow of manuscripts has grown, which proves that BJVCS has increasing relevance in the Brazilian and international scene. However, this causes an undesirable effect in some cases, which is the delay between the approval of a study and its publication. Many authors need to prove with certain urgency with the publication for the purposes of Masters, Doctoral or contests and promotions, in addition, the number of publications per author is critical for Advisors in “stricto sensu” Graduate Courses, because it is a factor very important in the classification of courses along the Capes. In this context, in order to minimize the consequences of this gap, after much work, the DOI (Digital Object Identifier) will be assigned for the articles already approved, but still in the area “Published Ahead of Print”, preserving the identity and the precedence of the study officially. Thus, the study can be cited and through consultation to DOI, it can be read even before its publication in the journal. The delay, on average, between the availability of the Ahead of Print article on site (www.rbccv.org.br/-publication proofs) and the DOI assignment is only two days. Superscript references In terms of the new XML markup of the journal, references should be identified in superscript and no more brackets. I call the attention of authors and reviewers for this change. It is very important that all are aware of the changes and follow the Standards of Vancouver. Questions can be answered in

I

Rev Bras Cir Cardiovasc | Braz J Cardiovasc Surg

the links or http://www.rbccv.org.br/page/6 or http://www. nlm.nih.gov/bsd/uniform_requirements.html or also by direct consultation with our team. 41st Congress of BSCVS The 41st Congress of the Brazilian Society of Cardiovascular Surgery, held 3-5 April in Porto de Galinhas, PE, was once again a great success, presenting the latest trends in the area and promoting harmonization among cardiac surgeons, as well as other health professionals such as nurses, physical therapists, perfusionists, residents and students. The awarded studies in the area of Cardiovascular ​​ Surgery, were as follows: Free Themes - 1st place: “Mechanical circulatory assistance in critically ill patients with left ventricular dysfunction: experience from a tertiary center”, by Dr. Fabio Biscegli Jatene (SP) and colleagues; 2nd place: “Attenuation of ischemic spinal cord injury by intrathecal injection of stem cells from human umbilical cord in mice”, by Dr. Gustavo Ieno Judas (SP) and colleagues; 3rd place: “Initial results after conventional aortic valve replacement in 906 patients over 70 years old - Brazilian Aortic Valve Replacement Study (BRAVARS)”, by Dr. Rui M. S. Almeida (PR) and colleagues. Posters - 1st place - “Left internal thoracic artery to the anterior interventricular: comparative study between single or sequential anastomoses by measuring flow by transit time”, by Dr. Rodrigo Milani (PR) and colleagues; 2nd place: “The use of mechanical circulatory support of short duration increases the survival of pediatric patients queued for heart transplantation”, by Dr. Luiz Fernando Caneo (SP) and colleagues; 3rd place: “Impact of the use of polyglactin yarn impregnated with triclosan in preventing saphenectomy wound infection in coronary artery bypass grafting: a prospective, double-blind, randomized clinical trial”, by Dr. Paulo Samuel Santos Filho (RJ) and colleagues. The BSCVS Professional of the Year award was delivered, with much justice, to Full Prof. Dr. Walter José Gomes, former President of our Society, for his tireless efforts and concern for increasingly improving scientific knowledge of Brazilian cardiovascular surgeons, as well as promoting greater integration between BSCVS and its international counterparts. During the Congress, we held a fruitful meeting of the Editorial Board of BJCVS. I appreciate the attendance and input from all present (Figure 1), which will certainly give more dynamism to our publication.

Fig. 1 - Participants of the meeting of the Editorial Board of the Brazilian Journal of Cardiovascular Surgery at the 41st Congress of the BSCVS in Porto de Galinhas, PE. Standing, from left to right: Dr. Mauro Paes Leme de Sá, Dr. Manuel Antunes, Dr. Renato Assad, Dr. Paulo Manoel Pêgo-Fernandes, Dr. Walter Gomes, Dr. Luciano Albuquerque and Dr. Ricardo Lima. Seated, from right to left: Ricardo Brandau, Dr. Domingo Braile, Dr. Paulo Brofman and Dr. Otoni Moreira Gomes

internal thoracic artery anastomosed to the left anterior descending artery compared to the left internal thoracic artery”, p. 148, and “Comparative assessment of the patency of the internal thoracic artery in the revascularization to left anterior descending artery: coronary CT angiography evaluation 6 months postoperatively”, p. 192. I emphasize the importance of this form of learning and encourage them to do the tests and give us feedback, so that we can improve them to meet the expectations. My warmest regards

Editor-in-Chief BJCVS

1

CME Items available for testing by the Continuing Medical Education (CME) system are: “Impact of type of procedure and surgeon on EuroSCORE operative risk validation”, p. 131; “Predictors of stroke in patients undergoing cardiac surgery”, p. 140; “Analysis of transit time flow of the right

REFERENCES

1. Van Noorden R. Science publishing: the trouble with retractions. Nature. 2011;478(7367):26-8. doi: 10.1038/478026a.

2. Crossref [Acesso 28 jun 2014]. Disponível em: http://www. crossref.org/

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Editorial

Brazilian Registry of Cardiovascular Surgery in Adults. From design to reality Registro Brasileiro de Cirurgias Cardiovasculares em Adultos. Do projeto à realidade

Walter J. Gomes1, PhD; Fábio B. Jatene2, PhD; Josalmir José M. Amaral3, PhD; José Leôncio A. Feitosa4, PhD; Rui M. S. Almeida5, PhD; Marcelo M. Cascudo6, PhD DOI: 10.5935/1678-9741.20140090

As Brazil is inserting itself in the international community of Cardiovascular Surgery for its full recognition, some steps need to be taken to reach the quality standards of first world countries. The introduction of the Brazilian Registry of Cardiovascular Surgery, for while in adults, shows a long-standing need which is important to know the reality of the country and develop strategies to deploy advances in quality and excellence. The project is an initiative of the Brazilian Society of Cardiovascular Surgery (BSCVS) and aims to document the practice of Cardiovascular Surgeries across the country, involving all Brazilian centers dedicated to specialty, including public hospitals (university and non-university) and also private ones. Surgical procedures included in the registry are: Myocardial Revascularization (open and endovascular), Aortic valve replacement (open and transcatheter), Atrial Fibrillation, Cardiac Transplantation, Mechanical Circulatory Assistance (from insertion of intra-aortic balloon to artificial heart) and Congenital heart defects in adults (> 18 years). We are going to create a database of clinical parameters of patients undergoing cardiovascular surgery in Brazil, involving the collection of standardized data among hospitals that perform these procedures. The study will follow the patients until discharge, extending the periods of 30 days, 6 months and 12 months for evaluation of major cardiovascular events.

The work will require effort, dedication and willingness of the participating centers and those responsible for data collection, since the project will be solely funded by BSCVS with budget constraints. We will collect the complete demographics of patients undergoing cardiovascular surgery in the participating hospitals, followed by data from the surgery and postoperative outcomes, including mortality. Data will be collected by local monitors of the participating centers and transmitted to a secure database located in the Hcor Institute of Education and Research in Sao Paulo. The stored data will be confidential (only the institution will have access to its information) and analyzed together to develop best practices in cardiovascular surgery in Brazilian hospitals, and assist in improving the quality of patient care through the development of statistical models analysis of risk factors, striving for excellence in results. In addition, the project aims to assess incidences of cardiovascular events and to obtain new data on quality of life in the short, medium and long term; identifying predictors of events that enable the development of risk scores. Interpretation of the data will document the current clinical practice, and adherence to evidence-based (Medical Guidelines) therapies. It will also serve to plan future programs to improve medical-surgical practice; comparing data from different countries and hospitals to optimize the results. As a byproduct, the information collected will allow the design of new studies and optimization of available resources. In short, the project: Brazilian Registry of Cardiovascular Surgery in Adults is a resource that was already imperative, but now appears as a reality with the participation of all the cardiovascular community. It is definitely filling the gap that separates us from the first world countries.

Escola Paulista de Medicina of Universidade Federal de São Paulo, São Paulo, SP, Brazil. 2 Instituto do Coração of Faculdade de Medicina of Universidade de São Paulo, São Paulo, SP, Brazil. 3 Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil. 4 Instituto Nacional de Cardiologia, Rio de Janeiro, RJ, Brazil. 5 Universidade Estadual do Oeste do Paraná, Cascavel, PR, Brazil. 6 Instituto do Coração, Natal, RN, Brazil. E-mail: wjgomes.dcir.epm.br 1

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Editorial

Increasing isolated right heart chambers in second trimester ultrasound: always a warning sign? Aumento isolado das câmaras cardíacas no ultrassom de segundo trimestre de gestação: sempre um sinal de alerta?

Milena Carvalho Carrilho1, Fernanda Silveira Bello de Barros1, MD; Edward Araujo Júnior1, MD, PhD

DOI: 10.5935/1678-9741.20140057

Congenital heart disease (CHD) is one of the leading causes of birth defects and occurs in approximately 1 in every 100 live births[1]. This condition has been attracting the attention of the medical community in terms of screening and diagnosis of CHDs. Because of the constant movement of the fetus during ultrasound examinations and the small size of the heart, it is challenging to obtaining good quality images and performs accurate analysis of intracardiac structures and outflow tracts. The increasing ability of medical professionals allied to recent technological advances, from the development of sector transducers with real-time imaging to two-dimensional studies and color mapping of blood flow to the advent of three-dimensional (3D) technology, has enabled new perspectives for earlier and more accurate diagnoses. Despite these medical advancements, analysis of the enlargement of the right cardiac chamber of the fetus remains a major challenge for sonographers and echocardiographers. In the normal fetal heart, physiological enlargement of the right atrium and a simultaneous increase in the right ventricle can be observed. Moreover, the right atrium is the only cardiac chamber that receives the entire cardiac output[2]. This situation demands special attention and caution when determining the boundaries between physiological and pathological processes, particularly when evaluating aortic coarctation, which can be erroneously considered as normal. Since 1988, the enlargement of the right cardiac chambers has drawn attention from specialists in fetal cardiology. Allan et al.[3] conducted a prospective study involving approximately 2000 pregnant women, and enlargement of the right ven-

tricle and pulmonary artery were found in 24 fetuses. Coarctation or interruption of the aorta was clinically suspected in 18 of these fetuses and confirmed in 10. Five cases of aortic coarctation were not detected by fetal echocardiography but were confirmed postnatally[3]. Starting in 2001, Hornung et al.[4] studied 43 fetuses with right ventricular enlargement over a 5-year period and verified that this condition had both cardiac and noncardiac origins. Fifteen patients presented enlargements of cardiac origin, 14 of which were caused by structural abnormalities; one patient had tachycardia. These structural abnormalities primarily included coarctation of the aorta (N=4) and ventricular septal defects (VSD; N=4). Nine patients with enlargement had associated extracardiac malformations, particularly chromosomal disorders, and 19 others had associated enlargement of the right ventricle without intra- or extracardiac anomalies[4]. Differential diagnosis should always involve the assessment of aortic coarctation when there is disproportionate enlargement of the right ventricular chamber, considering the low sensitivity and predictive values of the ventricular disproportion, corresponding to 62% and 33%, respectively[5]. The sensitivity and specificity values can decrease even further after the 34th week of gestation, when there is physiological enlargement of the right cardiac chamber[6]. Aortic coarctation accounts for 2%-6% CHD patients. Nonetheless, channel-dependent congenital cardiopathies are the least diagnosed in the prenatal period because of the high rate of false-negative results and the low diagnostic specificity; consequently, many newborns are considered healthy and are discharged. The prenatal diagnosis of aortic coarctation allows early intervention and improved prognosis[2,7]. After right chamber enlargement is diagnosed, physicians should initially ensure that it is an isolated occurrence and eliminate the possibility of occurrence of other conditions,

Federal University of São Paulo (UNIFESP), Department of Obstetrics, Fetal Cardiology Unit, São Paulo, SP, Brazil. E-mail: araujojred@terra.com.br 1

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Abbreviations, acronyms & symbols 3D Three-dimensional 3VT Three-vessel and tracheal CHD Congenital heart disease VSD Ventricular septal defects

including right ventricular outflow tract obstruction, hypoplasia of the left chambers, and restrictive atrial septum. An additional differential diagnosis of this isolated enlargement includes vein of Galen aneurismal malformations and the noncardiac diagnoses of aneuploidy, anemia, and restricted intrauterine growth caused by placental insufficiency[2,8]. A thorough assessment of the aorta through the three-vessel and tracheal (3VT) view is critical to determine the disproportion in the diameter of the great arteries. To decrease the high incidence of false-positive results related to the prenatal diagnosis of aortic coarctation, Pasquini et al.[6] included the measurement of the aortic isthmus in the 3VT method on the basis of the hypothesis that aortic arch hypoplasia is more common in the fetus, thus avoiding diagnostic errors arising from analysis of the aortic arch as a whole. Considering that the site of narrowing of the aortic isthmus is located immediately before the entry of the ductus arteriosus to the proximal descending aorta, this location can be used to measure the isthmus (Z-score) associated with gestational age[6]. Other cardiovascular conditions should be accurately identified in patients with enlargement of the right cardiac chambers, such as the presence of a persistent left superior vena cava, VSD, and a bicuspid aortic valve. These diagnostic findings may be overlooked and often mask the diagnosis of aortic coarctation[9,10]. In summary, the isolated enlargement of the right cardiac chamber is a normal finding in the most cases. However, aortic coarctation is a serious disease, and its early detection can improve patient recovery. For this reason, we recommend specialized fetal echocardiography in all pregnant women whose fetuses present with isolated enlargement of the right cardiac chamber detected by ultrasound during the second trimester.

1. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39(12):1890-900. 2. Lopes LM. Anomalias do arco aórtico. In: Lopes LM, ed. Atlas comentado de cardiologia fetal. São Paulo: RR Donnelley America Latina; 2003. p.258-68. 3. Allan LD, Chita SK, Anderson RH, Fagg N, Crawford DC, Tynan MJ. Coarctation of the aorta in prenatal life: an echocardiographic, anatomical, and functional study. Br Heart J. 1988;59(3):356-60. 4. Hornung TS, Heads A, Hunter AS. Right ventricular dilatation in the fetus: a study of associated features and outcome. Pediatr Cardiol. 2001;22(3):215-7. 5. Matsui H, Mellander M, Roughton M, Jicinska H, Gardiner HM. Morphological and physiological predictors of fetal aortic coarctation. Circulation. 2008;118(18):1793-801. 6. Pasquini L, Mellander M, Seale A, Matsui H, Roughton M, Ho SY, et al. Z-scores of the fetal aortic isthmus and duct: an aid to assessing arch hypoplasia. Ultrasound Obstet Gynecol. 2007;29(6):628-33. 7. Paladini D, Russo M, Teodoro A, Pacileo G, Capozzi G, Martinelli P, et al. Prenatal diagnosis of congenital heart disease in the Naples area during the years 1994-1999: the experience of a joint fetal-pediatric cardiology unit. Prenat Diagn. 2002;22(7):545-52. 8. Head CE, Jowett VC, Sharland GK, Simpson JM. Timing of presentation and postnatal outcome of infants suspected of having coarctation of the aorta during fetal life. Heart. 2005;91(8):1070-4. 9. Pasquini L, Fichera A, Tan T, Ho SY, Gardiner H. Left superior caval vein: a powerful indicator of fetal coarctation. Heart. 2005;91(4):539-40.

Authors’ roles & responsibilities MCC FSBB EAJ

REFERENCES

Drafting of the manuscript or revising its content critically Drafting of the manuscript or revising its content critically Final approval of manuscript

10. Paladini D, Volpe P, Russo MG, Vassallo M, Sclavo G, Gentile M. Aortic coarctation: prognostic indicators of survival in the fetus. Heart. 2004;90(11):1348-9.

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SOCIEDADE BRASILEIRA DE CIRURGIA CARDIOVASCULAR BRAZILIAN SOCIETY OF CARDIOVASCULAR SURGERY E-mail: revista@sbccv.org.br Sites: www.scielo.br/rbccv www.rbccv.org.br

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Rev Bras Cir Cardiovasc 2014;29(2):123-30

Silva LF, et al. - HorizontalARTICLE right axillary minithoracotomy: aesthetic and ORIGINAL effective option for atrial and ventricular septal defect repair in infants and toddlers

Horizontal right axillary minithoracotomy: aesthetic and effective option for atrial and ventricular septal defect repair in infants and toddlers Minitoracotomia axilar direita horizontal: opção estética e eficaz para correção de comunicação interventricular e interatrial em lactentes e crianças

Luciana da Fonseca da Silva1,2, PhD; José Pedro da Silva2, PhD; Aida L R Turquetto2; Sonia Meiken Franchi2; Cybelle M Cascudo2; Rodrigo Moreira Castro2; Walter José Gomes1, PhD; Christian Schreiber3, PhD

DOI: 10.5935/1678-9741.20140028

RBCCV 44205-1531

Abstract Introduction: Congenital heart defects treatment shows progressive reduction in morbidity and mortality, however, the scar, resulting from ventricular (VSD) and atrial septal defect (ASD) repair, may cause discomfort. Right axillary minithoracotomy approach, by avoiding the breast growth region, is an option for correction of these defects that may provide better aesthetic results at low cost. Since October 2011, we have been using this technique for repairing VSD and ASD defects as well as associated defects. Objectives: To evaluate the efficacy of this method in children undergoing correction of VSD and ASD, to compare perioperative clinical outcomes with those repaired by median sternotomy, and to evaluate the aesthetic result. Methods: Perioperative clinical data of 25 patients submitted to axillary thoracotomy were compared with data from a paired group of 25 patients with similar heart defects repaired by median sternotomy, from October 2011 to August 2012.

Results: Axillary approach was possible even in infants. There was no mortality and the main perioperative variables were similar in both groups, except for lower use of blood products in the axillary group (6/25) vs. control (13/25), with statistical difference (P =0.04). The VSD size varied from 7 to 15 mm in axillary group. Cannulation of the aorta and vena cavae was performed through the main incision, whose size ranged from 3 to 5 cm in the axillary group, with excellent aesthetic results. Conclusion: The axillary thoracotomy was effective, allowing for a heart defect repair similar to the median sternotomy, with more satisfactory aesthetic results and reduced blood transfusion, and it can be safely used in infants.

Escola Paulista de Medicina da Universidade Federal de São Paulo, (UNIFESP/EPM), São Paulo, SP, Brazil. 2 Hospital Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil. 3 Department of Cardiovascular Surgery, German Heart Center Munich at the Technical University Munich, Munich, Germany.

Work carried out at Hospital Beneficência Portuguesa de São Paulo, Escola Paulista de Medicina - UNIFESP, São Paulo SP, Brazil; Department of Cardiovascular Surgery, German Heart Center Munich at the Technical University Munich, Munich Germany.

Descriptors: Heart Septal Defects, Ventricular. Heart Septal Defects, Atrial. Surgical Procedures, Minimally Invasive.

1

No financial support.

Correspondence address: Rua Maestro Cardim, 769, sala 202 – Paraíso - São Paulo, SP, Brazil Zip code: 01323-001 E-mail: lufonseca@uol.com.br

Article received on April 8th, 2013 Article accepted on July 14th, 2013

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Silva LF, et al. - Horizontal right axillary minithoracotomy: aesthetic and effective option for atrial and ventricular septal defect repair in infants and toddlers

de crescimento da mama. Desde outubro de 2011, empregamos esta técnica para correção de CIA, CIV e defeitos associados. Objetivo: Avaliar a eficácia do método em crianças submetidas à correção de CIV e CIA, avaliar a evolução clínica perioperatória em comparação à esternotomia mediana e avaliar o resultado estético. Métodos: Dados clínicos perioperatórios de 25 pacientes submetidos à minitoracotomia axilar foram comparados com dados de grupo de 25 pacientes submetidos à correção de defeitos cardíacos semelhantes por esternotomia mediana, de outubro de 2011 a agosto de 2012. Resultados: A correção dos defeitos via axilar foi factível inclusive em lactentes. Não houve mortalidade e as principais variáveis perioperatórias foram similares em ambos os grupos, exceto pelo menor uso de hemoderivados no grupo axilar (6/25) x controle (13/25), com diferença estatística (P=0,04). A sequela ventricular nos pacientes do grupo axilar variou de 7 a 15 mm. A canulação da aorta e veias cavas foi realizada através da incisão principal, cujo tamanho variou de 3 a 5 cm no grupo axilar, com resultado estético excelente. Conclusão: A minitoracotomia axilar foi eficaz, permitiu correção do defeito cardíaco semelhante à esternotomia mediana, com resultado estético mais satisfatório e menor necessidade de transfusão sanguínea, podendo ser utilizada com segurança em lactentes.

Abbreviations, acronyms & symbols Ao AoC ASD CHD CIA CIV CL CPB HRAMT IVC MS PTFE RAT SVC VSD VSD

Aortic cannula Aortic clamp Atrial septal defect Congenital heart disease Comunicação interatrial Comunicação interventricular Cardioplegic line Cardiopulmonary bypass Horizontal right axillary mini thoracotomy Inferior vena cava Median sternotomy Polytetrafluoroethylene Right anterolateral thoracotomy Superior vena cava Approach through the right atriotomy Ventricular septal defect

Resumo Introdução: O tratamento dos defeitos cardíacos apresenta progressiva redução da morbimortalidade, porém, a cicatriz, sequela aparente do tratamento da comunicação interatrial (CIA) e interventricular (CIV), pode causar incômodo. A abordagem por minitoracotomia axilar é opção para correção destes defeitos, com possível melhor estética e baixo custo, além de evitar a região

Descritores: Comunicação Interventricular. Comunicação Interatrial. Procedimentos Cirúrgicos Minimamente Invasivos.

INTRODUCTION

the same incision for repair of ASD, using heart fibrillation, and no aortic cross-clamping. They demonstrated this technique to us, which we modified by opening the chest in the third intercostal space, cross-clamping the aorta and applying cardioplegic solution. This strategy has allowed us to repair more complex cases. The horizontal right axillary minithoracotomy (HRAMT) has shown even more superior cosmetic results when compared to conventional incisions by staying hidden under the resting arm, avoiding any interference in the development of breasts, as well as preventing the sectioning of muscles and glands and allowing for the treatment of restrictive VSDs[12,13]. However, its use in patients under 15 kg was not recommended by some authors, due to the difficulty of direct cannulation of the aorta[14]. Since October 2011, we have been employing this technique for correction of VSD, ASD and associated defects, extending its use to younger children (5 months), with direct cannulation of the vessels through the same incision in all patients.

The treatment of congenital heart defects has evolved with gradual reduction of morbidity and mortality, but the scar resulting from surgical treatment may be disturbing. The effective repair of ventricular septal defect (VSD) and atrial septal defect (ASD), with less aggressive approach to the patient, is the goal of minimally invasive surgery. The usual approach for correction of simple congenital heart disease (CHD) includes median sternotomy (MS) and right anterolateral thoracotomy (RAT)[1]. Newer minimally invasive approaches such as ministernotomy[2], trans-xiphoid approach without MS[3,4] and posterolateral thoracotomy[5,6] have been proposed for the treatment of children, attempting to avoid the distortion of breast growth that can be caused by RAT when applied in pre-pubescent girls[7,8]. The axillary minithoracotomy, originally proposed for thoracic surgery[9] was used as a vertical infra axillary minithoracotomy, associated with cardiopulmonary bypass (CPB) and ventricular fibrillation for ASD repair without clamping of the aorta[10]. Subsequently, its use was expanded to approach other heart diseases[11]. It offers the aesthetic benefit without increasing surgical costs, since it does not require special tools. Schreiber et al.[12] reported the use of horizontal minithoracotomy in the fourth intercostal space, aortic and bicaval cannulation through

Objective To evaluate the effectiveness of the HRAMT approach in children and infants undergoing VSD and ASD closure, to assess the quality of treatment offered to the HRAMT group, comparing the perioperative data with the group subjected to the usual treatment by MS, including the need for blood transfusion.

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To evaluate the aesthetic result of the thoracic incision in HRAMT and satisfaction of parents or guardians.

phrenic nerve. The heart was exposed adequately by opening the pericardium, and placing suitable stay sutures. The thymus gland was preserved. The pericardial incision was extended toward the aorta and a stabilizing 5.0 polypropylene suture was placed in the apex of right atrial appendage, for better aortic exposure. A Cooley-Satinsky clamp was tested for partial aortic clamping at the cannulation site, just in case it became necessary. After heparin infusion, two standard purse-string 5.0 or 6.0 polypropylene sutures were placed on the ascending aorta, and direct cannulation was performed with straight cannula, of suitable size for the patient's weight. Tapes were passed around the vena cavae. After placing standard purse-string sutures in superior vena cava and in the junction of the inferior vena cava with the right atrium, both vena cavae were cannulated and CPB was initiated. After mild systemic cooling, the aorta was cross clamped and blood cardioplegic solution was infused in the aortic root. The right atrium was opened longitudinally and some stay sutures were placed at the right atrium edge, which were gently pulled toward the chest opening, exposing the ASD. Usually, tricuspid valve leaflet proximal detachment is required for better subaortic VSD exposure. The subaortic region was explored in all patients and any subaortic membrane was resected when present. The VSD was closed with either polytetrafluoroethylene (PTFE) patch or autologous pericardial patch using 6.0 polypropylene running suture technique. The tricuspid valve was reattached. Saline solution was injected in the left ventricle to check for residual VSD. In case of ASD, it was closed with either PTFE or autologous pericardial patch, except for one patient in this series who had ASD amenable for direct closure with polypropylene 5.0 sutures. Mitral valve repair was carried out in one patient, with chordal reduction and annuloplasty with multiple interrupted sutures plicature at different locations of the mitral annulus. In one patient with previous diagnosis of partial anomalous pulmonary vein connection to the superior vena cava associated with ASD, the superior vena cava cannulation was made at a higher level. In this case the right atrial appendage was used to enlarge the superior vena cava, after redirection of pulmonary veins flow to the left atrium with a PTFE patch used to close the ASD.

METHODS Selection of individuals: This is a retrospective study with comparative analysis of HRAMT patients operated from October 2011 to August 2012 and paired patients operated by MS, for surgical repair of VSD, ASD and associated heart defects under CPB. All first 25 consecutive patients to whom the HRAMT approach was performed were included in the group named HRAMT. In order to balance the prognostic factors, the MS paired case control group patients were selected among the 247 patients undergoing treatment for the same types of heart defects from October 2011 to August 2012 by the same surgical team. For each individual of HRAMT group, a case control individual with the same heart defect, weight (for children assuming values ¹ 2 kg), age, and sex was selected. The defects covered in each group and their features are presented in the Table 1. Surgical technique HRAMT Group The patients were placed under mixed general anesthesia (inhalation plus intravenous) and continuous blood pressure monitoring was established by a left radial artery catheter placement. In addition, a double lumen catheter was placed either in the femoral vein or in the right subclavian vein. Pen marking of anterior and posterior axillary lines was done. The patient was placed in left semi-lateral position at 45° angle, the right arm was suspended at a right angle, in semi-flexion position, and a second line was traced from the scapular lower angle to the xiphoid appendage. The skin incision was performed in the middle portion of this line contained between the anterior and posterior axillary lines. This almost horizontal incision (3 to 5 cm) was done between the anterior and posterior axillary lines (bikini line in girls) and it may be at more cranial level in males (nipple level). The skin and subcutaneous tissues were retracted toward higher and anterior direction, without muscle section (sparing technique).The third intercostal space was opened and a retractor was placed. The pericardium was opened at 2 cm anterior to the Table 1. Preoperative characteristics of groups.

HRAMT (n=25) 68% 2 yr (2 yr - 5 yr) 13.5 kg (10.4 - 21) VSD: 4, VSD and ASD: 1 ASD: 18 ASD and PAPVR: 1 ASD and MR: 1

Female Age, median (percentile 25%-75%) Weight, median (percentile 25%-75%) Diagnoses

MS (n=25) 64% 3 yr (1.5 yr - 6 yr) 13 kg (9.6 - 23.5) VSD: 4, VSD and ASD: 1 ASD: 18 ASD and PAPVR: 1 ASD and MR: 1

HRAMT: Horizontal right axillary minithoracotomy; MS: Median sternotomy; y: years-old; VSD: Ventricular septal defect, ASD: Atrial septal defect, PAPVR: Partial anomalous pulmonary veins return, MR: Mitral regurgitation

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After deairing the heart, the aortic clamp was removed. CPB was interrupted after heartbeat ressumption and the entire blood was reinfused through the aortic cannula. The cannulas were removed and protamine infusion was done. Hemostasis was carefully done and the pericardium edges were partially approximated with interrupted polyester sutures, leaving holes to drain any liquid into the pleural space. One drainage tube was installed in right pleural space. The intercostal space was closed with a single absorbable suture 2.0 approximating the two adjacent ribs. Bupivacain anesthetic was injected in adjacent intercostal spaces, in the anterior and posterior region of the chest incision. The previously spared muscles were approximated with interrupted sutures. Subcutaneous tissue and skin were sutured with absorbable filaments. Figure 1 shows the view of the operative field, with the position of the cannulas in aorta and vena cavae, the clamped aorta, and the VSD exposure through the right atriotomy.

pericardium edges were retracted with sutures. Thymus gland was preserved. Heparin solution was infused and two standard purse-string 5.0 or 6.0 polypropylene sutures were placed on the ascending aorta for cannulation, which was performed with straight cannula suitable for the patient´s weight. Snaring tapes were passed around both vena cavae. After placing standard purse-string suture in the superior vena cava and in the junction of the inferior vena cava with the right atrium, bicaval cannulation was performed and CPB was initiated. The aorta was cross-clamped and cardioplegic solution was infused in aortic root. The right atrium was opened. The atrial septum and the tricuspid valve were exposed by stay sutures placement at the right atriotomy edges, which were gently pulled toward the chest opening. In subaortic VSD cases, the leaflet of tricuspid valve was detached at its basal aspect for better exposure. The subaortic region was explored in all patients and any subaortic membrane was resected when present. The VSD was closed with either PTFE or autologous pericardial patch of adequate size, using 6.0 polypropylene running suture techniques. After the tricuspid valve reattachment, saline solution was injected in left ventricle to test if VSD was completely closed. The ASD was closed with patch in all patients, when present. Mitral valvoplasty was carried out in one patient. In one patient with previous diagnosis of partial anomalous pulmonary vein connection to the superior vena cava associated with ASD, the superior vena cava cannulation was made at a higher level. In this case, a PTFE patch was used to close the ASD, and to redirect the right superior pulmonary vein flow to the left atrium, followed by flap rotation of the right atrial appendage to enlarge the superior vena cava. After deairing the heart, the aortic clamp was released. CPB was discontinued after normal heartbeat resumed. All the patient’s blood remaining in the membrane oxygenator and pump circuit was slowly reinfused through the aortic cannula. The aortic cannula was removed and protamine is administered. Hemostasis was carefully done and a mediastinal drainage tube was installed. The sternum was closed with steel wires. The subcutaneous tissues and the skin were sutured with absorbable sutures. The same type of surgical equipment was used in both MS and HRAMT groups. Control echocardiogram was carried out in all patients at the third or fourth postoperative day. The intraoperative use of red blood cells aimed at keeping the hematocrit above 20% during CPB in both groups was calculated using values from preoperative hematocrit, circulating volume for the patient’s weight, and volume added to the CPB machine. The use of packed red blood cells during the postoperative period followed the institutional postoperative intensive care unit routine, based on levels of hematocrit and evaluation of the patient´s clinical presentation (heart rate, blood pressure, use of vasoactive drugs, metabolic acidosis). In asymptomatic patients, transfusion was indicated when hemoglobin was less than 8 g/dL.

Fig. 1 - Operative surgical field aspect, with cannulas positioned in ascending aorta, superior and inferior vena cava. Aortic clamp and cardioplegic solution catheter positioned through the same incision. VSD approach through the right atriotomy. VSD: Ventricular septal defect, Ao: Aortic cannula, SVC: Superior vena cava cannula, IVC: Inferior vena cava cannula, AoC: Aortic clamp, CL: Cardioplegic line

MS Group The patients were placed under mixed general anesthesia (inhalation plus intravenous), continuos blood pressure was monitored through a catheter placed in the left radial artery. A double lumen catheter was placed either in the femoral vein or in the right subclavian vein. The patient was placed in supine position with a cushion under the manubrium. A MS longitudinal skin incision was made, usually measuring from 4 to 6 cm in children. The sternum was opened and a retractor was placed. The pericardium was opened in the median line. The

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The aesthetic result of the incision was evaluated by medical staff and the satisfaction of parents or child guardians was verified by phone or e-mail contact, done at six to 16 months after the surgery. The design of the study was approved by the Research Ethics Committee of the institution where the surgeries were carried out and informed consent were signed by parents authorizing the retrospective study of medical records and postoperative aesthetic satisfaction assessment.

main incision, preventing peripheral artery cannulation and its consequent risk. The correction of heart defects was possible even in infants, HRAMT being applicable in all patients to whom it was been proposed. The quality of treatment assessed by the analysis of variables shown in Table 2, which includes the perioperative data, was similar in both groups, except for the lesser use of blood products in the axillary group (6/25) than in the sternotomy incision group (13/25), with statistically significant difference (P=0.04). Six of the HRAMT patients and 11 patients in the MS group received intraoperative blood transfusion and two of the MS group patients received blood transfusion in the ICU. Use of special surgical equipment was not required in any patient. The postoperative surgical results were also similar in both groups; no residual VSD nor ASD was found in any patient. There was no mortality and the surgical complication incidence was similar in both groups, with mild to moderate pericardial effusion occurring in two cases in the HRAMT group and in one patient in MS group, without statistical difference, all three cases being solved with the use of oral anti-inflammatory. Incision size ranged from 3 to 5 cm (median 4 cm) in the HRAMT group. The size of the incision was not recorded routinely in patient´s medical files, which made the statistical comparison between the groups impossible in this retrospective study; however, our team sought to use small incisions even for the MS, usually ranging from 4 to 6 cm in children. The medical staff and the parents were satisfied with the results of HRAMT, considering it an excellent treatment option, due to the location of the incision, which is less exposed and has better aesthetics compared to the MS scar. Figures 2 and 3 show the immediate postoperative appearance of the incision in a patient from the HRAMT group. The incision is hidden under the arm.

Variables analyzed Operative duration; CPB and aortic clamping times; hematocrit and hemoglobin levels obtained at pre, peri, and post-operative periods; and the use of blood products. Additionally, mechanical ventilation, stay in the intensive care unit (ICU) and total hospital stay as well as mortality, complications, and aesthetics satisfaction were assessed. Statistical analysis All variables were analyzed using GraphPad Prism5, version 5.04. Continuous variables were expressed as mean and standard deviation. Categorical variable was expressed as the absolute number and proportion. Student’s T-test for paired samples was used to compare continuous variables. The Chi-square test was used to compare categorical variables. A confidence level of < 0.05 was used. RESULTS The VSD size did not differ between groups, their diameter measuring 7.8, 11, 11, and 15 mm in the four patients of the axillary incision (HRAMT) group. Cannulation of the aorta and vena cavae was possible in all patients through the

Table 2. Perioperative clinical data - groups comparison. Mean (±SD) ASD / VSD size (mm) CPB time (min) Aortic cross clamping time (min) Preoperative Hematocrit (%) Blood products use (nº of patients/ total) Postoperative bleeding (ml) Postoperative hematocrit (%) Day 1 MV time (hours) ICU stay (days) Hospital stay (days)

HRAMT (n=25) 12.5 (±4.9) / 10.4 (±3.1) 49 (±18) 28 (±11) 36.8 (±3.4) 6 / 25 108.9 (±64) 31.5 (±5.7) 6 (±4) 2 (±1) 6 (±2)

MS (n=25) 14.8 (±6.5) / 6.2 (±1.1) 54 (±32) 34 (±17) 36.7 (±3.2) 13 / 25 131.39 (±121.9) 32.5 (±5.6) 5 (±2) 2 (±1) 6 (±2)

P 0.42 / 0.08 0.35 0.14 0.83 0.04 0.25 0.92 0.53 0.26 0.32

SD: Standard deviation; HRAMT: Horizontal right axillary minithoracotomy; MS: Median sternotomy; ASD/VSD: Atrial septal defect/Ventricular septal defect; CPB cardiopulmonary bypass, MV: Mechanical ventilation, ICU: Intensive care unit

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Fig. 3 - Aesthetic aspect of the thorax with hidden incision under the arm

Fig. 2 - Incision aspect at the end of operation

DISCUSSION

The option of subxiphoid incision can be applied in smaller children, but it also requires femoral cannulation and the scar remains in the middle of the chest[3,4]. In this study, we have expanded the use of HRAMT to younger children, with non-restrictive VSDs, employing exclusively direct cannulation of the aorta and cavae, thereby avoiding the risk of peripheral vascular lesions. This was possible by accessing the heart through the third intercostal space, with traction of the pericardium on multiple points, which allowed greater exposure of the aorta, increasing cannulation safety. Access through the right atriotomy was used in all patients, with adequate exposure of the heart defect through the small remaining space after installation of all tubes and clamps. No patient required conversion to another type of approach or extension of the skin incision, although the initial skin incision could be extended in female patients, without reaching the breast growth area. There was no increase in CPB time, myocardial ischemia, mechanical ventilation time, ICU stay, nor hospital stay. In the group of patients covered by HRAMT, there was no need for femoral cannulation, avoiding future femoral stenosis and a new scar. In addition, HRAMT does not require any special type of equipment; therefore, it does not add costs to the surgical procedure. It is worth mentioning that patients’ weight in the HRAMT group ranged from 6.7 to 55 kg, and it was possible to perform the surgery in all of them. Actually, in our experience, surgery

The use of minimally invasive thoracic incisions in pediatric patients aims to get better aesthetic results along with the reduction of bleeding and postoperative complications, being employed for treatment of simple, such as the ductus arteriosus, or complex congenital heart defects[15-17]. The right lateral inframammary thoracotomy is widely used for treating simple congenital heart defects such as ASD. However, this approach carries the risk of compromising breast development and pectoral muscle, especially if performed before complete breast development and inframammary groove definition[14]. Therefore, it is not a good option for prepubescent girls due to high risk of breast distortion in the long-term follow-up[7]. The axillary minithoracotomy has the advantage of staying away from the breast growth region and it does not damage the muscles associated with the arm movement. The horizontal axillary approach was reappraised by Schreiber et al.[12] for ASD closure in children above 15 kg. Later, it was applied by Prêtre et al.[13] for the treatment of restrictive VSDs, with 3.8 cm incisions in children and cannulation of femoral artery, but causing the prolongation of CPB and aortic cross-clamping time. Prêtre et al.[13] work was criticized because they used femoral artery cannulation for CPB installation in children, which carries the additional risk, inherent to peripheral vessel cannulation.

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was easier in smaller patients, due to shallower chest depth and greater skin and chest elasticity, as has already been observed by Wang et al.[11], who performed axillary vertical minithoracotomy. The reduction in the blood products transfusion in the HRAMT group of patients can possibly be explained by greater blood loss caused by the sternotomy compared to the minithoracotomy. Preserving the integrity of the sternum bone is also important. There was no difference between the levels of hemoglobin in the pre, intra or postoperative, which reinforces the idea of reduced intraoperative blood loss in the HRAMT group. The high experience level of the surgeon who performed all stages of surgery in this initial group of patients undergoing HRAMT can also be a contributing factor in the reduction of blood loss in the intra and postoperative periods. This finding calls for further randomized prospective study, although it is difficult to carry out this type of study in groups with varied diseases. It is important to emphasize that opening the chest in the third intercostal space possibly increases the safety of HRAMT, since it provides good exposure of the ascending aorta, facilitating its cannulation, enabling a well conducted CPB, and giving cardioplegic solution, thereby resulting in effective myocardial protection. Appropriate experience and training should be a pre-requisite for the minimally invasive approach in the treatment of CHD[18]. The incidence of complications was not higher in the HRAMT group; there was appropriate treatment of all heart defects, without residual communication, emphasizing the safety and effectiveness of this technique. The aesthetic result was considered excellent and parents were very pleased with the location of the incision, considering it more aesthetic than the MS because it stays in a less exposed location. In female, horizontal skin incision was performed at a lower level, compared to previous publications[12,13] to enable the scar to stay hidden in the bikini line. Furthermore, it allows the extension of the skin incision toward the expected inframammary groove’s upcoming location, although, in our experience this was not required in any patient. Regarding the incision size, it is common in our team to use small incisions, even in the MS approach, but their size were not routinely recorded in patients’ medical files, which made it impossible to statistically compare the incision sizes between groups. Although our study was not randomized and has limitations, comparative study carried out with paired cases minimizes the bias of confounding variables. Possible limitations to the use of this HRAMT technique are the muscular apical VSDs or the presence of patent ductus arteriosus; however, the latter can be closed with transcatheter prosthesis in a hybrid procedure or prior to HRAMT procedure. So far, we have operated on 52 patients using HRAMT approach and we have had 15 cases of VSDs.

Some authors have emphasized that the challenges of surgery are the constant control the blood circulation and effective correction of heart defect, which is an even greater challenge when performed through a 5 cm incision[19]. However, in our series of cases, it was possible to perform effective surgical treatment of heart disease with adequate blood flow control in all cases, when needed, even with smaller incisions, without great effort, especially in infants. Nonetheless, we would like to reinforce that these good results were achieved by experienced surgeons and trained staff. CONCLUSION HRAMT (“bikini line incision”) has been effective, allowing the treatment of various heart defects, similar to that achieved by the standard sternotomy surgical approach, with reduced need for blood transfusion in this study. It has provided excellent cosmetic results, and it can be considered a safe alternative, even for infants. Authors’ roles & responsibilities LFS Main author JPS Coauthor ALRT survey data and spreadsheets, coauthor SMF Contact with relatives, coauthor CMC Survey Data, coauthor RMC Coauthor WJG Coauthor CS Coauthor

REFERENCES 1. Däbritz S, Sachweh J, Walter M, Messmer BJ. Closure of atrial septal defects via limited right anterolateral thoracotomy as a minimal invasive approach in female patients. Eur J Cardiothorac Surg. 1999;15(1):18-23. 2. Bichell DP, Geva T, Bacha EA, Mayer JE, Jonas RA, del Nido PJ. Minimal access approach for the repair of atrial septal defect: the initial 135 patients. Ann Thorac Surg. 2000;70(1):115-8. 3. Levinson ML, Fonger J. Minimally invasive atrial septal defect closure using the subxyphoid approach. Heart Surg Forum. 1998;1(1):49-53. 4. Barbero-Marcial M, Tanamati C, Jatene MB, Atik E, Jatene AD. Transxiphoid approach without median sternotomy for repair of atrial septal defect. Ann Thorac Surg 1998;65(3):771-4. 5. Metras D, Kreitmann B. Correction of cardiac defects through a right thoracotomy in children. J Thorac Cardiovasc Surg. 1999;117(5):1040-2.

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6. Houyel L, Petit J, Planche C, Sousa-Uva M, Roussin R, Belli E, et al. Right postero-lateral thoracotomy for open heart surgery in infants and children. Indications and results. Arch Mal Coeur Vaiss. 1999;92(5):641-6.

13. Prêtre R, Kadner A, Dave H, Dodge-Khatami A, Bettex D, Berger F. Right axillary incision: a cosmetically superior approach to repair a wide range of congenital cardiac defects. J Thorac Cardiovasc Surg. 2005;130(2):277-81.

7. Bleiziffer S, Schreiber C, Burgkart R, Regenfelder F, Kostolny M, Libera P, et al. The influence of right anterolateral thoracotomy in prepubescent female patients on late breast development and on the incidence of scoliosis. J Thorac Cardiovasc Surg. 2004;127(5):1474-80.

14. Schreiber C, Bleiziffer S, Kostolny M, Hörer J, Eicken A, Holper K, et al. Minimally invasive midaxillary muscle sparing thoracotomy for atrial septal defect closure in prepubescent patients. Ann Thorac Surg. 2005;80(2):673-6. 15. Santos JLV, Braile DM, Ardito RV, Zaiantchick M, Soares MJF, Rade W, et al. Ligation of patent ductus arteriosus: extrapleural technique. Rev Bras Cir Cardiovasc. 1992;7(1):14-21.

8.Cherup LL, Siewers RD, Futrell JW. Breast and pectoral muscle maldevelopment after anterolateral and posterolateral thoracotomies in children. Ann Thorac Surg. 1986;41(5):492-7.

16. Salerno PR, Jatene MB, Santos MA, Ponce F, Bosísio IBJ, Fontes VF, et al. Patent ductus arteriosus (PDA) closure with minithoracotomy: technique and results. Rev Bras Cir Cardiovasc. 2000;15(3):234-7.

9. Becker RM, Munro DD. Transaxillary minithoracotomy: the optimal approach for certain pulmonary and mediastinal lesions. Ann Thorac Surg. 1976;22(3):254-9. 10. Yang X, Wang D, Wu Q. Repair of atrial septal defect through a minimal right vertical infra-axillary thoracotomy in a beating heart. Ann Thorac Surg. 2001;71(6):2053-4.

17. Fonseca L, Silva JP, Franchi SM, Castro RM, Comparato DO, Baumgratz JF. Bidirectional Glenn procedure in the staged treatment of hypoplastic left heart syndrome: early and late results. Rev Bras Cir Cardiovasc. 2005;20(1):1-7.

11. Wang Q, Li Q, Zhang J, Wu Z, Zhou Q, Wang DJ. Ventricular septal defects closure using a minimal right vertical infraaxillary thoracotomy: seven-year experience in 274 patients. Ann Thorac Surg. 2010;89(2):552-5.

18. Formigari R, Di Donato RM, Mazzera E, Carotti A, Rinelli G, Parisi F, et al. Minimally invasive or interventional repair of atrial septal defects in children: experience in 171 cases and comparison with conventional strategies. J Am Coll Cardiol. 2001;37(6):1707-12.

12. Schreiber C, Bleiziffer S, Lange R. Midaxillary lateral thoracotomy for closure of atrial septal defects in pre-pubescent female children: reappraisal of an “old technique.” Cardiol Young. 2003;13(6):565-7.

19. Prêtre R. Editorial Comment: The axillary incision to repair congenital heart defects. Eur J Cardiothorac Surg. 2013;43(1):141-2.

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Atik FA & Cunha CR - Impact of type of procedure and surgeon on EuroORIGINAL ARTICLE SCORE operative risk validation

Impact of type of procedure and surgeon on EuroSCORE operative risk validation Impacto do tipo de procedimento e do fator cirurgião na validação do EuroSCORE

Fernando A. Atik1, MD; Claudio Ribeiro da Cunha1, MD

DOI: 10.5935/1678-9741.20140023

RBCCV 44205-1532

Abstract Objective: EuroSCORE has been used in cardiac surgery operative risk assessment, despite important variables were not included. The objective of this study was to validate EuroSCORE on mortality prediction in a Brazilian cardiovascular surgery center, defining the influence of type of procedure and surgical team. Methods: Between January 2006 and June 2011, 2320 consecutive adult patients were studied. According to additive EuroSCORE, patients were divided into low risk (score<2), medium risk (3 - 5), high risk (6 - 11) and very high risk (>12). The relation between observed mortality (O) and expected mortality (E) according to logistic EuroSCORE was calculated for each of the groups, types of procedures and surgeons with > 150 operations, and analyzed by logistic regression. Results: EuroSCORE correlated to the observed mortality (O/E=0.94; P<0.0001; area under the curve 0.78). However, it overestimated the mortality in very high risk patients (O/ E=0.74; P=0.001). EuroSCORE tended to overestimate isolated myocardial revascularization mortality (O/E=0.81; P=0.0001) and valve surgery mortality (O/E=0.89; P=0.007) and it tended to underestimate combined procedures mortality (O/E=1.09; P<0.0001). EuroSCORE overestimated surgeon A mortality (O/ E=0.46; P<0.0001) and underestimated surgeon B mortality (O/ E=1.3; P<0.0001), in every risk category.

Conclusion: In the present population, EuroSCORE overestimates mortality in very high risk patients, being influenced by type of procedure and surgical team. The most appropriate surgical team may minimize risks imposed by preoperative profiles.

Institute of Cardiology of Distrito Federal (ICDF), Brasília, DF, Brazil.

This study was carried out at Institute of Cardiology of Distrito Federal (ICDF), Brasília, DF, Brazil.

1

Descriptors: Cardiovascular Surgical Procedures. Risk Assessment/methods. Logistic Models. Quality of Health Care. Resumo Objetivo: O EuroSCORE tem sido utilizado na estimativa de risco em cirurgia cardíaca, apesar de fatores importantes não serem considerados. O objetivo foi validar o EuroSCORE na predição de mortalidade em cirurgia cardiovascular num centro brasileiro, definindo a influência do tipo de procedimento e da equipe cirúrgica responsável pelo paciente. Métodos: No período de janeiro de 2006 a junho de 2011, 2320 pacientes adultos consecutivos foram estudados. De acordo com o EuroSCORE aditivo, os pacientes foram divididos em risco baixo (escore <2), risco moderado (3 - 5), risco elevado (6 - 11) e risco muito elevado (>12). A relação entre a mortalidade observada (O) sobre a esperada (E) de acordo com o EuroSCORE logístico foi calculada para cada um dos grupos, procedimentos e cirurgiões com > de 150 operações, e analisada por regressão logística.

Correspondence address: Fernando A. Atik Instituto de Cardiologia do Distrito Federal (ICDF) Estrada Parque Contorno do Bosque, s/n - Brasília, DF, Brasil Zip code: 70670-204 E-mail: atikf@mac.com

No financial support. Article received on October 1st , 2013 Article accepted on February 13th, 2014

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combinadas (O/E=1,09; P<0,0001). O EuroSCORE descalibrou a mortalidade do cirurgião A (O/E=0,46; P<0,0001) e a do cirurgião B (O/E=1,3; P<0,0001), ambos em todos os graus de risco. Conclusão: Na população estudada, o EuroSCORE descalibrou a mortalidade em pacientes de risco muito elevado, podendo sofrer influência do tipo de operação e do cirurgião responsável. O cirurgião mais apto para cada gravidade de paciente pode minimizar o risco imposto por características pré-operatórias.

Abbreviations, acronyms & symbols AUC EuroSCORE ROC

Area under the curve European System for Cardiac Operative Risk Evaluation Receiver-operating characteristic

Resultados: O EuroSCORE calibrou com a mortalidade observada (O/E=0,94; P<0,0001; área abaixo da curva=0,78), apesar de descalibrar a mortalidade em pacientes de risco muito elevado (O/E=0,74; P=0,001). O EuroSCORE calibrou a mortalidade na revascularização do miocárdio isolada(O/E=0,81; P=0,0001) e cirurgia valvar (O/E=0,89; P=0,007), e a mortalidade nas operações

Descritores: Procedimentos Cirúrgicos Cardiovasculares. Medição de Risco/métodos. Modelos Logísticos. Qualidade da Assistência à Saúde.

INTRODUCTION

diac surgery because the vast majority of patients underwent isolated CABG, which may lead to misinterpretation in various possibilities of combined procedures[10]. The influence of the hospital unit or a system of national health outcome in cardiac surgery has been studied in this context[11]. Siregar et al.[12] showed the limitations of showing lists of performance of hospitals and surgeons in the study population of patients undergoing cardiovascular surgery in the Netherlands. The study shows that in a three-year period, there was great variability in the results of hospitals with wide confidence intervals, thus questioning the validity of such comparisons. The inaccuracy of mathematical models of risk, reflecting differences in severity of disease and risk factors not measured, may reflect results of random variations rather than real ones. The aim of this study was to validate the EuroSCORE in predicting cardiovascular mortality in a Brazilian center surgery, defining the influence of the type of procedure and surgeon factor.

The scores of preoperative risk aim to estimate the mortality of certain surgical procedures in order to meet the interests of individuals (patients and physicians), hospitals and health managers. The risk prediction is important in medical practice, as it allows objective comparisons between institutions and surgeons to adjust the characteristics of severity of disease. Moreover, the scores of preoperative risk are useful in clarifying and preoperative consent, in quality control of services and the selection or exclusion of patients in controlled clinical studies. The EuroSCORE (European System for Cardiac Operative Risk Evaluation), is one of the more widespread preoperative risk scores, and perhaps the most popular in cardiac surgery. It was created in 1999[1], with data collected between September and December 1995 in 128 European centers. In 2003, the logistic EuroSCORE was introduced using the same original database in order to improve the performance of the score in high risk patients[2]. External validation of the EuroSCORE in various populations around the world occurred initially with good results[3-5]. However, most authors have recently demonstrated that the logistic EuroSCORE overestimates the expected mortality, although some developing countries show the opposite[6-8]. The reasons for this discrepancy in model validation involve multiple factors: different characteristics of the exposed population, the hospitals and their treatment protocols, training teams and socioeconomic[9] differences. Moreover, the first version of the EuroSCORE did not take into account all types of surgical procedures used in car-

METHODS From January 2006 to June 2011, 2320 consecutive adult patients who had undergone surgery were included in this study. The mean age was 55 years ± 15, and 1330 (57.3%) patients were male. The preoperative, intraoperative and postoperative patient characteristics were prospectively collected and stored in an electronic database. All patients underwent surgery in the same hospital following the same protocols. The study was approved by the Research Ethics Committee under the registration number 069882/2013, in accordance with the standards of Helsinki.

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The procedures were coronary artery bypass grafting (CABG) isolated in 1056 (45.6%), valve surgery (Valve) isolated in 627 (27.1%), combined operations in 453 (19.6%) and others at rest. The latter included surgical treatment of isolated aortic diseases, congenital heart disease in adult, pericardiectomy, septal myectomy, resection of cardiac tumors, VSD repair or post-myocardial infarction heart failure and surgical treatment of endomyocardial fibrosis.

According to the additive EuroSCORE, patients were stratified into low risk (group 1: score <2), moderate risk (group 2: score 3-5), high risk (group 3: score 6-11) and very high risk (group 4: score> 12). The results of individual surgeons with > 150 operations were included in the analysis. The relationship between mortality observed (O) and the expected (E) according to the logistic EuroSCORE was calculated for each group, procedures and surgeons. Statistical Analysis Categorical variables were expressed by frequencies and percentages and continuous variables through the mean and standard deviation or with confidence interval of 95%. Comparison of categorical variables was performed using the chi-square test and continuous using Student’s T test, as indicated. Validation of the EuroSCORE for the population studied was performed, including calibration and discrimination. In the latter analysis, all patients were included. The correlation between mortality and the risk score, type of procedure and surgical team was obtained by logistic regression, ROC (receiver-operating characteristic curve) was obtained and calculated the area under the curve (AUC). In logistic regression analysis, the variables whose P value was less than or equal to 0.1 were included in the multivariate model. The latter was performed using the backward stepwise technique, and the variables were selected with a P value less than 0.05 as significant. Statistical analyzes were performed using JMP software, version 9.0, SAS Institute.

Table 1. Prevalence of variables included in the calculation of the EuroSCORE compared with data from the original publication. Variables Mean age (years) < 60 years 60 – 64 years 65 – 69 years 70 – 74 years > 75 years Female COPD Extracardiac arteriopathy Neurological dysfunction Previous cardiac Surgery Elevated creatinine Critical preoperative status Unstagle angina Moderate ventricular dysfunction Severe ventricular dysfunction Recent myocardial infarction Pulmonary hypertension Emergency Surgery Active endocarditis Procedures other than CABG Surgery on thoracic aorta

Study % (N=2320) 55 45.4 15.7 17 12.7 9.2 42.7 9.7 3.3 5.5 11.2 14.6 3.5 19.6 16.3 1.5 13 7.7 3.1 2.7 54.4 7.8

EuroSCORE % (N=19030) 62.5 33.2 17.8 20.7 17.9 9.6 27.8 3.9 11.3 1.4 7.3 1.8 4.1 8 25.6 5.8 9.7 2 4.9 1.1 36.4 2.4

The primary outcome was mortality at 30 days. There was no loss of patient follow up at 30 days. The operative risk score used was the first version of the EuroSCORE, published in 1999[1]. The calculation of the EuroSCORE was prospectively performed by a single examiner who strictly followed the definitions of pre- and intraoperative characteristics of patients. The calculation of the additive and logistic score of each patient was then determined electronically accessing http://www.EuroSCORE.org/calcold.html. Table 1 defines the prevalence of variables used in calculating the score compared to the same used in the formation of the original statistical model.

Fig. 1 - Relationship between the logistic EuroSCORE and 30-day mortality after cardiovascular surgery using the ROC curve

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Estimation of operative risk according to risk groups (additive EuroSCORE) As shown in Table 3, there were differences in estimating operative risk according to severity. The EuroSCORE is poorly calibrated for patients with moderate and high risk, and tended to overestimate mortality in patients at low risk (O/E = 0.65, 95% CI 0.29 to 1.44, P=0.006; AUC=0.6) despite the discrimination to be weak. However, the EuroSCORE overestimated mortality in patients at very high risk (O/E = 0.74, 95% CI 0.6 to 0.89, P=0.001; AUC = 0.69).

RESULTS In the population studied, the EuroSCORE calibrated with the observed mortality (O/E relationship 0.94, 95% CI 0.73 to 1.04, P <0.0001). The analysis of the ROC curve (Figure 1) revealed discriminatory low power (area under the curve = 0.78) of the EuroSCORE in predicting mortality when assessed all the study population. The sensitivity was 67.8% and specificity of 88%. The EuroSCORE> 7, and the cardiopulmonary bypass time greater than 120 minutes were identified as independent risk factors for mortality in this population, as shown in Table 2 which expresses the multivariate analysis of risk factors for mortality. Still, the surgeon A was inversely related to the primary event for the same model.

Estimation of operative risk according to the type of procedure Table 4 shows the different relationship of the estimation of operative risk according to the type of surgical procedure performed. The EuroSCORE tended to overestimate mortality in isolated CABG operations (O/E = 0.81, 95% CI 0.63 to 1.05, P=0.0001; AUC = 0.71) and in isolated valve operations (O/E = 0.89, 95% CI 0.73 to 1.1, P=0.007; AUC=0.69). Moreover, the EuroSCORE tended to underestimate mortality in the combined operations (O/E = 1.09, 95% CI 0.98 to 1.23, P<0.0001; AUC=0.79).

Estimation of operative risk according to emergency operation There was a higher mortality in emergency operations than in elective (33.8% vs. 5.3%, P<0.0001), but were consistent with the estimated risk by EuroSCORE. There was no difference in the surgeon factor (P=0.22) and in the type of procedure (P=0.11) with regard to mortality outcomes in emergency operations.

Table 2. Risk factors for 30-day mortality by multivariate logistic regression Variable Mortality† Intercept EuroSCORE > 7 CPB > 120 minutes Surgeon A (no)

Estimation ± SE

P

2.86 ± 0.13

<0.0001

0.89 ± 0.1

<0.0001

0.5 ± 0.1

<0.0001

0.35 ± 0.12

0.003

OR

CI 95%

7.41

5.19 – 10.75

4.29

2.99 – 6.23

1.9

1.22 – 3.09

† Hosmer-Lemeshow test, P=0.15; C-statistic 0.79. Legend: CPB - cardiopulmonary bypass

Table 3. Estimation of operative risk according to the risk group (additive EuroSCORE). N (%) Group 1 Group 2 Group 3 Group 4 Total

552 (23.8) 974 (42) 698 (30.1) 96 (4.1)

Mortality O % (IC95%) 0.9 (0.4 – 2.1) 3.5 (2.5 – 4.8) 10.6 (8.5 – 13.1) 35.5 (26.5 – 45.6) 6.3 (5.4 – 7.4)

Mortality E % (IC95%) 1.4 (1.3 – 1.5) 3 (2.9 – 3.1) 10.6 (10.1 – 11) 47.4 (43.9 – 51) 6.7 (6.3 – 7.1)

O/E

P

AUC

0.65 1.16 1 0.74 0.94

0.006 0.85 <0.0001 0.001 <0.0001

0.6 0.51 0.61 0.69 0.78

There were no exclusions in this analysis. O: observed in 30 days; E: expected for EuroSCORE; CI = confidence interval; O/E: ratio between observed mortality over expected; AUC: area under the ROC curve

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Table 4. Operative risk estimation according to the type of procedure. N (%) CABG Valve Combined

1055(49.4) 627(29.4) 454(21.2)

Mortality O % (IC95%) 3.1 (2.2 – 4.4) 5.7 (4.2 – 7.8) 14.1 (11.3 – 17.7)

Mortality E % (IC95%) 3.9 (3.5 – 4.2) 6.4 (5.7 – 7.1) 12.9 (12 – 13.8)

O/E

P

AUC

0.81 0.89 1.09

0.0001 0.007 <0.0001

0.71 0.69 0.79

In this analysis, 184 patients who did not fit the types of procedures listed above were excluded. O: observed in 30 days; E: expected for EuroSCORE; CI = confidence interval; O/E: ratio of observed mortality over expected; AUC: area under the ROC curve; CABG: isolated CABG; Valve: isolated valve surgery; Combined: any type of combined operation Table 5. Estimation of operative risk according to the surgeon factor. N (%) Surgeon A Surgeon B Surgeon C Surgeon D Surgeon E

565 (30.5) 491 (26.5) 173 (9.3) 448 (24.2) 176 (9.5)

Mortality O % (IC95%) 3.9 (2.6 – 5.8) 8.4 (6.2 – 11.1) 6.4 (3.6 – 11.1) 7.4 (5.3 – 10.2) 7.9 (4.8 – 12.9)

Mortality E % (IC95%) 8.4 (7.6 – 9.3) 6.4 (5.5 – 7.3) 9.1 (7.5 – 10.6) 6.3 (5.4 – 7.3) 6.5 (4.9 – 8)

O/E

P

AUC

0.46 1.3 0.71 1.16 1.23

<0.0001 <0.0001 <0.0001 <0.0001 0.001

0.89 0.76 0.86 0.73 0.87

In this analysis, 468 patients were excluded regarding the operations performed by 14 surgeons whose volume was less than 150 operations during the study period. O: observed in 30 days; E: expected for EuroSCORE; CI = confidence interval; O/E: ratio of observed mortality over expected; AUC: area under the ROC curve

Table 6. Relation between risk groups and the surgeon factor in estimating operative risk.

Group 1 Surgeon A Surgeon B Surgeon C Surgeon D Surgeon E Group 2 Surgeon A Surgeon B Surgeon C Surgeon D Surgeon E Group 3 Surgeon A Surgeon B Surgeon C Surgeon D Surgeon E Group 4 Surgeon A Surgeon B Surgeon C Surgeon D Surgeon E

N (%*)

Mortality O % (IC95%)

Mortality E % (IC95%)

O/E

P

128 (31.3) 102 (24.9) 24 (5.9) 119 (29.1) 36 (8.8)

0 2 (0.5 – 6.9) 0 3.4 (1.3 – 8.3) 0

1.5 (1.3 – 1.6) 1.5 (1.3 – 1.7) 1.3 (0.9 – 1.7) 1.6 (1.4 – 1.7) 1.3 (1 – 1.6)

0 1.3 0 2.1 0

<0.0001

229 (30.6) 198 (26.5) 61 (8.2) 179 (23.9) 81 (10.8)

1.3 (0.4 – 3.8) 4 (2.1 – 7.8) 1.7 (0.3 – 8.9) 3.9 (1.9 – 7.9) 2.5 (0.7 – 8.6)

2.9 (2.8 – 3) 3.1 (2.9 – 3.2) 2.8 (2.6 – 3) 3.4 (2.8 – 3.9) 2.9 (2.7 – 3.1)

0.45 1.29 0.61 1.15 0.86

<0.0001

169 (27.4) 180 (29.2) 77 (12.5) 134 (21.8) 56 (9.1)

4.1 (2 – 8.3) 15 (10.5 – 20.9) 7.8 (3.6 – 16) 12.7 (8.1 – 19.4) 16.1 (8.7 – 27.8)

10.9 (10 – 11.9) 10.6 (9.8 – 11.4) 11.3 (10 – 12.7) 10.3 (9,4 – 11.1) 11.5 (9.7 – 13.2)

0.38 1.42 0.69 1.23 1.4

<0.0001

39 (49.4) 11 (13.9) 10 (12.7) 16 (20.2) 3 (3.8)

30.7 (18.6 – 46.4) 36.4 (15.2 – 64.6) 40 (16.8 – 68.7) 31.3 (14.2 – 55.6) 100

52.6 (46.5 – 58.7) 44.8 (34.2 – 55.4) 48 (38.4 – 57.7) 41.5 (34.8 – 48.1) 71.2 (51.1 – 91.3)

0.58 0.81 0.83 0.76 1.4

<0.0001

In this analysis, 468 patients were excluded regarding the operations performed by 14 surgeons whose volume was less than 150 operations during the study period. *Percentage of patients operated in each risk group; O: observed in 30 days; E: expected for EuroSCORE; CI = confidence interval; O/E: ratio of observed mortality over expected; AUC: area under the ROC curve

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Table 7. Relation between types of procedure and the surgeon factor in estimating operative risk.

CABG Surgeon A Surgeon B Surgeon C Surgeon D Surgeon E Valve Surgeon A Surgeon B Surgeon C Surgeon D Surgeon E Combined Surgeon A Surgeon B Surgeon C Surgeon D Surgeon E

N (%*)

Mortality O % (IC95%)

Mortality E % (IC95%)

O/E

P

263 (32.2) 200 (24.4) 51 (6.2) 221 (27) 83 (10.2)

0.7 (0.2 – 2.7) 4 (2 – 7.7) 1.9 (0.3 – 10.3) 4.5 (2.5 – 8.1) 3.6 (1.2 – 10.1)

4.7 (3.9 – 5.4) 3.5 (3 – 4) 4.7 (2.5 – 6.8) 3.6 (3 – 4.2) 3.2 (2.5 – 3.9)

0.15 1.14 0.4 1.25 1.12

<0.0001

152 (30.6) 127 (25.6) 43 (8.7) 126 (25.4) 48 (9.7)

3.9 (1.8 – 8.3) 7.9 (4.3 – 13.9) 2.3 (0.4 – 12) 5.5 (2.7 – 11) 6.3 (2.1 – 16.8)

8.7 (6.5 – 10.8) 5.6 (4.7 – 6.4) 5.2 (3.9 – 6.4) 7.3 (5.7 – 9) 5.2 (3.7 – 6.7)

0.45 1.41 0.44 0.75 1.21

<0.0001

98 (24.2) 122 (30.1) 65 (16.1) 79 (19.5) 41 (10.1)

12.2 (7.1 – 20.2) 14.8 (9.5 – 22.1) 12.3 (6.4 – 22.5) 19 (11.9 – 29) 17.1 (8.5 – 31.3)

16.9 (12.5 – 21.3) 11.9 (9.7 – 14.2) 15.3 (11.5 – 19.2) 10.9 (8.2 – 13.5) 12 (7.4 – 16.6)

0.72 1.24 0.8 1.74 1.42

<0.0001

In this analysis, 601 patients were excluded relating to 14 surgeons whose volume was less than 150 operations during the study period or patients who do not fit the procedures listed above. *Percentage of patients operated within each type of procedure; O: observed in 30 days; E: expected for EuroSCORE; CI = confidence interval; O/E: ratio of observed mortality over expected; AUC: area under the ROC curve

Estimation of operative risk according to the surgeon factor The influence of the surgeon in estimating operative risk was variable, as shown in Table 5. The EuroSCORE overestimated mortality for the surgeon A (O/E = 0.46, 95% CI 0.35 to 0.61; P<0.0001, AUC = 0.89) and underestimated for the surgeon B (O/E = 1.3, 95% CI 1.09 to 1.56, P<0.0001; AUC=0.76). There was a tendency to overestimate mortality for surgeon C, and underestimate the surgeons D and E.

over all other surgeons who were similar in all sorts of procedures (P <0.0001). The surgeon factor neutralized the biggest trend of risk in combined operations. In combined operations, surgeons A (O/E=0.72, 95% CI 0.57 to 0.94, P<0.0001; AUC=0.93) and C (O/E=0.8; 95% from 0.56 to 1.17, P=0.0008; AUC=0.87) showed better results than predicted by EuroSCORE, unlike surgeons B (O/E=1.24, 95% CI 0.98 - 1.56, P=0.0003; AUC = 0.79), D (O/E=1.74, 95% CI 1.45 to 2.15, P=0.01; AUC=0.69) and And (O/E=1.42, 95% CI 1.15 to 1.89, P=0.03; AUC=0.82), as shown in Table 7. Moreover, the surgeon factor also influenced the tendency to overestimate the operations of CABG and valve. Surgeon B had a higher risk than predicted in both situations (CABG: O/E = 1.14, 95% CI 0.68 to 1.91, P=0.04, AUC=0.65/Valve: O/E=1.41, 95% CI 0.92 to 2.17, P=0.43; AUC=0.61). Meanwhile, the surgeon’s proved that the EuroSCORE overestimates the risk of these operations (CABG: O/E=0.16, 95% CI 0.05 to 0.5, P=0.05, AUC=0.88/Valve: O/E = 0.46, 95% CI 0.28 to 0.77, P=0.01; AUC=0.69).

Relationship between the surgeon factor and risk groups (additive EuroSCORE) As shown in Table 5, there were differences in patient according to surgeons, surgeons C and A faced the most severe cases according to the EuroSCORE as surgeons D and E the less severe (Wilcoxon P=0.006). The surgeon A showed superior results when compared to the predicted by the EuroSCORE in all risk groups, unlike the surgeon B, as shown in Table 6. Results from other surgeons were variable. Relationship between the surgeon factor and the type of procedure There were significant differences among surgeons with regard to the type of procedures performed by each. The surgeon C operated less isolated MRI and combined operations

DISCUSSION This study sought to examine the first version of the EuroSCORE, in order to validate the score in a Brazilian center

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for cardiovascular surgery, and determine the impact of the type of procedure and surgeon factor in predicting 30-day mortality. We observed that the EuroSCORE correlates with overall mortality of our service as well as others in our country[13] had already shown. The EuroSCORE overestimated mortality in patients at very high risk and there was still a tendency to overestimate mortality in low-risk patients. These findings are consistent with the most recent case series from developed countries[14], unlike other series[6-8] have shown exactly the opposite. The reasons for this discrepancy are various. First, there was a great progression of cases of perioperative care since the original publication of the EuroSCORE, which certainly had an impact in reducing operative mortality in centers of excellence. Moreover, these improvements were not incorporated in the same proportion and speed in centers of which the result is unsatisfactory. Structural problems in the health system and hospitals, teaming and unfavorable patient characteristics contribute to accentuate these differences. Thus, the risk scores present better performance when the preoperative characteristics and treatment regimens are comparable to those in which the score was derived. Any risk score can only be used reliably when tested in the local population and when treatment regimens did not show substantial differences after the development of risk score[9]. The recently launched review of the EuroSCORE II includes certain limitations of the first version, but needs validation in other populations. Only the validation of risk scores in different populations in different continents is essential for their clinical applicability. The creation of an own risk score that takes into account the peculiar characteristics of the population would be ideal[15]. Different risk scores may exist between the models and also with different weights that affect the risk prediction[16]. As regards the type of procedure, there was a tendency in this study to overestimate the mortality of isolated CABG and valve operations, and a tendency to underestimate the mortality of combined operations. Several studies in international[17,18] literature have shown the same results in coronary operations. Although the original database from EuroSCORE presents a minority of valve operations, our findings are also consistent with other studies in the literature[14,19,20], although the characteristics of the patients in our country are particularly different for the prevalence of rheumatic disease, large proportion of reoperations and pulmonary hypertension. The group of valve diseases has gained particular interest in the advent of percutaneous aortic prostheses, whose indication takes much into account the scores of operative risk as the current recommendation restricts inoperable[21] or high surgical risk cases. However, the indication of these procedures must be decided with great care without relying solely on risk scores, as they proved to be inadequate for this purpose.

Regarding the combined operations, our findings are also consistent with other studies[14]. This is the group most difficult to assess due to the variability of combining procedures. Due to the restricted denominator for each type individually, it is difficult to predict mortality accurately. The difficulty of comparison between hospitals and individuals is to adjust the complexity of cases among groups. Simple adjustment of mortality risk does not eliminate all selection biases and can influence the test results. However, the design of performance studies is observational and in the real world and with risk adjustment. Such analyzes would be comparable with a valid reference standard with the same characteristics of patients, usually within the same population of individuals[22]. Considering the same limitations noted above, the impact of the surgeon factor may be important in influencing the severity of patients and the type of procedure. This was further supported by the negative effect exerted by the surgeon A on mortality by multivariate analysis. Generally, the surgeon had a positive impact on all grades of risk, particularly in severe cases and combined operations, unlike the surgeon B. The influence of the surgeon unlike the hospital reinforces the notion that within a high complex service, heterogeneity of surgeons’ performance may exist determining impact on results. The surgical volume, training and technical and clinical experience of each team member must be taken into consideration at the time of surgical scheduling, as well as the expertise and personal familiarity with each procedure to ensure the best possible outcome for the patient. The formation and maintenance of integrated multidisciplinary teams engaged in developing systematic health care programs and quality control[23] programs have shown positive impact on surgical outcomes in cardiac surgery[24,25]. Based on our findings, it is important that the risk score has constant updating and validation in Brazilian centers. The risk score should not be used alone in indicating whether or not a surgical procedure, without being part of a broader context of clinical surgical discussion, because there are unmeasured factors that may influence the risk prediction. Limitations of the study The present study has several limitations inherent to its design mainly. Because of the risk scores were constructed for use in large populations, analysis of subgroups with smaller denominator reduces the statistical power and can lead to misleading interpretations. The differences in the proportion of patients undergoing different degrees of complexity among surgeons may have caused selection bias. However, we were careful to adjust the mortality rates for the same severity group of patients in order to minimize these limitations. The ideal, however, would have been adjusted for each value of the risk score, which would entail further reduced denominator.

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The authors acknowledge that there are no perfect mathematical models, and thus our findings may be subject to errors. Previous studies[12,26] have shown that there can be large fluctuations results in the classification of hospitals and surgeons, whose final interpretation questioned the statistical validity of the model. However, there is validity to demonstrate these results as a form of quality control, as usually the critical analysis of the results leads to subsequent improvement in outcomes[27].

6. Malik M, Chauhan F, Malik V, Gharde P, Kiran U, Pandey RM. Is EuroSCORE applicable to Indian patients undergoing cardiac surgery? Ann Card Anaesth. 2010;13(3):241-5. 7. Carvalho MRM, Souza e Silva NA, Klein CH, Oliveira GMM. Aplicação do EuroSCORE na cirurgia de revascularização miocárdica em hospitais públicos do Rio de Janeiro. Rev Bras Cir Cardiovasc. 2010;25(2):209-17. 8. Sá MPB, Soares EF, Santos CA, Figueiredo OJ, Lima ROA, Escobar RR, et al. EuroSCORE e mortalidade em cirurgia de revascularização miocárdica no Pronto Socorro Cardiológico de Pernambuco. Rev Bras Cir Cardiovasc. 2010;25(4):474-82.

CONCLUSION In the population studied, the first version of the EuroSCORE overestimates mortality in patients at very high risk and may be influenced by the type of surgery proposed and the surgeon factor. We must also choose the most appropriate surgeon for each severity from patient to minimize the risk imposed by preoperative characteristics.

9. Ivanov J, Tu JV, Naylor CD. Ready-made, recalibrated, or remodeled? Issues in the use of risk indexes for assessing mortality after coronary artery bypass graft surgery. Circulation. 1999;99(16):2098-104. 10. Karthik S, Srinivasan AK, Grayson AD, Jackson M, Sharpe DA, Keenan DJ, et al. Limitations of additive EuroSCORE for measuring risk stratified mortality in combined coronary and valve surgery. Eur J Cardiothorac Surg. 2004;26(2):318-22.

Authors’ roles & responsibilities FAA CRC

11. Asimakopoulos G, Al-Ruzzeh S, Ambler G, Omar RZ, Punjabi P, Amrani M, et al. An evaluation of existing risk stratification models as a tool for comparison of surgical performances for coronary artery bypass grafting between institutions. Eur J Cardiothorac Surg. 2003;23(6):935-41.

Analysis and interpretation of data; statistical analysis; final approval of the manuscript; conception and design of the study; writing of the manuscript Analysis and/or interpretation of data; final approval of the manuscript; conception and design of the study

12. Siregar S, Groenwold RH, Jansen EK, Bots ML, van der Graaf Y, van Herwerden LA. Limitations of ranking lists based on cardiac surgery mortality rates. Cir Cardiovasc Qual Outcomes. 2012;5(3):403-9. 13. Mejia OAV, Lisboa LAF, Puig LB, Dias RR, Dallan LA, Pomerantzeff PM, Stolf NAG. Os escores 2000 BernsteinParsonnet e EuroSCORE são similares na predição da mortalidade no Instituto do Coração-USP. Rev Bras Cir Cardiovasc. 2011;26(1):1-6.

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14. Ranucci M, Castelvecchio S, Menicanti LA, Scolletta S, Biagioli B, Giomarelli P. An adjusted EuroSCORE model for high-risk cardiac patients. Eur J Cardiothorac Surg. 2009;36(5):791-7.

2. Michel P, Roques F, Nashef SA; EuroSCORE Project Group. Logistic or additive EuroSCORE for high-risk patients? Eur J Cardiothorac Surg. 2003;23(5):684-7.

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4. Nashef SA, Roques F, Hammill BG, Peterson ED, Michel P, Grover FL, et al; EuroSCORE Project Group. Validation of European System for Cardiac Operative Risk Evaluation (EuroSCORE) in North American cardiac surgery. Eur J Cardiothorac Surg. 2002;22(1):101-5.

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18. Zheng Z, Li Y, Zhang S, Hu S; Chinese CABG Registry Study. The Chinese coronary bypass grafting registry study: how well does the EuroSCORE predict operative risk for Chinese population? Eur J Cardiothorac Surg. 2009;35(1):54-8.

23. Kurlansky PA, Argenziano M, Dunton R, Lancey R, Nast E, Stewart A, et al. Quality, not volume, determines outcome of coronary artery bypass surgery in a university-based community hospital network. J Thorac Cardiovasc Surg. 2012;143(2):287-93.

19. Parolari A, Pesce LL, Trezzi M, Cavallotti L, Kassem S, Loardi C, et al. EuroSCORE performance in valve surgery: a meta-analysis. Ann Thorac Surg. 2010,89(3):787-93.

24. Atik FA, Garcia MFMA, Santos LM, Chaves RB, Faber CN, Corso RB, et al. Resultados da implementação de modelo organizacional de um serviço de cirurgia cardiovascular. Rev Bras Cir Cardiovasc 2009;24:116-25.

20. Andrade ING, Moraes Neto FR, Oliveira JPSP, Silva ITC, Andrade TG, Moraes CRR. Avaliação do EuroSCORE como preditor de mortalidade em cirurgia cardíaca valvar no Instituto do Coração de Pernambuco. Rev Bras Cir Cardiovasc. 2010;25(1):11-8.

25. Atik FA. Quality improvement program decreases mortality after cardiac surgery. J Thorac Cardiovasc Surg. 2009;138(1):253-4. 26. Green J, Wintfeld N. Report cards on cardiac surgeons. Assessing New York State’s approach. N Engl J Med. 1995;332(18):1229-32.

21. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al; PARTNER Trial Investigators. Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363(17):1597-607.

27. Hannan EL, Sarrazin MS, Doran DR, Rosenthal GE. Provider profiling and quality improvement efforts in coronary artery bypass graft surgery: the effect on short-term mortality among Medicare beneficiaries. Med Care. 2003;41(10):1164-72.

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Santos HN, etORIGINAL al. - PredictorsARTICLE of stroke in patients undergoing cardiac surgery

Predictors of stroke in patients undergoing cardiac surgery Preditores de acidente vascular cerebral em pacientes submetidos à cirurgia cardíaca

Handerson Nunes dos Santos1,2, PhD; Ellen Hettwer Magedanz1, PhD; João Carlos Vieira da Costa Guaragna1,2, PhD; Natalia Nunes dos Santos1; Luciano Cabral Albuquerque3, PhD; Marco Antonio Goldani1; João Batista Petracco2; Luiz Carlos Bodanese1,2,3, PhD

DOI: 10.5935/1678-9741.20140025

RBCCV 44205-1533

Abstract Objective: To determine the risk factors related to the development of stroke in patients undergoing cardiac surgery. Methods: A historical cohort study. We included 4626 patients aged ≥ 18 years who underwent coronary artery bypass surgery, heart valve replacement surgery alone or heart valve surgery combined with coronary artery bypass grafting between January 1996 and December 2011. The relationship between risk predictors and stroke was assessed by logistic regression model with a significance level of 0.05. Results: The incidence of stroke was 3% in the overall sample. After logistic regression, the following risk predictors for stroke were found: age 50-65 years (OR=2.11 – 95% CI 1.054.23 – P=0.036) and age ≥66 years (OR=3.22 – 95% CI 1.6-6.47 – P=0.001), urgent and emergency surgery (OR=2.03 – 95% CI 1.20-3.45 – P=0.008), aortic valve disease (OR=2.32 – 95% CI 1.18-4.56 – P=0.014), history of atrial fibrillation (OR=1.88 – 95% CI 1.05-3.34 – P=0.032), peripheral artery disease (OR=1.81 – 95% CI 1.13-2.92 – P=0.014), history of cerebrovascular disease (OR=3.42 – 95% CI 2.19-5.35 – P<0.001) and cardiopulmonary bypass time > 110 minutes (OR=1.71 – 95% CI 1.16-2.53 –

P=0.007). Mortality was 31.9% in the stroke group and 8.5% in the control group (OR=5.06 – 95% CI 3.5-7.33 – P<0.001). Conclusion: The study identified the following risk predictors for stroke after cardiac surgery: age, urgent and emergency surgery, aortic valve disease, history of atrial fibrillation, peripheral artery disease, history of cerebrovascular disease and cardiopulmonary bypass time > 110 minutes.

Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil 2 Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul (HSLPUCRS), Porto Alegre, RS, Brazil 3 Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil

Correspondence adrress: Handerson Nunes dos Santos Av. Ipiranga, 6690 - 4º Andar, POCC - Jardim Botânico -Porto Alegre, RS, Brazil – Zip code: 90610-000 E-mail: handerson_santos@yahoo.com.br

Descriptors: Stroke. Myocardial Revascularization. Heart Valves. Risk Factors. Cardiac Surgical Procedures. Resumo Objetivos: Determinar os preditores de risco relacionados ao desenvolvimento de acidente vascular cerebral em pacientes que realizaram cirurgia cardíaca. Métodos: Estudo de coorte histórico. Incluímos 4626 pacientes com idade ≥ 18 anos submetidos à cirurgia de revascularização do miocárdio, cirurgia cardíaca valvar isolada ou cirurgia valvar associada com revascularização do miocárdio, de janeiro de 1996 e dezembro de 2011. A relação

1

This study was carried out at Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul (HSLPUCRS), Porto Alegre, RS, Brazil.

Article received on June 21st,2013 Article accepted on September 2nd, 2013

No financial support.

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3% na amostra total. A análise multivariada identificou como preditores de risco para o acidente vascular cerebral: idade 50-65 anos (OR=2,11 – 95% IC 1,05-4,23 – P=0,036) e idade ≥ 66 anos (OR=3,22 – 95% IC 1,6-6,47 – P=0,001), cirurgia de urgência/ emergência (OR=2,03 – 95% IC 1,20-3,45 – P=0,008), valvulopatia aórtica (OR=2,32 – 95% IC 1,18-4,56 – P=0,014), fibrilação atrial (OR=1,88 – 95% IC 1,05-3,34 – P=0,032), doença arterial obstrutiva periférica (OR=1,81 – 95% IC 1,13-2,92 – P=0,014), história de doença cerebrovascular (OR=3,42 – 95% IC 2,19-5,35 – P<0,001) e tempo de circulação extracorpórea >110 minutos (OR=1,71 – 95% IC 1,16-2,53 – P=0,007). A mortalidade foi 31,9% nos pacientes que sofreram AVC e 8,5% nos sem AVC (OR=5,06 – 95% IC 3,5-7,33 – P<0,001). Conclusão: Idade, cirurgia de urgência/emergência, doença de valva aórtica, história de fibrilação atrial, doença arterial obstrutiva periférica, história de doença cerebrovascular e tempo de circulação extracorpórea > 110 minutos foram preditores independentes para o desenvolvimento de AVC intra-hospitalar, em pacientes submetidos à cirurgia cardíaca.

Abbreviations, acronyms & symbols AF CABG CHF CI COPD CPB CVD DM EF HF ICU NYHA PAD POCS SAH SPSS TIA

Atrial fibrillation Coronary artery bypass graft Heart failure functional class Confidence interval Chronic Obstructive Pulmonary Disease Cardiopulmonary bypass Cerebrovascular disease Diabetes Mellitus Ejection fraction Heart failure Intensive Care Unit New York Heart Association Peripheral arterial disease Postoperative of Cardiac Surgery Systemic Arterial Hypertension Statistical Package for the Social Sciences Transient ischemic attack

entre os preditores de risco e o acidente vascular cerebral foi avaliada por modelo de regressão logística com nível de significância de 0,05. Resultados: A incidência de acidente vascular cerebral foi

Descritores: Acidente Vascular Cerebral. Revascularização Miocárdica. Valvas Cardíacas. Procedimentos Cirúrgicos Cardíacos. Fatores de Risco.

INTRODUCTION

balloon, unstable angina, history of heavy alcohol consumption, arrhythmia of atrial fibrillation (AF) type, previous bypass, and heart failure (HF)[4], history of cerebrovascular disease (CVD), hypertension (SAH) , peripheral arterial disease(PAD)[4,8], diabetes (DM)[8], emergency surgery and cardiopulmonary bypass (CPB) time >120 minutes[7,8]. Neurological complications are cited by different authors, according to the following criteria: type I, defined by neurological deficit of stroke type, transient ischemic attack (TIA), coma, anoxic encephalopathy, and brain death; and type II, in which the impairment of cognitive and intellectual functions is more evident[6,9]. The present study aimed to determine the predictors of risk related to the development of stroke in a non-selected cohort of patients undergoing cardiac surgery. We believe that the identification of predictors for the occurrence of this outcome in our country can help in developing measures to reduce its incidence.

Data published by the Heart Disease and Stroke Statistical Update 2012 revealed that, in the United States, stroke is a disease of high mortality rate: approximately one of every 18 deaths is related to stroke. Every year, approximately 795,000 people have a stroke, 610,000 of them for the first time. On average, every 40 seconds someone in America has a stroke. Among 45 to 64-year-old people, 8% to 12% of the strokes are ischemic. Every year the number of women affected by stroke outweighs the number of men by 55,000, and of all these strokes, 87 % are ischemic, 10% hemorrhagic, and 3% are subarachnoid hemorrhage[1]. In Brazil, circulatory diseases were responsible for over 326,000 deaths/year (28.7%) in 2010. Ischemic heart disease and cerebrovascular diseases together account for more than 199,000 deaths/year (17.6%) of a population of 1,136 million deaths/year. Stroke is responsible for approximately 100,000 deaths recorded annually, and it is one of the leading causes of deaths in the country[2]. In cardiac surgery, changes in the central nervous system range from 20% to 83% and in stroke, from 1% to 6%[3,4]. The most common stroke in cardiac surgery is ischemic, ranging from 53% to 85%[5] and estimated mortality is between 14% and 40.4%[5-7]. The main causes of this outcome in cardiac surgery are: advanced age, calcified aorta, use of intra-aortic

METHODS We performed a historical cohort observational study from variables obtained from the database of the postoperative Intensive Care Unit (ICU) of Postoperative of Cardiac Surgery (POCS), at Hospital São Lucas. The population is composed of 4626 patients over 18 years of age who underwent coronary

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artery bypass graft (CABG), heart valve surgery alone or heart valve surgery combined with CABG between January 1996 and December 2011. The variables assessed were: age; gender (male/female); heart failure functional class (CHF) according the New York Heart Association (NYHA) stratified into two groups: group 1 (Classes III and IV) and group 2 (Classes I and II); type of valvular disease; history of AF; history of CVD; DM; PAD; SAH; Chronic Obstructive Pulmonary Disease (COPD); surgical type; heart surgery; surgical character: urgency/emergency; renal disease, defined by history of dialytic or non-dialytic renal diseases and/or creatinine ≥ 1.5 mg/dL; left ventricular ejection fraction (EF); obesity: defined by body mass index ≥ 30 kg/m2; CPB time; surgical reintervention; return to POCS ICU in the same hospital; death; and postoperative hospitalization time. The outcome assessed was the occurrence of stroke in the postoperative cardiac surgery (CABG, heart valve surgery alone or heart valve surgery combined with CABG) during the entire period of hospitalization. Type I neurological deficit (stroke, TIA) was classified as any new neurologic deficit persisting for more than 24 hours, confirmed by clinical examination by a neurologist and brain imaging (computed tomography or magnetic resonance imaging), as well as stupor or coma at the time of discharge. The presence of previous cerebrovascular disease was considered by history of stroke, TIA or surgical repair (carotid endarterectomy) in anamnesis, luminal carotid artery stenosis of ≥ 50% on angiography, ultrasound or magnetic resonance angiography, or a combination thereof. Technical procedures, such as anesthesia, techniques of cardiopulmonary bypass, and cardioplegia, were performed according to the standards of the Cardiovascular Surgery Service of Hospital São Lucas. After surgery, all patients were transferred to the POCS ICU under mechanical ventilation[10]. For statistical analysis of the data, we used mean and standard deviation for Gaussian quantitative variables as well as median and minimum and maximum values ​​in asymmetrical situations. Categorical data were described by counts and percentages. Comparisons between means were performed using Student’s t test or its nonparametric substitute. Categorical variables were compared using the chi-square test or Fisher exact test. For multivariable situations we used the logistic regression model that allows the assessment of the effect of both quantitative and categorical variables on a binary event. The variables considered statistically significant were those with P<0.05 and confidence interval (CI) of 95%. Data were processed and assessed using SPSS (Statistical Package for the Social Sciences) version 18.0. This study did not use calculation of sample size. Failure to use the calculation of sample size for this study is justified because it used any number of patients entered into the database, except those meeting the exclusion criterion. This study was submitted to the Research Ethics Com-

mittee of PUCRS and received their assessment and approval under protocol number CEP 11/05631. RESULTS We selected a total of 4626 patients divided into three surgical types: CABG, heart valve surgery alone or heart valve surgery combined with CABG. The overall incidence of stroke was 3.0%, varying among the three surgical types, with higher incidence in combined procedures (5.4%). In the overall sample, mean age was 58.9±12.6 years, and men comprised 63.4% of the patients. The occurrence of stroke was 2.8% in men and 3.5% in women, with different incidence of death between genders when comparing stroke and non-stroke groups for percentage of deaths, incidence being 24.4% and 7.8%, respectively, in men, and 42.4% and 9.7%, respectively, in women. The mean hospital stay was 10.84±9.7 days (Table 1). In patients undergoing CABG, there was observed higher incidence of patients aged between 50 and 65 years, male, PAD, history of CVD, DM, hypertension, obese, smokers, COPD (similar to combined procedures) and patients with EF < 40%. However, these patients had lower percentages of aortic and mitral valve disease, and history of AF as well as improved CHF functional class, even with lower EF. Among the three surgical types, CABG had the lowest rates of surgical intervention, return to POCS ICU, hospitalization and death (Table 1). In patients undergoing cardiac valve surgery alone, we found a higher percentage of young patients, aged 18 to 49 years, with the lowest average age and a higher percentage of women (43.4%). This subgroup had the highest incidence of patients with history of AF, patients undergoing heart surgery and CHF functional class III/IV (similar to combined procedures); however, it was the subgroup with the best EF. We emphasize that in isolated cardiac valve surgery patients there was lower rates of urgent/emergency surgical procedures, PAD, history of CVD, DM, smoking, COPD and postoperative stroke (Table 1). In combined surgical procedures, we found a higher percentage of older patients with higher average age. This subgroup contained patients with higher rates of urgent/emergency surgical procedures, aortic and mitral valve disease, COPD, history of renal disease, and CHF functional class III/IV (similar to isolated valve surgery); however, this subgroup had the lowest EF. CPB time >110 minutes was present in most patients, and the average was higher than in the other groups. Combined procedure had a higher incidence of stroke, reintervention, return to POCS ICU, hospitalization and death (Table 1). Regarding preoperative and intraoperative variables, those that showed statistical significance (P<0.05) in the univariate analysis are: combined procedures (OR=1.85 – 95% IC 1.043.29 – P=0.035); age 50-65 years (OR=2.69 – 95% IC 1.375.28 – P=0.004) and ≥66 years (OR=4.72 – 95% IC 2.42-9.18 – P<0.001); urgent/emergency surgery (OR=2.47 – 95% IC 1.52-4.03 – P<0.001); aortic valve disease (OR=1.92 – 95% IC

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1.09-3.39 – P=0.034); CHF functional class III/IV (OR=1.67 – 95% IC 1.17-2.4 – P=0.006); history of AF (OR=1.84 – 95% IC 1.11-3.05 – P=0.026); PAD (OR=2.82 – 95% IC 1.82-4.34 – P<0,001); history of CVD (OR=4.45 – 95% IC 2.91-6.78 – P<0.001); DM (OR=1.64 – 95% IC 1.15-2.34 – P=0.008); COPD (OR=1.62 – 95% IC 1.08-2.42 – P=0.025); history of renal disease (OR=1.7 – 95% IC 1.08-2.66 – P=0.028); CPB time > 110 minutes (OR=2.03 – 95% IC 1.42-2.92 – P<0.001); reoperation (OR=2.62 – 95% IC 1.61-4.27 – P<0.001); returning to POCS ICU (OR=3.12 – 95% IC 1.89-5.16 – P<0.001); death (OR=5.06 – 95% IC 3.5-7.33 – P<0.001); and length of hospital stay (P<0.001) (Table 2).

After logistic regression, the present study identified eight variables associated with the development of stroke in the postoperative of cardiac surgery: age 50-65 years (OR=2.11 – 95% IC 1.05-4.23 – P=0.036) and ≥66 years (OR=3.22 – 95% IC 1.6-6.47 – P=0.001); urgent/emergency surgery (OR=2.03 – 95% IC 1.20-3.45 – P=0.008); aortic valve disease (OR=2.32 – 95% IC 1.18-4.56 – P=0.014); history of AF (OR=1.88 – 95% IC 1.05-3.34 – P=0.032); PAD (OR=1.81 – 95% IC 1.13-2.92 – P=0.014); history of CVD (OR=3.42 – 95% IC 2.19-5.35 – P<0.001); and CPB time >110 minutes (OR=1.71 – 95% IC 1.16-2.53 – P=0.007) (Table 3).

Table 1. General Patient's Characteristics. Variables Age - 18-49 years - 50-65 years - ≥66 years Age (mean±SD) Male Urgent/Emergency surgery Aortic valve disease Mitral valve disease III/IV CHF History of Atrial Fibrillation PAD History of CVD Prior Cardiac Surgery DM COPD SAH Obesity Smoking Ejection fraction <40% Ejection fraction (mean±SD) Prior Renal Disease Creatinine (mean±SD) CPB time >110 minutes CPB time (mean±SD) Postoperative stroke Reintervention Return to POCS Death during hospitalization Length of Stay (mean±SD)

CABG(%) n= 3318 (71.7)

Valve(%) n= 1051 (22.7)

CABG+Valve(%) n=257 (5.6)

551 (16.6) 1644 (49.5) 1123 (33.8) 60±11.2 2185 (65.9) 228 (6.9) 12 (0.4) 37 (1.1) 446 (13.8) 94 (2.8) 348 (10.5) 223 (6.7) 108 (3.3) 988 (29.8) 572 (17.2) 2395 (72.2) 407 (12.3) 1095 (33) 655 (19.7) 54±15 366 (11) 1.17±0.83 569 (17.4) 83±35 100 (3.0) 175 (5.3) 150 (4.5) 271 (8.2) 10.6±9.8

395 (36.7) 383 (36.4) 273 (26) 53,7±15.3 594 (56.6) 53 (5.0) 180 (17.1) 88 (8.4) 471 (45.2) 221 (21) 10 (1.0) 49 (4.7) 156 (14.8) 58 (5.5) 103 (9.8) 392 (37.3) 52 (4.9) 234 (22.3) 83 (7.9) 61±13 102 (9.7) 1.11±0.73 164 (15.7) 83±34 27 (2.6) 75 (7.1) 61 (5.8) 92 (8.8) 11.3±8.7

17 (6.6) 88 (34.2) 152 (59.1) 66,84±10.4 151 (58.8) 20 (7.8) 65 (25.3) 24 (9.3) 114 (45.2) 34 (13.2) 17 (6.6) 15 (5.8) 12 (4.7) 49 (19.1) 46 (17.9) 158 (61.5) 20 (7.8) 68 (26.5) 44 (17.1) 56±15 40 (15.6) 1.22±0.71 141 (55.5) 119±43 14 (5.4) 36 (14) 21 (8.2) 62 (24.1) 12.5±12.2

Total(%) n=4626 (100) 963 (20.8) 2115 (45.7) 1548 (33.5) 58,93±12.6 2930 (63.4) 301 (6.5) 257 (5.6) 149 (3.2) 1031 (22.8) 349 (7.5) 375 (8.1) 287 (6.2) 276 (6.0) 1095 (23.7) 721 (15.6) 2945 (63.7) 479 (10.4) 1397 (30.2) 782 (16.9) 56±15 508 (11) 1.16±0.80 874 (19.1) 85±37 141 (3.0) 286 (6.2) 232 (5.0) 425 (9.2) 10.8±9.7

N=population; CABG - cardiopulmonary bypass surgery; CVD - cerebrovascular disease; Stroke; SAH – systemic arterial hypertension; PAD - Peripheral Arterial Disease; DM - Diabetes Mellitus; CHF – Cardiac Heart Failure (as determined by the NYHA); COPD - Chronic Obstructive Pulmonary Disease; CPB – Cardiopulmonary Bypass; Prior Renal Disease – history of renal disease requiring dialysis or not and/or creatinine > 1.5 mg/dl

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Table 2. Variables associated with risk of stroke. Variables Surgical Type - CABG - Valve Replacement - CABG + Valve Replacement Age - 18-49 years - 50-65 years - ≥66 years Age (mean±SD) Male Urgent/Emergency surgery Aortic valve disease Mitral valve disease III/IV CHF History of Atrial Fibrillation PAD History of CVD Prior Cardiac Surgery DM COPD SAH Obesity Smoking Ejection fraction <40% Ejection fraction (mean±SD) Prior Renal Disease Creatinine (mean±SD) CPB time >110 minutes CPB time (mean±SD) Reintervention Return to POCS Death during hospitalization Length of Stay (mean±SD)

Stroke (n=141) %

No stroke (n=4485) %

OR

IC 95%

P

70.9 19.1 9.9

71.8 22.8 5.4

1 0.85 1.85

0.55 - 1.31 1.04 - 3.29

0.455 0.035

7.1 41.1 51.8 64.1±10.5 58.2 14.2 9.9 4.3 32.6 12.8 19.1 21.3 6.4 33.3 22.7 70.9 12.1 28.4 18.4 53±14.5 17 1.17±0.39 31.9 97±34 14.2 13.5 31.9 20.4±15.3

21.2 45.9 32.9 58.8±12.8 63.5 6.3 5.4 3.2 22.4 7.4 7.8 5.7 6 23.4 15.4 63.4 10.3 30.3 16.9 56.8±14.1 11.8 1.16±0.83 19.7 84±38 5.9 4.7 8.5 10.5±9.36

1 2.69 4.72 0.8 2.47 1.92 1.35 1.67 1.84 2.82 4.45 1.08 1.64 1.62 1.41 1.19 0.91 1.12 1.7 2.03 2.62 3.12 5.06 -

1.37 - 5.28 2.42 - 9.18 0.57 - 1.12 1.52 - 4.03 1.09 - 3.39 0.59 - 3.11 1.17 - 2.40 1.11 - 3.05 1.82 - 4.34 2.91 - 6.78 0.54 - 2.14 1.15 - 2.34 1.08 - 2.42 0.97 - 2.03 0.71 - 2.0 0.63 - 1.32 0.72 - 1.72 1.08 - 2.66 1.42 - 2.92 1.61 - 4.27 1.89 - 5.16 3.5 - 7.33 -

0.004 <0.001 <0.001 0.224 <0.001 0.034 0.462 0.006 0.026 <0.001 <0.001 0.975 0.008 0.025 0.083 0.594 0.698 0.704 0.039 0.028 0.817 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

N=population, OR = odds ratio, 95% CI=confidence interval, P = statistical significance 95%. CABG – coronary artery bypass grafting, CVD – cerebrovascular disease, SAH – systemic arterial hypertension, PAD - Peripheral Arterial Disease; DM - Diabetes Mellitus; CHF - Cardiac Heart Failure (as determined by the NYHA), COPD Chronic Obstructive Pulmonary Disease; CPB – Cardiopulmonary Bypass; Prior Renal Disease – history of renal disease requiring dialysis or not and/or creatinine > 1.5 mg/dl

DISCUSSION

In urgent/emergency surgeries, this study showed an OR of 2.03 (95% IC 1.2-3.42 – P=0.008) for the occurrence of stroke, with a percentage of 6.6% vs. 3% in the whole sample. Patients who developed stroke underwent additional urgent/emergency procedures in the ratio of 14.2% to 6.3%. It is believed that the combination of urgent/emergency surgery and stroke is linked to the severity of clinical criteria, which serves as indication for the procedure and the risks of cardioembolic events associated with them: evolving acute myocardial infarction with persistent angina or hemodynamic instability after unsuccessful percutaneous coronary intervention, mechanical complications of infarction such as free wall rupture, ventricular septal defect and rupture or dysfunction

In our study, age was an independent predictor for stroke in the postoperative period, in which the group of patients aged between 50 and 65 years had an OR of 2.11 (95% IC 1.05-4.23 – P=0.036) and the group aged ≥66 years had an OR of 3.22 (95% IC 1.6-6.47 – P=0.001). Furthermore, the average age in the group of patients affected by stroke was significantly higher (64±10.5 vs. 58.8±12.8 – P<0.001). This shows, as in other studies, that age is an important non-modifiable risk factor for cerebrovascular disease, confirming that the occurrence of postoperative stroke increases significantly among older patients[5,6].

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Table 3. Analysis of Logistic Regression. Variables Surgical Type - CABG - Valve Replacement - CABG + Valve Replacement Age - 18-49 years - 50-65 years - ≥66 years Male Urgent/Emergency surgery Aortic valve disease Mitral valve disease III/IV CHF History of Atrial Fibrillation PAD History of CVD Prior Cardiac Surgery DM COPD SAH Obesity Smoking Ejection fraction <40% Prior Renal Disease CPB time >110 minutes

OR

CI 95%

P

1 0.78 0.89

0.44 - 1.39 0.44 - 1.79

0.403 0.746

1 2.11 3.22 0.77 2.03 2.32 1.27 1.35 1.88 1.81 3.42 1.07 1.29 1.4 1.13 1.12 1.03 0.74 1.11 1.71

1.05 - 4.23 1.60 - 6.47 0.53 - 1.10 1.20 - 3.45 1.18 - 4.56 0.52 - 3.09 0.89 - 2.05 1.05 - 3.34 1.13 - 2.92 2.19 - 5.35 0.51 - 2.25 0.87 - 1.91 0.89 - 2.21 0.75 - 1.70 0.65 - 1.91 0.67 - 1.59 0.47 - 1.19 0.68 - 1.81 1.16 - 2.53

0.036 0.001 0.154 0.008 0.014 0.596 0.156 0.032 0.014 <0.001 0.849 0.204 0.15 0.56 0.69 0.885 0.216 0.67 0.007

N=population, OR = odds ratio, 95% CI=confidence interval, P = statistical significance 95%. CABG – coronary artery bypass grafting, CVD – cerebrovascular disease, SAH – systemic arterial hypertension, PAD - Peripheral Arterial Disease; DM - Diabetes Mellitus; CHF - Cardiac Heart Failure (as determined by the NYHA), COPD Chronic Obstructive Pulmonary Disease; CPB – Cardiopulmonary Bypass; Prior Renal Disease – history of renal disease requiring dialysis or not and/or creatinine > 1.5 mg/dl

of papillary muscle, which can lead to mitral valve prolapse and further contribute to severe hemodynamic repercussion or cardiogenic shock[11]. To Burcerius et al.[8], emergency surgery is secondary to unstable heart condition, being an independent predictor for stroke with an OR of 1.47 (95% IC 1.23 – 1.76), where unstable angina in patients with coronary artery disease and endocarditis were the main factors that indicated the need for urgent surgery. In patients undergoing urgent/emergency surgical procedures the death rate in the literature ranges from 54% to 63.8%[12,13]. In this study, death rate was 51.8% and we highlight that rate of death from stroke increased to 70%. In the present study, aortic valve disease showed an OR of 2.32 (95% IC 1.18-4.56 - P=0.014) for the occurrence of the stroke. GARY Registration (German Aortic Valve Registry), which in 2011 assessed 13,860 patients who underwent isolated aortic valve replacement, aortic valve replacement combined with CABG or transcatheter aortic valve implantation, demonstrated that the occurence of cerebrovascular events was 2%, 4% and 3.5% to 3.7% respectively[14]. This was confirmed in our study, where isolated valve procedures

had a smaller percentage of outcomes (2.6%) compared to combined procedures (5.4%). History of AF is a high risk factor for ischemic stroke by thromboembolism of central nervous system and inflammatory processes related to cardiac surgery can cause episodes of AF[15]. AF with unsatisfactory control of anticoagulation, intraoperative surgical manipulation or spontaneous recovery of sinus rhythm postoperatively can cause embolism due to the formation of clots in the left atrium[16]. In this study, history of AF was an independent predictor of risk with an OR of 1.88 (95% IC 1.05-3.34 – P=0.032). According to a European study, about one in every five cases of stroke are related to atrial fibrillation, and paroxysmal AF carries the same risk of stroke as permanent or persistent AF[17]. PAD was correlated with stroke in our series, with an OR of 1.81 (95% IC 1.13-2.92 – P=0.014). PAD is interpreted as a marker of generalized atherosclerosis and a predictor of myocardial infarction and stroke[18]. There is a high association between PAD, coronary artery disease and carotid artery disease, which predisposes these patients to an increased risk

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stroke (OR=5.06 - 95% IC 3.5-7.33 – P<0.001), with the percentage of deaths being 31.9% vs. 8.5%. This fact was evidenced by other authors, whose studies also showed that the group of patients who developed stroke had higher mortality rates than those of the control groups, 18.6% vs. 2.6%[21], from 8.1% to 14.1% vs. 0.8%[22], and 40.4% vs. 2.2%[7]. We believe that the identification of predictors may make it possible to stratify patients at potential risk for the development of stroke. In addition, it may offer guiding criteria for care and special handling of these patients, minimizing the impact of the disease and supporting the design of a risk score for the development of stroke in patients undergoing cardiac surgery. We can consider the use of a cardiac surgery postoperative unit database as a limiting factor of this study, which was not initially modeled to assess systematically and prospectively this outcome. However, we believe that this factor did not affect the validity of the results.

of myocardial infarction, ischemic stroke and vascular death, with the relative risk of mortality increased by three times for all causes, and by six times for vascular death, as seen by Durazzo et al.[18]. According to Rosa & Portal[19], carotid disease increases by four times the risk of perioperative stroke. PAD is more prevalent after the fourth decade of life, with the risk increasing two to three times every 10 years, and is associated with the following cardiovascular risk factors: smoking, DM, hypertension, and dyslipidemia[18,20]. In the present study, history of CVD may be an important risk factor for the development of postoperative stroke with an OR of 3.42 (95% IC 2.19-5.35 – P<0.001) in logistic regression. Different authors[8,21] mention that history of CVD is an independent predictor of perioperative stroke and postoperative cardiac surgery, confirming the results found in our study. According to Bucerius et al.[8], history of CVD can demonstrate the existence of pathological condition of the cerebrovascular system or condition of stenosis of the carotid arteries. CPB time in our study was statistically significant with an increase in patients who developed postoperative stroke (84±37 vs. 97±34 minutes, P<0.001). CPB time >110 minutes was present in 31.9% of patients with stroke and in 19.7% of those without stroke, presenting an OR of 1.71 (95% IC 1.162.53 – P=0.007), similar to other studies[22], which associated stroke to a CPB time greater than 120 minutes, with an OR of 1.42 (95% IC 1.17-1.72)[8]. The association between CPB and postoperative changes in the central nervous system is potentially related to the presence of severe atheromatous disease of the ascending aorta and carotid arteries, inadequate anticoagulation during CPB, age, changes in body temperature during surgery, hyperglycemia, intraoperative acid-base correction methods, micro and macroembolization during CPB, intracardiac procedures and advanced cerebral vascular disease[23]. In this study, patients undergoing CABG combined with valve replacement showed higher mean CPB time (119±43 minutes) when compared to the average time of patients who underwent CABG (83±35 minutes) and those who underwent isolated valve replacement (83±34 minutes) and consequently increased incidence of stroke: 5.4% vs. 3% vs. 2.6%, respectively. Hedberg et al.[22] demonstrated higher rates of stroke in combined procedures, divided into early and late, such as 5.7% vs. 2.5 % in CABG, along with increased CPB time of 143 minutes vs.75 minutes. Furthermore, elderly patients with comorbidities such as hypertension and diabetes, may be at increased risk due to changes in auto regulation of cerebral blood flow[24]. According to Vicchio et al.[25], mortality rate differs between isolated aortic valve replacement (7.8%) and aortic valve replacement associated with CABG (15.2%) (P=0.019), as confirmed in this study where the mortality rate for CABG was 8.2%, 8.8% for isolated valve replacement and 24.1% for combined procedures. It was also found that the risk of death among patients increases five times in the presence of the

CONCLUSION Stroke is still a prevalent complication after cardiac surgery in adults and occurred in 3% of the population. The logistic regression model identified the following risk factors for the development of stroke type I, during cardiac surgery postoperative: age over 50 years, urgent and emergency surgery, aortic valve disease, history of AF, PAD, prior stroke, and cardiopulmonary bypass with time greater than 110 minutes.

Authors’ roles & responsibilities HNS EHM JCVCG NNS LCA MAG JBP LCB

Main author Data analysis and writing Data collection and data arrangement Reference search Writing and review Data collection Data survey Adviser in master’s degree dissertation which resulted in this article

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15. Zimerman LI, Fenelon G, Martinelli Filho M, Grupi C, Atié J, Filho AL, et al. Sociedade Brasileira de Cardiologia. Diretrizes brasileiras de fibrilação atrial. Arq Bras Cardiol. 2009;92(6 supl. 1):1-39.

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16. Ahonen J, Salmenperä M. Brain injury after adult cardiac surgery. Acta Anaesthesiol Scand. 2004;48(1):4-19.

5. Pires SL, Gagliardi RJ, Gorzoni ML. Study of the main risk factors frequencies for ischemic cerebrovascular disease in elderly patients. Arq Neuropsiquiatr. 2004;62(3B):844-51.

17. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31(19):2369-429.

6. Guaragna JCVC, Bolsi DC, Jaeger CP, Melchior R, Petracco JB, Facchi LM, et al. Preditores de disfunção neurológica maior após cirurgia de revascularização miocárdica isolada. Rev Bras Cir Cardiovasc. 2006;21(2):173-9.

18. Durazzo AES, Sitrângulo Jr. CJ, Presti C, Silva ES, De Luccia N. Doença arterial obstrutiva periférica: que atenção temos dispensado à abordagem clínica dos pacientes? J Vasc Br. 2005;4(3):255-64.

7. Knapik P, Ciesla D, Wawrzynczyk M, Knapik M, Borkowski J, Zembala M. Incidence and prediction of permanent neurological deficits after cardiac surgery - are the existing models of prediction truly global? Eur J Cardiothorac Surg. 2010;37(3):717-23.

19. Rosa MP, Portal VL. Estenose carotídea e cirurgia de revascularização miocárdica. Rev Assoc Med Bras. 2011;57(3):323-7.

8. Bucerius J, Gummert JF, Borger MA, Walther T, Doll N, Onnasch JF, et al. Stroke after cardiac surgery: a risk factor analysis of 16,184 consecutive adult patients. Ann Thorac Surg. 2003;75(2):472-8.

20. Layden J, Michaels J, Bermingham S, Higgins B; Guideline Development Group. Diagnosis and management of lower limb peripheral arterial disease: summary of NICE guidance. BMJ. 2012;345:e4947.

9. Newman MF, Mathew JP, Grocott HP, Mackensen GB, Monk T, Welsh-Bohmer KA, et al. Central nervous system injury associated with cardiac surgery. Lancet. 2006;368(9536):694-703.

21. D’Ancona G, Saez de Ibarra JI, Baillot R, Mathieu P, Doyle D, Metras J, et al. Determinants of stroke after coronary artery bypass grafting. Eur J Cardiothorac Surg. 2003;24(4):552-6.

10. Guaragna LP, Alba DPD, Goulart PdR, Guaragna JCVC, Bodanese LC, Magedanz EH, et al. O impacto da obesidade na morbi-mortalidade de pacientes submetidos à cirurgia de revascularização miocárdica. Scientia Med. 2008;18(2):75-80.

22. Hedberg M, Boivie P, Engström KG. Early and delayed stroke after coronary surgery: an analysis of risk factors and the impact on short- and long-term survival. Eur J Cardiothorac Surg. 2011;40(2):379-87.

11. Andrade JP, Piegas LS, Timerman A, Feitosa G, Rossi Neto JM, Nicolau JC, et al. IV Diretriz da Sociedade Brasileira de Cardiologia sobre Tratamento do infarto agudo do miocárdio com supradesnível do segmento ST. Arq Bras Cardiol. 2009;93(6 Suppl 2):e179-264.

23. Lelis RGB, Auler Jr JOC. Lesão neurológica em cirurgia Cardíaca: aspectos fisiopatológicos. Rev Bras Anestesiol. 2004;54(4):607-17.

12. Guaragna JCVC, Bodanese LC, Bueno FL, Goldani MA. Proposta de escore de risco pré-operatório para pacientes candidatos à cirurgia cardíaca valvar. Arq Bras Cardiol. 2010;94(4):541-8.

24. McKhann GM, Grega MA, Borowicz LM, Jr., Baumgartner WA, Selnes OA. Stroke and encephalopathy after cardiac surgery: an update. Stroke. 2006;37(2):562-71.

13. Cadore MP, Guaragna JC, Anacker JF, Albuquerque LC, Bodanese LC, Piccoli JC, et al. A score proposal to evaluate surgical risk in patients submitted to myocardial revascularization surgery. Rev Bras Cir Cardiovasc. 2010;25(4):447-56.

25. Vicchio M, Feo MD, Giordano S, Provenzano R, Cotrufo M, Nappi G. Coronary artery bypass grafting associated to aortic valve replacement in the elderly: survival and quality of life. J Cardiothorac Surg. 2012;7:13.

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Milani R, et al. - Analysis of transit time flow of the right internal thoracic ORIGINAL ARTICLE artery anastomosed to the left anterior descending artery compared to the left internal thoracic artery

Analysis of transit time flow of the right internal thoracic artery anastomosed to the left anterior descending artery compared to the left internal thoracic artery

Análise da medida de fluxo por tempo de trânsito da artéria torácica interna direita anastomosada para a artéria interventricular anterior comparada com a artéria torácica interna esquerda

Rodrigo Milani1. MD. MsC. PhD; Daniela de Moraes1. MD; Aline Sanches1. MD; Rodrigo Jardim1. MD; Thais Lumikoski1. MD; Gabriela Miotto1. MD; Vitor Hugo Santana1. MD; Paulo Roberto Brofman1. MsC. PhD

DOI: 10.5935/1678-9741.20140061

RBCCV 44205-1534

Abstract Introduction: We evaluated with transit time flow the performance of the right and left thoracic arteries when used as a graft for the left anterior descending artery. Methods: Fifty patients undergoing surgery for myocardial revascularization without cardiopulmonary bypass were divided into two groups. In group A patients received graft of right internal mammary artery to the anterior interventricular branch. In group B patients received graft of left internal mammary artery to the same branch. At the end of the operation the flow was assessed by measuring transit time. Results: In group A. mean age was 60.6±9.49 years. The average height and weight of the group was 80.4±10.32 kg and 169.2±6.86 cm. The average number of grafts per patient in this group was 3.28±1.49. The mean flow and distal resistance obtained in right internal thoracic artery was 42.1±23.4 ml/min and 2.8±0.9 respectively. In group B. the mean age was 59.8±9.7 years. The average height and weight of this group was 77.7±14.22 kg and 166.0±8.2 cm. The average number of grafts per patient in this group was 3.08 ±0.82. The mean flow and distal resistance

observed in this group was 34.2±19.1 ml/min and 2.0±0.7. There were no deaths in this series. Conclusion: Right internal mammary artery presented a similar behavior to left internal mammary artery when anastomosed to the anterior interventricular branch of the left coronary artery. There was no statistical difference between the measured flow obtained between both arteries.

Pontifícia Universidade Católica do Paraná (PUCPR). Curitiba,PR, Brazil.

This study was carried out at Santa Casa de Misericórdia de Curitiba. Curitiba. PR. Brazil; Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, PR, Brazil.

1

Descriptors: Mammary Arteries. Coronary Artery Bypass. off-Pump. Internal Mammary-Coronary Artery Anastomosis. Resumo Introdução: Avaliamos por meio da medida de fluxo por tempo de trânsito o desempenho das artérias torácicas direita e esquerda quando utilizadas como enxerto para revascularização da artéria interventricular anterior. Métodos: Cinquenta pacientes submetidos à operação para revascularização do miocárdio sem circulação extracorpórea foram divididos em dois grupos. No grupo A. os pacientes rece-

Correspondence address: Rodrigo Milani Rua Cezar Correia de Souza Jr. 54 – Curitiba. PR. Brazil – Zip code: 82015-220 E-mail: rodrigo.milani@sbccv.org.br

No financial support.

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Article received on December 19th, 2013 Article accepted on March 14th, 2014

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O fluxo médio e a resistência distal obtidos na artéria torácica interna direita foi de 42.1±23.4 ml/min e 2.8±0.9 respectivamente. No grupo B. a idade média foi de 59.8±9.7 anos. A média de peso e altura deste grupo foi de 77.7±14.2215.7 Kg e 166.0±8.2 cm. A média de pontes por paciente neste grupo foi de 3.08±0.82. O fluxo médio e a resistência distal observados neste grupo foi de 34.2±19.1ml⁄min e 2.0±0.7. Não houve óbitos nesta série. Conclusão: A artéria torácica interna direita apresentou um comportamento similar ao da artéria torácica interna esquerda quando anastomosada ao ramo interventricular anterior da coronária esquerda. Não houve diferença estatística entre a medida de fluxo obtida entre ambas as artérias.

Abbreviations. acronyms & symbols AHA NYHA PI STS

American Heart Association New York Heart Association Pulsatility Index Society for Thoracic Surgery

beram enxerto de artéria torácica interna direita para o ramo interventricular anterior. No grupo B. os pacientes receberam enxerto de artéria torácica interna esquerda para o mesmo ramo. Ao término da operação. o fluxo foi avaliado por meio da medida de fluxo por tempo de trânsito. Resultados: No grupo A. idade média foi de 60.6±9.49 anos. A média de peso e altura do grupo foi de 80.4±10.32 Kg e 169.2±6.86 cm. A média de pontes por paciente neste grupo foi de 3.28±1.49.

Descritores: Revascularização Miocárdica. Anastomose de Artéria Torácica Interna-Coronária. Artéria Torácica Interna.

INTRODUCTION

Most authors agree that the use of both thoracic arteries is beneficial. They also believe that the right internal thoracic artery should be used mainly in the left coronary system. especially in the circumflex artery and its branches. by making a retro-aortic[14] passage. The use of the right internal thoracic artery to the anterior interventricular branch is no consensus. In the last joint guideline from the American Heart Association (AHA) and the Society for Thoracic Surgery (STS)[15]. when the best distribution of grafts according to the coronary vessels was assessed. the use of the left internal thoracic artery to the anterior interventricular branch received recommendation IB by keeping as the main graft for this branch. while the use of the right internal thoracic artery to the same branch was IIA class. In the present study we assessed fifty patients divided into two groups of twenty-five comparing them by measuring the flow for traffic time and the behavior of both thoracic arteries grafted to the anterior interventricular branch of the left coronary. Our main aim was to determine whether the flow obtained at the anastomosis of the right internal thoracic artery to the anterior interventricular branch is similar to the data obtained with the “gold standard” which is the anastomosis of the left internal thoracic artery to the same branch of the left coronary artery.

The first reports of experimental work for a possible myocardial revascularization are from the mid 50’s. A group of researchers from the Soviet Union made the anastomosis of the left internal thoracic artery to the anterior interventricular branch in dogs[1]. This work served as the basis for the reports of the first cases in humans[2]. In 1967. when this study was presented at a cardiology symposium in Leningrad. the majority of those present agreed to a resolution that said coronary surgery was impossible and had no future. After more than 40 years after these initial reports. the surgeries for myocardial revascularization have become one of the most performed surgeries in the world and certainly the most studied. Several studies[3-6] show that even after so much time passed and the steady advance of medicine in the last decades it remains the treatment of choice for patients with severe coronary disease. Obtaining consistent long-term results after performing this type of procedure depends mainly on the grafts to be used. The superiority of arterial grafts over saphenous vein grafts. especially the internal thoracic artery is well documented[7-9]. Studies comparing these two types of grafts show a higher patency rate of 90% in 10 years for the internal thoracic artery versus 50% of saphenous vein grafts. being reflected this difference in increased patient survival. Furthermore. several studies from different groups were presented showing that the use of both internal thoracic arteries has a significant survival when a period of 20 years after surgery is evaluated[10-13].

METHODS In this retrospective study. we assessed 50 patients undergoing coronary artery bypass grafting without cardiopulmo-

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nary bypass. divided into two groups of 25 patients each. In group A. there are patients who received graft of right internal thoracic artery to the anterior interventricular branch. In group B. patients who received left internal thoracic artery to the same branch. In this study. we excluded all patients who required a procedure associated with revascularization. as well as patients who possibly undergoing cardiopulmonary bypass. In none of the fifty patients conversion to cardiopulmonary bypass was required. In both groups. we used general anesthesia. and the approach was median sternotomy. The manner on which the anesthesia was performed and how the grafts were obtained have been subject to previous publication[16]. In both groups. the internal thoracic artery was obtained using skeletonization. The strategy of revascularization differs somewhat between groups. In both cases. we used a dose of 2 mg/kg of heparin. The initial approach was the same. with the pericardium opened widely. pulled in its anterior edge on both sides. With the help of a polyester tape 90 cm long and 3 cm wide. a section by Lima[17] was performed. This was applied between the inferior vena cava and the left inferior pulmonary vein to better exposure of the heart without significant changes of hemodynamics. In all fifty patients a suction tissue stabilizer (Octopuss II ®. Medtronic) to perform anastomosis was used. Moreover. in most cases. it was performed with an intraluminal shunt. The strategy of revascularization. on which graft would be directed to coronary branch was decided at the time of operation. Rather. we chose the retroaortic right internal thoracic artery to the circumflex artery and its branches and the left internal thoracic artery to the anterior interventricular branch. The anastomoses are also preferably performed ​​in the middle third of the coronary artery and. if the graft did not reach the target artery satisfactorily we reversed the distribution. In group A. the operation started by anastomosis of the right internal thoracic artery to the anterior interventricular branch. followed. in cases where it was necessary. through the sidewall and finally through the anterior interventricular branch. In group B. the operation started by the anastomoses of the inferior wall. followed by sidewall and finally the anterior interventricular branch. The approach taken in group B. leaving the anterior interventricular artery last is due to a fear of injury by traction. This could occur while performing an anastomosis in the sidewall of an increased ventricle with the anastomosis of the left internal thoracic artery already performed to the anterior interventricular branch. At the end of the anastomoses after heparin reversal. systolic blood pressure was maintained around 110 mmHg and a heart rate average ranging between 80 and 100 beats per minute. No patient in the series needed use of vasoactive drugs to obtain the desired pressure. Moreover. with “3mm probe”

(Figure 1) connected to the flowmeter Medistim brand. model Butterfly Flowmeter. flow measures by transit time and review of the pulsatility index. PI (Figure 2) were performed. To obtain these values​​. the patients were kept under apnea for a period of around 10 seconds. and the “probe” applied to the selected graft. According to the device manufacturer. flows higher than 10 ml/min. and a pulsatility index which measures the distal strength below 5 means an anastomosis of good quality. After evaluation of the anastomoses. the revision of hemostasis and closure of the chest were performed. Next. still under general anesthesia. patients were referred to the intensive care unit. This study received a favorable opinion from the Research Ethics Committee of our institution under number 20827713.2.0000.0020.

Fig. 1 - 3 mm Probe

Fig. 2 - Flow analysis of internal thoracic artery

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Statistical Analysis To evaluate the association between two dichotomous qualitative variables we considered the Fisher exact test. The correlation between quantitative variables was evaluated by estimating the Pearson correlation coefficient. To compare the two groups with respect to quantitative variables we used the Student’s t test for independent samples. These comparisons. considering more than two groups were performed using a model of analysis of variance factor (ANOVA). For multivariate analysis a model of Multiple Linear Regression was adjusted. P values ​​<0.05 were considered statistically significant. Data were analyzed using the SPSS v.20.0 software.

In group A. seven (28%) had undergone previous coronary angioplasty and eight (32%) had presented myocardial infarction against four (16%) who had undergone angioplasty in group B and four (16%) with history of myocardial infarction. There was no statistical difference between the groups regarding previous coronary angioplasty or old myocardial infarction. Regarding the left ventricular function. if normal. moderate or poor compromise. Table 2 presents the data from both groups. There was no statistical difference between the groups when evaluating left ventricular function (P: 0.461). In the assessment of functional class. no patient in group A (0%) were in NYHA class I. 15 (60%) in class II. seven (28%) in class III. and three (12%) in class IV . In group B. three (12%) were in class I. 14 (56%) in class II. seven (28%) in class III and one (4%) in class IV. There was no statistical difference (P=0.258) between the two groups. Table 3 presents the distribution of the number of individual grafts per patient in each group. The central point of this study is the evaluation of coronary flow. The evaluation of the measured flow through the transit time showed an average flow of 42.2 ± 23.4 ml/min in Group A and 34.2 ± 19.1 ml/min in group B. featuring a statistically significant difference in favor of group A. We tested the null hypothesis that the mean FLOW is the same in both groups (RLL and LLL). versus the alternative hypothesis of means that are not all the same. Table 4 and Figure 3 shows the results obtained. Finally. we assessed the pulsatility index. PI. that determines the resistance after the anastomosis. The device manufacturer provides measurement values ​​for flow traffic time of less than 5 as indicative of a good quality anastomosis. In group A. the mean PI was 2.8±0.9 and in group B 2.0±0.7. Table 5 shows the results obtained from both groups. Figure 4 shows a representation of the behavior of pulsatility index in both groups.

RESULTS We assessed 50 patients undergoing coronary artery bypass grafting without cardiopulmonary bypass were divided into two groups of 25 each. In group A we put patients who received internal thoracic artery to the anterior interventricular branch. In group B we put patients who received a graft of the left internal thoracic artery graft to the same coronary branch. In group A. the mean age was 60.6 ± 9.49 ranging between 44 and 82 years and in group B 59.8 ± 9.7 between 43 and 80 years. Patients in group A had a mean weight of 80.4 ± 10.32 kg. The mean weight from B group was 77.7 ± 15.7 kg. The average height of the group A was 169.2 ± 6.86 cm and in group B 166.0 ± 8.2 cm. Table 1 shows the values of age. weight. height and body mass index for both groups: In assessing risk factors for coronary disease. in group A 21 (84%) patients were hypertensive. compared with 18 (72%) in group B (P=0.496). 10 (40%) patients in group A were diabetics against five (20%) in group B (P=0.217) and 6 (24%) patients in group A were smokers against seven (28%) in group B (P=1).

Table 1. Quantitative variables. Weight Height BMI Age

Group B A B A B A B A

n 25 25 25 25 25 25 25 25

Mean 77.7 80.4 166.0 169.2 28.1 28.1 59.8 60.6

Median 79.0 80.0 165.0 170.0 27.3 28.2 59.0 61.0

Minimum 43.0 55.0 153.0 159.0 17.9 20.2 43.0 44.0

Maximum 115.0 94.0 180.0 180.0 47.0 34.5 80.0 82.0

BMI – Body Mass Index

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Standard deviation 15.7 10.32 8.2 6.86 5.3 3.31 9.7 9.49

P* value 0.485 0.131 0.945 0.759

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Table 2. Left ventricular function.

Table 3. Individual grafts. Group

B

LV Normal

12 48.00% 8 32.00% 5 20.00% 25

Moderate Poor Total

Number of grafts

A

B 3 12.00% 6 24.00% 12 48.00% 4 16.00% 0 0.00% 25

1

13 52.00% 10 40.00% 2 8.00% 25

2 3 4 6 Total

Group

Table 4. Flow measurement. Group B A

Fluow n Mean 25 34.2 25 42.2

Median Minimum Maximum 31.0 13.0 82.0 34.0 16.0 94.0

Standard deviation 19.1 23.4

P-Value* 0.197

Table 5. Pulsatility index. Group B A

PI n 25 25

Mean 2.0 2.8

Median 2.0 2.9

Minimum 1.0 1.3

Fig. 3 - Flow Performance

Maximum 3.8 4.3

Standard deviation P-Value* 0.7 0.9 0.003

Fig. 4 - Pulsatility index

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A 0 0.00% 8 32.00% 13 52.00% 3 12.00% 1 4.00% 25

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DISCUSSION

lar branch. Of these. 43 had normal PI flow and. in the other three after anastomosis is performed again the PI flow has been normalized. Based on these data. the authors concluded that the measured flow by transit time is simple. reproducible and easy to perform. Moreover. they concluded that a low flow in the graft with a high PI indicates need for revision of the anastomosis and after that the values ​​tend to normalize. They also confirmed that this type of flow measurement is cost-effective and probably prevents hemodynamic instability in the immediate postoperative period. Leong et al.[27] assessed 116 patients with a total of 322 grafts. with 125 arterial and 197 venous. They performed the measurement of flow by transit time. The average flow for the internal thoracic artery to the anterior interventricular branch was 37.4 ± 23.5 ml/min and 21.2 to 36 ml/min in the other grafts. In six patients the anastomosis error was detected and that being performed again. The authors found no statistical difference between PI flow or arterial and venous grafts. They concluded stating that this type of coronary flowmetry provides important and reliable information about the patency of each graft individually. It is able to accurately detect folds. twists and significant stenoses in grafts. allowing their immediate correction. In our country. Cerqueira Neto et al.[28] published a study showing the measured flow of the left internal thoracic artery to the anterior interventricular branch in patients who underwent surgery with and without cardiopulmonary bypass. concluding that there is no difference in flow between these two situations. In our series. we assessed two groups of 25 patients each. comparing the performance of the left internal thoracic artery to the right internal thoracic artery. when grafted to the anterior interventricular branch. Many surgeons still have some fear of putting the right internal thoracic artery to the anterior interventricular branch. The two groups were similar with respect to weight. height and age. In the group in which the right internal thoracic artery was used there were more diabetic patients. but without statistical difference. When evaluating flow. the group of left internal thoracic artery had an average flow of 34.2±19.1 versus 42.2±23.4 ml/ min in the right thoracic artery group. Despite the increase. there was no significant difference between the two groups. In assessing the pulsatility index. PI. the first group had a mean PI of 2.0±0.7 vs. 2.8±0.9 in the second group. Despite the difference between the groups is significant (P=0.003). the values ​​obtained in the group in which the thoracic artery was used showed values ​​within the normal range. or that is. a PI below 5. In this present series. despite the use of two internal thoracic arteries in most patients. there were no cases of mediastinitis. There was no mortality.

During the past 20 years. numerous studies have been published related to the prevention. diagnosis and surgical treatment of coronary artery disease[18.19]. In these studies. the advantage on the use of the thoracic artery is clearly demonstrated due to its superior patency. showing consistent longterm results and thus leading to an increased survival. This mainly occurs in groups where getting better results over the years is less frequent as in women and diabetics. Currently. the most widely used strategy in coronary artery bypass operations is the use of an internal thoracic artery accompanied the other saphenous vein grafts[20.21]. However. atherosclerosis of saphenous vein is responsible for the failure of CABG during the study. A growing number of diabetics has been referred for surgery due to poor results with coronary angioplasty. There was a reduction in mortality. 5.8% vs. 20.6%. with respect to results obtained in patients who received at least one internal thoracic artery[22]. The left internal thoracic artery presents patency greater than 90% after 10 years of its implantation. This is because less than 1% of them develops atherosclerosis with severe impairment[23]. As already emphasized above. the use of the mammary artery improves survival of patients. Studies show that when using both internal thoracic arteries. the survival increases significantly in 20 years[11-13]. Study presented by Ribeiro et al.[24] shows very little difference from the histological point of view between left and right internal thoracic arteries. noting only that the distal segment of the elastic layer is more prominent. With these results clearly established. the central focus revolves around what is the best distribution for thoracic arteries. which vessel should receive the second thoracic artery. and especially if it is appropriate to use the right internal thoracic artery to the anterior interventricular branch of left coronary. As noted earlier. our main distribution is the same advocated by Gerola et al.[14] with the right internal thoracic artery directed to the circumflex artery and its branches through a retroaortic course. The flow measurement by transit time became available for clinical use in the late 90s[25,26]. It is a quick. simple and objective way to verify the quality of the anastomosis in coronary surgeries. Flows below 10 ml/min associated with a pulsatility index greater than 5 indicate problems. The pulsatility index. PI. is a number obtained by dividing the difference between the maximum flow and minimum flow by mean flow[26]. One of the first studies on the flow measurement by transit time was published in 1998 by Walpoth et al.[25]. In this study. the authors assessed 46 anastomoses of the left internal thoracic artery to the anterior interventricu-

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CONCLUSION

5. Bidstrup BP. Underwood SR. Sapsford RN. Streets EM. Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac Cardiovasc Surg. 1993;105(1):147-52.

The results obtained in our study suggest that the right internal thoracic artery when anastomosed to the anterior interventricular branch presents an initial behavior very similar to that of the left internal thoracic artery. In cases where the left internal thoracic artery needs to be anastomosed to another coronary branch or that it is not available. the right internal thoracic artery should be considered as the substitute of choice. The initial flow obtained when comparing the right and left arteries showed no significant difference.

6. Barner HB. Mudd JG. Mark AL. Ahmad N. Dickens JF. Patency of internal mammary-coronary grafts. Circulation. 1992;54(6 Suppl):III70-3. 7. Sabik JF 3rd. Lytle BW. Blackstone EH. Houghtaling PL. Cosgrove DM. Comparison of saphenous vein and internal thoracic artery graft patency by coronary system. Ann Thorac Surg. 2005;79(2):544-51. 8. Benzon E. Choplain JN. Maguid YA. Aziz AA. Barra JA. Failure of internal thoracic artery grafts: conclusions from coronary angiography mid-term follow-up. Ann Thorac Surg. 2003;76(3):754-9.

Authors’ roles & responsibilities RM

DM AS RJ TL GM VHS PRB

Analysis and interpretation of data. final approval of the manuscript; conception and design of the study; implementation of operations and/or experiments; writing of the manuscript or revising it critically for its content Analysis and interpretation of data; conception and design of the study; writing of the manuscript or revising it critically for its content Analysis and interpretation of data; conception and design of the study; writing of the manuscript or revising it critically for its content Help in operations and data collection; performing operations and experiments Help in operations and data collection; performing operations and experiments Help in operations and data collection; performing operations and experiments Help in operations and data collection; performing operations and experiments Writing and revision of the article; analysis and interpretation of data

9. Caes FL. Van Nooten GJ. Use of internal mammary artery for emergency grafting after failed coronary angioplasty. Ann Thorac Surg. 1994;57(5):1295-9. 10. Lytle BW. Blackstone EH. Loop FD. Houghtaling PL. Arnold JH. Akhrass R. et al. Two internal thoracic artery grafts are better than one. J Thorac Cardiovasc Surg. 1999;117(5):855-72. 11. Calafiore AM. Di Mauro M. Di Giammarco G. Teodori G. Iacò AL. Mazzei V. et al. Single versus bilateral internal mammary artery for isolated first myocardial revascularization in multivessel disease: long-term clinical results in medically treated diabetic patients. Ann Thorac Surg. 2005;80(3):888-95. 12. Martins SK. Santos MA. Tirado FHP. Martins Jr FCE. Malat HF. Jatene AD. et al. Revascularização do miocárdio com emprego de ambas artérias mamárias internas em pacientes com diabetes mellitus. Rev Bras Cir Cardiovasc. 2007;22(3):291-6. 13. Milani R. Brofman PR. Guimarães M. Barboza L. Tchaick RM. Meister Filho H. et al. Dupla artéria torácica esqueletizada versus convencional na revascularização do miocárdio sem CEC em diabéticos. Rev Bras Cir Cardiovasc. 2008;23(3):351-7.

REFERENCES

14. Gerola LR. Puig LB. Moreira LFP. Gemha GP. Cividanes GVI. Santos RCM. et al. Dez anos de experiência com a artéria torácica interna direita através do seio transverso na revascularização da artéria circunflexa e seus ramos. Rev Bras Cir Cardiovasc. 1993;8(4):259-65.

1. Kolesov VI. Potashov LV. Surgery of coronary arteries. Eksp Khir Anesteziol. 1965;10(2):3-8. 2. Kolesov VI. Mammary artery-coronary artery anastomosis as method of treatment for angina pectoris. J Thorac Cardiovasc Surg. 1967;54(4):535-44. 3. Grondin CM. Campeau L. Lespérance J. Enjalbert M. Bourassa MG. Comparison of late changes in internal mammary artery and saphenous vein grafts in two consecutive series of patients 10 years after operation. Circulation. 1984;70(3 Pt 2):I208-12.

15. Hills LD. Smith PK. Anderson JL. Bittl JA. Bridges CR. Byrne JG. et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124(23):e652-735.

4. Loop FD. Lytle BW. Cosgrove DM. Stewart RW. Goormastic M. Williams GW. et al. Influence of the internal-mammary artery graft on 10-year survival and other cardiac events. N Engl J Med. 1986;314(1):1-6.

16. Milani RM. Análise dos resultados imediatos da operação para revascularização do miocárdio sem pinçamento total da aorta [Dissertação de mestrado]. Curitiba: Universidade Federal do Paraná; 2000.

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17. Lima RC. Padronização técnica de revascularização da artéria circunflexa e seus ramos sem circulação extracorpórea [Tese de doutorado]. São Paulo: Escola Paulista de Medicina; 1999.

23. Gurné O. Chenu P. Buche M. Louagie Y. Eucher P. Marchandise B. et al. Adaptive mechanisms of arterial and venous coronary bypass grafts to an increase in flow demand. Heart. 1999;82(3):336-42.

18. Edwards FH. Carey JS. Grover FL. Bero JW. Hartz RS. Impact of gender on coronary bypass operative mortality. Ann Thorac Surg. 1998;66(1):125-31.

24. Ribeiro MF. Kneubil MC. Aquino MS. Gomes GN. Mazzili P. Buffolo E. et al. Histomorphometric differences between the left and right internal thoracic arteries in humans. Rev Bras Cir Cardiovasc. 2008;23(1):1-6.

19. Carey JS. Cukingnan RA. Singer LK. Health status after myocardial revascularization: inferior results in women. Ann Thorac Surg. 1995;59(1):112-7.

25. Walpoth BH. Bosshard A. Genyk I. Kipfer B. Berdat PA. Hess OM. et al. Transit-time flow measurement for detection of early graft failure during myocardial revascularization. Ann Thorac Surg. 1998;66(3):1097-100.

20. Calafiore AM. Di Mauro M. Di Giammarco G. Contini M. Vitolla G. Iacò AL. et al. Effect of diabetes on early and late survival after isolated first coronary bypass surgery in multivessel disease. J Thorac Cardiovasc Surg. 2003;125(1):144-54.

26. D’Ancona G. Karamanoukian HL. Bergsland J. Is intraoperative measurement of coronary blood flow: a good predictor of graft patency? Eur J Cardiothorac Surg. 2001;20(5):1075-7.

21. Lev-Ran O. Braunstein R. Nesher N. Ben-Gal Y. Bolotin G. Uretzky G. Bilateral versus single internal thoracic artery grafting in oral-treated diabetic subsets: comparative seven-year outcome analysis. Ann Thorac Surg. 2004;77(6):2039-45.

27. Leong DK. Ashok V. Nishkantha A. Shan YH. Sim EK. Transittime flow measurement is essential in coronary artery bypass grafting. Ann Thorac Surg. 2005;79(3):854-7.

22. The BARI Investigators. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 1997;96(6):1761-9.

28. Cerqueira Neto FM. Guedes MA. Soares LE. Almeida GS. Guimarães AR. Barreto MA. et al. Flowmetry of left internal thoracic artery graft to left anterior descending artery: comparison between on-pump and off-pump surgery. Rev Bras Cir Cardiovasc. 2012;27(2):283-9.

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Oliveira MAB, et al. - Comparison of fractal dimension and Shannon entropy ORIGINAL ARTICLE in myocytes from rats treated with histidine-tryptophan-glutamate and histidine-tryptophan cetoglutarate

Comparison of fractal dimension and Shannon entropy in myocytes from rats treated with histidine-tryptophan-glutamate and histidinetryptophan cetoglutarate Comparação da dimensão fractal e entropia de Shannon em miócitos de ratos submetidos à cardioplegia utilizando solução histidina-triptofano-cetoglutarato e histidina-triptofano com glutamato

Marcos Aurélio Barboza de Oliveira1, MD; Antônio Carlos Brandi2, MD; Carlos Alberto dos Santos2, MD; Paulo Henrique Husseni Botelho2, MD; José Luís Lasso Cortez3, MD; Moacir Fernandes de Godoy4, PhD; Domingo Marcolino Braile5, MsC, PhD

DOI: 10.5935/1678-9741.20140052

RBCCV 44205-1535

Abstract Introduction: Solutions that cause elective cardiac arrest are constantly evolving. but the ideal compound has not yet been found. The authors compare a new cardioplegic solution with histidine-tryptophan-glutamate (Group 2) and other one with histidine-tryptophan-cetoglutarate (Group 1) in a model of isolated rat heart. Objective: To quantify the fractal dimension and Shannon entropy in rat myocytes subjected to cardioplegia solution using histidine-tryptophan with glutamate in an experimental model. considering the caspase markers. IL-8 and KI-67. Methods: Twenty male Wistar rats were anesthetized and heparinized. The chest was opened. the heart was withdrawn and 40 ml/kg of cardioplegia (with histidine-tryptophan-cetoglutarate or histidine-tryptophan-glutamate solution) was infused. The hearts were kept for 2 hours at 4°C in the same solution. and

thereafter placed in the Langendorff apparatus for 30 min with Ringer-Locke solution. Analyzes were performed for immunohistochemical caspase. IL-8 and KI-67. Results: The fractal dimension and Shannon entropy were not different between groups histidine-tryptophan-glutamate and histidine-tryptophan-acetoglutarate. Conclusion: The amount of information measured by Shannon entropy and the distribution thereof (given by fractal dimension) of the slices treated with histidine-tryptophan-cetoglutarate and histidine-tryptophan-glutamate were not different. showing that the histidine-tryptophan-glutamate solution is as good as histidine-tryptophan-acetoglutarate to preserve myocytes in isolated rat heart.

Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil; Centro Universitário de Votuporanga (UNIFEV), Santa Casa Votuporanga, Votuporanga, SP, Brasil. 2 Hospital de Base São José do Rio Preto. São José do Rio Preto, SP, Brazil. 3 Santa Casa Votuporanga, Votuporanga, SP, Brazil. 4 Departamento de Cardiologia e Cirurgia Cardiovascular da Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, Brazil. Transdisciplinary Unit for Chaos and Complexity Study (NUTECC-CNPq), São José do Rio Preto, Brazil. 5 Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil.

Correspondence address: Marcos Aurélio Barboza de Oliveira Avenida República do Líbano,2700 - casa 80 São José do Rio Preto. SP. Brazil - Zip code: 15092-440 E-mail: m_aurelio@sbccv.org.br

Descriptors: Heart Arrest. induced. Apoptosis. Myocardial Ischemia.

1

This study was carried out at S Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil. No financial support. Article received on November 19th, 2013 Article accepted on February 23rd, 2014

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e infundido 40 ml/Kg de solução cardioplégica apropriada. Os corações foram mantidos por 2 horas na mesma solução a 4oC e. após esse período. colocados em aparato de Langendorff por 30 minutos com solução de Ringer Locke. Foram feitas análises imunohistoquímicas para caspase. IL-8 e KI-67. Resultados: A dimensão fractal e a entropia de Shannon dos corações submetidos à parada cardíaca eletiva nos grupos 1 e 2 não foram diferentes. Conclusão: A quantidade de informações avaliada pela entropia de Shannon e a distribuição das mesmas (dada pela dimensão fractal) nas lâminas de coração de rato submetidas à cardioplegia com solução histidina-triptofano-acetoglutarato ou histidina-triptofano-glutamato não foram diferentes. o que mostra que a solução de histidina-triptofano-glutamato é tão boa quanto a histidina-triptofano-cetoglutarato na preservação dos miócitos em modelo de coração isolado de rato.

Abbreviations. acronyms & symbols HTG Histidina-triptofano-glutamato HTK Histidina-triptofano-cetoglutarato IP Intraperitoneal

Resumo Introdução: As soluções que provocam parada cardíaca eletiva estão em constante evolução. porém. o composto ideal ainda não foi encontrado. Os autores comparam uma nova solução cardioplégica com histidina-triptofano-glutamato (Grupo 2) com histidina-triptofano-cetoglutarato (Grupo 1) em modelo de coração isolado de rato. Objetivo: Quantificar a dimensão fractal e entropia de Shannon em miócitos de rato submetidos à cardioplegia utilizando solução histidina-triptofano com glutamato em modelo experimental. considerando-se os marcadores caspase. IL-8 e Ki-67. Métodos: Vinte ratos machos de raça Wistar foram anestesiados e heparinizados. O tórax foi aberto. realizado cardiectomia

Descritores: Parada Cardíaca Induzida. Apoptose. Isquemia Miocárdica.

INTRODUCTION

Cardioplegic solutions with low calcium concentration as the HTK can cause the so-called “calcium paradox”. destabilizing the cell membrane. which culminates in necrosis. leukocyte margination and apoptosis[10]. Histological changes induced by cardioplegic solutions could generate change in the amount and distribution of the information contained on the blade. It is well known that tissue structural changes can be quantified by the fractal dimension and Shannon entropy[11.12]. The analysis of fractal dimension and Shannon entropy have been recently used in several areas of medicine such as cardiology. neurology. ophthalmology and radiology[11.13] and are useful in characterizing irregular and complex [11.13.14] structures. Using fractal analysis. Arruda et al.[11] and Douglas et al.[12] correlated the degree of dedifferentiation and tumor invasiveness in prostate cancer and degree of rejection of cardiac tumors. respectively. This study aims to assess if the study solution histidine-tryptophan-glutamate (HTG) is better than HTK (standard solution) by fractal dimension and Shannon entropy in rat myocytes. considering the caspase markers. IL-8 and KI-67.

During cardiac surgery it is usual the temporary arrest of the heart. allowing the surgeon to perform the surgery within the cardiac cavities environment free of blood and movement. Before there was any solution that produces safe cardiac arrest. it was by Gibbon in 1953 the merit of using a technique described by Senning in experimental atrial septal defect closure in dogs using ventricular fibrillation[1]. In 1955. Melrose et al.[2] introduced the concept of chemical stopping using solution containing 2.5% potassium citrate. which depolarizes the cell membrane and the conduct of the action potential. However. the high concentration of potassium caused focal myocardial necrosis and death in many patients. resulting in discontinuation of hyperkalemic cardioplegia as protective solution for nearly 20 years. In the mid 70s. alternative cardioplegia containing less potassium than Melrose’ solution were successfully introduced as the solution of St. Thomas[3]. low-volume blood cardioplegia[4.5] and solution of histidine-tryptophan-ketoglutarate (HTK)[6]. Despite these advances. the ideal cardioplegic solution has not yet been developed[7.8]. The substitution of glutamate ketoglutarate has impact still uncertain on the behavior of the myocardial muscle. but it will be an effective way to indirectly assess their incorporation into the Krebs cycle. removing the mitochondrial pyruvate. thus preventing acidosis which is notoriously damaging both to the cell as their enzymatic mechanisms[9].

METHODS After approval by the Research Ethics Committee on Animal Experimentation of the Faculty of Medicine of São José do Rio Preto (Protocol number 015/2012). 20 male Wistar rats (10 in each group). were used. weighing 280 ± 29 grams.

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All animals received care according to the recommendations of the Committee on Care and Use of Laboratory Animals - Institute of Laboratory Animal Resources (ILAR) National Research Council. United States[15].

Three threads of epicardial pacemaker were inserted at equidistant points from the ventricles to the electrocardiographic documentation of cardiac events. The time of onset of ventricular fibrillation and the first heartbeat counted from the start of infusion of Ringer Locke solution was noted. After 30 minutes of infusion of Ringer Locke solution. the experiment was discontinued. The hearts were removed from the Langendorff system and fragments of the cardiac apex. which were stored in sterile Falcon tubes containing 10% formalin for subsequent histological and immunohistochemical preparation.

Experimental Protocol The animals were anesthetized with an injection of 65 mg/kg intraperitoneal (IP) of sodium pentobarbital and received systemic heparin (500 IU/kg). After opening the chest. cardiectomy was performed. Hearts received Ringer’s lactate solution to “wash” the coronary tree and then cardioplegic solution according their group. The hearts in this phase of the experiment were divided into two groups. Group 1 used HTK solution at 4°C and in Group 2. solution of histidine-tryptophan-glutamate (HTG) at 4°C. Table 1 shows the composition of each solution. In all cases the infusion of cardioplegia was taken as a single dose 40 ml/kg at the aortic root. followed by immersion of the organ in the same solution for 2 hours at 4°C. After this time. the hearts were placed in a Langendorff system and perfused with Locke Ringer buffer oxygenated normothermic solution and a constant pressure of 100 cm H2O for gravitational method for 30 minutes. The drainage of the right ventricle was performed by opening the pulmonary artery. and preserved the right atrium in order to preserve the sinus node[16].

Histological and immunohistochemical technical preparation Initially. the material was embedded in paraffin. a procedure that provides resistance allowing for cutting thickness of 3 m and placed on silanized slides. The silanization of the blades consisted in preparing these with an adhesive fixing the fragment to the blades preventing their detachment during the immunohistochemical procedure. For this. they were immersed in acetone PA (2 minutes). 4% silane solution diluted with acetone (2 minutes) and again in acetone PA (4 to 5 dips). The drying of the slides was performed in an oven at 60ºC. The block was attached to the microtome. the slice thickness was set to 3 m and the cuts placed on silanized blade identified and left in an oven at 60°C for 24 hours. The blade went through the process of deparaffinization in xylene. followed by hydration in absolute alcohol I. II and III. finishing with six dives in tap water. incubated with 3% hydrogen peroxide for 30 minutes to block endogenous peroxidase. Antigen retrieval was performed in the steamer with specific buffer for each antibody for 30 minutes (Table 2). Then the slides were covered up with a solution containing fetal bovine serum (BSA) and incubated with the primary antibody. After this step. the slides were washed in PBS and incubated for 15 minutes with Starr Trek Universal HRP Detection kit (Biocare Medical®). which consisted in biotinylated secondary antibody for 1 hour and streptavidin-peroxidase complex for 30 minutes. followed by washing with PBS for 15 minutes. The revelation was performed with substrate

Table 1. Composition of solutions used Substance HTK (g/L) Sodium chloride 0.8766 Potassium chloride 0.671 Magnesium chloride 0.8132 Calcium chloride 0.0022 Potassium-hydrogen-2-ketoglutarate 0.1842 Glutamate --Histidine 27.9289 Histidine chloride. H2O 3.7733 Tryptophan 0.4085 Mannitol 5.4651 Water for injection a 1000 ml

HTG (g/L) 0.8766 0.671 0.8132 0.0022 --0.1842 27.9289 3.7733 0.4085 5.4651 a 1000 ml

HTK: Histidine-tryptophan ketoglutarate; HTG: histidinetryptophan-glutamate

Table 2. Relation of antibodies used Antibody anti-KI-67 anti-Caspase 3 anti-IL-8

Specificity Monoclonal Polyclonal Monoclonal

Dilution 1:200 1:1000 1:50

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chromogen (DAB Betazoidchromogen) Starr Trek Universal HRP Detection kit (Biocare Medical®) for 2 to 5 minutes and counter-stained with Harrys hematoxylin for 40 seconds. The tissues were dehydrated in alcohol and bathed in ascending degree in xylene before mounting the slides in ERV-MOUNT amid (Erviegas®). Negative control of reactions were obtained by omitting the primary antibody. Tonsil tissue was used for Ki-67 reactions and Caspase 3 and as positive control breast tissue for IL-8 reaction. Slides were photographed and enzyme quantified by AxioVision software on X40 magnification Axioskop 2 Zeiss microscope. For each sample. three regions of cardiac tissue were selected.

Ringer Locke. demonstrated by clear staining in the ventricular wall. The average heart rate after 5 minutes of perfusion (233±36 and 188±53.4 beats per minute. respectively) showed a significant difference (P=0.0086). The time of onset of ventricular fibrillation (49±28.2 and 45±17 seconds. respectively) and the time of first heartbeat (153±78 and 117±96.8 seconds respectively) showed no significant difference (P=0.5869 and P=0.187. respectively). Analysis of fractal dimension and Shannon entropy The fractal dimension using the caspase marker was 1.59 ± 0.09 (no unit) for group 1 and 1.55±0.13 for group 2. respectively (P=0.4400). KI-67 1.53±0.13 and 1.54±0.18. respectively (P=0.9595) and IL-8. 1.52 ± 0.15 and 1.51 ± 0.12. respectively (P=0.9164) (Figure 1). The Shannon entropy with the caspase was 0.4±0.07 bits for group 1 and 0.38±0.08 bits for group 2 (P=0.5487). KI-67 0.36±0.1 bits and 0.37±0.13 bits. respectively (P = 0.9149). and IL-8 0.35±0.11 bits and 0.35±0.08 bits. respectively (P=0.9678) (Figure 2).

Fractal dimension and Shannon entropy The photographed slides were then binarized for reading of fractal dimension and Shannon entropy. They were estimated by the Box-counting method with the aid of the ImageJ software of the US National Institute of Health (NIH). widely used in the literature and available for free on the Internet (http://rsbweb.nih.gov/ij/). This program considers the Box-counting in two dimensions. allowing the quantification of the distribution of pixels in space. thus not considering the image texture. The influence of this is that two images with the same distribution of pixels. a binarized and one in gray levels. possess the same DF. With this. the DF calculated with ImageJ will be always between 0 and 2. not distinguishing different textures.

DISCUSSION Although the effect of replacing ketoglutarate by glutamate in solution with histidine and tryptophan is still not known. glutamate has well-documented role when placed as a constituent of cardioplegic solution. The addition of glutamate in the perfusate maintains intracellular ATP and decreases both lactate as pyruvate. which would contribute to acidosis. Exogenous glutamate and its transamination products normally restore its contents decreased in the hypoxic myocardium. increase the concentration of succinate. which also leads to increased formation of ATP through anaerobic mitochondria pathway. thereby increasing the resistance to ischemia myocytes[9]. Another process that is intrinsically related to ischemia-reperfusion injury is apoptosis[17.18]. These changes are made by a family of proteases called caspases[19]. The degree of caspase activation is directly related to the degree of apoptosis[20]. In contrast to apoptosis. necrosis is an irreversible process of cell death in which there is disruption of the cell membrane overflow with the overflow of cytosol to the extracellular environment. leukocyte margination and inflammatory cascade activation[20.21]. In contrast to the cell death the mammalian hearts show little proliferative capacity after birth. One of the markers used to assess cell proliferation is the Ki-67[22]. With this marker. Walsh et al.[23] show that 12%-23% of fetal rat cardiomyocytes exhibit proliferative activity. going to 1%-8% by the 7th day and virtually undetectable from the 14th day. Thus. we selected the analysis of caspase-8 and IL-67 KI for assessment of apoptosis. necrosis. cell proliferation. respectively.

Statistical Analysis The data were subjected to the Kolmogorov-Smirnov test and subsequently the parametric analysis by Student’s t test or nonparametric Mann-Whitney test and Fisher exact test for categorical data. Results were expressed as mean ± standard deviation or median (25.75 percentile). when necessary. P value <0.05 was considered significant. The program GraphPad Instat statistical calculations and Prism 6.0. both for Windows ® were used. RESULTS The average weight of the animals was 277.4±24.6 (Group 1) and 288±34.5 g (Group 2). respectively. with no significant difference between groups (P=0.4396). Regarding the average volume of Ringer Locke collected from coronary sinus after 30 minutes (363.1±177.3 and 277.4±33.7 ml. respectively). there was no significant difference between groups (P = 0.1923). Findings during perfusion with cardioplegic solution and Ringer Locke All hearts showed adequate perfusion of cardioplegia and

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Fig. 1 - Histograms showing distribution of fractal dimension in: (A) caspase. (B) IL-8 and (C) KI-67. Group 1: solution with histidine-tryptophan-ketoglutarate. Group 2: solution with histidinetryptophan-glutamate.

Fig. 2 - Histograms showing distribution of entropy in: (A) caspase. (B) IL-8 and (C) KI-67. Group 1: solution with histidine-tryptophanketoglutarate. Group 2: solution with histidine-tryptophanglutamate.

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The fractal dimension is a useful parameter for the characterization of complex irregular structures. but when viewed mathematically. its analysis denotes regular figures with self-similarity features. or that is. resemble themselves when observed in different scales[24]. The fractal dimension of the object account the effective number of degrees of freedom in the dynamical system. and therefore quantifies its complexity. Thus. it appears that images showing higher fractal dimensions are consequently more complex. However. we cannot quantify this complexity only by the visual aspect. The fractal dimension would then remedy this difficulty by adding a numeric value [12]. The size of the boxes for calculating the fractal dimension in the Box-counting method was standardized at 4. 8. 16. 32 and 64 pixels. It is known that the pixel size depends on the degree of resolution used. As commented by Tambasco et al. [24] . the size of the box used to bear a certain relationship with the studied structure. because it can be so small that. in fact. were being evaluating the subcomponents of the structure or so great that. in fact. were being included in the measurement of components surrounding the structure of interest and not the structure itself. These values​​. however. are the default values ​​used in the literature and therefore probably not caused interference in the results[12]. In our study. there was no significant difference in fractal dimension between groups. Thus. we consider that the distribution of the information contained in the slides of hearts treated with HTK solutions or HTG were not different. An important contribution in Information Theory introduced by CE Shannon in 1948 was the concept of entropy as the amount of information in a system[25]. It is noteworthy that one should not confuse “entropy state” of Thermodynamics with “entropy concept” of the Information Theory[26]. According to Shannon. if X is the set of all messages of x. and p (x) is the probability (ranging from 0 to 1) of a message x. then the entropy of X will be[26]: The Shannon entropy quantifies the degree of “uncertainty” or degree of “complexity” of information. With this formulation it is easy to understand that if the probability of occurrence of a particular event is 100%. or that is. if P=1 (no uncertainty). then the entropy contained in the message is zero (log 1 = zero)[26].

probability of each intensity of gray can be obtained easily by constructing a histogram of frequencies[26]. Zero entropy of an image is obtained when all the pixels have the same color or the same amount of gray (100% probability. or that is 1; log 1=0). On the other hand. the maximum entropy may occur when the image contained the same amount of pixel for each intensities presented. Thus. we demonstrate that entropy is not related to the spatial layout of information. Two images may have the same number of pixels with the same intensity and therefore the total entropy is the same. but spatially distributed [26] in a different manner. In our study. there was no significant difference between the Shannon entropy between groups. Thus. we consider that the information contained in the slides of hearts treated with HTK or HTG solutions were not different. The literature shows several studies in which there is a statistical difference between groups assessed with fractal dimension and Shannon entropy. drawing the reader’s attention on its imaging discriminative character. but presenting no relevance when the results found did not reach statistical significance. as occurred in our study. The interpretation of the results of this study is that the HTG group did not alter the amount or distribution of the imaging information of rat hearts when compared to those treated with HTK. Shannon entropy and the fractal dimension quantifies the distribution and the degree of complexity of the image. respectively. Thus. this technique is not comparable with Western-Blot or PCR. as these quantify the total amount of proteins studied and not their distribution or degree of complexity in the tissue. CONCLUSION The amount and distribution of the information assessed by the Shannon entropy and fractal dimension on blades of rat heart undergoing cardioplegia with HTK or HTG solutions were not different. which shows that the HTG solution is as good as HTK in preserving myocytes in isolated rat heart model.

Authors’ Roles & Responsibilities MABO ACB CAS PHHB JLLC MFG DMB

Considering that an image is the result of a stochastic process in which the pi probability of the calculation of Shannon entropy may correspond to the probability of a pixel presents a given intensity or gray color (ranging from 0 to 255). This

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Main Author Elaboration of Graphics Elaboration of Graphics Handling of animals Handling of animals Co-advisor and aid in final writing Advisor and aid in final writing

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Oliveira MAB, et al. - Comparison of fractal dimension and Shannon entropy in myocytes from rats treated with histidine-tryptophan-glutamate and histidine-tryptophan cetoglutarate

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2. Melrose DG. Dreyer B. Bentall HH. Baker JB. Elective cardiac arrest. Lancet. 1955;266(6879):21-2. 3. Fallouh HB. Kentish JC. Chambers DJ. Targeting for cardioplegia: arresting agents and their safety. Curr Opin Pharmacol. 2009;9(2):220-6.

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4. Braile DM. Cardioplegia isotérmica anterógrada retrógrada de baixo volume. São José do Rio Preto. 1997. 27p.

17. Xu YJ. Saini HK. Zhang M. Elimban V. Dhalla NS. MAPK activation and apoptotic alterations in hearts subjected to calcium paradox are attenuated by taurine. Cardiovasc Res. 2006;72(1):163-74.

5. Lima-Oliveira APM. Azevedo-Oliveira MTV. Taboga SR. Godoy MF. Braile DM. Cardioplegia utilizando baixo volume de agentes cardioplégicos: estudo morfológico em coração isolado de coelhos. Rev Bras Cir Cardiovasc. 2003;18(3):227-34.

18. Fischer UM. Cox Jr CS. Laine GA. Mehlhorn U. Bloch W. Allen SJ. Induction of cardioplegic arrest immediately activates the myocardial apoptosis signal pathway. Am J Physiol Heart Circ Physiol. 2007;292(3):H1630-3.

6. Bretschneider HJ. Survival time and recuperative time of the heart in normothermia and hypotermia. Verh Dtsch Ges Kreislaufforsch. 1964;30:11-34.

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7. Scrascia G. Guida P. Rotunno C. De Palo M. Mastro F. Pignatelli A. et al. Myocardial protection during aortic surgery: comparison between Bretschneider-HTK and cold blood cardioplegia. Perfusion. 2011;26(5):427-33. 8. Holper K. Meisner H. Hähnel C. Massoudy P. Technical refinements in myocardial protection: infants-adults. Thorac Cardiovasc Surg. 1998;46 Suppl 2 292-5; discussion 6-7.

20. Lee S. Huang CS. Kawamura T. Shigemura N. Stolz DB. Billiar TR. et al. Superior myocardial preservation with HTK solution over Celsior in rat hearts with prolonged cold ischemia. Surgery. 2010;148(2):463-73.

9. Pisarenko OI. Solomatina ES. Ivanov VE. Studneva IM. Kapelko VI. Smirnov VN. On the mechanism of enhanced ATP formation in hypoxic myocardium caused by glutamic acid. Basic Res Cardiol. 1985;80(2):126-34.

21. Anselmi A. Abbate A. Girola F. Nasso G. Biondi-Zoccai GG. Possati G. et al. Myocardial ischemia. stunning. inflammation. and apoptosis during cardiac surgery: a review of evidence. Eur J Cardiothorac Surg. 2004;25(3):304-11.

10. Rebeyka IM. Axford-Gatley RA. Bush BG. del Nido PJ. Mickle DA. Romaschin AD. et al. Calcium paradox in an in vivo model of multidose cardioplegia and moderate hypothermia. Prevention with diltiazem or trace calcium levels. J Thorac Cardiovasc Surg. 1990;99(3):475-83.

22. Lee Y. To proliferate or not to proliferate. Cardiovasc Res. 2010;86(3):347-8. 23. Walsh S. Pontén A. Fleischmann BK. Jovinge S. Cardiomyocyte cell cycle control and growth estimation in vivo: an analysis based on cardiomyocyte nuclei. Cardiovasc Res. 2010;86(3):365-73.

11. Arruda PFF. Gatti M. Facio Jr FN. Arruda JGF. Moreira RD. Murta LO. et al. Quantification of fractal dimension and Shannon’s entropy in histological diagnosis of prostate cancer. BMC Clin Pathol. 2013;13:6.

24. Tambasco M. Costello BM. Kouznetsov A. Yau A. Magliocco AM. Quantifying the architectural complexity of microscopic images of histology specimens. Micron. 2009;40(4):486-94. 25. Shannon CE. 1948. A Mathematical Theory of Communication [Acesso 2/12/2013]. http://archive.org/details/ bellsystemtechni27amerrich

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26. Arruda PFF. Quantificação da dimensão fractal e entropia de Shannon no diagnóstico histológico do câncer de próstata [Tese de doutorado]. São José do Rio Preto: FAMERP: Faculdade de Medicina de São José do Rio Preto; 2011. 80p.

13. Keipes M. Ries F. Dicato M. Of the British coastline and the interest of fractals in medicine. Biomed Pharmacother. 1993;47(9):409-15.

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Araujo ASG, ORIGINAL et al. - Pain and cardiorespiratory responses of children during ARTICLE physiotherapy after heart surgery

Pain and cardiorespiratory responses of children during physiotherapy after heart surgery Dor e respostas cardiorrespiratórias durante a fisioterapia de crianças no pós-operatório de cirurgia cardíaca

Adriana Sanches Garcia Araujo1; Jyrson Guilherme Klamt1, MD, PhD; Walter Villela de Andrade Vicente1, MD, PhD; Luis Vicente Garcia1, MD, PhD

DOI: 10.5935/1678-9741.20140024

RBCCV 44205-1536

Abstract Objective: The aim of the present study was to determine the occurrence of pain and changes in blood pressure, heart rate, respiratory rate, and arterial oxygen saturation associated with physiotherapy in children undergoing cardiac surgery. Methods: Eighteen extubated children were assessed for the presence of pain using the face, legs, activity, cry, consolability scale, and blood pressure, heart rate, respiratory rate and arterial oxygen saturation were simultaneously recorded. The physiological parameters were measured at the following time periods: immediately before physiotherapy, five and 10 minutes after the beginning of physiotherapy, and five minutes after its end. Pain was assessed immediately before physiotherapy, ten minutes after the beginning of physiotherapy and five minutes after its end. Pain and physiological changes were assessed by the Friedman test and the correlation between the physiological parameters and the pain scores was assessed by the Spearman test. Results: Pain increased during physiotherapy and decreased significantly after it compared to pre-physiotherapy scores. Systolic blood pressure and heart rate increased significantly after 10 minutes of the beginning of physiotherapy. Arterial oxygen saturation tended to decrease during physiotherapy and to increase after it, although without significance. The correlation between

pain scores and the physiological variables was significant only for systolic blood pressure and heart rate ten minutes after the beginning of physiotherapy. Conclusion: Manipulation after the beginning of physiotherapy seems to be accompanied by significant pain and by important associated cardiovascular changes. Apparent analgesia and improved respiratory function were observed after respiratory physiotherapy.

Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HC-FMRP-USP), Ribeirão Preto, SP, Brazil

Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo Av. dos Bandeirantes, 3900 - Monte Alegre (Campus da USP) Ribeirão Preto, SP, Brazil - Zip code: 14048-900 E-mail: jgklamt@fmrp.usp.br

Descriptors: Physical therapy (Specialty). Pain, Postoperative. Heart defects, Congenital. Thoracic surgery. Pediatrics. Resumo Objetivo: O objetivo desse estudo foi avaliar as ocorrências de dor e as alterações na pressão arterial, frequência cardíaca, frequência respiratória, saturação arterial de oxigênio associadas à fisioterapia em crianças no pós-operatório de cirurgia cardíaca. Métodos: Em dezoito crianças entubadas, foram avaliadas a dor pela escala face, pernas, atividade, choro e consolabilidade e registradas simultaneamente as pressão arterial, frequência cardíaca, frequência respiratória e saturação arterial de oxigênio. Os parâmetros fisiológicos foram medidos nos momentos: imediatamente antes, após cinco e dez minutos do início da fisioterapia,

1

This study was carried out at the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HC-FMRP-USP), Ribeirão Preto, SP, Brazil. No financial support. Correspondence address: Jyrson Guilherme Klamt

Article received on March 26th, 2013 Article accepted on August 19th, 2013

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Resultados: A dor aumentou e reduziu significativamente durante e após, respectivamente, a fisioterapia, em relação aos valores pré-fisioterapia. A pressão arterial sistólica e a frequência cardíaca aumentaram significativamente após 10 minutos do inicio da fisioterapia. Houve tendência de redução da saturação arterial de oxigênio durante a fisioterapia e elevação após, porém, sem significância. A correlação entre os escores de dor foi significativa apenas para pressão arterial sistólica e frequência cardíaca durante a fisioterapia. Conclusão: A manipulação durante a fisioterapia parece ser acompanhada de dor significativa e associada às alterações importantes da pressão arterial e frequência cardíaca. Uma aparente analgesia e melhora da função respiratória foi observada após a fisioterapia respiratória.

Abbreviations, acronyms & symbols BP HR RR SpO2 PICU DBP rs

Blood pressure Heart rate Respiratory rate Arterial oxygen saturation Pediatric Intensive Care Unit Diastolic blood pressure Spearman correlation coefficient

ao término e após cinco minutos do término da fisioterapia. A dor foi avaliada imediatamente antes, dez minutos do início da e após cinco minutos do término da fisioterapia. A dor e as alterações fisiológicas foram analisadas pelo teste de Friedman e a correlação entre os parâmetros fisiológicos e os escores de dor foi analisada pelo teste de Spearman.

Descritores: Fisioterapia (Especialidade). Dor pós-Operatória. Cardiopatias congênitas. Cirurgia torácica. Criança.

INTRODUCTION

who presented important respiratory discomfort. Data were collected in the Pediatric Intensive Care Unit (PICU) of the University Hospital, Faculdade de Medicina de Ribeirão Preto, during the period from January to November 2004. The physiological variables systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and arterial oxygen saturation (SpO2) were measured using a multiparameter monitor (Dixtal®). Respiratory rate (RR) was determined according to the number of thoracic expansions. The pain scale used was the FLACC: Face, Legs, Activity, Cry, Consolability, with a maximum score of 10 points[8]. Routine physiotherapy (chest wall vibration, expiratory flow maneuvers, directed cough, autogenic drainage, and postural drainage) was applied by the cardiorespiratory physiotherapist in charge according to individual necessities. The physiological variables were recorded immediately before the beginning of physiotherapy (Pre time), 5 (Time 5) and 10 (Time 10) minutes after the beginning of physiotherapy, at the end of physiotherapy (Time E), and 5 minutes after the end of physiotherapy (Post 5 Time). The pain scores were recorded at the Pre, 10 and Post 5 Times. Data were statistically assessed by the nonparametric Friedman test and the correlation between the physiological variables and the pain scale was calculated using the Spearman correlation coefficient (rs). The level of significance was set at 5% (P<0.05).

Pain after pediatric cardiac surgery can be intense if not adequately controlled and may increase due to patient manipulation, coughing and systematically applied physiotherapy procedures[1-3]. The intensification of pain may be associated with hemodynamic responses (acute increases in blood pressure and heart rate), superficial respiration and hypoxia (low SpO2)[1,4]. The efficacy of respiratory physiotherapy in the postoperative routine in the intensive care unit has been well established regarding the respiratory, cardiovascular and psychological rehabilitation of children undergoing cardiac surgery with cardiopulmonary bypass[1,5,6]. However, few reports are available on the intensity of pain and the associated physiological changes during maneuvers of physiotherapy in this clinical situation[1,6,7]. Thus, this question was considered in the present observational study. METHODS The study was approved by the Research Ethics Committee of the University Hospital, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (Faculty of Medicine of Ribeirão Preto, University of São Paulo). Eighteen children aged 1 month to 2 years who had undergone cardiac surgery and with an indication of postoperative physiotherapy were studied. The persons legally responsible for the children signed written informed consent to participate. Exclusion criteria were: sedated, intubated, hemodynamically unstable children, children with neurological, psychological or motor retardation, with previous pneumopathy such as bronchial asthma, bronchiectasis, and cystic fibrosis, and children who had suffered cardiac arrest during surgery and

RESULTS Eighteen children (11 girls and 7 boys) aged 1 to 24 months (mean±SD: 12.5±10.3) and weighing 3.2 to 16.5 kg (mean±SD: 9.8±6.1) were studied. The diagnoses of the congenital heart diseases are listed in Table 1.

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Table 1. Diagnosis of congenital heart diseases. Diagnosis n Atrial septal defect (ASD) 1 Ventricular septal defect (VSD) 1 Patent ductus arteriosus (PDA) 5 ASD,VSD, PDA 1 VSD, PDA 4 Pulmonary atresia, ASD,VSD, PDA 1 Total atrioventricular canal 1 Aortic coarctation 1 Tricuspid atresia, right ventricular hypoplasia, ASD,VSD 2 Transposition of the great vessels, IAC 1 Total 18

Fig. 2 – Changes SBP, DBP, H, SpO2, and RR during physiotherapy in 18 children after cardiac surgery. Data represent mean. *Significantly different from Pre Time Fig. 1 – Pain during physiotherapy assessed by FLACC scale in 18 children after cardiac surgery. Data represent the median. *Significantly different campared to Pre Time

There was a significant increase in pain scores on the FLACC scale during physiotherapy, followed by a reduction after the procedure compared to Pre Time values (Figure 1). SBP and HR increased significantly at Time period 10, whereas DBP and SpO2 did not change. After physiotherapy, SBP and HR returned to the initial values and SpO2 tended to increase (Figure 2). A significant positive correlation was observed at Time 10 (during physiotherapy) between pain scores and SAP (r=0.49; P=0.042) and between pain and HR (r=0.48; P=0.041).

diopulmonary bypass, which was correlated with increased SBP and HR. After physiotherapy, the scores obtained on the FLACC scale showed values that corresponded to the absence of pain, indicating an apparent analgesic effect of physiotherapy. The discrete increase in SpO2 after physiotherapy may indicate improved oxygenation. DBP and RR did not change during physiotherapy. The hemodynamic responses produced by physiotherapy, although they were within the physiological variation for the respective ages, may have been a consequence of the pain or discomfort felt by the patients during respiratory physiotherapy, although changes in the regulatory mechanisms present in the postoperative period after cardiac surgery may also have contributed. Indeed, some vagal suppression was demonstrated, while the sympathetic system operated on a normal scale[9]. This imbalanced interaction of the neuroveg-

DISCUSSION The present prospective cohort study showed a sharp increase in pain during the physiotherapy maneuvers in children extubated in the PICU after cardiac surgery with car-

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etative nervous system may explain the tendency to a greater hemodynamic response to movement and aspiration and the higher incidence of tachycardia during the postoperative period[9]. On the other hand, the relative stability of BP, HR, RR and SpO2 during the physiotherapy procedures may indicate the quality of analgesia administered and may have been a factor for the correlation with marginal significance between the hemodynamic variables and pain[10]. In contrast to this paradigm, children who are intubated and sedated during the postoperative period frequently show hemodynamic instability and episodes of bradycardia during manipulation, caused by vagal hyperactivity due to intense stimulation[5]. Respiratory physiotherapy is essential for cardiorespiratory rehabilitation during the postoperative period of cardiac surgery and should be started as soon has hemodynamic stability occurs[1,11]. Manipulation, compression maneuvers and coughing during physiotherapy may intensify pain or discomfort, in agreement with the increase in pain scores. Surprisingly, however, apparent analgesia was detected immediately after the end of physiotherapy. We have no explanation for this finding and we can only propose that the pattern of somatosensory stimulation and affective care may possibly activate mechanisms of endogenous control of pain[12]. The determination of the consistency of this finding requires future investigation. In conclusion, respiratory physiotherapy after cardiac surgery causes pain associated with tolerable increased systolic blood pressure and heart rate in children. However, the pain may be followed by apparent analgesia.

ED, et al. Changes in respiratory mechanics among infants undergoing heart surgery. Anesth Analg. 2004;98(1):49-55. 3. von Ungern-Sternberg BS, Petak F, Saudan S, Pellegrini M, Erb TO, Habre W; Swiss Paediatric Respiratory Research Group. Effect of cardiopulmonary bypass and aortic clamping on functional residual capacity and ventilation distribution in children. J Thorac Cardiovasc Surg. 2007;134(5):1193-8. 4. Finley GA, McGrath PJ. Physiological measures of pain. In: Measurement of pain in infants and children. vol. 10. Seattle: IASP Press; 1998. p.59-81. 5. Ramelet AS, Abu-Saad HH, Bulsara MK, Rees N, McDonald S. Capturing postoperative pain responses in critically ill infants aged 0 to 9 months. Pediatr Crit Care Med. 2006;7(1):19-26. 6. Cavenaghi S, Moura SC, Silva TH, Venturinelli TD, Marino LH, Lamari NM. Importance of pre- and postoperative physiotherapy in pediatric cardiac. Rev Bras Cir Cardiovasc. 2009;24(3):397-400. 7. Felcar JM, Guitti JC, Marson AC, Cardoso JR. Preoperative physiotherapy in prevention of pulmonary complications in pediatric cardiac surgery. Rev Bras Cir Cardiovasc. 2008;23(3):383-8. 8. Voepel-Lewis T, Merkel S, Tait AR, Trzcinka A, Malviya S. The reliability of the face, legs, activity, cry, consolability observational tool as a measure of pain in children with cognitive impairment. Anesth Analg. 2002;95(5):1224-9. 9. Bauernschmitt R, Malberg H, Wessel N, Kopp B, Schirmbeck EU, Lange R. Impairment of cardiovascular autonomic control in patients early after cardiac surgery. Eur J Cardiothorac Surg. 2004;25(3):320-6.

Authors’ roles & responsibilities ASG Coauthor JGK Corresponding author WVAV Coauthor LVG Coauthor

10. Mueller XM, Tinguely F, Tevaearai HT, Revelly JP, Chioléro R, von Segesser LK. Pain location, distribution, and intensity after cardiac surgery. Chest. 2000;118(2):391-6. 11. Caséca MB, Andrade LB, Britto MC. Pulmonary function assessment in children and teenagers before and after surgical treatment for rheumatic valve disease. J Pediatr (Rio J). 2006;82(2):144-50.

REFERENCES 1. Silva ME, Feuser MR, Silva MP, Uhlig S, Parazzi PL, Rosa GJ, et al. Pediatric cardiac surgery: what expect from physiotherapeutic intervention? Rev Bras Cir Cardiovasc. 2011;26(2):264-72.

12. Hatem TP, Lira PI, Mattos SS. The therapeutic effects of music in children following cardiac surgery. J Pediatr (Rio J). 2006;82(3):186-92.

2. Stayer SA, Diaz LK, East DL, Gouvion JN, Vencill TL, McKenzie

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Conterno LO,ORIGINAL et al. - Impact of hospital infections on patients outcomes ARTICLE undergoing cardiac surgery at Santa Casa de Misericórdia de Marília

Impact of hospital infections on patients outcomes undergoing cardiac surgery at Santa Casa de Misericórdia de Marília Impacto das infecções hospitalares na evolução de pacientes submetidos à cirurgia cardíaca na Santa Casa de Misericórdia de Marília

Lucieni Oliveira Conterno1,2,3, PhD; Silvana Martins Dias Toni3; Rubiana Gonçalves Konkiewitz3,4,5; Elaine Salla Guedes3; Rubens Tofano de Barros6,7, PhD; Marcos Gradim Tiveron7, MD

DOI: 10.5935/1678-9741.20140037

RBCCV 44205-1537

Abstract Objective: this study aimed to determine the incidence of nosocomial infections, the risk factors and the impact of these infections on mortality among patients undergoing to cardiac surgery. Methods: Retrospective cohort study of 2060 consecutive patients from 2006 to 2012 at the Santa Casa de Misericórdia de Marília. Results: 351 nosocomial infections were diagnosed (17%), 227 non-surgical infections and 124 surgical wound infections. Major infections were mediastinitis (2.0%), urinary tract infection (2.8%), pneumonia (2.3%), and bloodstream infection (1.7%). The in-hospital mortality was 6.4%. Independent variables associated with non-surgical infections were age ≥ 60 years (OR 1.59, 95% CI 1.09 to 2.31), ICU stay ≥ 2 days (OR 5, 49, 95% CI 2.98 to 10, 09), mechanical ventilation ≥ 2 days (OR11, 93, 95% CI 6.1 to 23.08), use of urinary catheter ≥ 3 days (OR 4.85 95% CI 2.95 -7.99). Non-surgical nosocomial infections were more frequent in patients with surgical wound infection (32.3% versus 7.2%, OR 6.1, 95% CI 4.03 to 9.24). Independent variables associated with mortality were age greater than 60 years (OR 2.0;

95% CI 1.4 to3.0), use of vasoactive drugs (OR 3.4, 95% CI 1.9 to 6, 0), insulin use (OR 1.8; 95% CI 1.2 to 2.8), surgical reintervention (OR 4.4; 95% CI 2.1 to 9.0) pneumonia (OR 4.3; 95% CI 2.1 to 8.9) and bloodstream infection (OR = 4.7, 95% CI 2.0 to 11.2). Conclusion: Non-surgical hospital infections are common in patients undergoing cardiac surgery; they increase the chance of surgical wound infection and mortality.

Hospital Infection at University of Ottawa, Ottawa, Canada. Marilia Medical School (Famema), Marília, SP, Brazil. 3 Hospital Infection Control Service at Santa Casa de Misericordia de Marília, Marília, SP, Brazil 4 Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil 5 University of Taubaté (UNITAU), Taubaté, SP, Brazil 6 University of Campinas (UNICAMP), Campinas, SP, Brazil 7 Hospital Santa Casa de Misericordia de Marília, Marília, SP, Brazil

Aid Support Line, Project No. 2010/196281

Descriptors: Cross Infection. Risk Factors. Mortality. Thoracic Surgery. Surgical Wound Infection. Resumo Objetivo: O objetivo deste estudo foi determinar as taxas das infecções hospitalares, os fatores de risco associados e o impacto destas infecções na mortalidade dos pacientes submetidos à cirurgia cardíaca. Métodos: coorte retrospectivo que incluiu 2060 pacientes consecutivos, no período de 2006 a 2012 na Santa Casa de Misericórdia de Marília.

1 2

Correspondence address: Lucieni Oliveira Conterno Santa Casa de Misericórdia de Marília Avenida Vicente Ferreira 828, Cascata - Marília, SP, Brazil Zip code: 17515-900 E-mail: lucieni@famema.br

This study was carried out at Santa Casa de Misericórdia de Marília, Marília Medical School (FAMEMA), Marília, SP, Brazil

Article received on June 20th, 2013 Article accepted on October 17th, 2013

Financial support: This study was supported by FAPESP, Regular Research

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rente sanguínea (1,7%). A mortalidade global intra-hospitalar foi de 6,4%. As variáveis independentes associadas às infecções não cirúrgicas foram: idade ≥ 60 anos (OR 1,59; IC95%1,092,31), internação em UTI ≥ 2 dias (OR5,49; IC95% 2,98-10,09), ventilação mecânica ≥ 2 dias (OR11,93; IC95% 6,1 - 23,08), uso de sonda vesical ≥3 dias (OR 4,85 IC95% 2,95 -7,99). Infecções hospitalares não cirúrgicas foram mais frequentes em pacientes com infecção cirúrgica (32,3% versus 7,2%; OR 6,1; IC95% 4,03- 9,24). As variáveis independentes associadas a mortalidade foram: idade ≥60 anos (OR= 2,0 ; IC 95% 1,4-3,0), uso de droga vasopressora (OR 3,4; IC95% 1,9-6,0), uso de insulina (OR=1,8; IC 95% 1,2-2,8), reintervenção cirúrgica (OR=4,4 IC95% 2,1-9,0) pneumonia (OR=4,3 IC95% 2,1-8,9) e infecção da corrente sanguíneas (OR=4,7; IC95% 2,0-11,2). Conclusão: infecções hospitalares não cirúrgicas são frequentes pós cirurgia cardíaca, e aumentam a chance de infecção cirúrgica e a mortalidade.

Abbreviations, acronyms & symbols BMI CABG COPD CVC DM HI HICS ICU MV PBSI SSI UC UTI VAP

Body mass index Coronary artery bypass grafting Chronic obstructive pulmonary disease Central venous catheter Diabetes mellitus Hospital infection Hospital infection control service Intensive care unit Mechanical ventilation Primary bloodstream infection Surgical site infection Urinary catheter Urinary tract infection Ventilator-associated pneumonia

Resultados: Foram diagnosticadas 351 infecções hospitalares (17%), sendo 227 infecções não cirúrgicas e 124 infecções cirúrgicas. As principais infecções foram: mediastinite (2,0%), infecção urinária (2,8%), pneumonia (2,3%), infecção da cor-

Descritores: Infecção Hospitalar. Procedimentos Cirúrgicos Cardíacos. Fatores de Risco. Mortalidade. Infecção da Ferida Operatória.

INTRODUCTION The hospital infections (HI) represent one of the most common complications in hospitalized patients undergoing surgical procedures. IH rates vary from 5% to 20% and are associated with increased morbidity, mortality, length of hospital stay and hospital costs[1,2]. Patients undergoing cardiac surgery are particularly susceptible to these infections, and surgical site infections (SSI) are the most studied due to the most serious consequences associated both to patients and hospital. These patients also have several risk factors for nonsurgical HI, such admission to ICU (intensive care unit), use over variable time of invasive devices such as central venous catheter (CVC), urinary catheter (UC) and mechanical ventilation (MV)[3,4]. Published data suggest that rates of HI postoperatively in these patients may vary from 3.5% to 21%, the most frequent being the ventilator-associated pneumonia (VAP), catheter-associated urinary tract infections (CAUTI), primary bloodstream infection (PBSI) or CVC infection[5,6]. The overall mortality of these patients developing HI can reach 25%[1-3]. However, there are few studies in Brazil that assessed the impact of non-surgical infections in outcomes of these patients. Thus, the aim of this study was to determine the rate of HI (surgical and nonsurgical) among patients undergoing cardiac surgery, the risk factors and the impact of these infections on patient outcomes.

case-control, using data from the Hospital Infections Control Service (HICS). The HICS performs active surveillance of HI, tracking daily all surgical patients, using a standardized form of data collection. The HICS participates in the diagnostic and therapeutic discussion of HI cases with the medical team. The diagnostic criteria of HI used were those recommended by the Center for Diseases Control and Prevention (CDC)[7]. All patients who underwent cardiac surgery during 20062012 had their data assessed since their admission until discharge or death. Despite not having been performed systematically surveillance after discharge of HI by the HICS, all patients were followed-up postoperatively during the outpatient care by the surgical team. The cases requiring hospital readmission, guidance on the use of antibiotics, dressings or with positive cultures were assessed by the HICS. Therefore, we defined as cases the patients diagnosed with postoperative wound infection of the sternal region and compared with those without this diagnosis (control); in the same way, patients who survived (control) were compared to those who died (case) during hospital stay, in order to determine the variables associated with these outcomes. Risk factors for SSI on the site of removal of the graft were not assessed. The scores of the European System for Risk Assessment in Cardiac Surgery (EuroSCORE) were not calculated because not all variables were systematically recorded in the early years of the study. This study was performed at the Santa Casa de Misericordia de Marilia, which is a philanthropic tertiary hospital with 200 beds and regional reference of SUS (Unified Health System) for cardiac surgery. It has a cardiac ICU and a general ICU with eight beds each.

METHODS We performed a retrospective cohort study with nested

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A descriptive analysis of the data by calculating the mean and standard deviation for continuous variables and proportions of categorical variables was performed. The Pearson chi-square test was used to compare proportions, the Student t test was used to compare means. The P value of<0.05 was considered statistically significant. Possible risk factors statistically significant in univariate analysis were included in multiple logistic regression analysis by forward conditional technique to identify the variables associated with the occurrence of HI and death. The calibration of the model (goodness of fit) was estimated using the Hosmer Lemeshow test (HL) (high values of P means that the model is fit to the data). We used the SPSS (Statistical Package for Social Science) version 18.0 for Windows (SPSS INC., Chicago, IL) for data analysis. This study was approved by the Research Ethics Committee under number 094/10.

were performed more than one procedure in the same surgery. Surgical revision for bleeding was performed in 60 (2.9%) patients. In this population, males predominated (63%), the average age was 58 +14.5 years. Presence of risk factors and or cardiovascular disease were identified in 1475 (71.6%) patients, highlighting prior acute myocardial infarction (15.6%), hypertension (63.8%), dyslipidemia (32%), diabetes mellitus (23.5%), smoking (19.7%). Antibiotic prophylaxis was performed in 96.7% (n=1983) of procedures, regardless performing saphenous vein grafting for obtaining the graft. First-generation cephalosporin was used in 98 % (1944 ) of cases. From 2010 an aminoglycoside was added to the prophylactic regimen of 23% (449) of patients who had > 4 days of preoperative hospital stay; in 2012, of 254 patients who underwent heart surgery in this year, 12.2% (n=31) received vancomycin associated with aminoglycoside in prophylactic regimen. The average hospital stay was 13.36+12.4 days and in-hospital overall mortality was 6.4% (n=132). Table 1 shows the general characteristics of the patients and the preoperative and postoperative periods. 351 HI were diagnosed in 265 (12.9%) patients, corresponding to an incidence of 17% and 124 SSI (35.3%) and 227 (64.7%) infections in other topographies. Forty patients with SSI (32.3%) also had infection in other topography. The most frequent HI and their rates are described in Table 2.

RESULTS In the period from 2006 to 2012, 2060 surgeries were performed. Coronary artery bypass grafting (CABG) was performed in 1375 (66.8%) patients, valve surgery in 466 (22.6%) and other cardiac surgeries (which included aneurysm, congenital heart disease, aortic coarctation, Bentall De Bono) were performed in 219 (10.6%) patients. The grafts more used were internal thoracic artery and saphenous vein in 767 (37.2%) patients, in 304 (14.8%) patients

Table 1. Characteristics of patients and procedures performed. No. % No. of Patients 2060 100 Age > =60 years 1082 52.4 BMI > = 30kg/m2 423 20.5 Acute myocardial infarction 322 15.6 Hypertension 1314 63.8 Dyslipidemia 659 32.0 Diabetes mellitus 484 23.5 Smoking 406 19.7 Preoperative hospitalization in days ± SD 4.0 ± 4.0 Mean surgical time in minutes± SD 206+ 80.8 Time of cardiopulmonary bypass in minutes+ SD 81.6 ± 32.0 Insulin use in the postoperative 693 33.6 Vasoactive drug use of postoperative 1229 59.6 Patients using CVC in the postoperative 1769 85.8 Average time in days of UC use ±SD 4.5 + 5.1 Patients using UC in the postoperative 1799 87.3 Average time in days of CVD + SD 4.3 ±6.4 Patients under MV in the postoperative 873 42.3 Average time in days under MV ± SD 2.0 + 4.4 Average ICU days ± SD 4.0 ±7.4 Average days of hospital stay± SD 13.3 ± 12.3 Death 132 6.4 CVC: central venous catheter; MV: mechanical ventilation; UC: urinary catheter; ICU: intensive care unit, SD: standard deviation

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Table 2. Main hospital infections. No of HI 351 265 124 57 52 39 35 18

Total of hospital infection Total of patients with hospital infection Surgical site infection Urinary tract infection Pneumonia associated ventilation Tracheobronchitis Primary bloodstream infection Vascular Catheter Infection

incidence 17 12.9 6 2.8 2.5 1.9 1.7 0.8

% of total HI 35. 3 16.2 14.7 11.1 9.9 5.1

HI: hospital infection

The overall rate of SSI was 6.0% (n=124), varying with the type of surgery, 7.0% in CABG surgeries (n=96), 4.9% (n=23) in the valve surgeries and 2.3% (n=5) in the other surgeries. Complication occurred in 2.0% (n=41) patients. Infection at the saphenous occurred in 2.2% (19/ 856) of patients who had saphenous resection for obtaining graft. The etiologic agent was identified in 69 (55.6%) cases with SSI and the gram negative bacteria were the most frequently isolated, highlighting the Klebsiella pneumoniae (26.0%), and Pseudomonas aeruginosa (13.0%). Twenty-eight percent (n=5) were of Klebsiella pneumoniae producing extended spectrum beta-lactamases (ESBL). Klebsiella pneumoniae producing carbapenemase (KPC) were

not identified. Sensitivity to gentamicin, amikacin, cefepime, imipenem was 77.7%, 83.3%, 72.2% and 94.4% among isolates of Klebsiella pneumoniae and 77.7%, 88.8%, 100% and 100% among isolates of Pseudomonas aeruginosa. Staphylococcus aureus was isolated in 21% (n=15) of cases, 33% (n=5) were resistant to oxacillin. The etiologic agents identified were not related to baseline patient characteristics or surgical procedure. Tables 3, 4 and 5 describe the results of the univariate analysis for the occurrence of SSI in the sternum, non-surgical HI and evolution to death. Tables 6, 7 and 8 describe the results of logistic regression analysis for the occurrence of SSI, nonsurgical HI and death.

Table 3. Variables associated with the occurrence of nonsurgical hospital infection. With HI % Without HI No. of Patients 180 8.7 1880 Age <60 years 55 5.6 927 => 60 years 125 11.6 953 Preoperative hospitalization in days ± SD 5.3 +5.0 5.3 +5.0 3.8 ± 3.8 Postoperative insulin Yes 75 10.8 618 No 105 7.7 1262 Postoperative vasoactive drug Yes 154 12.5 1075 No 26 3.1 804 Use of urinary catheter ≥ 3days 144 27.1 388 <3 days 36 2.4 1492 Use of vascular catheter ≥ 3days 132 20.1 526 <3 days 48 3.4 1354 Respirator ≥ 2 days 170 13.0 1 139 < 2 days 10 1.3 741 Mean ICU stay in days ± SD 15.8 ± 6.7 15.8 ± 6.7 2.9 ± 4.4 Mean hospital stay in days + SD 33 ± 7.4 33 ± 7.4 11.5 ± 7.5 Death 35 19.4 97 Survival 145 83.0 1 708 HI: hospital infection, SD: standard deviation; ICU: intensive care unit

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% 91.3 94.4 88.4 3.8 ± 3.8

P <0.0001 0.001

89.2 92.3 87.5 96.9 72.9 97.6 79.9 93.7 87.0 98.7 2.9 ± 4.4 11.5 ± 7.5 5.2 92.5

0.01 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001

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Table 4. Variables associated with the occurrence of surgical site infection (SSI). Surgical site infection No No. % No. % 124 6 1936 94 46 4.7 936 95.3 78 7.2 1000 92.8 38 9.0 385 91.0 71 5.3 1274 94.7 Yes

No. patients Age < 60 years > = 60 years Body mass index ≥ 30kg/m2 < 30 Kg/m2 Preoperative hospitalization in days± SD Mean surgical time in minutes ±SD Average time of cardiopulmonary bypass in minutes ± SD

P

0.01 0.008 0.002

5.4±4.9 231±81.0 91±35.0

3.9±4.0 204±80.5 81± 31.7

< 0.0001 0.005

Surgical reintervention Yes No

18 30.0 106 5.3

42 70.0 1894 94.7

<0.0001

Postoperative insulin use Yes No

60 8.7 64 4.7

633 91.3 1303 95.3

0.001

Postoperative vasoactive drug use Yes No

102 8.3 22 2.7

1127 91.7 808 97.3

<0.0001

Urinary tract infection Yes No

8 14.0 116 5.8

49 86.0 1887 94.2

0.01

Ventilation associated pneumonia Yes No

10 19.2 114 5.7

42 80.8 1894 94.3

0.001

Vascular catheter infection Yes No

7 38.9 117 5.7

11 61.1 1925 94.3

<0.0001

Bloodstream infection Yes No

102 8.6 114 5.6

25 7 1.4 1911 94.4

<0.0001

12.6 +17.1 32.5 +29.1 45 17 220 83.0

3.5 +5.9 12.1 + 9.1 87 4.8 1 707 92.5

Mean of ICU stay in days ± SD Mean of hospital stay in days ± SD Death Survival ICU: intensive care unit; SD standard desviation

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< 0.0001 < 0.0001 < 0.0001

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Table 5. Variables associated with evolution in the univariate analysis.

Age <60 years = >60 Body mass index> = 30Kg/m2 < 30Kg/m2 Mean of preoperative hospital stay in days± SD Mean time of cardiopulmonary bypass in minutes ± SD

Death N % 34 3.5 98 9.1 35 8.5 75 5.6 5.7 ± 9 105 ± 59.4

Survival N % 948 96.5 980 90.0 378 91.5 1270 94.4 3.9+3.9 80 ± 28.5

Surgical reintervention Yes No

10 43.5 122 6

13 1915

Postoperative use of insulin Yes No

63 9.1 69 5.0

630 90.9 1298 95.0

<0.0001

Postoperative use of vasoactive drug Yes No

111 9.0 21 2.5

1118 91.0 809 97.5

<0.0001

Mediastinitis Yes No

10 24.4 122 6.0

31 75.6 1897 94.0

<0.0001

Pneumonia Yes No

13 25. 0 119 5.9

39 75.0 1889 94.1

<0.0001

Tracheobronchitis Yes No

6 15.4 126 6.2

33 84.6 1895 93.8

0.03

Primary Bloodstream infection Yes No

11 31.4 121 6.0

24 68.6 1904 94.0

<0.0001

Secondary sepsis Yes No

12 37.5 120 5.9

20 62.5 1908 94.1

0.001

56.5 94.0

P <0.0001 0.03 0.001 <0.0001

<0.0001

Table 6. Variables associated with the occurrence of non-surgical infection in logistic regression analysis. B Coefficient Odds Ratio Age > = 60 years 0.46 1.59 ICU stay > 2days 1.70 5.49 Use of urinary catheter ≥ 3days 1.58 4.85 Mechanical ventilation ≥ 2days 2.47 11.93 Constant -3.346 CI: 95% confidence interval; Hosmer & Lemeshow test P = 0.23, 91.2% correct prediction

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95% CI 1.09-.31 2.98-10.09 2.95-7.99 6.1-23.08

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Table 7. Variables associated with the occurrence of surgical site infection in logistic regression analysis. B Coefficient 0.91 0.55 1.28 1.9 0.99 1.92 -3.840

Postoperative use of vasoactive drugs Postoperative use of insulin Primary bloodstream infection Vascular catheter infection Pneumonia Surgical reintervention Constant

Odds Ratio 2.9 1.7 3.6 6.8 2.7 6.8

95% CI 1.5 - 4.1 1.2 - 2.6 1.6-8.3 2.3-19.8 1.2-5.9 3.6 - 12.7

CI: 95% confidence interval; Hosmer & Lemeshow test P=1; 94.1% correct prediction Table 8. Variables associated with evolution in the logistic regression analysis. B Coefficient 0.72 1.11 0.54 1.4 1.55 1.52 -4.34

Age≥60 years Postoperative use of vasoactive drugs Postoperative use of insulin Pneumonia Primary infection of the bloodstream Surgical reintervention Constant

Odds Ratio 2.0 3.4 1.8 4.3 4.7 4.4

95% CI 1.4-3.0 1.9-6.0 1.2-2.8 2.1-8.9 2.0-11.2 2.1-9.0

CI: 95% confidence interval; Hosmer & Lemeshow test P=1; correct prediction 93,5%

DISCUSSION

gery, with reported median time from surgery until diagnosis of sternal SSI of 15 days[10,11]. In study by Berg et al.[11], in Norway, where the average hospital stay was 6 days, most of the SSI on the sternal wound was diagnosed after discharge. In our study, however, as the average length of stay was very high (13.3+12.3 days) and the surgical team performed systematically assessment of patients postoperatively; therefore we believe that losses in cases with sternal SSI, if it occurred, were small and limited to superficial infections. Regarding the non-surgical infection, the surveillance only during hospital stay has been considered appropriate. In this study, the non-surgical HI were more frequent among older patients and those who stayed longer in the ICU, as it is known as the hospital sector with the highest rates of HI, as reported by other authors[1,12]. Likewise, the use and length of stay of UC, MV and CVC were associated with the occurrence of nonsurgical HI, in logistic regression analysis. These are the factors most frequently reported in several studies[3,4,6,8,9]. Invasive devices break down the natural barrier of defense and can be a gateway to microorganisms during its insertion or manipulation. It is estimated that 50% to 70% of these infections could be prevented if strategies considered effective were implemented and systematically incorporated into the daily care of these patients, for example, the early removal of invasive devices[2]. In the medical literature, it has been described mediastinitis occurrence from 0.4% to 5% of the patients. In our study, the observed overall rate of SSI was 6.4% and the rate of mediastinitis was 2.0%, similar to values reported by Brazilian authors, who reported rates of mediastinitis from 1.3% to 5.6%[13-15].

Patients undergoing cardiac surgery are more likely to develop HI because several risk factors for coronary heart disease are also considered at risk for the development of HI, including advanced age, diabetes mellitus, obesity and smoking. In addition, these patients remained in the ICU for a variable time, where they are subjected to multiple invasive procedures[1-6,8,9]. This study assessed the occurrence of HI, including 2060 patients from a single center undergoing cardiac surgery, and noted an overall rate of 17.0% of HI, while 64.7% of these infections were HI unrelated to the surgical site, highlighting UTI (2.8%), VAP (2.5%), Primary Blodstream Infection (PBSI) (1.7%) and infection of the site of insertion of the CVC (0.8%). The overall in-hospital mortality observed was 6.4%, being higher in patients ≥ 60 years, who required reoperation for bleeding, which used vasoactive drugs postoperatively, and had VAP or PBSI. HI rates reported in patients undergoing cardiac surgery are variable. In the study by Bouza et al.[5], involving 42 hospitals in 13 European countries, the prevalence of HI was 26.8%. Other studies including one center reported overall rates of HI 3.5% to 21%[3, 8,9]. These variations are probably related to differences in the population studied, the characteristics of the hospital and the care process, as well as the type of epidemiological surveillance adopted and the degree of compliance to control measures advocated. In general, it is recommended surveillance of SSI after discharge, since they may appear within 30 days after sur-

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The rate of infection at the site of the graft removal (2.2%) is among those described by other authors[10,11], however, this study did not assess the factors associated with its occurrence. In this study, the risk factors associated with the occurrence of SSI of sternal wound, in the logistic regression analysis were: surgical reintervention, use of vasoactive drugs and insulin postoperatively, VAP diagnosis and PBSI. Surgical reintervention is considered an important risk factor for SSI, probably due to greater surgical manipulation and delayed sternal closure. In the present study, this event has increased by six times the chance of SSI and four times the chance of dying as described by other authors[15-18]. Hemodynamic instability or postoperative shock have been identified as associated with the development of mediastinitis and nonsurgical HI[3,8]. The use of vasoactive drugs postoperatively was interpreted as a marker of hemodynamic instability, which increased the chance of SSI 2.9 times (OR 2.9 95% CI 1,5 to 4,1). Despite DM being one of the risk factors most often associated with the SSI, in this study this was not observed. There was association between insulin use and the occurrence of postoperative SSI, however, insulin may have been necessary due to previously undiagnosed DM or by hyperglycemia secondary to surgical stress, usually seen in major surgery[19]. Thus, this finding should be interpreted with caution, because confounding variables not adequately controlled may explain this result. It is known that infections at other sites increase the risk for SSI because they can represent the gateway to the microorganisms colonize the wound, or transmission by contact or blood[6]. In our study, patients with SSI had also more UTI, VAP, CVC infection, PBSI, when compared with those without SSI. Although it was not possible in all cases clearly establish what is the temporal relationship of these infections, they can be interpreted as adverse events arising from the coexistence of multiple risk factors present in this population. In the study by Le Guillou et al.[6] 5% to 15% of SSI in cardiac surgery were assigned to CVC-related infections, both when the same agent was isolated in both topographies or not. PBSI has been described as one of the most frequent HI in this population of patients with major impact on the evolution, because some of the risk factors reported for this infection overlap factors associated with SSI, such as age, COPD, duration of mechanical ventilation[4,5,20]. As noted by other authors[9,16], the duration of hospitalization was higher among patients with SSI compared with those without SSI, as well as among patients with nonsurgical HI compared with those without infection. One cannot say if the prolonged staying was cause or consequence of SSI or other infections, but it can certainly be considered a marker of increased morbidity and increased costs associated with care, one of the main consequences of HI for the health system. At Santa Casa de Marilia has been more frequent isolation of gram negative bacteria (Klebsiella pneumoniae and Pseudomonas aeruginosa), more than Staphylococcus aureus, in cul-

tures of surgical specimens. One possible explanation may be advanced age, prolonged hospital stay during preoperative period, diabetes mellitus, which were prevalent in this population, and are considered risk factors for SSI for gram negative[21]. This prompted a review of the scheme of an antibiotic prophylaxis for patients with prolonged preoperative hospital stay. From 2010, aminoglycoside was associated to cefazolin in 23% of cases, in order to expand coverage for gram negative bacteria in patients with preoperative hospitalization > 4 days. There is little evidence to support the use of aminoglycoside as a prophylactic drug in cardiac surgery, in addition to exist a concern with adverse events related to the use of this group of antimicrobials. However, gentamicin associated with other antibiotics with anti-staphylococcal action has been adopted in some hospitals in England, due to high rates of Clostridium difficile infection and its association with the use of cephalosporins, which are now little used. The study by Insker[22] that assessed antibiotic prophylaxis use in 23 English cardiac centers found that 61% of these used gentamicin associated with flucloxacillin. Vancomycin was not the standard antibiotic prophylaxis of the Santa Casa de Marília during the study period, since most of the S. aureus isolates from surgical patients were sensitive to oxacillin. However, in 2012 vancomycin already was part of the prophylactic scheme of 12.2% of patients with prolonged preoperative hospitalization, in order to also try to ensure better coverage for oxacillin-resistant Staphylococcus aureus. Due to the changes that may be occurring in bacteria isolated from the SSI and the sensitivity pattern, we believe it is imperative to continue monitoring the rates of SSI and the etiologic agents involved in order to assess the impact and appropriateness of prophylactic standard and the used for specific patient groups in this institution. The global in-hospital mortality was 6.4% and statistically different between patients with and without SSI (17 % versus 4.8%, OR), VAP (25% versus 5.9%), tracheobronchitis (15.4% versus 6.2%), PBSI (31.4% versus 6.0%). In the literature, the mortality reported in patients undergoing cardiac surgery who develop HI varies from 4% for UTI[3] to 35% for VAP[4]. Mortality among patients with mediastinitis was 24.4% and 6.0% among patients without this complication. Mediastinitis increased by five times the chance of dying (OR 5.0 95% CI 2.4 10.50). These rates are similar to those described by national and international authors, who reported a mortality rate between 14% to 42%[13,14,17]. There was no statistically significant difference in mortality when the infection was superficial or deep. The logistic regression analysis identified independent association between mortality and the following variables: age ≥ 60 years, use of vasoactive drug postoperatively, VAP, PBSI and surgical reintervention. However, SSI was not an independent variable associated with death in this series. Kollef et al.[3] assessed the impact of SSI after cardiac surgery and also identified VAP and PBSI as independent risk factors for multiple organ dysfunction and mortality.

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It has long been known that age is considered an independent risk factor for mortality, particularly when associated with the occurrence of infection[12]. Rahamanian et al.[23] in a study involving more than 6000 patients identified the following variables associated with death in patients undergoing cardiac surgery: age > 70 years (OR 1.4 95 CI 1.1 to 1.9), sepsis (OR 1.6 95% CI 1.0 to 2.6), reoperation ( OR 1.5 95% CI 1.1 to 2.1) and hemodynamic instability (OR 2.2 95% CI 1.2 to 3.9), data very similar to our study. Pneumonia and bloodstream infection are independent risk factors for hospital mortality in ICU patients, with attributed mortality ranging from 5% to 70%[2,20]. In the study performed in eight European countries[4], the mortality among patients undergoing cardiac surgery who developed pneumonia was 35%. Our study has some limitations because it is an observational study, performed in a single hospital and the identification of HI after discharge have been performed in the ambulatory by the surgical teams, and only then assessed by HICS. Although the length of hospital stay was long, there is the possibility that the HICS has not been called to assess some patients, particularly those with superficial infections, not requiring hospital readmission; or cultures were not collected for their diagnosis and did not require antibiotic orientation. We believe that patients with deep infection or mediastinitis were all included. Another aspect to be mentioned is that, although the main objective was assess risk factors for nonsurgical HI and its impact on patient outcomes, overall mortality observed was not adjusted for the EuroSCORE values, because not all variables were recorded for its calculation in the initial years of study. However, the results of this study confirm the risk factors and the negative impact of non surgical HI on outcomes of these patients and points to some possible improvement. It is known that the incidence of HI among patients undergoing cardiac surgery depends on factors related to the hospital, the patient’s characteristics, invasive procedures, the preventive measures that are implemented and the level of compliance of health professionals to these measures[24]. In this sense, it is necessary that strategies with proven effectiveness for the prevention of surgical site and nonsurgical HI be planned before be actually adopted. Special attention should be given to the factors liable to modification related to the care process, and to the multiple risk factors for the occurrence of HI present in this population. Such measures require major behavioral changes, which should be encouraged by in-service education, audit and continuous feedback, since the benefits of its application can only be achieved when the membership compliance reaches 100%, a scenario still far from being achieved in most hospitals[2,25].

SSI. The use of postoperative vasoactive drugs and surgical reintervention were identified as risk factors for both sternal SSI or nonsurgical infections. The sternal SSI was associated with the occurrence of pneumonia, bloodstream infection and the use of insulin in the postoperative period. Gram-negative bacteria were the most frequently identified in these infections. The age, length of ICU stay, length of stay of UC, CVC and MV were predictors of the development of nonsurgical HI. Independent variables associated with mortality were age, VAP, PBSI, surgical reintervention, use of insulin and vasoactive drugs postoperatively.

Authors’ roles & responsibilities LOC SMDT RGK ESG RTB MGT

Idealizer of the project, coordination of data collection, analysis and interpretation of data, writing of the manuscript. Participated in the idealization of the project, data collection and writing of the manuscript. Participated on data collection, interpretation of data and writing of the manuscript. Participated in the data collection, drafting the manuscript. Participated on idealization of the project and writing of the manuscript. Participated on idealization of the project and writing of the manuscript.

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CONCLUSIONS Patients who underwent cardiac surgery had increased chance of developing infections in various topographies, particularly UTI, VAP, PBSI and CVC infection, besides the

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6. Le Guillou V, Tavolacci MP, Baste JM, Hubscher C, Bedoit E, Bessou JP, et al. Surgical site infection after central venous catheterrelated infection in cardiac surgery. Analysis of a cohort of 7557 patients. J Hosp Infect. 2011;79(3):236-41.

16. Steingrimsson S, Gottfredsson M, Kristinsson KG, Gudbjartsson T. Deep sternal wound in-fections following open heart surgery in Iceland: a population-based study. Scand Cardio-vasc J. 2008;42(3):208-13.

7. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36(5):309-32.

17. Risnes I, Abdelnoor M, Almdah SM, Svennevig JL. Mediastinitis after coronary artery by-pass grafting risk factors and long-term survival. Ann Thorac Surg. 2010;89(5):1502-9.

8. Fowler VG Jr, O’Brien SM, Muhlbaier LH, Corey GR, Ferguson TB, Peterson ED. Clinical predictors of major infections after cardiac surgery. Circulation. 2005; 30;112(9 Suppl):I358-65.

18. Filsoufi F, Castillo JG, Rahmanian PB, Broumand SR, Silvay G, Carpentier A, et al. Epide-miology of deep sternal wound infection in cardiac surgery. J Cardiothorac Vasc Anesth. 2009;23(4):488-94.

9. De Santo LS, Bancone C, Santarpino G, Romano G, De Feo M, Scardone M, et al. Microbi-ologically documented nosocomial infections after cardiac surgery: an 18-month prospective tertiary care center report. Eur J Cardiothorac Surg. 2008;33(4):666-72.

19. Knapik P, Nadziakiewicz P, Urbanska E, Saucha W, Herdynska M, Zembala M. Cardiopul-monary bypass increases postoperative glycemia and insulin consumption after coronary surgery. Ann Thorac Surg. 2009;87(6):1859-65.

10. Manniën J, Wille JC, Kloek JJ, van Benthem BH. Surveillance and epidemiology of surgical site infections after cardiothoracic surgery in The Netherlands, 2002-2007. J Thorac Cardio-vasc Surg. 2011;141(4):899-904.

20. Riera M, Ibáñez J, Herrero J, Ignacio Sáez De Ibarra J, Enríquez F, Campillo C, et al. Respiratory tract in-fections after cardiac surgery: impact on hospital morbidity and mortality. J Cardiovasc Surg (Torino). 2010;51(6):907-14.

11. Berg TC, Kjørstad KE, Akselsen PE, Seim BE, Løwer HL, Stenvik MN et al. National sur-veillance of surgical site infections after coronary artery bypass grafting in Norway: inci-dence and risk factors. Eur J Cardiothorac Surg. 2011;40(6):1291-7.

21. Garey KW, Kumar N, Dao T, Tam VH, Gentry LO. Risk factors for postoperative chest wound infections due to gramnegative bactéria in cardiac surgery patients. J Chemother. 2006;18(4):402-8.

12. Vosylius S, Sipylaite J, Ivaskevicius J. Determinants of outcome in elderly patients admitted to the intensive care unit. Age Ageing. 2005;34(2):157-62.

22. Inkster T. Antibiotic prophylaxis for cardiac surgery: a shift away from traditional cephalosporins? J Cardiothorac Vasc Anesth. 2009;23(6):933-5.

13. Sá MP, Soares EF, Santos CA, Figueiredo OJ, Lima RO, Escobar RR, et al. Risk factors for mediastinitis after coronary artery bypass grafting surgery. Rev Bras Cir Cardio-vasc.2011;26(1):27-35.

23. Rahmanian PB, Adams DH, Castillo JG, Carpentier A, Filsoufi F. Predicting hospital mor-tality and analysis of long-term survival after major noncardiac complications in cardiac surgery patients. Ann Thorac Surg. 2010;90(4):1221-9.

14. Tiveron MG, Fiorelli AI, Mota EM, Mejia OAV, Brandão CMA, Dallan LAO, et al. Fatores de risco pré-operatórios para mediastinite após cirurgia cardíaca: análise de 2768 pacientes. Rev Bras Cir Cardiovasc. 2012;27(2):203-10.

24. Cove ME, Spelman DW, MacLaren G. Infectious complications of cardiac surgery: a clinical review. J Cardiothorac Vasc Anesth. 2012;26(6):1094-100.

15. Magedanz EH, Bodanese LC, Guaragna JCVC, Albuquerque LC, Martins V, Minossi SD, et al. Elaboração de escore de risco para mediastinite pós-cirurgia de revascularização do miocárdio. Rev Bras Cir Cardiovasc. 2010;25(2):154-9.

25. Flodgren G, Conterno LO, Mayhew A, Omar O, Pereira CR, Shepperd S. Interventions to improve professional adherence to guidelines for prevention of device-related infections. Cochrane Database Syst Rev. 2013;3:CD006559.

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Paula JGR, et ORIGINAL al. - Management of multivessel coronary disease after primary ARTICLE angioplasty: staged reintervention versus optimized clinical treatment and two-year follow-up

Management of multivessel coronary disease after primary angioplasty: staged reintervention versus optimized clinical treatment and two-year follow-up Manejo da doença coronária multiarterial após angioplastia primária: reintervenção estadiada versus tratamento clínico otimizado e seguimento de 2 anos

José Guilherme Rodrigues de Paula1; Moacir Fernandes de Godoy1, PhD; Márcio Antônio dos Santos1; Flávio Corrêa Pivatelli1; Alan Vinicius Gamero Osti1; Luciano Folchine Trindade1; Diego Novelli1; Marcelo Arruda Nakazone1 DOI: 10.5935/1678-9741.20140051

RBCCV 44205-1538

Abstract Objective: In the clinical scenario of ST-segment elevation acute myocardial infarction, several patients with multivessel coronary atherosclerotic disease are discharged without a defined strategy to monitor the residual atherosclerotic lesions. The clinical endpoints evaluated were cardiovascular death, symptoms of angina pectoris, rehospitalization for a new acute coronary syndrome, and the necessity of reintervention during the two-year follow-up. Methods: This observational, prospective, and historical study included multivessel coronary atherosclerotic disease patients who were admitted to a tertiary care university hospital with ST-segment elevation acute myocardial infarction and underwent primary percutaneous coronary intervention with stent implantation only at the culprit lesion site; these patients were monitored in the outpatient clinic according to two treatments: the Clinical Group - CG (optimized pharmacological therapy associated with counseling for a healthy diet and cardiac rehabilitation) or the Intervention Group - IG (new staged percutaneous coronary intervention or surgical coronary artery bypass graft surgery combined with the previously prescribed treatment). Results: Of 143 patients consecutively admitted with ST-segment elevation acute myocardial infarction, 57 were eligible for

the study (CG=44 and IG=13). Regarding the clinical endpoints, the cardiovascular death rate did not differ between the CG and IG. The symptom of angina pectoris and the rehospitalization rate for a new episode of acute coronary syndrome were accentuated in the CG (P=0.020 and P=0.049, respectively) mainly in individuals with evidence of ischemia evidenced by myocardial scintigraphy (P<0.001 and P=0.001, respectively) which culminated in an even greater need for reintervention (P=0.001) in this subgroup of patients. Conclusion: The staged intervention was demonstrated to be safe and able to reduce angina pectoris and rehospitalization for a new episode of acute coronary syndrome. In addition, it decreases the likelihood of unplanned reinterventions of patients without ischemia evidenced by myocardial scintigraphy.

Hospital de Base (HB)/Faculdade de Medicina de São José do Rio Preto (FAMERP). São José do Rio Preto, SP, Brazil.

Correspondence address: José Guilherme Rodrigues de Paula Hospital de Base de S. José do Rio Preto – Laboratório de Hemodinâmica e Cardiologia Intervencionista Av. Brigadeiro Faria Lima, 5544 – São José do Rio Preto, SP, Brazil Zip code: 15090-000 E-mail: jgrdp@hotmail.com

Descriptors: Myocardial infarction. Coronary disease. Angioplasty. Scintigraphy. Mortality. Resumo Objetivo: No cenário do Infarto Agudo do Miocárdio com Supradesnível do Segmento ST, diversos pacientes com doença coronária aterosclerótica multiarterial recebem alta hospitalar

1

Work carried out at Interventional Cardiology Unit from Hospital de Base (HB)/Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil.

Article received on November 13th, 2013 Article accepted on February 26th, 2014

No financial support.

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macológica otimizada associada à orientação dietética saudável e reabilitação cardiovascular) ou Grupo Intervenção - GI (nova ICP estadiada ou revascularização miocárdica cirúrgica aliada ao tratamento previamente descrito). Resultados: De 143 pacientes consecutivamente admitidos com Infarto Agudo do Miocárdio com Supradesnível do Segmento ST, 57 foram elegíveis para o estudo (GC=44 e GI=13). Em relação aos desfechos, o GI não diferiu do GC quanto à taxa de óbito cardiovascular. O sintoma de angina de peito e a taxa de reinternação por novo episódio de síndrome coronária aguda destacam-se no GC (P=0,020 e P=0,049; respectivamente), principalmente nos indivíduos com evidência de isquemia à cintilografia miocárdica (P<0,001 e P=0,001; respectivamente) culminando, inclusive, com maior necessidade de reintervenção (P=0,001) neste subgrupo de pacientes. Conclusão: A intervenção estadiada mostra-se segura e capaz de reduzir angina de peito e reinternação por novo episódio de síndrome coronária aguda. Além disso, diminui a probabilidade de reintervenções não planejadas em pacientes com ausência de isquemia à cintilografia miocárdica.

Abbreviations, Acronyms & Symbols STEMI MCAD ACS PCI CG IG CAD BARI

ST-segment elevation acute myocardial infarction Multivessel Coronary Atherosclerotic Disease Acute Coronary Syndrome Percutaneous Coronary Intervention Clinical Group Intervention Group Coronary Artery Disease Bypass Angioplasty Revascularization Investigation

sem estratégia definida para seguimento de coronariopatia residual. Avaliamos o desfecho composto por morte cardiovascular, sintoma de angina de peito, reinternação por nova síndrome coronária aguda ou necessidade de reintervenção no seguimento de dois anos. Métodos: Estudo observacional, prospectivo, histórico, incluindo portadores de doença coronária aterosclerótica multiarterial admitidos em serviço terciário universitário com Infarto Agudo do Miocárdio com Supradesnível do Segmento ST submetidos à intervenção coronária percutânea primária com implante de stent apenas na lesão culpada e conduzidos ambulatorialmente conforme duas terapêuticas: Grupo Clínico - GC (terapia far-

Descritores: Infarto do Miocárdio. Doença das Coronárias. Angioplastia. Cintilografia; Mortalidade.

INTRODUCTION

approaches, with or without coronary stent implantation[16], concepts such as cost-effectiveness and ischemia-free survival or re-intervention justify the real concern of the assistant cardiologist regarding the appropriate clinical monitoring of these patients. In this context, a recent review published by Andrade et al.[17] demonstrated that the comparison between percutaneous and surgical revascularization approaches is controversial even when it is based only on the most robust randomized clinical trials and mainly when it includes studies conducted in different stages of the interventional cardiology (period of exclusive use of balloon catheters compared with the subsequent advent of conventional coronary stents and, more recently, drug-eluting stents) and studies using different surgical techniques, considering whether the myocardial revascularization is associated to the cardiopulmonary bypass. Therefore, this study aimed to assess the incidence of the clinical endpoints (cardiovascular death, symptoms of angina pectoris, rehospitalization for a new acute coronary syndrome (ACS), or the necessity of reintervention during the two-year follow-up) in MCAD patients who were admitted with STEMI and underwent primary PCI for exclusive treatment of the culprit lesion. After their hospital discharge, these patients were initially monitored according to two

The primary percutaneous coronary intervention (PCI) for exclusive treatment of the culprit lesion in an acute ischemic event remains in the current guidelines[1-3] as the strategy recommended for managing patients with ST-segment elevation acute myocardial infarction (STEMI) who are hemodynamically stable. Although retrospective records and multicenter clinical trials demonstrate the occurrence of multivessel coronary atherosclerotic disease (MCAD) in approximately 40 to 65% of these individuals[4-7] and even a poor prognosis associated with this diffuse atherosclerotic involvement, several scientific pieces of evidence support this recommendation[8-13]. However, these guidelines do not include clear recommendations for managing residual MCAD after angiographic success in primary PCI. In addition, information from national records[14,15] involving patients with MCAD admitted with STEMI and who underwent primary PCI do not specify strategies to monitor significant residual lesions that are not treated in the initial procedure. Considering the worldwide evidence that indicates a reduced number of surgical revascularizations compared with a simultaneous and significant increase in the percutaneous

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aspects: elective approach of residual lesions or optimized clinical treatment.

administration of 200 mg macerated acetylsalicylic acid and the oral administration of 600 mg clopidogrel bisulfate or 300 mg clopidogrel bisulfate for patients aged >75 years), as predicted in the current recommendations[1-3,18-20] for all 57 patients included in this analysis when they were admitted to the emergency care sector of this hospital unit and prior to the coronary angiography procedure. Moreover, during the hospitalization period, these patients received optimized pharmacological therapy considering the drugs that are standardized in the Brazilian public health service. In this case, the treatment included the dual antiplatelet therapy (acetylsalicylic acid and clopidogrel bisulfate) recommended for the maintenance phase after the PCI in addition to the administration of an angiotensin-converting enzyme inhibitor or angiotensin II AT1 receptor blocker, beta-blockers, and statins. The prescription given to the patients at the time of hospital discharge also encouraged them to maintain the use of these drugs during the outpatient follow-up. In this case, the optimized pharmacological therapy was considered by the assistant medical team to be the prescription of the target dose or maximum tolerated daily dose of beta-blockers and angiotensin-converting enzyme inhibitor/angiotensin II AT1 receptor blocker for all patients assessed in this study if no contra-indication for these drugs were present. Regarding statins, the patients initially received 80 mg/day atorvastatin between the first and fourth day of STEMI. This dosage was subsequently re-assessed in an outpatient clinic to maintain the therapeutic targets for a serum level of low-density lipoprotein cholesterol fraction. These procedures were followed during all outpatient follow-ups according to the recommendations of the current national guidelines[1,21,22].

METHODS Study population In total, 143 patients were consecutively admitted to the clinical emergency unit of a tertiary care university hospital in the northwestern region of Sao Paulo State, Brazil, from January 2009 to December 2010. These patients presented a definitive diagnosis of STEMI that included the clinical presentation of chest pain or an equivalent ischemic event compatible with the ACS occurring within 12 hours of the onset of symptoms and a 12-lead electrocardiogram evidencing ST-segment elevation ≥2 mm in men and ≥1.5 mm in women in at least two precordial leads or ≥1 mm in at least two continuous peripheral leads, or a new or presumed-new bundle branch block[3]. Of these patients, 139 (97.2%) were referred for primary PCI, and four (2.8%) underwent intravenous fibrinolytic therapy with streptokinase. Coronary angiography demonstrated MCAD (defined by visual assessment as a ≥70% diameter stenosis of three or more epicardial coronary arteries or their major branches) in 63 patients (45.3%) who were referred to the hemodynamic laboratory (including the culprit artery in the ischemic event and excluding cases with a ≥50% obstructive lesion in the left coronary artery). However, this analysis considered 57 individuals after excluding six patients who died during the hospitalization from causes related to the index ischemic event (four deaths due to septic shock and two deaths due to cardiogenic shock). To establish a comparison between the pre-specified clinical endpoints, this sample was divided into two groups according to the strategy initially adopted by the team of assistant cardiologists regarding the monitoring of MCAD in the following individuals: a Clinical Group (CG) that comprised patients who were discharged from the hospital to have the MCAD monitored in an outpatient clinic under a “conservative” medical therapy (optimized pharmacological therapy associated with counseling for a healthy diet and cardiac rehabilitation) and an Intervention Group (IG) that included individuals who underwent the staged PCI or elective surgical myocardial revascularization approximately one month after the primary PCI with a bare metal stent implantation that was performed on the occasion of the STEMI. This study did not aim to assess the clinical endpoints separately in specific subgroups of patients considering the comorbidities, personal history, or clinical severity of the presentation of the qualifying ischemic event.

Invasive procedure and outpatient follow-up The angiography study considered the same arterial puncture sites for both procedures (angiography and coronary angioplasty). Procedures such as aspiration thrombectomy during PCI and the intravenous administration of glycoprotein IIb/IIIa inhibitors were decided exclusively by the assistant hemodynamicist. In the primary PCI scenario, the subgroup of patients with type 2 diabetes mellitus did not receive any different procedures with respect to the percutaneous technique or choice of implanted coronary stent. In this case, the only difference consisted in the outpatient follow-up with the endocrinology team of this service, aiming for adequate glycemic control and the secondary prevention of vascular complications in these patients. All patients included in this study were monitored in the outpatient cardiology service of this institution, considering the clinical evolution after PCI and the manifestation of symptoms including angina pectoris or an equivalent ischemic event, in addition to using myocardial scintigraphy to detect ischemia caused by residual coronary artery disease associated with physical or pharmacological stress.

Pharmacological therapy A careful review of the medical records confirmed the administration of dual antiplatelet therapy (including the oral

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Data collection After project approval by the local Research Ethics Committee (Certificate of Presentation for Ethical Consideration [Certificado de Apresentação para Apreciação Ética - CAAE] number 12662313.3.0000.5415) according to the Declaration of Helsinki, the demographic information of patients eligible for this analysis and the data regarding their hospital evolution were obtained from an extensive review of the medical records of individuals who were admitted with STEMI and underwent invasive coronary stratification in the hemodynamics service of this institution during the analyzed period. The telephone number to contact all patients who were included in this study was obtained at the end of the two-year follow-up after the PCI, and all the follow-up outpatient appointments were carefully reviewed to confirm the clinical endpoints of interest.

In this sample, the IG consisted of 13 patients who underwent emergency treatment only on the culprit lesion associated with the STEMI, followed by hospital discharge with scheduling for elective procedures on the residual coronary lesions. In this context, 11 of these patients underwent staged angioplasty of the remaining lesions approximately six weeks after the index ischemic event (procedures performed without description of any complications, including the absence of periprocedural reinfarction, in which there was primary angiographic success – the establishment of TIMI-3 flow and less than 30% residual stenosis – in all patients). The other two patients underwent coronary artery bypass grafting using cardiopulmonary bypass approximately 37 days after STEMI, including an initial month of treatment with dual antiplatelet therapy (acetylsalicylic acid and clopidogrel bisulfate), and one week after discontinuing the daily use of thienopyridine derivative. In addition, the CG included 44 patients who had follow-up outpatient appointments in the cardiology service under a “conservative” strategy. The radial access was used in 85.9% of patients who underwent coronary angiography. The median door-to-balloon time in this sample was 81 minutes, ranging from 32 to 187 minutes. MCAD was characterized in our study population, with a mean of 3.6 significant coronary lesions per patient. The primary angioplasty included conventional coronary stent implantation (bare metal) in 100% of our sample, resulting in primary angiographic success (reestablishment of TIMI-3 flow after PCI) in 82.4% of the individuals. Table 2 presents additional information about the invasive procedures, including culprit coronary lesions associated with the STEMI and treated during the PCI, in addition to the data regarding residual lesions in both assessed groups. In this case, the higher percentage of ramus diagonalis as the residual lesion in the IG (8.7%) compared with the CG (0%; P=0.023) is highlighted as the only statistically significant difference between the groups.

Statistical analysis Data were entered into an Excel® (Microsoft Corp., Redmond, USA) spreadsheet and analyzed with the StatsDirect statistical software version 2.7.8 (11/08/2011). Categorical variables were described as a frequency and percentage and were analyzed with the Fisher exact test. Quantitative variables that presented a Gaussian distribution were compared with an unpaired t-test. For variables without a normal distribution, the Mann-Whitney test was used. An α error of 5% was assumed, and P≤0.05 was considered significant. RESULTS The baseline clinical characteristics of patients who were admitted to this service with definitive criteria for STEMI and who underwent primary angioplasty were similar between the IG and the CG (P>0.05 for all variables; Table 1), including the risk factors for coronary artery disease (CAD) and the Killip-Kimball classification.

Table 1. Baseline clinical characteristics of patients admitted with STEMI and who underwent primary PCI. Variable Age (years) Male Type 2 Diabetes Mellitus Dyslipidemia Systemic Arterial Hypertension Tobacco Smoking FH-positive for Premature CAD Sedentarism Overweight/Obesity Killip Class I at Admission

Intervention Group (N=13) Median (Min - Max) or n (%) 62 (51 – 81) 9 (69.2) 7 (53.8) 7 (53.8) 9 (69.3) 6 (46.1) 4 (30.7) 9 (69.2) 9 (69.2) 10 (76.9)

Clinical Group (N=44) Median (Min - Max) or n (%) 65 (44 – 84) 33 (75.0) 23 (52.2) 24 (54.5) 34 (77.2) 20 (45.4) 10 (22.7) 30 (68.1) 25 (56.8) 35 (79.5)

P Value* 0.655 0.681 0.927 0.962 0.566 0.962 0.566 0.962 0.450 1.000

STEMI= ST-segment elevation in acute myocardial infarction; PCI= percutaneous coronary intervention; N= number of individuals; n= number of events; Min= minimum value; Max= maximum value; FH= family history; CAD= coronary artery disease; * Fisher’s exact test

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Table 2. Angiographic data from patients admitted with STEMI and undergoing primary PCI with bare metal stent implantation. Variables Information Regarding the Procedures Radial Access Door-to-balloon Time for the PCI (min) Use of a GP IIb/IIIa Inhibitor Aspiration Thrombectomy During the PCI TIMI-3 Flow after the PCI LVEF ≥ 50% on Ventriculography

Culprit Lesions Approached During the PCI Anterior Descending Artery Diagonal Branch Circumflex Artery Right Coronary Artery Posterior Descending Branch Residual Lesions After the PCI Anterior Descending Artery Diagonal Branch Ramus Diagonalis Circumflex Artery Marginal Branch Right Coronary Artery Posterior Descending Branch Posterior Ventricular Branch

Intervention Group (N=13) Median (Min - Max) or n (%) 11 (84.6) 84 (46 – 187) 1 (7.7) 3 (23) 10 (76.9) 10 (77.0) 6 (46.1) 0 (0) 1 (7.8) 6 (46.1) 0 (0) 4 (17.5) 3 (13.0) 2 (8.7) 5 (21.7) 3 (13.0) 4 (17.5) 1 (4.3) 1 (4.3)

Clinical Group (N=44) Median (Min - Max) or n (%)

P Value *

38 (86.4) 81 (32 - 172) 5 (11.4) 9 (20.5) 37 (84.1) 34 (73.3)

1.000 0.697 1.000 1.000 0.680 0.956

18 (40.9) 1 (2.3) 4 (9.0) 20 (45.5) 1 (2.3)

0.759 1.000 1.000 1.000 1.000

23 (18.6) 22 (17.7) 0 (0) 27 (21.8) 23 (18.6) 19 (15.3) 2 (1.6) 8 (6.4)

1.000 0.766 0.023 1.000 0.766 0.760 0.402 1.000

STEMI= ST-segment elevation in acute myocardial infarction; PCI= percutaneous coronary intervention; N= number of individuals; n= number of events; Min= minimum value; Max= maximum value; min= minutes; GP= glycoprotein; LVEF= left ventricular ejection fraction; *Fisher’s exact test

Table 3. Clinical endpoints in the 2-year follow-up of patients who underwent primary PCI only in the culprit lesion associated with the STEMI. Clinical Endpoints Cardiovascular Death Angina Pectoris Rehospitalization for an ACS Necessity for Reintervention

Intervention Group (a) (N=13) n (%) 0 (0) 2 (15.4) 1 (7.7) 1 (7.7)

Clinical Group (b) (N=44) n (%) 4 (9.1) 23 (52.3) 16 (36.4) 15 (34.1)

Clinical Group Scintigraphy with Detection of Ischemia (c) (N=24) n (%) 4 (16.7) 23 (95.8) 16 (66.7) 15 (62.5)

P Value * (axb)

P Value * (axc)

0.344 0.020 0.049 0.066

0.160 <0.001 0.001 0.001

PCI= percutaneous coronary intervention; STEMI= ST-segment elevation in acute myocardial infarction; N= number of individuals; n= number of events; ACS= acute coronary syndrome; * Fisher’s exact test

Myocardial scintigraphic examinations performed in the outpatient clinic approximately six months after the PCI detected the presence of ischemia with a moderate-to-large extension into territories compatible with the residual coronary lesions in 54.5% of the CG patients. By contrast, the IG had only one case of ischemia evidenced by myocardial scintigraphy, which occurred in a patient who had symptoms of angina pectoris after the staged angioplasty. Subsequently, this patient was diagnosed with in-stent restenosis at the culprit lesion associated with STEMI and then underwent zotarolimus-eluting

coronary stent implantation (Endeavor®) with angiographic success, progressing without any signs or symptoms indicative of residual ischemia. Regarding the assessed clinical endpoints, there were no differences between the IG and the CG with respect to the cardiovascular death rate (P>0.05) in the two-year follow-up after performing the primary PCI, regardless of the presence of myocardial ischemia evidenced in an outpatient clinic by a non-invasive stratification method (Table 3) and the presence of consequent left ventricular systolic dysfunction observed

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during the angiography coronary performed for qualifying ischemic events (data not shown). Although without a significant difference (P=0.269), in this case, the Kaplan-Meier analysis demonstrated a marked decrease in the death-free survival rate for the CG within the first six months of follow-up (Figure 1).

The verification of MCAD in individuals admitted with STEMI implies an increased morbidity and mortality compared to those individuals with a single coronary lesion[23]. In our sample, such diffuse atherosclerotic involvement was observed in 45.3% of patients who underwent angiography coronary, corroborating national[14,15] and international data[6,7] in the literature. In this scenario, in which the current guidelines[1-3] do not recommend primary PCI in arteries not related to the index ischemic event in the absence of hemodynamic instability – as opposed to results recently published[24,25] that were performed during a period of great technological advancement in the endovascular area combined with the current therapy with new antiplatelet agents and glycoprotein IIb/IIIa inhibitors – this study is distinguished by its unprecedented comparison of long-term cardiovascular endpoints in “real world” Brazilian individuals who underwent staged angioplasty or a unique clinical treatment. All patients from the IG were electively treated within a period up to 60 days after hospital discharge, to obtain complete revascularization. In this group, the staged PCI might have been clinically oriented, guided by objective evidence of residual ischemia, or suggested by the interventional cardiologist at the time of initial angiography coronary. To date, only two other analyses were performed in a similar scenario[12,26], and both revealed a reduction in long-term mortality. In this context, although the cardiovascular death rate is more frequent in the CG than in the IG, our results demonstrated no significant difference in cardiovascular mortality between the groups, as evidenced in other populations[27,28]. The similar baseline characteristics and variables associated with the invasive procedures between IG and CG, also including the culprit coronary lesions associated with STEMI and addressed in primary PCI are factors that strengthen our findings. Although diabetic patients generally constitute the preferred indication for coronary artery bypass surgery[29], we found no trend for adverse clinical endpoints among the IG patients, which consisted of more than 50% of patients with type 2 diabetes mellitus who predominantly underwent PCI with bare metal stent implantation. These findings, which at first appear to disagree with the literature and current recommendations regarding the treatment of diabetic patients with multivessel disease, remind us that the main evidence against the percutaneous coronary angioplasty in diabetic patients originated during the period of exclusive balloon catheter use, i.e., these data originated from occasional results of the BARI (Bypass Angioplasty Revascularization Investigation)[30-33]. The evolution of patients initially treated in a “conservative” approach demonstrated the significantly higher proportions of endpoints such as angina pectoris and rehospitalization for an ACS when compared to the IG, especially in individuals with ischemia diagnosed by myocardial scintigraphy performed in an outpatient clinic. In this case, the protective effect obtained with the staged revascularization in the IG might occur due

Fig. 1 - Kaplan-Meier actuarial death-free survival curve in the patients from the Intervention Group (continuous line; IG) versus patients from the Clinical Group (dashed line; CG) after primary percutaneous coronary intervention

In addition, the symptom of angina pectoris was evident in more than 50% of individuals from the CG (P=0.020), representing almost all patients with evidence of ischemia by the myocardial scintigraphy (95.8% of individuals; P<0.001), compared with the IG (15.4%). Nonetheless, in this context, the rehospitalization rate for a new episode of ACS was significantly higher in the CG (36.4%; P=0.049), especially among those patients with positive myocardial scintigraphy results for ischemia (66.7%; P=0.001), culminating in an even greater necessity for reintervention (P=0.001) in this subgroup of patients compared with the IG (7.7% for both comparisons; Table 3). DISCUSSION The findings of the current study demonstrate that in a “real world” clinical scenario including patients with MCAD who were admitted with STEMI and underwent primary PCI for exclusive treatment of the culprit lesion, both strategies initially scheduled for outpatient follow-up (elective angioplasty of residual lesions and clinical treatment) did not differ in the cardiovascular mortality over two years. However, the interventionist strategy program (surgical or percutaneous) is highlighted for reducing symptoms such as angina pectoris and rehospitalization for a new episode of ACS. Furthermore, the myocardial scintigraphy confirms its accuracy for predicting such endpoints and the necessity for reintervention in groups of patients on optimized clinical treatment.

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to the most complete treatment of other potentially unstable atherosclerotic plaques[34,35]. In addition, another reasonable explanation would be the fact that the inflammatory reaction triggered during the ACS process responsible for the plaque instability in STEMI was not limited to the culprit lesion, consequently compromising the entire coronary tree[23]. Although it did not occur in our sample, Meliga et al.[36] reported that the complete revascularization of these patients should not be based only on angiographic findings but ideally should be guided by evidence of correlated ischemia, as justified by the high risk of periprocedural ischemic complications. The increased requirement for other approaches in the CG patients with positive myocardial scintigraphy results for ischemia warns for strict outpatient follow-ups in patients with significant residual CAD, including the consideration of this imaging test as a complementary diagnostic method in selected cases, even in patients under optimized therapy[10]. In our sample, the high percentage of individuals with angina pectoris symptoms in this subgroup of patients, many of them readmitted for a new episode of ACS during the predetermined follow-up visit, highlights myocardial scintigraphy for the early discriminatory accuracy of individuals potentially vulnerable to the occurrence of major cardiovascular events[7]. In this context, although there is no general recommendation regarding the ideal period indicated for noninvasive re-stratification of these patients in the current guidelines[1-3], our results suggest that myocardial scintigraphy may help identify individuals at high risk for new cardiovascular events during the first six months after primary PCI.

recommendations regarding the MCAD approach in the STEMI scenario.

Authors’ roles & responsibilities JGRP MFG MAS FCP AVGO LFT DN MAN

Design of the project; collecting data; statistical analysis; discussion of results; manuscript writing. Statistical analysis; discussion of results Collecting data Collecting data Collecting data Collecting data Collecting data Design of the project; Statistical analysis; discussion of results; manuscript writing

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Study limitations This study demonstrates the experience of a single tertiary care university hospital with primary PCI in the STEMI scenario and staged approaches of residual MCAD. Additionally, like any observational study, this analysis is prone to selection bias regarding the choice of the follow-up strategy, including complete revascularization or medical treatment alone. Finally, the small number of subjects in each group might limit the prognostic assessment of the considered patients, in addition to affecting the statistical power of the study and the consequent interpretation of the pre-specified clinical endpoints, thereby preventing the development of definitive conclusions.

3. American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions, O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78-140. 4. Waldecker B, Waas W, Haberbosch W, Voss R, Heizmann H, Tillmanns H, et al. Long-term follow-up after direct percutaneous transluminal coronary angioplasty for acute myocardial infarction. J Am Coll Cardiol. 1998;32(5):1320-5.

CONCLUSION

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Our results suggest that the multivessel approach considering the staged PCI appears to be safe and able to reduce angina pectoris and rehospitalization for a new episode of ACS. In addition, it decreases the likelihood of unplanned reintervention in patients without detectable ischemia on the myocardial scintigraphy. Additional investigations including randomized clinical trials are necessary to produce sufficiently robust evidence that will contribute to updating the current

6. Moreno R, García E, Soriano J, Abeytua M, López de Sá E, Acosta J, et al. Early coronary angioplasty for acute myocardial infarction: predictors of a poor outcome in a non-selected population. J Invas Cardiol. 2001;13(3):202-10.

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8. Muller DW, Topol EJ, Ellis SG, Sigmon KN, Lee K, Califf RM, et al. Multivessel coronary artery disease: a key predictor of shortterm prognosis after reperfusion therapy for acute myocardial infarction. Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group. Am Heart J. 1991;121(4 Pt 1):1042-9.

19. Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB, et al; CURRENT-OASIS 7 trial investigators. Double-dose versus standard-dose clopidogrel and highdose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet. 2010;376(9748):1233-43.

9. Jaski BE, Cohen JD, Trausch J, Marsh DG, Bail GR, Overlie PA, et al. Outcome of urgent percutaneous transluminal coronary angioplasty in acute myocardial infarction: comparison of singlevessel versus multivessel coronary artery disease. Am Heart J. 1992;124(6):1427-33.

20. Patrono C, Andreotti F, Arnesen H, Badimon L, Biagent C, Collet JP, et al. Antiplatelet agents for the treatment and prevention of atherothrombosis. Eur Heart J. 2011;32(23):2922-32.

10. Corpus RA, House JA, Marso SP, Grantham JA, Huber KC Jr, Laster SB, et al. Multivessel percutaneous coronary intervention in patients with multivessel disease and acute myocardial infarction. Am Heart J. 2004;148(3):493-500.

21. Sociedade Brasileira de Cardiologia / Sociedade Brasileira de Hipertensão / Sociedade Brasileira de Nefrologia. VI Brazilian guidelines of hypertension. Arq Bras Cardiol. 2010;95(1 Suppl 1):1-51.

11. Rigattieri S, Biondi-Zoccai G, Silvestri P, Di Russo C, Musto C, Ferraiuolo G, et al. Management of multivessel coronary disease after ST elevation myocardial infarction treated by primary angioplasty. J Intervent Cardiol. 2008;21(1):1-7.

22. Xavier HT, Izar MC, Faria Neto JR, Assad MH, Rocha VZ, Sposito AC, et al. V diretriz brasileira de dislipidemias e prevenção da aterosclerose. Arq Bras Cardiol. 2013;101(4 Suppl 1):1-20.

12. Hannan EL, Samadashvili Z, Walford G, Holmes DR Jr, Jacobs AK, Stamato NJ, et al. Culprit vessel percutaneous intervention versus multivessel and staged percutaneous coronary intervention for ST-segment elevation myocardial infarction patients with multivessel disease. JACC Cardiovasc Interv. 2010;3(1):22-31.

23. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O’Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med. 2000;343(13):915-22. 24. Qarawani D, Nahir M, Abboud M, Hazanov Y, Hasin Y. Culprit only versus complete coronary revascularization during primary PCI. Int J Cardiol. 2008;123(3):288-92.

13. Kornowski R, Mehran R, Dangas G, Nikolsky E, Assali A, Claessen BE, et al; HORIZONS-AMI Trial Investigators. Prognostic impact of staged versus “one-time” multivessel percutaneous intervention in acute myocardial infarction: analysis from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol. 2011;58(7):704-11.

25. Varani E, Balducelli M, Aquilina M, Vecchi G, Hussien MN, Frassineti V, et al. Single or multivessel percutaneous coronary intervention in ST-elevation myocardial infarction patients. Catheter Cardiovasc Interv. 2008;72(7):927-33. 26. Jensen LO, Thayssen P, Farkas DK, Hougaard M, Terkelsen CJ, Tilsted HH, et al. Culprit only or multivessel percutaneous coronary interventions in patients with ST-segment elevation myocardial infarction multivessel disease. EuroIntervention. 2012;8(4):456-64.

14. Sousa AGMR, Costa Jr. JR, Abizaid A, Buitrón F, Constantini C, Marchant E, et al. Perfil demográfico e resultados imediatos dos pacientes submetidos à angioplastia primária no Registro SOLACI. Rev Bras Cardiol Invas. 2009;17(3):335-9. 15. Matte BS, Bergoli LCC, Balvedi JA, Zago AC. Perfil da intervenção coronária percutânea no infarto agudo do miocárdio com supradesnivelamento do segmento ST no Brasil de 2006 a 2010: Registro CENIC. Rev Bras Cardiol Invas. 2011;19(2):131-7.

27. Politi L, Sgura F, Rossi R, Monopoli D, Guerri E, Leuzzi C, et al. A randomised trial of target-vessel versus multi-vessel revascularisation in ST-elevation myocardial infarction: major adverse cardiac events during long-term follow-up. Heart. 2010;96(9):662-7.

16. Almeida RMS. Is the best option of treatment being offered to patients with multiple coronary artery diseases? Rev Bras Cir Cardiovasc. 2006;21(2):III-VI. 17. Andrade PJ, Medeiros MM, Andrade AT, Lima AA. Coronary angioplasty versus CABG: review of randomized trials. Arq Bras Cardiol. 2011;97(3):e60-9.

28. Navarese EP, De Servi S, Buffon A, Suryapranata H, De Luca G. Clinical impact of simultaneous complete revascularization vs. culprit only primary angioplasty in patients with ST-elevation myocardial infarction and multivessel disease: a meta-analysis. J Thromb Thrombolysis. 2011;31(2):217-25.

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29. Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC,

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Dallas AP; et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/ STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44-e164.

PTCA in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 1997;96(6):1761-9. 33. Writing Group for the Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Five-year clinical and functional outcome comparing bypass surgery and angioplasty in patients with multivessel coronary disease. A multicenter randomized trial. JAMA. 1997;277(9):715-21.

30. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med. 1996;335(4):217-25.

34. Kalarus Z, Lenarczyk R, Kowalczyk J, Kowalski O, Gasior M, Was T, et al. Importance of complete revascularization in patients with acute myocardial infarction treated with percutaneous coronary intervention. Am Heart J. 2007;153(2):304-12.

31. Berger PB, Velianou JL, Aslanidou Vlachos H, Feit F, Jacobs AK, Faxon DP, et al. Survival following coronary angioplasty versus coronary artery bypass surgery in anatomic subsets in which coronary artery bypass surgery improves survival compared with medical therapy. Results from the Bypass Angioplasty Revascularization Investigation (BARI). J Am Coll Cardiol. 2001;38(5):1440-9.

35. Lisboa LAF, Dallan LAO, Puig LB, Abreu Filho C, Leca RC, Dallan LAP, et al. Midterm follow-up with exclusive use of arterial grafts in complete myocardial revascularization of patients with triple vessel coronary artery disease. Rev Bras Cir Cardiovasc. 2004;19(1):9-16. 36. Meliga E, Fiorina C, Valgimigli M, Belli R, Gagnor A, Sheiban I, et al. Early angio-guided complete revascularization versus culprit vessel PCI followed by ischemia-guided staged PCI in STEMI patients with multivessel disease. J Interv Cardiol. 2011;24(6):535-41.

32. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and

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Isik O, et al. -ORIGINAL High postoperative serum levels of surfactant type B as novel ARTICLE prognostic markers for congenital heart surgery

High postoperative serum levels of surfactant type B as novel prognostic markers for congenital heart surgery Níveis séricos pós-operatórios tipo surfactante B elevados como novos marcadores prognósticos para cirurgia cardíaca congênita

Onur Isık1, MD; Olcay Murat Disli2; Tolga Bas2, MD; Hakan Aydın1, MD; Murat Koç1, MD; Ali Kutsal1

DOI: 10.5935/1678-9741.20140039

RBCCV 44205-1539

Abstract Objective: Congenital heart diseases are observed in 5 to 8 of every 1000 live births. The presence of a valuable biomarker during the surgical periods may aid the clinician in a more accurate prognosis during treatment. Methods: For this reason, surfactant protein B plasma levels may help to evaluate patients with cardiac problems diminishing the alveolocapillary membrane stability. In this study, plasma levels of this biomarker were measured in the preoperative and postoperative periods. This study was conducted to detect the differences between pulmonary hypertensive and normotensive patients. The differences before and after cardiopulmonary bypass were examined. Results: The differences in cardiopulmonary bypass time, cross-clamp time , inotropic support dose, and duration of intensive care of patients with and without pulmonary hypertensive were found to be statistically significant (P<0.05). The results revealed that this pathophysiological state was related to other variables that were studied. We believe that the differences in preoperative and postoperative SPB levels could be attributed to alveolocapillary membrane damage and alveolar surfactant dysfunction. We found that this pathophysiological condition was significantly associated with postoperative parameters. Conclusion: The findings of the current study showed that

surfactant protein B was present in the blood of patients with a congenital heart disease during the preoperative period. Long by-pass times may exert damage to the alveolocapillary membrane in patients with pulmonary hypertension and preoperative heart failure, and it is recommended to keep the option of surfactant therapy in mind during the postoperative course at the intensive care unit before preparing the patients for extubation.

Dr. Sami Ulus Maternity and Children’s Research and Education Hospital, Department of Cardiovascular Surgery, Ankara, Turkey. 2 Inonu University, Turgut Ozal Medical Center, Department of Cardiovascular Surgery, Malatya, Turkey.

Correspondence address: Onur Isık Dr. Sami Ulus Maternity and Children’s Research and Education Hospital Department of Cardiovascular Surgery Babur street no 14 - Altindag Ankara, Turkey E-mail: dr.onur.aras@gmail.com

Descriptors: Heart Surgery. Biological Markers. Pulmonary Surfactant-Associated Protein B. Heart Defects, Congenital. Resumo Objetivo: As cardiopatias congênitas são observadas em 5 a 8 em cada 1.000 nascidos vivos. A presença de um biomarcador importante durante os períodos cirúrgicos pode auxiliar o clínico a um prognóstico mais preciso durante o tratamento. Métodos: Por esta razão, os níveis plasmáticos de proteína B do surfactante podem ajudar a avaliar os pacientes com problemas cardíacos, diminuindo a estabilidade da membrana alvéolo-capilar. Neste estudo, os níveis plasmáticos deste biomarcador foram medidos nos períodos pré-operatório e pós-operatório. Este estudo foi realizado para detectar as dife-

1

This study was carried out at Dr. Sami Ulus Maternity and Children’s Research and Education Hospital, Ankara, Turkey; Department of Cardiovascular Surgery, Dr. Sami Ulus Maternity and Children’s Research and Education Hospital, Altindag Ankara, Turkey.

Article received on August 5th, 2013 Article accepted on November 28th, 2013

No financial support.

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nado a outras variáveis ​​que foram estudadas. Acreditamos que as diferenças nos níveis de SPB pré-operatório e pós-operatório pode ser atribuída a danos na membrana alvéolo-capilar e disfunção do surfactante alveolar. Descobrimos que esta condição fisiopatológica foi significativamente associada com parâmetros pós-operatórios. Conclusão: Os resultados do estudo mostraram que a proteína B surfactante estava presente no sangue de pacientes com doença cardíaca congênita no pré-operatório. Longos tempos de circulação extracorpórea podem exercer danos na membrana alvéolo-capilar em pacientes com hipertensão pulmonar e insuficiência cardíaca pré-operatória, e recomenda-se manter a opção de terapia com surfactante em mente durante o período pós-operatório na unidade de terapia intensiva antes de preparar os pacientes para a extubação.

Abbreviations, Acronyms & Symbols CPB DMV PH SPA SPB SPC SPD XCT

cardiopulmonary bypass duration of mechanical ventilation pulmonary hypertension Surfactant protein A surfactant protein B surfactant protein C surfactant protein D cross-clamp time

renças entre pacientes hipertensos e normotensos em nível pulmonar. As diferenças antes e depois da circulação extracorpórea foram examinadas. Resultados: As diferenças no tempo de circulação extracorpórea, tempo de pinçamento, a dose de drogas vasoativas, e a duração da terapia intensiva de pacientes com e sem hipertensão pulmonar foram estatisticamente significativas (P<0,05). Os resultados revelaram que este estado fisiopatológico foi relacio-

Descritores: Cirurgia Torácica. Marcadores Biológicos. Proteína B Associada a Surfactante Pulmonar. Cardiopatias Congênitas.

INTRODUCTION

icine (Date: 16/10/2012, Number: 70), and written informed consent was obtained from the patients’ families. Thirty patients who were admitted to our clinic for open heart surgery due to congenital heart disease, who were diagnosed using catheter angiography in 2011, and who had undergone surgery by the same surgeon were included in the study. The detailed description of the patients’ congenital heart diseases and the performed surgeries are presented in Table 1.

Cardiac surgery has been a rapidly developing scientific area that has experienced many innovations in the second half of the last century. The rapid advances in surgery have created a need for markers to guide intensive care follow-up[1]. The discovery of a biomarker that will guide the postoperative intensive care follow-up, aid in anticipating complications, shape treatment, and facilitate decision-making for the duration of intensive care follow-up has great benefits. Furthermore, the biomarker’s ability to provide results in a short time and reliability is beneficial, as well. Surfactant protein B (SPB) can be used for the aforementioned purposes; since it is not present in the peripheral blood of healthy individuals, but rather enters into the peripheral bloodstream as a result of a pressure imbalance in the pulmonary alveolocapillary membrane due to heart failure[1]. SPB is used as a biological marker to determine the degree of pulmonary dysfunction in adult patients with heart failure and the detection of the response to medical treatment. However, the research on the use of SPB in congenital cardiac surgery has not been sufficient yet[2]. This study examined the levels of SPB protein in the peripheral blood of patients with congenital heart disease undergoing open heart surgery, in the preoperative and postoperative periods. The study further investigated their relationships with mortality and morbidity by comparing these values with routine variables obtained in intensive care follow-ups.

Table 1. Patient diagnose and performed surgery. Diagnose Procedure n (%) Sec ASD Primary Closure 5 (16) P. VSD Patch Closure 8 (27) PAPVC Interatrial baffle reconstruction 2 (7) Aortic Rg. Mechanical AVR 2 (7) AVSD Australian Technique 2 (7) TOF Total Correction (transannular patch) 2 (7) TGA Arterial Switch 5 (16) T. Arteriozus Total Correction (12 mm valved tube graft) 3 (10) ALCAPA Detachment reatachment 1 (3) ASD: Secundum type atrial septal defect, P. VSD: Perimembranous type ventricular septal defect, PAPVC: Partial abnormal pulmonary venous connection, AVSD: Atrio ventricular septal defect, TOF: Tetralogy of fallot, T. Arteriozus: Truncus arteriozus, ALCAPA: Abnormal left coronary artery from pulmonary artery)

All patients with congenital heart disease were examined in two groups; patients with (group 1, n1=13) or without (group 2, n2=17) pulmonary hypertension. Pulmonary hypertension was defined as systolic pulmonary artery pressure higher than 50% of the systolic systemic pressure[3]. Patients were also assessed regarding inotropic medication they received, total cardiopulmonary bypass (CPB)

METHODS Ethics approval was obtained from Clinical Research Ethics Review Board of Ankara University Faculty of Med-

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and aortic cross-clamp time (XCT), duration of mechanical ventilation and pressure support ventilation, liver and kidney functions in the postoperative period, intensive care time, and discharge time. All patients underwent median sternotomy and aorto-bicaval cannulation. During CPB, hypothermia (up to 28-32°C) was used with respect to the patient’s cardiac pathology. Diastolic cardiac arrest was achieved using topical cold and antegrade hypothermic crystalloid cardioplegia. After induction of anesthesia, blood samples were taken from all patients to investigate the BNP and the surfactant protein B. Then, the samples were centrifuged at 1000 rpm at room temperature (22°C) for 15 minutes. Separated plasma was placed in a polypropylene tube and stored at -20°C. Tests for hemodynamic data, arterial blood gas samples, and samples for BNP and surfactant protein B values were repeated in the first hour after the surgery. In addition, patients’ inotropic treatment needs after surgery, CPB time, cross-clamp (XCT), duration of mechanical ventilation (DMV), and pressure support in providing the appropriate tidal volume were recorded. The collected plasma samples were studied using a Human Pulmonary Surfactant Associated Protein B ELISA kit (Cusabio Biotech Co. Ltd. Wuhan, PR China).

of 0.50 with an estimated standard deviation of differences of 0.40 and with a significance level (alpha) of 0.05 using a twotailed paired t-test. The quantitative variables were represented as median (min-max). Kolmogorov Smirnov test was used as a goodness of fit test to assess the normality of the sample distribution. Mann-Whitney U-test and Wilcoxon test, where appropriate, were used for the comparison of all quantitative variables. Spearman’s rho correlation coefficient was used in the correlation analyses. P values <0.05 were considered as statistically significant. SPSS for Windows 21.0 statistical software was used for data analysis. RESULTS Patients were divided into two groups according to pulmonary artery pressure, measured with catheter angiography in the preoperative examination. 13 patients were included in the group of patients with pulmonary hypertension (PH), whereas 17 patients were included in the group of patients without PH. Table 2 presents the comparison of patients with and without PH in terms of CPB time, XCT time, duration of mechanical ventilation, duration of intensive care, and discharge time of patients. The differences in CPB time, XCT, inotropic support dose, and duration of intensive care of patients with and without PH were found to be statistically significant (P<0.05), whilst duration of mechanical ventilation, pressure support ventilation and discharge time were not statistically significant (P>0.05). Table 3 demonstrates SPB serum levels before and after surgery. In patients with and without PH, the differences between the SPB blood values in the preoperative and postoperative periods were observed to be statistically significant (P<0.05). The levels of pre-SPB and post-SPB between the groups were not found to be significant (P>0.05). Table 4 defines the BNP levels before and after surgery. The increases in BNP values, which were simultaneously studied with SPB, were found to be significant (P<0.05). Whereas the levels of pre-BNP and post-BNP between the groups were not statistically significant (P>0.05). When two groups were formed of patients who died in the postoperative period and who were discharged, the increases of percentage in SPB levels of these patients were observed to be statistically significant (P<0.05).

Measurement of Surfactant Protein B Microtiter surfaces that were pre-coated with a specific antibody against surfactant protein B were used in this kit. Then, the samples were properly placed on a micro-surface together with avidin-conjugated horseradish peroxidase, which was prepared with antibodies specific to biotin-conjugated SPB, and were later incubated. Next, a tetramethylbenzidine substrate solution was added to each sample. Color change was observed only in the samples containing SPB, i.e. samples containing biotin-conjugated antibodies and enzyme-conjugated avidin. For the samples terminating with the enzyme substrate reaction, the samples were spectrophotometrically measured at a wavelength of 450 nm after the addition of sulfuric acid solution. The SPB concentration in the samples was calculated by a comparison of the standard slope of normal values. Statistical Analysis Based on post-hoc power analysis, a sample size of 13 achieved 99% power to detect a mean of paired differences

Table 2. Descriptive statistics of patients with and without PH. Variable CPB Time, min XCC Time, min Duration of mechanical ventilation, min Duration of intensive care, min Discharge time, min

Without PH (n1=17) Median (Min - Max) 106 (53 - 486) 60 (34 - 97) 5 (1-16) 1 (1-2) 11 (7-370)

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With PH, (n2=13) Median (Min - Max) 68 (20 - 190) 41 (10 - 110) 7 (3-384) 1 (1-17) 7 (6-14)

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P value 0.025 0.016 0.11 0.043 0.12

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Table 3. SPB serum levels before and after surgery. Variable Pre-SPB serum levels Post-SPB serum levels P value

Without PH (n1=17) Median (Min - Max) 2.95 (2.42 – 4.31) 3.48 (2.96 – 5.35) <0.001

With PH, (n2=13) Median (Min - Max) 3.18 (2.46 - 3.74) 3.51 (3.00 – 4.23) 0.002

P value 0.29 0.80

Table 4. BNP levels before and after surgery. Variable Pre-BNP levels Post-BNP levels P value

Without PH (n1=17) Median (Min - Max) 129 (44-18208) 161 (68-35000) <0.001

Significant increases were found in SPB levels of the patient group requiring prolonged mechanical ventilation and pressure support ventilation in the preoperative and postoperative periods (P<0.05). Positive correlations were found between CPB time and XCT time (Spearman’s rho=0.92, P<0.001) and hospital stay duration (Spearman’s rho=0.53, P=0.02). Positive correlations were detected between mechanical ventilation time and hospital stay duration (Spearman’s rho=0.63, P=0.005) and discharge time (Spearman’s rho=0.49, P=0.04). Similarly, discharge time was positively correlated with duration of intensive care (Spearman’s rho=0.70, P=0.001) and discharge time (Spearman’s rho=0.49, P=0.04).

With PH, (n2=13) Median (Min - Max) 170 (32-1250) 900 (54-18000) 0.001

P value 0.39 0.32

tory and circulatory physiopathology by passing through the alveolocapillary membrane due to its molecular size. The halflife of this protein in the blood is short about 3 to 12 minutes. Although SPB is not the smallest of the surfactant proteins in the alveoli, it is the smallest surfactant that can be measured in the bloodstream. At the same time, alveolar concentration of SPB also changes after these transformations[8,9]. Because of these characteristics, SPB has become the subject of research in acute and chronic lung injuries, heart failures, and congenital lung diseases. Dyspnea is a major finding resulting from pulmonary edema that occurs with congestive heart failure. Based on this fact, De Pasquale et al.[8] used SPB blood levels as a biomarker of lung function and status in follow-ups of patients with heart failure. Since SPB blood levels have a tendency to increase in all pulmonary diseases, this marker was used only in the follow-up of lung status in patients with congestive heart failure and damaged alveolocapillary membranes. They explained that during patient follow-ups, SPB levels were increased in decompensation periods of heart failure, and that compensation had a low course of progression with medical treatment. The researchers described SPB as a useful biomarker for anticipation of the future progression of the patients with congestive heart failure in the clinical follow-ups. West et al.[10] showed the structural fragility of the alveolocapillary barrier under high pulmonary pressure and designated this situation as ’stress failure’. Pascual-Figal et al.[11] compared the SPB blood levels of patients with heart failure to SPB blood levels of normal, healthy people and found that blood levels of this protein were significantly higher in patients with heart failure. De Pasquale et al.[12] categorized the patients in their research according to the NYHA functional classification and 6-minute walk test, and they found the differences in SPB levels in blood samples of these patients to be in accordance with the functional groups. Magri et al.[13] monitored patients with congestive heart failure and explained that SPB values

DISCUSSION Lung epithelial cells provide a large surface area allowing for gas exchange between capillary vessels. The greatest problem of such a large and hydrated area is the collapse of the alveolar surfaces in the expiratory phase of respiration. This problem is solved by a lipid-rich surface generated by pulmonary surfactant protein on the epithelial cells, separating alveolar gas and liquids. Pulmonary surfactant phospholipids decrease the surface tension to negligible levels by forming mono- and multi-layers[4]. There are four types of surfactant protein in the alveoli, namely: Surfactant protein B (SPA), Surfactant derived protein B (SPB), surfactant protein C (SPC) and surfactant protein C (SPD). Although the chemical structures of these proteins are different, their tasks within the alveoli overlap each other. The functions of these proteins are to prevent alveolar collapse at the end of expiration, to create a large surface area for gas exchange, and to perform immunoregulation against external aggressors[5-7]. Among these proteins, SPB is different in terms of its entrance into the blood after the pressure changes in the respira-

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were increased in the peripheral blood samples of patients with heart failure, and also that these values were directly related to the damage of gas diffusion in the lungs. Researchers also reported that SPB blood levels correlated with the degree of heart failure. The results of this study were similar. SPB levels were higher in the pulmonary hypertension group and this subgroup’s clinical condition was worse than the group without pulmonary hypertension. Pulmonary dysfunction after cardiac surgery is a significant morbidity despite advancing heart-lung pump technology and developing intensive care conditions. This dysfunction includes a wide range of consequences from severe ARDS tables to more moderate extubation delays or mild respiratory failures. Anesthesia, cardiopulmonary bypass, and surgical trauma are included together in the etiology of this dysfunction[14,15]. Tennenberg et al.[16] in their study aimed at enlightening how lung physiology changed after CPB, asserted that lung function was impaired. They related the impairment of lung function with the decrease in lung volume, the decrease in carbon monoxide transfer, and the increase in alveolar-arterial oxygen pressure gradient. They suggested that these changes were not caused by the increase in pulmonary endothelial permeability. Cox et al.[17] investigated the cause of postoperative pulmonary dysfunction occurring after CPB and considered that cardiopulmonary bypass triggered the dysfunction through leukocyte and complement activation. They indicated that this system could result in the deterioration of gas exchange in the postoperative period, increased alveolar-arterial oxygen gradient, and decreased pulmonary compliance; these factors were reflected as atelectasis and as an increase in respiratory workload depending on the clinical status of the patient. Although the researchers explained the mechanism of action as such, they did not report any differences between the control group and patients without any pulmonary disease in the preoperative period and with good myocardial performance in terms of lung dysfunction[15,16]. Following total correction of the primary congenital heart disease, the patients without pulmonary hypertension made a good recovery and had an uneventful postoperative course. We believe that the literature findings which were discussed in the preceding paragraph are the underlying reasons for this good outcome. On the other hand, patients in the pulmonary hypertension group had various respiratory system complications, as well as longer discharge times. Griese et al.[18] argued that CPB caused acute lung injury in various degrees and asserted that complex congenital heart patients under the age of one year were the most risky candidates of this group. They explained the mechanism of this injury as the mediators released from activated platelets following the contact of blood with non-physiological surfaces, the activation of the complement system, the activation of the kallikrein-kinin system, and the development of interstitial edema in the pulmonary capillary

endothelium following the sequestration of activated PMN (polymorphonuclear) cells into pulmonary alveoli. They suggested that this edema directly impaired the intra-alveolar surfactant metabolism. In order to demonstrate this, the researchers took alveolar lavage samples from infants with complex congenital heart disease with long CPB times and with poor general conditions in the postoperative period; they assessed the samples in terms of surfactant activity and found functional disorders afterwards[18]. Preoperative SPB blood levels of all patients included in the study were high due to alveolocapillary membrane damage that was caused by the hypoxia or the left to right shunt of various degrees, which developed as secondary to the congenital heart anomaly. SPB values, measured in all patients within the preoperative and postoperative periods, had a tendency to increase due to alveolocapillary membrane damage, resulting both from the immunological and acute pressure changes, which took place during and after CPB. The fact that there was an increase in SPB in the blood, which was higher in patients with pulmonary hypertension before and after surgery, suggested that high pulmonary blood pressure damaged alveolocapillary membrane more severely in this patient group and these patients suffered greater pulmonary damage from CPB. Higher pressure required to obtain normal tidal volume in mechanical ventilation in patients with higher SPB levels in the postoperative period suggested that this was accordant with the fact that these patients were more complex cardiac patients, they required longer CPB times, consequently suffering from greater alveolar surfactant dysfunction, and had more severe alveolocapillary membrane damage. Study Limitations The current study had certain limitations, including small sample size, variability in age and primary pathologies in the subgroups; however, the groups were divided according to the pulmonary artery pressures. CONCLUSION SPB is a protein that is normally undetectable in peripheral circulation, but it enters into the bloodstream when the structure of the alveolocapillary membrane is disrupted for any reason. In the current study, SPB was present in the blood in patients with congenital heart disease (pulmonary hypertension, heart failure, hypoxic pathophysiology) in the preoperative period. We believe that the significant differences in preoperative and postoperative surfactant type B levels could be attributed to alveolocapillary membrane damage and alveolar surfactant dysfunction. We found that this pathophysiological condition was significantly associated with several postoperative parameters; however, there was no positive correlation between the given parameters.

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Long by-pass times may exert damage to the alveolocapillary membrane in patients with pulmonary hypertension and preoperative heart failure, and it is recommended to keep the option of surfactant therapy in mind during the postoperative course at the intensive care unit before preparing the patients for extubation. The findings of the current study should be reproduced and validated on a larger sample population to be able to use SPB as an indicator of mortality and morbidity in the intensive care follow-ups of patients who underwent open heart surgery due to congenital heart disease. Overall, this study showed that surfactant protein B plasma levels may provide useful as a prognostic marker for all phases of pediatric cardiac surgeries.

Respiratory Distress Syndrome: Clinical Implications. Med Gen Med. 1999;1(3) [Accessed 2014 May 29]. Available at: http:// www.medscape.com/viewarticle/408742 7. Parra E, Alcaraz A, Cruz A, Aguilella VM, Pérez-Gil J. Hydrophobic pulmonary surfactant proteins SP-B and SP-C induce pore formation in planar lipid membranes: evidence for proteolipid pores. Biophys J. 2013;104(1):146-55. 8. De Pasquale CG, Arnolda LF, Doyle IR, Aylward PE, Chew DP, Bersten AD. Plasma surfactant protein-B: A novel biomarker in chronic heart failure. Circulation. 2004;110(9):1091-6. 9. Guyton AC, Hall JE, editors. Textbook of Medical Physiology. Michigan: Elsevier Saunders; 2005. 10. West JB, Tsukimoto K, Mathieu-Costello O, Prediletto R. Stress failure in pulmonary capillaries. J Appl Physiol (1985). 1991;70(4):1731-42. 11. Pascual-Figal DA, Sánchez-Más J, de la Morena G, Casas T, Garrido IP, Ruipérez JA, et al. Pulmonary surfactant protein B in the peripheral circulation and functional impairment in patients with chronic heart failure. Rev Esp Cardiol. 2009;62(2):136-42.

Authors’ roles & responsibilities OI OMD TB HA MK AK

Primary responsibility for protocol development, outcome assessment, preliminary data analysis and writing the manuscript Participated in the development of the protocol and preliminary data analysis and writing the manuscript Participated in the outcome assessment Participated in the development of the protocol Participated in the writing the manuscript Participated in the development of the protocol

12. De Pasquale CG, Bersten AD, Doyle IR, Aylward PE, Arnolda LF. Infarct-induced chronic heart failure increases bidirectional protein movement across the alveolocapillary barrier. Am J Physiol Heart Circ Physiol. 2003;284(6):H2136-45. 13. Magrì D, Brioschi M, Banfi C, Schmid JP, Palermo P, Contini M, et al. Circulating plasma surfactant protein type B as biological marker of alveolar-capillary barrier damage in chronic heart failure. Circ Heart Fail. 2009;2(3):175-80.

1. Whitsett JA, Weaver TE. Hydrophobic surfactant proteins in lung function and disease. N Engl J Med. 2002;347(26):2141-8.

14. Bersten AD, Hunt T, Nicholas TE, Doyle IR. Elevated plasma surfactant protein-B predicts development of acute respiratory distress syndrome in patients with acute respiratory failure. Am J Respir Crit Care Med. 2001;164(4):648-52.

2. Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005;5(1):58-68.

15. Matthay MA, Wiener-Kronish JP. Respiratory management after cardiac surgery. Chest 1989;95(2):424-34.

3. Banjar HH. Review of management guidelines of pulmonary arterial hypertension in the pediatric population. PVRI Rev. 2010;2(3):100-13.

16. Tennenberg SD, Clardy CW, Bailey WW, Solomkin JS. Complement activation and lung permeability during cardiopulmonary bypass. Ann Thorac Surg. 1990;50(4):597-601.

4. Ryan MA, Akinbi HT, Serrano AG, Perez-Gil J, Wu H, McCormack FX, et al. Antimicrobial activity of native and synthetic surfactant protein B peptides. J Immunol. 2006;176(1):416-25.

17. Cox CM, Ascione R, Cohen AM, Davies IM, Ryder IG, Angelini GD. Effect of cardiopulmonary bypass on pulmonary gas exchange: a prospective randomized study. Ann Thorac Surg. 2000;69(1):140-5.

REFERENCES

5. Hawgood S. Surfactant protein B: Structure and function. Biol Neonate. 2004;85(4):285-9.

18. Griese M, Wilnhammer C, Jansen S, Rinker C. Cardiopulmonary bypass reduces pulmonary surfactant activity in infants. Thorac Cardiovasc Surg. 1999;118(2):237-44.

6. Floros J, Lin Z. Genetic Variability of Surfactant Protein-B and

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Deininger MO, et al. - Comparative analysis of the patency of the internal ORIGINAL ARTICLE thoracic artery in the CABG of left anterior descending artery: 6-month postoperative coronary CT angiography evaluation

Comparative analysis of the patency of the internal thoracic artery in the CABG of left anterior descending artery: 6-month postoperative coronary CT angiography evaluation Análise comparativa da perviedade das artérias torácicas internas na revascularização da região anterior do coração. Avaliação por angiotomografia no 6º mês de pós-operatório

Maurilio Onofre Deininger1, PhD; Luiz Felipe Pinho Moreira2, MD, PhD; Luiz Alberto Oliveira Dallan2, MD, PhD; Orlando Gomes de Oliveira1; Daniel Marcelo Silva Magalhães1; José Reinaldo de Moura Coelho1; Eugênia di Giuseppe Deininger1; Norland de Souza Lopes1; Ricardo Wanderley Queiroga1; Elizabeth Ferreira Belmont1

DOI: 10.5935/1678-9741.20140032

RBCCV 44205-1540

Abstract Objective: To assess the patency of the pedicled right internal thoracic artery with an anteroaortic course and compare it to the patency of the left internal thoracic artery , in anastomosis to the left anterior descending artery in coronary artery bypass grafting by using coronary CT angiography at 6 months postoperatively. Methods: Between December 2008 and December 2011, 100 patients were selected to undergo a prospective coronary artery bypass grafting procedure without cardiopulmonary bypass. The patients were randomly divided by a computer-generated list into Group-1 (G-1) and Group-2 (G-2), comprising 50 patients each, the technique used was known at the beginning of the surgery. In G-1, coronary artery bypass grafting was performed using the left internal thoracic artery for the left anterior descending and the free right internal thoracic artery for the circumflex, and in G-2, coronary artery bypass grafting was performed using the right internal thoracic artery pedicled to the left anterior descending and the left internal thoracic artery pedicled to the circumflex territory.

Results: The groups were similar with regard to the preoperative clinical data. A male predominance of 75.6% and 88% was observed in G-1 and G-2, respectively. Five patients migrated from G-1 to G-2 because of atheromatous disease in the ascending aorta. The average number of distal anastomoses was 3.48 (SD=0.72) in G-1 and 3.20 (SD=0.76) in G-2. Coronary CT angiography in 96 re-evaluated patients showed that all ITAs, right or left, used in situ for the left anterior descending were patent. There were no deaths in either group. Conclusion: Coronary artery bypass grafting surgery involving anastomosis of the anteroaortic right internal thoracic artery to the left anterior descending artery has an outcome similar to that obtained using the left internal thoracic artery for the same coronary site.

1

Hospital Unimed João Pessoa /Hospital Memorial São Francisco, João Pessoa, PB, Brazil. 2 nstituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.

This study was carried out at Hospital Unimed João Pessoa, João Pessoa, PB, Brasil; Hospital Memorial São Francisco, João Pessoa, PB, Brazil; Hospital Universitário Lauro Wanderley da Universidade Federal da Paraíba (UFPB), João Pessoa, PB, Brazil.

Correspondence address: Maurílio Onofre Deininger Rua Giacomo Porto 145/3001, Miramar - João Pessoa, PB – Brazil - Zip code: 58022-110 E-mail: maurilio.od@gmail.com

No financial support.

Descriptors: Mammary Arteries. Myocardial Revascularization. Cardiopulmonary Bypass. Coronary Artery Disease.

Article received on May 15th, 2013 Article accepted on November 17th, 2013

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a artéria torácica interna direita livre para ramos da circunflexa. Os pacientes do G-2 receberam artéria torácica interna direita pediculada para o ramo interventricular anterior e complementação da revascularização do miocárdio com artéria torácica interna esquerda, pediculada, para ramos da circunflexa. Resultados: Os grupos eram semelhantes quanto aos dados clínicos de pré-operatório. Houve predominância do sexo masculino, 75,6% e 88% nos grupos 1 e 2 respectivamente. Cinco pacientes migraram do G-1 para o G-2 devido à doença ateromatosa na aorta ascendente. A média de anastomoses distais no G-1 foi de 3,48 (DP=0,72), e no G-2 foi de 3,20 (DP=0,76). Os resultados das angiotomografias coronarianas em 96 pacientes reestudados mostraram que todas as artérias torácicas internas, direita ou esquerda, utilizadas pediculadas para a região anterior do coração encontravam-se pérvias. Não houve óbitos em nenhum dos grupos. Conclusão: A cirurgia de revascularização do miocárdio com utilização da artéria torácica interna direita pediculada, anterógrada para o ramo interventricular anterior, apresenta resultado semelhante ao da artéria torácica interna esquerda utilizada para essa mesma coronária.

Abbreviations, acronyms & symbols RITA AIB CABG LITA CPB CX CAD ITA

Right internal thoracic artery Anterior interventricular branch Coronary artery bypass grafting Left internal thoracic artery Cardiopulmonary bypass Circumflex Coronary artery disease Internal thoracic arteries

Resumo Objetivo: Analisar a perviedade da artéria torácica interna direita pediculada, anteroaórtica em anastomose para o ramo interventricular anterior na revascularização do miocárdio, em relação à artéria torácica interna esquerda, com o uso de angiotomografia coronária, no 6° mês de pós-operatório. Métodos: No período de dezembro de 2008 a dezembro de 2011, 100 pacientes foram selecionados, prospectivamente, para cirurgia de revascularização do miocárdio sem circulação extracorpórea. Foram agrupados em Grupo-1 (G-1) e Grupo-2 (G-2), com 50 pacientes cada, randomização por computador e conhecimento da técnica no início da cirurgia. No G-1, os pacientes receberam artéria torácica interna esquerda para o ramo interventricular anterior e complementação da revascularização do miocárdio com

Descritores: Artéria Torácica Interna. Revascularização Miocárdica. Circulação Extracorpórea. Doença da Artéria Coronariana

use of both internal thoracic arteries (ITAs) in relation to the use of only one, in particular the use of the left internal thoracic artery (LITA) to the anterior interventricular branch (AIB), considered the gold standard in CABG because of the excellent long-term patency. However, the right internal thoracic artery (RITA) shows results very similar to those obtained by the LITA when used for the AIB, depending on the strategy for using it. Some authors observed that RITA performs better as a second arterial graft compared to the radial artery, especially in relation to the occurrence of cardiac events such as perioperative myocardial infarction (MI) due to vasospasm that can occur in up to 10% of patients [2]. The RITA when used for the right coronary artery (RCA) and its branches, showed no results similar to those obtained when used for the left coronary (LC) system, with patency similar to the saphenous vein. Thus, RITA became used for LC as compound graft with the LITA, as a free graft, retroaortic for branches of the circumflex (CX)[3], sometimes antegrade for AIB[4,5].

INTRODUCTION The treatment of coronary artery disease (CAD) is one of the most investigated issues in the medical field worldwide and the surgery for coronary artery bypass grafting (CABG) remains an excellent therapeutic option for the treatment of obstructive CAD, especially in cases where there the choice of drug or percutaneous treatment. The saphenous vein is still widely used for aortic/coronary graft, due to its ease of collection, preparation and be used for making multiple grafts. However, this graft may develop intimal hyperplasia and atherosclerotic lesion, showing occlusion rates of 10% to 15% in the first year after surgery; yet, after ten years only 60% of vein grafts are patent and of these only 50% are free of significant stenosis. In addition, complications may occur in the lower limb which its collection [1] was performed. The internal thoracic artery (ITA) rarely develops atherosclerosis, and its diameter is usually compatible with coronary artery to be revascularized. Currently, several studies show the superiority of the

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There is still a fear for the use of both ITAs in some subgroups of patients, such as elderly, obese and diabetic patients. However, some authors have observed that the skeletonization of ITAs and CABG surgery when performed without CPB cause a reduction in the incidence of sternal infection, and this benefit is more evident in diabetic patients, where there may be a 60% reduction in the occurrence of this complication, allowing removal of both ITAs, without offering additional risk for infectious complications of the sternum[6,7]. Others noted that the use of pedicled ITA and use of CPB are independent risk factors for mediastinitis in surgery for CABG[8]. Various arterial conduits are used aiming to reduce the likelihood of future reoperations, especially both ITAs, or an ITA combined with another compound graft, with “Y” anastomosis[9]. However, in this technique all the blood flow to the grafted coronary ends up being from only one source of supply, usually the LITA. A reduction in its flow, due to spasm, can result in drastic consequences such as global ischemia of the left coronary territory. The hypothesis of our research is that if we use the antegrade RITA, in single or sequential graft, for the AIB territory, we could use the LITA to the territory of CX. Taking into account the excellent long-term results with the use of both ITAs and the fact that in this way, the entire left coronary system was revascularized with arterial grafts only, or that is, RITA and LITA, all in situ, allowing two sources of blood supply. This could decrease the chance of a patient requiring reoperation for myocardial revascularization. But for this surgery becomes routine therapeutic option, it is necessary that the RITA to the anterior region of the heart shows as good results as the LITA when used in this same manner. The primary aim of this study was to assess the patency of the pedicled RITA used, in the anteroaortic position in anastomosis to the anterior region of the heart in CABG compared with LITA used for that region of the heart. The secondary aim was to assess the occurrence of death or cardiac events such as myocardial infarction (MI), recurrent angina or need for reintervention (reoperation for CABG or coronary angioplasty), as well as assessing the patency of the other grafts. We assessed the immediate surgical results and in a period of 6 months postoperatively.

with the approval of these committees and under the supervision of the Surgical Unit of Surgery Division of Coronary Heart Institute at Clinics Hospital of the Faculty of Medicine, Universidade de São Paulo. The surgeries were performed from December 2008 to December 2011. For purposes of randomization, it was necessary for patients or guardians agree and sign the written informed consent (IC), after being informed of it by a member of staff. This research was designed presented as an assessment of 100 patients who underwent cardiac surgery for OPCAB, prospectively, randomly by computer taken before the beginning of the study and knowledge of the surgeon regarding the selected group only at the beginning of surgery, or that is, which graft would be placed in the AIB territory (RITA or LITA), patients did not know which technique would be used. The number of patients was calculated according to the probability of a difference of 15% occlusion higher than the standard, LITA to the RIA, for a value of error probability of 0.05 and a power of 80% sample with P of 0.05%. There was no conflict of interest of none of the researchers involved in this research project. Patients were selected from coronary angiographies, which were evaluated by at least two surgeons and the surgical team and they should reveal coronary artery disease in at least two vessels of the territory of the left coronary artery with significant stenosis (> 70%), presenting angina stable or unstable, urgent or emergency surgery, and left ventricular ejection fraction (LV-EF) of > 30%. Patients with coronary artery bypass grafting combined with another procedure, cardiogenic shock circulatory assistance, use of intra-aortic balloon pump, LV-EF < 30% and reoperations were excluded. Obese or diabetic patients were not excluded, or even it has not been established age limit. Once filled these criteria, the patient would be selected and invited to participate. In order to provide similarity to the groups, we draw two strategies of using the RITA and grouped the patients in Group-1 (G-1) and Group-2 (G-2), both with 50 randomized patients. Being comparatively studied the patency of the right and left internal thoracic arteries, they were dissected using skeletonization and used in situ for the AIB territory. In G-1, the LITA was used in situ with anastomosis in the AIB territory, and complementing revascularization with the free RITA to the territory of CX, used in sequential anastomoses when needed, and another graft to the RC territory. In G-2, the RITA was used in situ, anterograde with anastomosis in the AIB territory and complementing revascularization with LITA, also in situ for the territory of CX, used in sequential anastomoses when needed, and another graft to the RC territory. Clinical characteristics were cataloged during the preoperative period to assess the similarity between groups. The occurrence of perioperative MI was assessed considering ST segment elevation greater than 1 mm in the limb leads or 2

METHODS This study was performed upon presentation of its research protocol for the Research Ethics Committee of the Lauro Wanderley University Hospital of the Universidade Federal da Paraíba and Ethics Committee for Analysis of Research Projects (CAPPesq) of the Clinical Board of the Clinics Hospital and the Faculty of Medicine of the Universidade de São Paulo, under the research protocol number 0844/08, CAPPesq, December 17, 2008. This project was performed

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mm in precordial leads in at least two contiguous leads, or some area of ​​necrosis that did not exist in the preoperative ECG. We also analyzed elevation of creatine kinase (CKMB) above 100 IU/l in the first two days of postoperative troponin I level or above 2.5 ng/ mL within 48 hours after surgery, as quoted by Leal[10]. To assess the patency of coronary grafts we used multislice CT angiography studies with 64 channels in patients in both groups at six months after surgery. We used a Philips CT scanner (Brilliance CT). With schemes of 120 kV and irradiation 800-1000 mA, 0.67 mm cuts were performed, using wherever possible the 75% stage. The period of apnea to capture images was around 15 seconds. In patients with heart rate (HR) above 65 beats per minute (bpm) a beta-blocker (metoprolol) at a dose of 2.5 mg to 15mg (titrating to achieve HR less than 65 bpm) was used. As the patients had already undergone coronary artery bypass grafting, calcium score was not performed. We performed a median sternotomy. Special attention was paid to pericardiotomy, once we opened it up along with the plane of the top of the ascending aorta and, thereafter, we

proceeded to “U” opening. Thus, we leave a pericardial patch so that covering the RITA and avoiding that the latter be attached to the sternum. Figure 1 shows details of the opening of the pericardium. Initially we performed an anastomosis in the AIB territory, then we performed an anastomosis in the RC territory. This strategy allows more securely the medial traction of the heart to expose the side wall, since it is higher, and sometimes can lead to hemodynamic instability. For better exposure of the coronary arteries, we used the Lima’s point[11], suction stabilizer and intracoronary shunt to allow for more comfort during anastomosis. When the RITA was used for the anterior region of the heart, it was positioned across the mediastinum anteriorly. Initially a tunnel with blunt dissection was performed through the pericardial and pleural fat, anterior to the right phrenic nerve at the most cranial portion of the aorta. Thus, the RITA is covered with mediastinal fat and pericardial patch, previously isolated, making a tunnel on the aorta, allowing the RITA stay in the free space between the aorta and the sternum, eliminating the possibility of the first attaches the latter (Figure 2).

A

B

C D Fig. 1 - (A, B, C and B) Drawing showing details of the opening of the pericardium and tunneling through the mediastinal fat to protect the RITA

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A

B

C D Fig. 2 - (A, B, C and D) Surgical picture showing details of the pericardial patch, tunneling through the mediastinal fat and final vision with the right internal thoracic artery completely protected

It was assessed as the primary endpoint the graft patency of ITAs used to graft the RIA and as a secondary endpoint, the occurrence of death or cardiac events such as MI, recurrent angina and need for reoperation. The observation period lasted until the time of angiography, or that is, until the period of six months postoperatively. For statistical analysis, Chi-square and Fisher’s exact test were used to compare proportions and Student’s t test for numeric values ​​with results expressed as mean and standard deviation. The software used was GraphPad Prism 5.2. RESULTS

mal anastomosis site and, because of this, we avoid handling. However, in one of these patients the RITA has not reached the place at AIB where the anastomosis would be performed due to the atheromatous disease of this coronary, which required its anastomosis in distal portion. So, we chose to perform anastomosis of the LITA for AIB and RITA in “Y” anastomosis into the left marginal (LM); thus, this patient was excluded since he no longer belongs to both groups. Thus, the G-2 now has 54 patients. Clinical characteristics of preoperative parameters were similar in both groups. The data are shown in Table 1. We found patients with obesity grade I to III, and it is not revealed an isolated risk factor for sternal infection. Not mediastinitis occurred in any patient of the two groups. One patient in the G-1 had osteomyelitis without progress to mediastinitis, whose symptoms appeared on day 42 postoperatively and required surgical intervention, with a good outcome after the procedure. No patient had perioperative MI. One patient in the G-1 had angina in the 5th month after surgery, he performed coro-

186 patients eligible for randomization were allocated. However, 86 were excluded due to reasons such as not patient acceptance and inability to continue the study. Therefore, these 100 patients were selected for randomization and grouped into G-1 and G-2, each with 50 patients. In the G-1 there was migration of five patients to G-2, because the aorta showed atheromatous disease at the proxi-

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Table 1. Variables analyzed in the preoperative period. Preoperative variable Gender: Male Female Age Stable angina Unstable angina CHF (NYHA) - I / II CHF (NYHA) - III / IV Previous MI > 30 days Previous MI < 30 days Smoking Diabetes Dyslipidemia Obesity (BMI > 30) Arterial Hypertension Previous angioplasty LVEF 30/40 LVEF 41/50 LVEF > 50 Emergency surgery CPB use COPD Biarterial commitment Triarterial commitment Multiarterial commitment

Group 1

Group 2

P

34 (75.6%) 11 (24.4%) M = 60.44 DP = 9.08 35 (77.7%) 9 (20%) 32 (71.1%) 13 (28.9%) 24 (53.3%) 4 (8.8%) 22 (48.8%) 21 (46.6%) 36 (80%) 11 (24.2%) 30 (66.6%) 17 (37.7%) 1 (2.2%) 9 (20%) 35 (77.8%) 9 (20%) 0 6 (13%) 1 (2.3%) 19 (42.2%) 25 (55.5%)

48 (88.8%) 06 (12%) M = 59.44 DP = 9.85 44 (81.4%) 10 (18.6%) 35 (64.8%) 19 (35.2%) 28 (51.8%) 4 (7.4%) 37 (68.5%) 20 (37.03%) 50 (92.5%) 16 (29.6%) 37 (68.5%) 18 (33.3%) 2 (3.7%) 9 (16.7%) 43 (79.6%) 11 (20.3%) 0 6 (11.1%) 5 (9.2%) 29 (53.7%) 20 (37.1%)

NS NS NS NS NS NS NS 0.083 NS NS NS NS NS NS NS NS NS NS NS NS NS

CHF - congestive heart failure, NYHA - New York Heart Association, MI - myocardial infarction, BMI - Body mass index, EF - ejection fraction, LV - left ventricle, CPB - cardiopulmonary bypass, COPD - Chronic obstructive pulmonary disease, M - Mean, SD - standard deviation, NS - not significant

nary angiography, which showed graft patency of the LITA and RITA; this showing restenosis of angioplasty for RC that was performed prior to surgery. One patient in the G-2 had angina on 3rd month postoperatively; myocardial scintigraphy was performed that showed signs of ischemia, then performing coronary angiography showing patency of the three arterial and one venous grafts. The length of ICU stay ranged from 2 to 5 days in G-1 and in G-2 from 2 to 4 days. The main reason for the increase in ICU stay was the need for reoperation for bleeding in G-1 and the occurrence of postoperative arrhythmia in the G-2. The hospital stay ranged from 6 to 11 days in G-1 and in G-2 from 6 to 9 days. There were no deaths in either group, nor any permanent neurological complications, or need for revascularization, percutaneous or surgical, in any patients in the two groups during the observation period of 6 months. Table 2 shows surgical and postoperative data. Coronary angiography was performed at 6 months postoperatively and was re-studied in 96 patients. None of the ITAs, both right or the left, grafted in AIB, showed occlusion or stenosis. Table 3 shows the results of CT angiography.

On angiography, a patient from G-1 presented with occlusion of the distal anastomosis of the free RITA on a LM branch, but on this exam the coronary artery showed no obstructive lesion and myocardial scintigraphy showed no ischemia in this area. Another patient in this group had moderate lesion in the proximal anastomosis of the RITA in the ascending aorta; also, myocardial scintigraphy was performed and showed no ischemia. Another patient in this group showed decrease in the caliber of the distal RITA anastomosed in the LM branch; on preoperative coronary angiography, this showed an obstructive lesion of 70% and angiography did not evidence obstructive lesion. In two other patients there was evidence of mild stenosis at the proximal anastomosis of the RITA in the ascending aorta. In three patients the saphenous vein graft anastomosed to the RC territory presented occluded, but in none of these patients surgical or percutaneous reintervention was needed. In two patients, the RC was occluded with collateral filling and the other patient was asymptomatic without evident ischemia on myocardial scintigraphy; the distal bed of the right posterior descending coronary artery was of small caliber; so we chose the clinical follow-up.

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Table 2. Surgical and postoperative data. Surgical and postoperative data Anastomoses / patient (M) Mortality Arrhythmia (AF / flutter) Bleeding volume Use of blood products Reoperation for bleeding Extubation in the OR Time of ICU stay (M) Time of hospital stay (M)

Group 1 3.48 (DP=0.72) 0 6 (13%) 380 (DP=134.24) 14 (31.1%) 2 (4.4%) 38 (84.4%) 2.6 (DP=0.83) 7.2 (DP=0.81)

Group 2 3.2 (DP=0.76) 0 8 (14.8%) 350 (DP=117.95) 10 (18.51) 0 52 (96.2%) 2.59 (DP=0.63) 7.09 (DP=0.78)

P NS NS NS NS NS NS NS NS NS

AF - Atrial Fibrillation, OS - Operating Room, ICU - Intensive care unit, M - Medium, NS - not significant

Table 3. Results of coronary CT angiography. We compute the moderate, significant obstructive lesions or occlusions. Results of CT angiography LITA (No. anastomosis / patent) RITA (No. anastomosis / patent) Saphenous (No. anastomosis / patent) RA (No. anastomosis / patent)

Group 1 (44 angio tc) 44/44 (100%) 44/41 (93.18%) 30/26 (86.66%) 2/1 (50%)

Group 2 (52 angio tc) 52/50 (96.15%) 52/52 (100%) 31/29 (87.09%) 3/3 (100%)

P NS NS NS NS

LITA - Left internal thoracic artery, RITA - Right internal thoracic artery, AR - Radial artery, CT Angiography Multislice CT angiography studies with 64 channels, NS - Not significant

In G-2, coronary angiography of two patients showed occlusion of the LITA pedicle graft to the CX branches and they did not show obstructive lesions; myocardial scintigraphy showed no ischemia. Another patient showed moderate reduction in the caliber of a distal in situ LITA, used for sequential anastomosis for two LM branches, and obstructive lesion of the last LM branch was slight; it has not been demonstrated ischemia on myocardial scintigraphy. In two patients the graft of the saphenous vein to branches of the RC were occluded, in one patient this coronary artery was already occluded and had collateral filling through AIB, and in the other patient the obstructive lesion was mild according to angiography (50%); CT angiography also showed mild obstructive lesion; there was no ischemia on myocardial scintigraphy and we chose for clinical treatment. Figure 3 shows images of coronary CT angiography and Figure 4 shows images of CT angiography as for positioning of RITA in relation to the sternum.

this surgery is not yet routinely used in major centers around the world. It is known that the use of both ITAs increases surgical time and requires more refined technique, beyond the fear of the risk of sternal infection or severe bleeding; so, there are still doubts and controversies regarding the best surgical strategy. Thus, the use of both ITAs is still not routinely performed in all services and in all subgroups of patients. As a consequence, the utilization rates of ITAs ranges from 4% to 30%, even in countries like USA, Japan and some of Europe[12]. Some studies have shown the use of anteroaortic RITA for AIB with results similar to the LITA, finding 97.2% patency of the LITA for AIB and 96% of the RITA for that same coronary, with follow-up of 80 months[13]. This technique allows the entire left coronary system is revascularized with independent sources of blood supply, using both ITAs in situ, or that is, RITA for AIB territory and LITA for CX territory. There is also the option to use the retro-RITA, however, in this technique, when CABG is performed without CPB, this anastomosis is hampered by the need to draw the heart, distancing the coronary from the graft. On the other hand, in anteroaortic position this mentioned difficulty does not occurs, however, a limitation to the

DISCUSSION Currently, the evidence is very clear in showing the superiority in the use of both ITAs in CABG surgery. Even so,

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A

A

B

C

D

B

Fig. 4 - (A, B, C and D) - CT angiography showing the positioning of the right internal thoracic artery showing its distance from the sternum

C

RITA reach the AIB (20.1 vs. 16.4 cm, P<0.001.); Besides the reduction in infectious complications in diabetic patients sternum (2.2% vs. 10.0%, P<0.05)[15]. The reduction in the risk of sternal osteomyelitis with this technique is due to the preservation of the blood supply and lymphatic drainage, in addition to lead to increased flow compared to the non-skeletonized ITA[16]. Some authors observed that the long-term benefit can be obtained when both ITAs are used for entering the EC territory[17]. The other option for using both in situ ITAs to the left coronary system is the retroaortic RITA[3,18]. However, other authors cite limitations in using this technique such as: the length cannot reach two or three LM branches for sequential anastomosis, especially in off-pump surgery; the course of retroaortic RITA may present some disadvantages, such as difficulty in controlling any bleeding of any branch or aortic artery compression or kinks not detected[19]. In the analysis of the primary endpoint, comparing the patency of ITAs in anastomosis for AIB in CABG, all used in situ, they were patent by angiography evaluation. In the analysis of secondary endpoints there were no deaths in both groups, and no need for surgical or percutaneous intervention, nor any permanent neurological complications. In G-1, the ITAs used as a free graft with proximal anastomosis in the ascending aorta, presented a patency rate of

D

Fig. 3 - (A and B) Coronary CT angiography showing positioning of the right internal thoracic artery (RITA) in the cranial portion of the ascending aorta, anastomosed to the anterior interventricular branch (AIB). C) Left internal thoracic artery (LITA) anastomosed to AIB/ diagonal (sequential) and RITA (free) to the left marginal (LM). D) LITA (in situ) anastomosed in diagonals/LM (sequential)

use of this technique is the crossing of the mediastinum by RITA and may lead to graft injury in the event of a reoperation. Some authors, concerned about the possibility of injury to the graft advocated the use of PTFE tube or patch of pedicled thymic fat, all with the aim to protect the RITA when crossing the mediastinum[4,14]. But there are no prospective randomized studies, to assess the patency of both internal thoracic arteries (ITAs) for AIB. Another limitation to the use of the RITA to the anterior region of the heart is the difficulty to achieve the desired anastomosis site, in the event of the need for distal anastomosis. When we use the skeletonized ITA the length of this artery increases against the pedicle artery, thus allowing the

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93.18% (41/44). This result is comparable with the literature showing a lower permeability in this technique when compared to the in situ graft[20]. In G-2, LITA, that was used for the CX territory presented a patency rate of 94.2% (49/52). In all patients in whom LITA was used for the CX territory and that showed occlusion or stenotic lesion were associated with mild obstructive coronary lesion or no lesion in this method of analysis. It is noteworthy that these patients had coronary angiography in stenotic lesions > 70%, an inclusion criterion in the study. Some authors assessed the remodeling of ITA and found that the predictors of occlusion are: quality of distal coronary bed, calibrous accessory branches leading to the theft of flow and native flow through the coronary bed; and it may be the reason for the result found by angiography in patients who received the LITA to the CX territory [21]. The best results, when using both ITAs, are obtained when they are used in situ for the LC territory, preferably in significant obstructive lesions or occluded arteries. Patency is determined not only by the nature of the biology of graft but also by the flow competition and the degree of stenosis of the coronary territory and the deterioration of the graft is related to obstructive lesion of the coronary branch when it is less than 75%[22]. Venous grafts used for the RC territory showed a patency of 90% and 93.5% in the G-1 and G-2 respectively. The saphenous vein when used for the RC territory features many satisfactory results, comparable to ATI used to that region of the heart. None of the patients in both groups had high troponin I levels above the established as the cutoff point, or electrocardiographic changes suggestive of a perioperative MI. The on-pump surgery leads to less cell injury compared with the conventional method of CABG surgery, and normal blood troponin level is not certain clue of patent grafts. The opposite is also true, or that is, high levels do not necessarily indicate that the graft is occluded, but only that there was a significant myocardial injury during or after the procedure[23]. The need for blood products was small, when the patient presented bleeding above the expected, we seek to intervene as early as possible to reduce the need for blood products as well as hemodynamic instability. Delayed indication for surgical reexploration for more than 12 hours, implies greater blood loss, with consequent increased need for blood products, in addition to higher mortality and higher incidence of renal and neurological complications and longer hospitalization in the ICU and hospital. BMI was very similar in both groups. Some authors report no use of both ITAs in obese women and in patients with BMI ≥ 30 due to the high risk of sternal osteomyelitis[24]. On the other hand, others do not consider obesity as an independent risk factor for sternal complications[25]. In several patients we performed four arterial anastomo-

sis to the LC territory, which was possible thanks to the sequential anastomosis by using both ITAs. This shows that through good surgical strategy it is possible to perform a full OPCAB using both ITAs. CONCLUSION Coronary artery bypass grafting using antegrade in situ RITA for AIB territory, when compared to the in situ LITA, anastomosed in the same region, presents the same results in an evaluation period of 6 months, as assessed by angiography coronary with multislice 64 channels, with results showing 100% grafts’ patency. The OPCAB surgery with use of both ITAs for LC territory proved to be safe, effective and feasible, even in patients with multivessel disease, with no deaths in an observation period of 6 months.

Authors’ roles & responsibilities MOD Main Author LFPM Coauthor LAOD Coauthor OGO Coauthor DMSM Coauthor JRMC Coauthor EGD Coauthor NSL Coauthor RWQ Coauthor EFB Coauthor

REFERENCES 1. Dallan LAO, Oliveira SA, Lisboa LA, Platania F, Jatene FB, Iglézias JCR, et al. Revascularização completa do miocárdio com uso exclusivo de enxertos arteriais. Rev Bras Cir Cardiovasc. 1998;13(3):187-93. 2- Ruttmann E, Fischler N, Sakic A, Chevtchik O, Alber H, Schistek R, et al. Second internal thoracic artery versus radial artery in coronary artery bypass grafting: a long-term, propensity scorematched follow-up study. Circulation. 2011;124(12):1321-9. 3- Puig LB, França Neto L, Rati M, Ramires JA, da Luz PL, Pillegi F, et al. A technique of anastomosis of the right internal mammary artery to the circumflex artery and its branches. Ann Thorac Surg. 1984;38(5):533-4. 4- Zacharias A. Protection of the right internal mammary artery in the retrosternal position with stented grafts. Ann Thorac Surg. 1995;60(6):1826-8.

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5- Lev-Ran O, Pevni D, Matsa M, Paz Y, Kramer A, Mohr R. Arterial myocardial revascularization with in situ crossover right internal thoracic artery to left anterior descending artery. Ann Thorac Surg. 2001;72(3):798-803.

midterm results of pedicled versus skeletonized conduits. Ann Thorac Surg. 1999;67(6):1637-42. 16. Kurlansky PA, Traad EA, Dorman MJ, Galbut DL, Zucker M, Ebra G. Thirty-year follow-up defines survival benefit for second internal mammary artery in propensity-matched groups. Ann Thorac Surg. 2010;90(1):101-8.

6- Saso S, James D, Vecht JA, Kidher E, Kokotsakis J, Malinovski V, et al. Effect of skeletonization of the internal thoracic artery for coronary revascularization on the incidence of sternal wound infection. Ann Thorac Surg. 2010;89(2):661-70.

17. Shah PJ, Bui K, Blackmore S, Gordon I, Hare DL, Fuller J, et al. Has the in situ right internal thoracic artery been overlooked? An angiographic study of the radial artery, internal thoracic arteries and saphenous vein graft patencies in symptomatic patients. Eur J Cardiothorac Surg. 2005;27(5):870-5.

7- Nakano J, Okabayashi H, Hanyu M, Soga Y, Nomoto T, Arai Y, et al. Risk factors for wound infection after off-pump coronary artery bypass grafting: should bilateral internal thoracic arteries be harvested in patients with diabetes? J Thorac Cardiovasc Surg. 2008;135(3):540-5.

18. Gomes WJ, Tavares GB, Jaramillo JI, Alves FA, Torrijos JMG, Catani R, et al. Revascularização da artéria marginal com uso da artéria torácica interna direita pediculada retroaórtica sem circulação extracorpórea. Rev Bras Cir Cardiovasc. 2005;20(1):33-8.

8- Sá MPBO, Soares EF, Santos CA, Figueiredo OJ, Lima ROA, Escobar RR, et al. Fatores de risco para mediastinite após cirurgia de revascularização miocárdica. Rev Bras Cir Cardiovasc. 2011;26(1):27-35.

19. Fukui T, Takanashi S, Hosoda Y, Suehiro S. In situ bilateral skeletonized internal thoracic arterial grafting for left-side myocardial revascularization using an off-pump technique. Interact Cardiovasc Thorac Surg. 2006;5(4):413-7.

9- Abdouni AA, Lisboa LAF, Puig LB, Tossuniam CE, Dallan LAO, Jatene FB, et al. Seguimento a longo prazo de pacientes submetidos à revascularização do miocárdio com uso exclusivo de enxertos arteriais. Rev Bras Cir Cardiovasc. 2008;23(4):494-500.

20. Buxton BF, Ruengsakulrach P, Fuller J, Rosalion A, Reid CM, Tatoulis J. The right internal thoracic artery graft–benefits of grafting the left coronary system and native vessels with a high grade stenosis. Eur J Cardiothorac Surg. 2000;18(3):255-61.

10- Leal JCF, Braile DM, Godoy MF, Purini Neto J, Paula Neto A, Ramin SL, et al. Avaliação imediata da troponina I cardíaca em pacientes submetidos à revascularização do miocárdio. Rev Bras Cir Cardiovasc. 1999;14(3):247-53.

21. Rocha BC, Puig LB, Martinez Filho EE, Oliveira SA. Remodelamento da artéria torácica interna direita: novo método de análise pela área coronariana revascularizada. Rev Bras Cir Cardiovasc. 2006;21(2):143-8.

11. Lima RC. Padronização técnica da revascularização do miocárdio da artéria circunflexa e seus ramos sem circulação extracorpórea [Tese de Doutorado]. São Paulo: Universidade Federal de São Paulo. Escola Paulista de Medicina, 1999.

22. Tatoulis J, Buxton BF, Fuller JA. The right internal thoracic artery: is it underutilized? Curr Opin Cardiol. 2011;26(2):528-35.

12. Kinoshita T, Asai T. Bilateral internal thoracic artery grafting: current state of the art. Innovations (Phila). 2011;6(2):77-83.

23. Braile DM, Leal JCF, Soares MJ, Godoi MF, Paiva O, Petrucci Júnior O, et al. Revascularização do miocárdio com cirurgia minimamente invasiva (MIDCAB): resultados em 46 pacientes. Rev Bras Cir Cardiovasc. 1998;13(3):194-7.

13. Ascione R, Underwood MJ, Lloyd CT, Jeremy JY, Bryan AJ, Angelini GD. Clinical and angiographic outcome of different surgical strategies of bilateral internal mammary artery grafting. Ann Thorac Surg. 2001;72(3):959-65.

24. Kieser TM, Lewin AM, Graham MM, Martin BJ, Galbraith PD, Rabi DM, et al; APPROACH Investigators. Outcomes associated with bilateral internal thoracic artery grafting: the importance of age. Ann Thorac Surg. 2011;92(4):1269-76.

14. Gatti G, Pappalardo A, Gon L, Zingone B. Protecting the crossover right internal thoracic artery bypass graft with a pedicled thymus flap. Ann Thorac Surg. 2006;82(5):1919-21.

25. Gansera B, Schmidtler F, Gillrath G, Angelis I, Wenke K, Weingartner J, et al. Does bilateral ITA grafting increase perioperative complications? Outcome of 4462 patients with bilateral versus 4204 patients with single ITA bypass. Eur J Cardiothorac Surg. 2006;30(2):318-23.

15. Calafiore AM, Vitolla G, Iaco AL, Fino C, Di Giammarco G, Marchesani F, et al. Bilateral internal mammary artery grafting:

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Ramos CMG,ORIGINAL et al. - Myocardial regeneration after implantation of porcine ARTICLE small intestinal submucosa in the left ventricle

Myocardial regeneration after implantation of porcine small intestinal submucosa in the left ventricle Regeneração miocárdica após implante de submucosa intestinal suína no ventrículo esquerdo

Cassiana Maria Garcez Ramos1, MD; Julio César Francisco2, PhD; Marcia Olandoski1, MD, PhD; Katherine Athayde Teixeira de Carvalho3, MD, PhD; Ricardo Cunha3, MD, PhD; Bruna Olandoski Erbano4; Lianna Ferrari Jorge1, MD; Cristina Pellegrino Baena1, MD, PhD; Vivian Ferreira do Amaral1,2, MD, PhD; Lucia Noronha1, MD, PhD; Rafael Michel de Macedo1, MD, PhD; José Rocha Faria-Neto1, PhD; Luiz César Guarita-Souza, MD, PhD2 DOI: 10.5935/1678-9741.20140070

RBCCV 44205-1541

Abstract Introduction: Most cardiomyocytes do not regenerate after myocardial infarction. Porcine small intestinal submucosa has been shown to be effective in tissue repair. Objective: To evaluate myocardial tissue regeneration and functional effects of SIS implantation in pigs after left ventriculotomy. Methods: Fifteen pigs were assigned to two groups: porcine small intestinal submucosa (SIS) (N=10) and control (N=5). The SIS group underwent a mini sternotomy, left ventriculotomy and placement of a SIS patch. The control group underwent a sham procedure. Echocardiography was performed before and 60 days after the surgical procedure. Histological analysis was performed with hematoxylin-eosin stain and markers for actin 1A4, anti sarcomeric actin, connexin43 and factor VIII. Results: Weight gain was similar in both groups. Echocardiography analysis revealed no difference between groups regarding end diastolic and systolic diameters and left ventricular ejection fraction, both pre (P=0.118, P=0.313, P=0.944) and post procedure (P=0.333, P=0.522, P=0.628). Both groups showed an increase in end diastolic (P<0,001 for both) and systolic diameter 60 days after surgery (P=0.005, SIS group and P=0.004, control group). New cardiomyocytes, blood vessels and inflammatory reactions were histologically identified in the SIS group.

Conclusion: SIS implantation in pigs after left ventriculotomy was associated with angiomuscular regeneration and no damage in cardiac function.

Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, PR, Brazil. Pontifícia Universidade Católica do Paraná (PUCPR), Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil. 3 Faculdade Pequeno Príncipe, Curitiba, PR, Brazil. 4 Faculdade Evangélica do Paraná (FEPAR), Curitiba, PR, Brazil.

This study was carried out at Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, PR, Brazil

Descriptors: Intestinal Mucosa. Regeneration. Myocardium. Resumo Introdução: A grande maioria dos cardiomiócitos não tem capacidade de regeneração após o infarto do miocárdio. A submucosa do intestino porcino tem-se mostrado eficiente como reparador tecidual. Objetivo: Analisar a capacidade de regeneração tecidual miocárdica e o efeito funcional do implante da submucosa do intestino porcino após ventriculotomia esquerda em porcos. Métodos: Quinze porcos foram separados em dois grupos: submucosa (N=10) e controle (N=5). Os animais do grupo submucosa foram submetidos a uma mini esternotomia inferior e ao implante da submucosa porcina na ventriculotomia esquerda. No grupo controle, foi realizada apenas a mini-esternotomia. Foi realizada análise ecocardiográfica no pré-operatório e 60 dias após o procedimento cirúrgico. A análise histológica foi feita com hematoxilina-eosila e marcadores para Actina 1A4, anti-actina sarcomérica, conexina43 e fator VIII.

1 2

No financial support.

Correspondence address: Luiz César Guarita Souza Pontifícia Universidade Católica do Paraná (PUCPR) Rua Imaculada Conceição, 1155 - Prado Velho – Curitiba, PR, Brazil Zip code: 80215-901 E-mail: guaritasouzalc@hotmail.com

Article received on March 24th, 2014 Article accepted on May 5th, 2014

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relação ao diâmetro sistólico final, diâmetro diastólico final e fração de ejeção ventricular esquerda, tanto no pré (P=0.118, P=0.313, P=0.944) quanto no pós-operatório (P=0.333, P=0.522, P=0.628). Ambos os grupos mostraram um aumento no diâmetro sistólico final (P=0.005, grupo submucosa e P=0.004, grupo controle) e diâmetro diastólico final (P<0,001 para ambos) 60 dias após a cirurgia. À histologia, identificou-se a presença de novos cardiomiócitos, fibras musculares lisas, vasos sanguíneos e reação inflamatória no grupo submucosa. Conclusão: O implante de submucosa intestinal porcina após ventriculotomia esquerda está associado a regeneração angiomuscular, sem prejuízo da função cardíaca.

Abbreviations, acronyms & symbols CF CEUA H&E LVEF LVEDD LVESD PBS SIS

Cardiac frequency Committee of Ethics in Research in Animal Use of the PUCPR Hematoxylin and Eosin Left ventricular ejection fraction Left Ventricular End Diastolic Diameter Left Ventricular End Systolic Diameter Phosphate-buffered Saline Porcine small intestinal submucosa

Resultados: O ganho de peso foi semelhante entre os grupos. Considerando a análise ecocardiográfica, não foi identificada diferença estatisticamente significativa entre os grupos com

Descritores: Mucosa Intestinal. Regeneração. Miocárdio.

INTRODUCTION

intestinal segment was inverted and the mucosa was removed by scraping, taking precautions to not cut the tissue. After reversal of the inverted segment, the seromuscular extract was removed in the same manner. The resulting tissue consisting of the submucosal layer of the small intestine was washed in an isotonic saline solution and stored in a 10% neomycin sulfate solution. Decontamination was performed with a stabilized chlorine dioxide (0.04%) saline solution using a shaker (Bureau 109M, New Ethics Ltda.) for 24 hours[6,8].

Although several studies have suggested that mitotic division occurs in the heart, the vast majority of cardiomyocytes do not have the ability to regenerate after myocardial infarction. Myocardial infarction leads to deterioration of contractile element function and, if ventricular remodeling is extensive in the infarcted area, heart failure may occur[1]. Tissue regeneration after transmural fibrosis remains a major concern. Porcine small intestinal submucosa (SIS) is a xenogeneic membrane, classified as biodegradable material since it has natural properties that allow for use as a biomaterial[2,3]. Through extensive research in various areas of medicine, SIS has been shown to be versatile and efficient in tissue repair. It does not trigger an antigenic response and is capable of inducing regeneration of the native tissue in which it was deployed[4,5]. Tissue replacement in the body and development of new grafts using biomaterials are major challenges in regenerative surgery. SIS is an alternative that should be further studied[6]. Thus, the aim of this study is to assess the ability of myocardial tissue regeneration following SIS implant after left ventriculotomy in pigs.

Experimental Model This experimental study included 15 (Landrace) adult pigs, with an average weight of 13.75 kg. The animals were randomized 2:1 and divided into two groups: • SIS group (N=10): SIS implantation after left ventriculotomy; • Control group (N=5): Mini lower sternotomy. The animals were anesthetized with intramuscular administration of pre hydrochloride (1.0 mg/kg), ketamine (20 mg/kg) and acepromazine maleate 1% (0.05 mg/kg) and received prophylactic antibiotics (gentamicin sulfate 5 mg/kg). The pigs were monitored with an electrocardiogram, pulse oximetry and denitrization with oxygen at 100%, anesthetized with propofol at a dose of 6 mg/kg and intubated. The animals were kept under a mechanical ventilation system with a 50% mix of oxygen and nitrous oxide. Transoperative analgesics included intravenous 2 mg/ kg morphine, 2 mg/kg lidocaine, and 2 mg/kg ketamine. The immediate post operatory analgesic administered was 1.1 mg/ kg flunixin meglumine, and in the subsequent post operatory periods 50 mg/kg of intramuscular tramadol was administered. The animals were placed in a dorsal decubitus position. An incision was performed from the sixth intercostal space to the xiphoid appendix in the lower third of the sternum, and subsequently to the lower inferior sternotomy. The pericardium was opened, and the left and right ventricles were visible.

METHODS All experiments were performed in accordance with the Guiding for the Care and Use of Laboratory Animals approved by the American Physiological Society[7] and the EU Directive 2010/63/EU for animal experiments. This project was presented to CEUA (Committee of Ethics in Research in Animal Use of the PUCPR) and approved under article number 563 on 02/09/2010. Submucosa Preparation and Decontamination SIS was obtained by resection of the proximal jejunum segment of healthy pigs. The mesentery was removed, the

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While the heart was beating, partial clamping of the left ventricular apex was performed excluding the anterior interventricular coronary, and a left ventriculotomy of approximately 30 mm in diameter was performed (Figures 1A/B). SIS implantation was performed (approximately 60 mm x 30 mm, double layered) on the apical portion of the left ventricle with a polypropylene 5.0 wire suture (Figures 1C/D). The animals were extubated, monitored in the recovery laboratory, and followed for a period of 60 days. Control group animals underwent mini sternotomy, pericardial opening, and subsequent wound synthesis.

ac frequency (CF, bpm), left ventricular end systolic diameter (LVESD, mm), left ventricular end diastolic diameter (LVEDD, mm), fractional shortening and left ventricular ejection fraction (LVEF, %). An Agilent echocardiogram equipment (model Sonos 5500; Andover, MA, USA) equipped with high frequency, high resolution transducers (12 MHz and 15 MHz, model 21390A, Agilent, Palo Alto, CA, USA) and a capacity of 120 (Hertz) frames per second was used. Measurements were taken in M-mode to obtain images of a transversal section of the heart on the short axis. Diameters of the aorta, left atrium, right ventricle at end diastole, septum, and posterior wall at end diastole were assessed. Fractional shortening was obtained using the software provided on the equipment. The LVEF was obtained by LVEDD cubed minus LVESD cubed divided by LVEDD cubed. All measurements were performed three times by the same technician, who was blinded to treatment, and mean values were recorded[10].

Functional Assessment The animals underwent echocardiographic analysis at two time points: pre-surgery and 60 days after the procedure, based on the recommendations of the American Society of Echocardiography[9]. The following parameters were assessed (M-mode): cardi-

Fig. 1 - A) Partial clamp of the left ventricular apex; B) Left apical ventriculotomy;Â C) Implant of the submucosa in the LV apex. Partial suture with polypropylene 5.0 continuous suture; D) Submucosa implanted in the LV apex.

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Animals were euthanized after the procedure by intraperitoneal injection of Thiopentax (0.5 g sodium pentathol).

to 54.2±10.9 kg [P<0.001] and 14.3±2.1 kg to 59.6±8.8 kg [P<0.001], respectively). Differences in mean weight were not significantly different between groups at both pre- and post-operative time points (P=0.456 and P=0.320, respectively) (Table 1).

Histological Assessment Hearts were removed, quickly washed in phosphate-buffered saline (PBS) (Gibco, Life Technologies, São Paulo, Brazil) and cryopreserved in liquid nitrogen. Serial transverse sections (8 mm) were obtained from a Leica cryostat (model 1850). Slides were stained with hematoxylin and eosin (H&E) and modified with Gomori’s trichrome for morphological assessment. Immunohistochemistry was performed with anti-fast myosin antibody for immunofluorescence (Sigma, St. Louis, MO) at a dilution of 1:400. Slides were then incubated with secondary biotin-labeled affinity-isolated anti-rabbit and anti-mouse immunoglobulins (LSAB® Kit, Peroxidase; DAKO Corp., Carpinteria, CA). Antigenic recovery of monoclonal mouse anti-human actin (smooth muscle) clone 1A4, monoclonal mouse anti-human von Willebrand factor, and monoclonal mouse anti-actin (sarcomeric) clone alpha-Sr-1 (Dako Cytomation, Denmark) was performed by enzymatic digestion and 0.1% trypsin diluted in PBS, pH 7.4, in a 37°C oven for one hour. H&E staining identified inflammatory responses and morphological characteristics. Factor VIII identified endothelial cells and blood vessels, actin 1A4 identified smooth muscle fibers and sarcomeric anti-actin indicated cardiomyocytes.

Histology In the macroscopic analysis, it was identified an integration between the myocardium and SIS, not presenting a clear cleavage plane between them. Using H&E, connective tissue in the SIS and in the transition zone between the SIS and the myocardium was identified. The presence of lymphocytes in the transition zone between the SIS and native myocardium were also observed, suggesting signs of a local inflammatory response to the sutures. No lymphocytic cells were identified in the central SIS region. New muscle fibers with a single central nucleus were identified in both the transition zone between the SIS and myocardium and the SIS itself. Endothelial cells and newly formed blood vessels were also observed (Figure 2A/B/C/D/E/F). Factor VIII identified the presence of new blood vessels in both the transition zone between the SIS and myocardium and the SIS (Figure 2G/H). Actin 1A4 identified smooth muscle fibers in the walls of the blood vessels marked by factor VIII. Actin 1A4 negatively stained muscle fibers in the implanted SIS (Figure 2I/J/K). Sarcomeric anti actin antibody positively marked new cardiomyocytes in both the transition zone as well as in the implanted SIS (Figure 2L/M).

Statistical Analyses Statistical analyses were performed using SPSS version 14.0. Groups were compared using Student’s t-test for independent samples. Comparisons between pre- and post-operative results were performed by Student’s t-test for paired samples. The condition of normality was evaluated by the Shapiro-Wilk test. P-values <0.05 were considered statistically significant.

Echocardiography The SIS and control groups had similar mean left ventricular ejection fraction (LVEF) at the preoperative assessment (68.18±7.7% vs. 68.43±2.9%, P=0.944). At the post-implant assessment, mean LVEF were also similar (73.78±9.6% vs. 71.55±3.4%, P=0.628). Intra-group assessment identified a variation from 68.18±7.7% to 73.78±9.6% (P=0.240) in the SIS group between the preoperative period and 60 days after surgery. In the control group for the same time period, a variation of 68.43±2.9% to 71.55±3.4% (P=0.262) was observed (Table 2).

RESULTS Weight Between preoperative assessment and 60 days after surgery, the mean weight of the animals in both the control and SIS groups significantly increased (from 13.2±3.6 kg

Table 1. Inter- and intra-group weight analysis (kg) between pre-operative evaluation and 60 days after surgery. Weight pre Weight pos Group SIS Control

Group SIS Control SIS Control P (pre x post) <0.001 <0.001

n 10 5 10 5

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Standard Deviation 2.06 3.56 8.83 10.94

P 0.456 0.320

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Fig. 2 – A,B) Myocardium (M), transition zone between myocardium and the submucosa (ZT), submucosa (S), H-E (hematoxylin-eosin). 20X and 40X.

Fig. 2 – C,D) Submucosa (S), blood vessels (o) and inflammatory reaction with lymphocytes around the suture, H-E (hematoxylin-eosin). 20X and 40X.

Fig. 2 – E,F) Submucosa (S), transition zone between the myocardium and the submucosa (ZT), muscle fiber (+) and blood vessel (o), H-E (hematoxylin-eosin). 10X and 20X.

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Fig. 2 - G,H) Submucosa (S), endothelial cells and blood vessels(l). Factor VIII, 40X and 100X.

Fig. 2 – I) Submucosa (S), smooth muscle fiber (λ), muscle fiber negative for actin 1A4 (+) and blood vessels (o). Actin 1A4, 40X.

Fig. 2 – J,K) Submucosa (S), blood vessels (o), smooth muscle fiber (λ) and muscle fiber negative for actin 1A4 (+). Actin 1A4, 40X.

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Fig. 2 – L,M) Submucosa (S). Cardiomyocyte positively marked (n). Sarcomeric anti-actin, 10X and 40X. Table 2. Inter- and intra-group left ventricular ejection fraction (EF) analysis (%) between pre-operative evaluation and 60 days after surgery. Group SIS Control EF pos SIS Control Group P (pre x post) SIS 0.240 0.262 Control SIS - Porcine small intestinal submucosa EF pre

n 10 5 10 5

Mean 68.18 68.43 73.78 71.55

Standard Deviation 7.67 2.92 9.60 3.43

P 0.944 0.628

Table 3. Inter- and intra-group left ventricular end systolic diameter analysis (mm) between pre-operative evaluation and 60 days after surgery. Group n Mean Standard Deviation SIS 10 23.95 2.73 Control 5 22.40 2.61 LVESD post SIS 10 30.00 5.60 Control 5 28.20 3.27 Group P (pre x post) SIS 0.005 Control 0.004 LVESD - Left ventricular end systolic diameter; SIS - Porcine small intestinal submucosa LVESD pre

In the SIS and control groups, preoperative mean left ventricular end systolic diameter (LVESD) were 23.95±2.7 mm and 22.4±2.6 mm, respectively (P=0.313). In post-operative assessment, mean LVESDs were 30±5.6 mm in the SIS group and 28.2±3.3 mm in the control group (P=0.522). Increases from 23.95±2.7 mm to 30±5.6 mm (P=0.005) in the SIS group and 22.4±2.6 mm to 28.2±3.3 mm (P=0.004) in the control group were identified between pre- and post-operative time periods (Table 3).

P 0.313 0.522

With respect to end diastolic diameter (LVEDD) inter-group preoperative assessment identified mean values of 36.43±3.2 mm in the SIS group and 33.2±3.1 mm in the control group (P=0.118). In post-operative assessment, 48.4±7.5 mm was observed in the SIS group and 44.8±3.3 mm in the control group (P=0.333). In intra-group analysis between the pre- and post-operative periods, we identified an increase in LVEDD in both the SIS and control groups (36.43±3.2 mm to 48.4±7.5 mm [P<0.001] and 33.2±3.1 mm to 44.8±3.3 mm [P<0.001], respectively) (Table 4).

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Table 4. Inter- and intra-group left ventricular end diastolic diameter analysis (mm) between pre-operative evaluation and 60 days after surgery. Mean Group n Standard Deviation 36.43 SIS 10 3.20 33.20 Control 5 4.15 LVEDD post SIS 10 48.40 7.53 44.80 Control 5 3.35 Group P (pre x post) SIS <0.001 Control <0.001 LVEDD - Left Ventricular End Diastolic Diameter; SIS - Porcine small intestinal submucosa LVEDD pre

P 0.118 0.333

intra-coronary venous sinus, and intramuscular endocavity. However, this therapy in not favorable in some cases due to the manner in which the cells are transported to the myocardium. Nakamuta et al.[17] performed a study comparing several forms of stem cell injection into the myocardium and found intramuscular injection to be more efficient. Injection with a fibrin sealant presented an even greater increase in potentiality. Several articles have reported that cellular loss in a single intramuscular injection can be more than 80%, and thus injection of the greatest number of cells possible is necessary. For this reason, use of bioactive grafts is an interesting option because there is less cellular loss and better adhesion of the graft to the host[17]. Although there is an increasing tendency towards use of minimally invasive procedures, the basic causes of a disease cannot be treated using techniques with limited access at the cost of not achieving a thorough therapeutic treatment. Another important aspect is to define the objective of treatment using these new materials (i.e., cellular or mechanical repair) and subsequently define the delivery method into the myocardium. In the present study, the primary objective was mechanical repair, followed by tissue repair. The technique used for the SIS implant in the present study followed the current tendency of using less invasive procedures. As such, a mini-sternotomy was performed, which can decrease morbidity and mortality given that the pig sternum provides significant support for the animal. The SIS obtained in development of this study was from the Landrace species, and the animals utilized were from the same species. Although the procedure was not autologous, the use of grafts in animals of the same species reduces susceptibility to immunological responses, despite that fact that many researchers have suggested that the SIS is immunogenic[18]. Immunogenicity is of fundamental importance in using xenogenic grafts. As previously noted, the majority of researchers affirm that SIS is acellular and does not carry immunological information. However, Zhang et al.[19] showed that the SIS presents with porcine characteristics even after decellularization and sterilization based on PCR identification of pig DNA on submucosal plaque after skin implantation, which can trigger a local inflammatory response. These data were obtained after SIS implantation in the rotator cuff

DISCUSSION The aim of many clinical and experimental studies is to find ideal materials with all of the fundamental characteristics of biocompatibility. SIS has demonstrated superior results to other collagen-based materials due to its three-dimensional structure and the presence of growth factors and structural proteins, such as glycoproteins and proteoglycans. The combination of these factors promotes migration, cellular matrix interaction, cell differentiation and growth, which are all essential processes for tissue regeneration[3,11]. Decellularized matrices in an injectable form such as a gel have been utilized with the intent to impede progression of cardiac failure after myocardial infarction. These matrices can originate from the intestinal submucosa, as suggested by Chiu & Radisic[12], or even from the pericardium, as Seif-Naraghi et al.[13] suggested. However, Singelyn et al.[14] confirmed that although synthetic material has the capacity to allow neoangiogenesis due to its porous structure, it is not a bioactive substitute for damaged myocardium and does not allow for effective integration between the injected material and the integral myocardium. The fundamental objective of an injectable biomaterial for post infarction cardiac repair is to form an in situ graft for cellular colonization and to consequently reduce left ventricular wall tension and theoretically stabilize ventricular remodeling. However, these traits were not identified in studies of stem cell injection in the bone marrow[15] or submucosa utilization in a gel form[16]. Implants made of injectable biomaterial may not have the same capacity to reverse ventricular remodeling given that its action is regional and does not affect the integral myocardium despite some degree of benefit. Synergic effects between growth factors can increase biological effects beyond that of a single isolated factor. The capacity of injectable material to promote effects, such as cell adhesion and migration, in infarction healing can improve the therapeutic response. Components of the SIS include proteoglycans, glycosominoglycans, collagen, fibronectin, vascular growth factors, and fibroblasts. These natural components can promote interactions between host cells and the injected material, creating multiple cellular adhesions[2]. One example of catheter access is stem cell injection, which has been utilized in the peripheral venous system, the

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in mice and rabbits and calls into question other studies that have suggested the opposite. However, identification of a pig gene on the transplanted membrane and the presence of an inflammatory response can be explained. Tissues that carry DNA and are supposedly non-immunogenic, even without containing whole cells or leftover DNA in acellular tissue, are capable of inducing an innate immune response (inflammatory). Zhang et al.[19] suggested this hypothesis given that mastocytes and lymphocytes were identified in the receptor regions. The lesion itself in these animal models could have triggered the inflammatory process. In the present study, we identified lymphocytic cells by H&E at the site of the implant, indicating an inflammatory reaction. These cells were next to the suture line that grafted the SIS to native myocardium (in the transition zone). This reaction could have been triggered by a granuloma response to foreign bodies by the suture and not by the SIS. No lymphocytes were identified in the central region of implanted SIS. Morphological analysis of the SIS using H&E identified new blood vessels and fibers with muscular characteristics (a central single nucleus suggestive of cardiac muscle). This was confirmed by negative actin 1A4 staining of the muscle fibers adjacent to the myocardium and positive specific staining with the sarcomeric anti-actin antibody, corroborating development of new cardiomyocytes. Factor VIII, which identified endothelial cells and blood vessels, positively stained cells in the SIS, confirming the capacity of the membrane to form new vessels. These vessels were identified both in the transition zone between the SIS and the myocardium and in the internal portion of the implanted membrane. Actin 1A4 staining, which is specific for smooth muscle fibers, identified muscle fibers in blood vessel walls, while muscle fibers were negatively stained in the region adjacent to the SIS. This suggests that these were not smooth muscle fibers. Because they morphologically presented with a single central nucleus, we can infer that the fibers were striated, or cardiomyocytes. The sarcomeric anti-actin antibody positively stained muscle fibers in both the transition zone and the SIS, effectively confirming the presence of new cardiomyocytes. The presence of new blood vessels, new smooth muscle fibers, and cardiomyocytes in both the transition zone and the body of the SIS suggests angiomuscular regeneration and supports the hypothesis of cardiac tissue regeneration. Evidence of new cardiomyocytes was supported by three points: anti sarcomeric antibody staining (specific for cardiomyocytes), morphological characteristics of the muscle fibers with H&E (central single nucleus), and negative staining with the actin 1A4 antibody. One hypothesis regarding substitution of the extracellular matrix by host tissue, as suggested in some articles, states that a combination of cartilaginous tissue, fibrotic connective tissue, and adipose tissue is present in addition to cardiomyocytes and blood vessels. The presence of connective

collagen in these studies was not unexpected given that it is well established that damaged or absent adult myocardial tissue can be substituted by scar tissue. However, according to Badylak et al.[20], simultaneous presence of other tissue types, including adipose, connective and cartilaginous tissue should not occur. Neither cartilaginous nor adipose tissue were identified in the implanted SIS in the present study, only loose connective tissue. Upon macroscopic analysis, a suture was identified in the middle of the thickened tissue after implant of the SIS. This wire used to perform the implant was situated on the external surface of the myocardium above the epicardium, indicating integration of the membrane with the myocardium as suggested by Cayan et al.[5]. The manner in which these cells colonized the implanted SIS could have been a consequence of direct colonization of the submucosal edge, which was in direct contact with the myocardium. Growth factors such as VEGF may have stimulated development of endothelial cells, which are precursors of blood vessels, to consequently generate new blood vessels. Development of new cardiomyocytes could be explained by the fact that cardiac resident cells, also called cardiac stem cells, may have undergone hyperplasia and, under the stimuli of growth factors such as PDGF and fibrinectin to recruit host cells, proliferated toward the membrane. Stimulus from neoangiogenesis may be another explanation for cardiomyocyte formation in the transition zone. Growth factors in the SIS could have stimulated proliferation of cardiac cells that colonized on the SIS toward the extremities and the center of the membrane. One important detail was thickening of the SIS observed at the time of euthanasia without calcification, suggesting bioactivity. In other words, the membrane grew together with the heart, integrating with the host tissue. Echocardiographic functional analysis showed that SIS and control groups were similar with respect to LVESD, LVEDD, and LVEF in both the pre-and post-operative periods. These data are comparable with each other without methodological bias. The SIS implanted after left ventriculotomy did not cause deterioration of cardiac function or ventricular remodeling. Within groups, there was an increase in left ventricular end systolic and diastolic diameters between the pre implant period and 60 days after the procedure, although the LVEF was maintained. This could be a result of animal growth given that weight increased significantly after 60 days. It is important to point out that the two groups presented gains proportional to their weight. Although in the present study we did not identify functional improvement in the SIS group, the proposed experimental model did not present ventricular dysfunction and showed development of new vessels in the transition zone. Thus, we demonstrated improved vascularization of this tissue in support of the hypothesis of Lionetti et al.[21]. These authors defend the

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theory that the autocrine and paracrine mechanisms, mediated by factors released by resident cells, perform essential roles in the repair process following heart failure. Such signs can influence the function of cardiac stem cells through several mechanisms, including survival of cardiomyocytes and neogenesis. In addition to promoting cytoprotection and angionesis, paracrine factors released by resident cardiac cells can alter cardiac and local extracellular matrix metabolism, interfering in post lesion favorable remodeling. Intracellular signs may be activated and modulated temporally and spatially with several effects in general, depending on the microenvironment as a result of the alteration in the lesioned myocardium. Chemical, mechanical or genetic activation of cardiac cells has been demonstrated to release peptides that protect the tissue against ischemic lesions. These mechanisms can help in the process of supplying specific proteins produced by these cells for new pharmacological therapy in cardiac regeneration. Although medication-based therapy to treat heart failure can lead to better cardiac function, it cannot induce tissue repair or regeneration. Angiogenesis is fundamental for vascular supply to the grafted tissue in formation. Proliferation and migration of endothelial cells induced by chemotactic factors present in the extracellular matrix and adjacent cells promotes neoangiogenesis[22-25]. These endothelial cells give origin to vascular tubes, stems and capillaries. This process occurs in the first weeks (2-6 weeks) after the graft implant. In the present study, we identified cell groupings stained in the graft and formation of new blood vessels morphologically characterized by H&E and specifically marked by factor VIII and smooth muscle fibers stained by the 1A4 antibody on the neovessel wall in the SIS. A contractile graft was proposed by Hata et al.[26] using fetal cardiomyocyte cultures in the SIS. However, this technique can transfer the immunogenicity of fetal cardiomyocytes, which may interfere in the colonization process of the host tissue in the short and long term and can present the same collateral effects as synthetic grafts. The ideal mechanism for contractile graft formation is development by the organism’s own muscle fibers. Although Dar et al.[27] cultivated cardiac cells in an alginate membrane, it was not possible to stimulate formation of new cardiomyocytes. In contrast, Matsubayashi et al.[28] performed cell culture in vascular smooth muscle of the aorta in rats on sponge polymer plates reinforced with poly-L lactic acid for two weeks and observed tissue formation. The use of cardiomyocytes in some types of culture does not yield positive results, as shown by Guarita-Souza et al.[29] who reported that differentiated cells significantly reduced their capacity for hyperplasia, contrary to fetal cardiomyocytes, smooth and skeletal muscle cells. The choice of the left ventriculotomy in the present study originated from Nakamuta et al.[17], in which an experimental model of a lesion in the right ventricle implanted with SIS is described. There was doubt as to the membrane’s resistance when implanted into a system with greater pressure. From a

mechanical and cellular repair standpoint, the authors identified 70% recovery in contractile force of muscular fibers formed on the SIS and identified not only muscular and blood vessels, but also cartilage, fibrotic and adipose tissue. In the present study, we identified endothelial cells, blood vessels and cardiomyocytes in the transition zone and in the body of the SIS, however, cartilaginous cells were not observed. With respect to tissue resistance of the SIS, left ventricular pressure in both the immediate and late post-operative periods was maintained. A double layer of membrane could have aided in the process. Long term resistance was satisfactory given that while the SIS was differentiating through angiomuscular regeneration, it was integrating with the adjacent myocardium and creating greater adherence and resistance. Another reason for using a left ventriculotomy and SIS implant was the lack of studies using this experimental model (integral myocardium without infarction or induced myocardiopathy). The aim of this study was to perform mechanical repair and subsequently assess the capacity of cellular regeneration in the transition zones between the SIS and myocardium. In models using myocardial infarction, fibrosis impedes direct contact with the myocardium and can block access to growth factors. Some authors may have prioritized utilizing the extracellular matrix in a gel form because this type of graft can remain between layers with fibrosis. Design of the present study with only two groups was based on the fact that SIS implanted in the left ventricle has not been previously described in the literature, and therefore we do not have initial results to compare with other types of grafts. The inclusion of a control group without intervention in the myocardium was supported by the fact that if we had performed left ventriculotomy and subsequent suture of the ventricular apex, we may have induced fibrosis, which could have interfered in comparison with the study group and created a methodological bias. We would have been comparing the SIS group with fibrosis rather than native myocardium. A third group with PTFE and/or bovine pericardium was not proposed because the aim was to define what would happen using SIS implanted in the left ventricle and not to define which graft was better. It is important to differentiate experimental animal models of myocardial infarct from transmural myocardial infarction given that several studies have reported the use of submucosa injection in a gel form for myocardial infarct without identification of compromise in the ventricular wall. Physiopathologically, the behavior of the two models is different from a tissue repair standpoint. Infarction models with thick myocardium have better regeneration potential because cardiomyocytes are stunned and could benefit from neoangiogenesis induced by the SIS itself, which has been shown in similar studies using mononuclear stem cells. However, transmural infarction presents a thin ventricular wall without cardiomyocytes, and thus the repair mechanism by the graft should be mechanical and not cellular.

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With respect to post left ventriculotomy assessment, it is important to confirm preservation of cardiac contractile function even after SIS implantation. There was neither ventricular dysfunction nor remodeling despite an identified increase in systolic and diastolic diameters. Based on these results, we suggest that the SIS can be utilized as repair in aneurysmectomy surgery of the left ventricle and acts in two different ways: actively by correcting a mechanical defect, reducing ventricular dilatation and minimizing ventricular remodeling as suggested by Hsu et al.[30]; and passively by forming new blood vessels and muscle fibers around the implanted membrane in the transition zone between the SIS and the integral myocardium. These two processes could reduce late development of congestive heart failure.

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CONCLUSION We conclude that 60 days after surgical procedure, the SIS integrated with the myocardium and new blood vessel were formed, as well as new cardiomyocytes, suggesting a angiomuscular regeneration.

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DISCLOSURE STATEMENT The authors declare no conflicts of interest.

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Authors’ roles & responsibilities CMGR

JCF MO KATC RC BOE LFJ CPB VFA LN RMM JRFN LCGS

Analysis and/or interpretation of data; final approval of the manuscript; conception and design of the study; implementation of operations and/or experiments; writing of the manuscript or revising it critically for its content Conception and design of the study; implementation of operations and/or experiments; writing of the manuscript or revising it critically for its content Analysis and/or interpretation of data; statistical analysis Final approval of the manuscript; conception and design of the study; writing of the manuscript or revising it critically for its content Final approval of the manuscript; conception and design of the study; implementation of operations and/or experiments Final approval of the manuscript; writing of the manuscript or revising it critically for its content Aid in surgery Paper discussion Aind in surgery Analysis of slides in pathological anatomy Paper review Analysis and/or interpretation of data; final approval of the manuscript; writing of the manuscript or revising it critically for its content Analysis and/or interpretation of data; final approval of the manuscript; conception and design of the study; implementation of operations and/or experiments; writing of the manuscript or revising it critically for its content

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26. Hata H, Bär A, Dorfman S, Vukadinovic Z, Sawa Y, Haverich A, et al. Engineering a novel three-dimensional contractile myocardial patch with cell sheets and decellularised matrix. Eur J Cardiothorac Surg. 2010;38(4):450-5.

18. Palmer EM, Beilfuss BA, Nagai T, Semnani RT, Badylak SF, van Seventer GA. Human helper T cell activation and differentiation is suppressed by porcine small intestinal submucosa. Tissue Eng. 2002;8(5):893-900.

27. Dar A, Shachar M, Leor J, Cohen S. Optimization of cardiac cell seeding and distribution in 3D porous alginate scaffolds. Biotechnol Bioeng. 2002;80(3):305-12.

19. Zhang J, Wang GY, Xiao YP, Fan LY, Wang Q. The biomechanical behavior and host response to porcine-derived small intestine submucosa, pericardium and dermal matrix acellular grafts in a rat abdominal defect model. Biomaterials. 2011;32(29):7086-95.

28. Matsubayashi K, Fedak PW, Mickle DA, Weisel RD, Ozawa T, Li RK. Improved left ventricular aneurysm repair with bioengineered vascular smooth muscle grafts. Circulation. 2003;108 Suppl 1:II219-25.

20. Badylak S, Obermiller J, Geddes L, Matheny R. Extracellular matrix for myocardial repair. Heart Surg Forum. 2003;6(2):E20-6. 21. Lionetti V, Recchia FA. New therapies for the failing heart: transgenes versus trans-cells. Transl Res. 2010;156(3):130-5.

29. Souza LCG, Carvalho RG, Pouzet B, Vilquin JT, Garcin I, MenaschĂŠ P, et al. The transplant of cardiac cells and myoblast skeletal cells in myocardial infarction. Rev Bras Cir Cardiovasc. 2002;17(4):312-22.

22. Bel A, Messas E, Agbulut O, Richard P, Samuel JL, Bruneval P, et al. Transplantation of autologous fresh bone marrow into infarcted myocardium: a word of caution. Circulation. 2003;108 Suppl 1:II247-52.

30. Hsu CC, Chen YW, Hao CL, Chong JT, Lee CI, Tan HT, et al. Comparison of automated 4D-MSPECT and visual analysis for evaluating myocardial perfusion in coronary artery disease. Kaohsiung J Med Sci. 2008;24(9):445-52.

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Gómez FA & ORIGINAL Ballesteros LE - Morphologic expression of the left coronary ARTICLE artery in pigs. An approach in relation to human heart

Morphologic expression of the left coronary artery in pigs. An approach in relation to human heart Expressão morfológica da artéria coronária esquerda em porcos. Abordagem em relação ao coração humano

Fabian Alejandro Gómez1, MSc; Luis Ernesto Ballesteros1, MSc

DOI: 10.5935/1678-9741.20140027

RBCCV 44205-1542

Abstract Introduction: In spite of its importance as an experimental model, the information on the left coronary artery in pigs is sparse. Objective: To determine the morphologic features of the left coronary artery in pigs. Methods: We evaluated 158 pig hearts. The left coronary artery was perfused with synthetic resin after their ostia had been catheterized. Diameters and courses of the vascular beds were measured with an electronic caliper (Mitutoyo®). Results: The diameter of left coronary artery was 6.98 ± 1.56 mm and its length was 3.51±0.99 mm. It was found to end up by bifurcating itself into the anterior interventricular artery and the circumflex artery in 79% of the cases, and by trifurcating in 21% of the cases, with the presence of the diagonal artery. The anterior interventricular artery ended up at the apex in 79.7% of the cases, and the circumflex artery at the posterior aspect of the left ventricle in 64% of the case, this artery never reached the posterior interventricular sulcus. An anastomosis between the terminal branches of the anterior interventricular artery and the posterior interventricular artery was found in 7.6% of the specimens. The antero-superior branch of the anterior interven-

tricular artery occurred in 89.9% of the hearts. A left marginal branch was observed in 87.9% of the cases with a diameter of 2.25±0.55 mm. Conclusion: Compared with humans, pigs have shorter left coronary artery trunks and branches; even the circumflex artery never reaches the posterior interventricular sulcus. Our findings are useful for the design of experimental hemodynamic and procedural models.

Universidad Industrial de Santander, Bucaramanga, Colombia.

Work carried out at Universidad Industrial de Santander Bucaramanga, Colombia.

1

Descriptors: Coronary Vessels. Coronary Circulation. Heart Resumo Introdução: Apesar de sua importância como modelo experimental, a informação sobre a artéria coronária esquerda em suínos é escassa. Objetivo: Determinar as características morfológicas da artéria coronária esquerda em suínos. Métodos: Foram avaliados 158 corações de porcos. A artéria coronária esquerda foram perfundidos com resina sintética após a sua óstios foram cateterizados. Diâmetros e cursos dos leitos vasculares foram medidos com um paquímetro eletrônico (Mitutoyo®).

Correspondence address: Luis Ernesto Ballesteros Universidad Industrial de Santander Departamento de Ciencias Básicas, Facultad de Salud Cra 32 # 29-31 - Bucaramanga, Colombia.

No financial support. Article received on January 28th, 2013 Article accepted on July 11th, 2013

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dos casos, sendo a artéria marginal na face posterior do ventrículo esquerdo em 64% dos casos, esta artéria nunca chegou ao sulco interventricular posterior. Uma anastomose entre os ramos terminais da artéria interventricular anterior e artéria interventricular posterior foi encontrado em 7,6% das amostras. O ramo ântero-superior da artéria interventricular anterior ocorreu em 89,9% dos corações. Um ramo marginal esquerda foi observado em 87,9% dos casos, com diâmetro de 2,25±0,55 mm. Conclusão: Em comparação com os seres humanos, os porcos têm troncos das artérias coronárias esquerdas mais curtos e ramos; até a artéria circunflexa nunca atinge o sulco interventricular posterior. Nossos resultados são úteis para a concepção de hemodinâmica experimental e modelos processuais.

Abbreviations, acronyms & symbols LCA CXA AIA LDA LBC PIA LMB

Left coronary artery Circumflex artery Anterior interventricular artery Left diagonal artery Left branch of the cone Posterior interventricular artery Left marginal branch

Resultados: O diâmetro da artéria coronária esquerda foi 6,98±1,56 mm e seu comprimento era de 3,51±0,99 mm. Verificouse que acabam bifurcando-se no interior da artéria descendente anterior e da artéria circunflexa em 79 % dos casos, e dividindo-se em três em 21% dos casos, com a presença da artéria diagonal. A artéria interventricular anterior acabou no ápice em 79,7%

Descritores: Vasos Coronários. Circulação Coronária. Coração.

INTRODUCTION

LCA in pigs have been conducted with small samples and are limited to qualitative descriptions[2,3,9]. The importance of the study of the LCA in pigs lies in the utilization of this species as an experimental model for cardiovascular surgery, hemodynamics, and for compared anatomy teaching - learning processes[3,9,11]. Similarly, given the large similarity existing between the hearts of humans and pigs, this work intends to enrich the knowledge on the coronary circulation in pigs to improve the applications using this animal species.

The left coronary artery (LCA) in pigs is the main vessel that provides irrigation to the heart. The LCA irrigates most of the left ventricle and atrium, including the interventricular septum. It emerges from the left aortic sinus, runs to the left behind of the pulmonary trunk, and ends up by bifurcating into the anterior interventricular artery (AIA) and the circumflex artery (CXA). Occasionally, the LCA trifurcates itself, also giving origin to the left diagonal artery (LDA), characteristic which has been described in humans with a frequency of 9-55% and in pigs at 20%[1-3]. The AIA descends through the homonym sulcus and emits septal branches, left branch of the cone (LBC), and right and left ventricular branches. The first left ventricular branch is called anterosuperior branch, and it usually has a good diameter and is projected towards the mid and lower thirds of the obtuse margin of the heart, with a frequency of 81-82% in humans. This branch has not been described in pigs. The AIA extends to the cardiac apex and commonly sends terminal branches to the posterior interventricular sulcus, which may anastomose with the posterior interventricular artery (PIA)[3]. The AIA ending in the apex has been described in a range of 6-33%, while at the posteroinferior aspect has been described in human hearts with a frequency of 42-80%[4-6]. The CXA presents two segments: The first one runs along the left atrioventricular sulcus to the obtuse margin of the heart, whereas the second segment continues through the posterior atrioventricular sulcus and may occasionally ends up at the crux cordis. The main branches of the CXA are the left marginal branch (LMB), left atrial branches and left ventricular branches[3]. In human hearts the CXA has been described as ending up as the PIA (left dominance), with an incidence of 5-20%[7,8] whereas in pigs this morphologic feature occurs rarely[3,9,10]. The sparse studies referring to the

METHODS This cross-over descriptive study assessed the LCA of 158 hearts of commercial stock pigs (Pietrain, Landrace Belga and Large White mixed breeds) destined to sacrifice with a mean age of 5 months, obtained from the Vijagual Refrigerating Plant of Bucaramanga - Colombia. The organs were subjected to an exsanguination process in a water source for 6 hours. After the LCA was marked with a silk suture at its origin, it was catheterized through its ostium and perfused with polyester resin (80% palatal GP41L and 20% styrene) impregnated with red mineral. Then, the hearts were subjected to a partial corrosion process with a 15% KOH (potassium hydroxide) in order to remove the subepicardial fat located at the interventricular and atrioventricular sulci. The diameters of the LCA and its branches were measured at their origins using a digital caliper (Mitutoyo®); lengths were determined, and the finalization of the AIA was typified at the lower third of the anterior interventricular sulcus, at the apex, or at the posterior aspect of the heart. Similarly, the finalization of the CXA was assessed at the obtuse margin of the heart, at the posterior aspect of the left ventricle, at the crux cordis, or at the posterior interventricular sulcus. The branches anterosuperior (ASB) and LMB were characterized

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with respect to diameters, lengths, and irrigated ventricular segments. The data were annotated in a physical matrix and recorded in a digital medium using Excel tables. Photographs of all of the pieces analyzed were taken to support the observations. The continuous variables were analyzed using the t test, whereas the discrete variables were analyzed using Pearson’s χ2 test and Fisher’s exact test. The results were evaluated using the “Epi – Info 3.5.3” statistical program. The significance level used for this research was (P<0,05).

ended up more frequently (39.4%) at the mid third of the obtuse margin of the heart (Table 3). The ACX length was 80±16.26 mm being lower with respect to the length of the AIA (P=0,6317). The CXA ended up at the posterior aspect of the left ventricle in 101 hearts (64%); in 55 samples (34.8%) it reached the crux cordis (Figure 4), whereas in two cases (1.2%) it was short and ended up as the LMB. Its proximal diameter was 3.68±0.79 mm; its mid diameter was 2.75±0.55 mm, and its distal diameter was 1.66±0.55 mm. The smaller proximal diameter

RESULTS The mean weight of the 158 hearts obtained from pigs sacrificed when weighing 90 kilograms was 360±61.21 grams. The LCA had a diameter of 6.98±1.37 mm and a length of 3.51±0.96 mm. This artery bifurcated into the AIA and CXA in 125 hearts (79%) and trifurcated with an additional LDA in 33 specimens (21%), 22% of which were males and 20% females. (Table 1). The LDA had a diameter of 2.7±0.72 mm and a length of 72.1±20.48 mm. It ended up at the lower third of the obtuse margin of the heart in 16 specimens (61.5%), whereas in 7 (27%) it ended up at the mid third. In 3 specimens (11.5%) it was short and only reached the upper third of the said margin. The LBC was observed in 109 specimens (69%), with a diameter of 1.25±0.39 mm; with the distance from its emergence to the left coronary ostium measuring 18.54±5.34 mm (Figure 1). The AIA length was 95.6±15.25 mm. The AIA ended up at the apex in the majority of the cases (79.7%) both in males and in females, whereas its termination at the lower segment of the posterior aspect was 12.7%, a non-significant statistical difference (P=0.59) (Table 2). The AIA had on average 5±2.05 right ventricular branches and 5±2.11 left ventricular branches. Its proximal diameter was 4.06±0.73 mm; the mid diameter was of 2.82±0.54 mm, and its distal diameter was of 1.61±0.36 mm. The presence of an anastomosis between the terminal branches of the posterior interventricular artery and the AIA was found in 12 specimens (7.6%) (Figure 2). The ASB of the AIA was found in 142 hearts (89.9%), with a diameter of 1.84±0.68 mm and a length of 45.75±21.39 mm. The distance between its emergence and the left coronary ostium was of 24.63±7.42 mm (Figure 3). This branch

Fig. 1 - Obtuse edge of the heart. LA: Left Atrium. LV: Left Ventricle. RV: Right Ventricle AIA: Anterior Interventricular Artery. CXA: Circumflex Artery. LDA: Left Diagonal Artery

Table 1. Division of the left coronary artery in anterior interventricular artery (AIA), circumflex artery (CXA) and left diagonal artery (LDA), by gender discrimination. Bifurcation (AIA y CXA) Trifurcation(AIA, CXA Y LDA) Total

Total sample 125 33 158

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% 79 21 100

Males 69 19 88

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% 78 22 100

Females 56 14 70

% 80 20 100

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G贸mez FA & Ballesteros LE - Morphologic expression of the left coronary artery in pigs. An approach in relation to human heart

Table 2. Finish of anterior interventricular artery in homonym groove, cardiac apex and posterior surface, by gender discrimination. Middle third Lower third Cardiac apex Posterior surface Total

Total sample 3 9 126 20 158

% 1.9 5.7 79.7 12.7 100

Males 3 4 71 10 88

% 3.4 4.4 81 11.2 100

Females 5 55 10 70

% 7.1 78.6 14.3 100

Fig. 2 - Anastomosis between branches of the anterior and posterior interventricular arteries. LV: Left Ventricle. RV: Right Ventricle. AIA: Anterior Interventricular Artery. PIA: Posterior Interventricular Artery. (*): Anastomosis near the apex of the heart

of the CXA with respect to the AIA was not statistically significant (P=0.0905). The LMB was found in 139 hearts (87.9%), ending up at the mid third of the obtuse margin of the heart in 72 specimens (51.7%). In 46 (33%) specimens ended up at the lower third, whereas in 15 specimens (11%) they ended up at the level of the apex. It was very short, reaching the upper third in 6 cases (4.3%). Its proximal diameter was 2.25卤0.55 mm,

Fig. 3 - Anterior view of the heart. LV: Left Ventricle. RV: Right Ventricle. AIA: Anterior Interventricular Artery. CXA: Circumflex Artery. Arrow: Antero Superior Branch, finishing in the middle third of heart obtuse edge

Table 3. Finish of anterosuperior branch (ASB) of anterior interventricular artery (AIA) on the obtuse side of the heart, by gender discrimination. Upper third Middle third Lower third Cardiac apex Total

Total sample 40 56 43 3 142

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% 28.2 39.4 30.3 2.1 100

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% 21.8 47.4 27 3.8 100

Females 23 19 22 64

% 36 30 34 100

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Fig. 4 - Posterior view of the heart. LV: Left Ventricle. RA: Right Atrium. RCA: Right Coronary Artery. PIA: Posterior Interventricular Artery. CXA: Circumflex Artery, ending near the crux cordis

Fig. 5 - Obtuse edge of the heart. LA: Left Atrium. LV: Left Ventricle. AIA: Anterior Interventricular Artery. CXA: Circumflex Artery. LMB: Left Marginal Branch, ending at the apex of the heart

and its distal diameter was 1.23±0.32 mm. It has a length of 63.13±14.97 mm and the distance from its point of finalization to the apex was 36.59±13.84 mm (Figure 5).

The diameter of the LCA has not been reported in pigs, and we consider that our finding (6.98 mm) is considerably greater than what has been reported in humans[8,13,15,20], a trend that is maintained with the diameters of all of the branches, taking into account that the hearts evaluated were obtained from pigs with a mean weight of 90 kilograms. The bifurcated expression of the LCA (AIA and CXA) observed in 79% of the cases and trifurcated (AIA, CXA, and LDA) in the 21% of the samples evaluated, is consistent with the report by Jordão et al.[1]; but not with the works by Kato et al.[2], Sahni et al.[3], and Crick et al.[9] who reported the bifurcate expression in the 100% of the pig hearts they evaluated. This disagreement may be understood by the different criteria utilized to characterize and name the branches that irrigate the obtuse aspect the pig hearts. The bifurcation of the LCA has been reported in humans with a frequency of between 40-70%, the trifurcate expression with a frequen-

DISCUSSION The length of the LCA was 4-5 mm in pigs[3,12] and in humans of 6-15 mm[13-16] reported in prior studies is longer than that found in this study (3.51 mm), an important issue to bear in mind for the training in the passing of catheters for experimental cardiovascular surgery models. LCAs shorter than 6 mm have been recorded in humans with an incidence of 7-15%[16-18]. Short coronary arteries are considered as risk factors for an appropriate coronary perfusion during aortic valve replacements, because the catheter may be inserted into one of the terminal branches and thus cause ischemic areas with potential arrhythmias, myocardial infarctions, or both[16,19].

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cy of 9-55%, and a tetrafurcate expression between 5-7% of the heart specimens studied[13,15,16,21]. In agreement with prior studies in pig hearts, our work failed to observe the tetrafurcate division of the LCA. This morphologic expression differs slightly from the left coronary irrigation of humans. The LDA ending up at the lower third of the obtuse margin of the heart in 61.5% of the specimens is in disagreement with the findings of Jordão et al.[1] who reported a short LDA (22.4 mm) ending up at the upper third in 95% of the cases. Some studies in human hearts indicate a predominance of LDA penetrating the myocardium at the level of the mid third of the ventricular surface[21,22], whereas some other works report a predominance of the LDA ending up at the upper third[15]. Length variations of the diagonal branches are particularly relevant in cardiac surgery because their subepicardial portion is commonly used to implant a bypass graft, so the existence of a short LDA limits the likelihood to perform this type of procedures[23]. ASB have not been described in studies with pigs. The occurrence of this vessel in our series (89.9%) is slightly more common than that reported by works conducted in humans[15,22], with which there is concordance in the finalization at the mid third of the left ventricle. Our findings concerning the length and diameter of the ASB (45.7 and 1.84 mm) are similar to reports in humans[15,22]. The LBC has only been reported before by Sahni et al.[3] who described it as a short branch with no subepicardial anastomosis with the right branch of the cone, a morphologic feature that is consistent with what was observed in our work. The AIA ending up at the level of the apex in 79% of the cases is consistent with the findings by Sahni et al.[3] with only minor differences as to the number of left ventricular branches emitted by this artery (3-4), in comparison with our work (5 branches). In humans, it has been reported to end up at the lower segment of the posterior interventricular sulcus in 42-80% of the cases, and at the apex in the 6-33% of the subjects[5,6,13,24,25]. The site where the AIA ends up can be considered as a difference in the cardiac irrigation of humans and pigs. The presence of anastomosis between the terminal branches of the AIA and the posterior interventricular artery has been described by Lumb et al.[12] in a qualitative manner, and was observed in 7.6% of the specimens of our series, with this morphologic expression being relevant as protective of the coronary irrigation. The distal segment of the AIA that, after overcoming the apex, is distributed into the neighboring territory of the diaphragmatic aspect, irrigates the area not reached by the posterior interventricular artery. This anatomic expression should be taken into account when assessing myocardial infarctions located in the lower segment of the posterior wall of the heart, because the arterial obstruction could compromise the distal portion of the AIA instead of the posterior interventricular branch as it is commonly believed.

In agreement with most prior studies[3,9,12] the CXA did not end up at the posterior interventricular sulcus in any of our specimens; it mostly ended up at the posterior aspect of the left ventricle (64%) and to a lower percentage at the crux cordis. The study by Weaver et al.[10], who reported the CXA ending up as the posterior interventricular artery in 5% of the cases should be highlighted. The CXA has been reported as ending up at the posterior interventricular sulcus with a frequency of 7 – 23% in human hearts, with this being the feature of the left coronary dominance[5,8,13,14,21]. The LMB has not been sufficiently characterized in either humans or pigs. The occurrence of this vessel as reported by Sahni et al.[3] is similar to our finding (87.9%). Short CXAs have been described as ending up as the LMB with a frequency of 13-25.3% in human hearts[5,8,13,21]. In the majority of the cases the marginal branches are seen to irrigate segments of the obtuse aspect of the heart through collateral branches with horizontal or oblique courses. CONCLUSION • Compared with humans, pigs have shorter LCA trunks and branches; even the CXA never reaches the posterior interventricular sulcus. • The greater diameter of the LCA and its branches found in the present study in comparison with what has been reported in humans is probably due to the greater weight of the hearts of the pigs evaluated. • The incidence of a trifurcate division of the LCA in pigs is situated in a mid range with respect to what has been reported in human hearts. • The ASB, LMB, and LDA with their good length and diameter, are relevant players for the irrigation of the obtuse aspect and posterior wall of the left ventricle in pig hearts. • The qualitative and morphometric knowledge of the LCA and its branches in pigs supports the utilization of this species for experimental models. ACKNOWLEDGEMENTS To Vijagual Refrigerating Plant in the city of Bucaramanga – Colombia and to Dr. Luz Stella Cortés, DMV for donating the pieces to conduct this investigation.

Authors’ roles & responsibilities FAG LEB

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Characterization of the left coronary artery in pigs, coronary vessels injection, records of findings, and writing the paper Characterization of the left coronary artery in pigs, coronary vessels injection, records of findings, and writing the paper

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Teixeira Sobrinho M, et al. - Preoperative therapy restores ventilatory ORIGINAL ARTICLE parameters and reduces length of stay in patients undergoing myocardial revascularization

Preoperative therapy restores ventilatory parameters and reduces length of stay in patients undergoing myocardial revascularization Fisioterapia pré-operatória restabelece parâmetros ventilatórios e reduz tempo de internação após revascularização do miocárdio

Moises Teixeira Sobrinho1, MD; Gabriel Negretti Guirado1, MD; Marcos Augusto de Moraes Silva2, MD, PhD

DOI: 10.5935/1678-9741.20140021

RBCCV 44205-1543

Abstract Introduction: The frequency of surgical procedures has increased steadily in recent decades, including the myocardial revascularization. Objectives: To demonstrate the importance of physiotherapy in the preoperative period of cardiac surgery in relation to the reduction of hospital stay, changes in lung volumes and respiratory muscle strength. Methods: We conducted a prospective study with patients undergoing myocardial revascularization, the Hospital das Clínicas da Universidade Estadual Paulista (UNESP)/Botucatu - SP. We evaluated 70 patients of both genders, aged between 40 and 75 years, subdivided into two groups: group I - 35 patients of both genders, who received a written protocol guidance, breathing exercises and respiratory muscle training in the preoperative period and group II - 35 patients of both genders, who received only orientation of the ward on the day of surgery. This study was approved by the Ethics Committee of UNESP / Botucatu - SP. Results: Maximal inspiratory pressure in third postoperative day and fifth postoperative day and significant difference between groups, being better for the intervention group. Expiratory pressure was significant in fifth postoperative day in the intervention group compared to controls. The difference of length of hospital stay in the postoperative was found between the groups with shorter hospital stay in the group receiving preoperative therapy. Conclusion: Physical therapy plays an important role in the

preoperative period, so that individuals in the intervention group more readily restored the parameters evaluated before surgery, in addition, there was a decrease in the time of the postoperative hospital stay. Thus, it is thought the cost-effectiveness of a program of preoperative physiotherapy.

Hospital das Clinicas da Faculdade de Medicina de Botucatu-SP (UNESP), Botucatu, SP, Brazil. 2 Hospital das Clinicas da Faculdade de Medicina de Botucatu (UNESP), Cardiovascular Surgery Service, Botucatu, SP, Brazil.

Distrito de Rubião Junior s/n – Botucatu, SP, Brazil – Zip code: 18618-970 E-mail: mtsobrinho@ig.com.br

Descriptors: Thoracic Surgery. Breathing Exercises. Physical Therapy (Specialty). Resumo Introdução: Procedimentos cirúrgicos aumentaram progressivamente nas últimas décadas, inclusive a revascularização do miocárdio(RM). Objetivos: Demonstrar a importância da fisioterapia no préoperatório de cirurgia cardíaca, em relação à redução do tempo de internação hospitalar, alteração de volumes pulmonares e força muscular respiratória. Métodos: Foi realizado estudo clínico prospectivo, com pacientes submetidos à revascularização do miocárdio, no Hospital das Clínicas da Universidade Estadual PaulistaUNESP / Botucatu SP. Foram avaliados 70 pacientes de ambos os gêneros, com faixa etária entre 40 a 75 anos, randomizados por meio programa computadorizado em dois grupos: Grupo I - 35 pacientes de ambos os sexos, que receberam um protocolo de orientação por escrito, exercícios respiratórios e treinamento muscular respiratório no

1

No financial support.

Correspondence address: Moises Teixeira Sobrinho Hospital das Clinicas da Faculdade de Medicina de Botucatu-SP - UNESP

Article received on April 2sd, 2013 Article accepted on July 8th, 2013

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dia da cirurgia. Trabalho foi aprovado pelo Comitê de Ética da Universidade Estadual PaulistaUNESP / Botucatu - SP. Resultados: A avaliação das pressões inspiratórias máximas evidenciou aumento significativo no terceiro dia pós-operatório e quinto dia pós-operatório para o grupo de intervenção e análise das pressões expiratórias máximas apresentou valores significativos apenas no quinto dia pós-operatório para o grupo intervenção em relação ao grupo controle, observando-se ainda que o grupo submetido ao protocolo de tratamento fisioterapêutico pré-operatório apresentou menor tempo de internação hospitalar. Conclusão: A fisioterapia possui papel importante no préoperatório, de modo que indivíduos do grupo intervenção restauraram com maior presteza os parâmetros avaliados antes da cirurgia, além disso, houve diminuição no tempo de internação pós-operatório.

Abbreviations, acronyms & symbols BMI Body mass index CABG Coronary artery bypass graft surgery CPB Cardiopulmonary bypass Cpm Cycles per minute FRC Functional residual capacity HDL-cholesterol High-density lipoprotein cholesterol ICU Intensive care unit LDL-cholesterol Low-density lipoprotein cholesterol MEP Maximal voluntary expiratory MIP Measurement of inspiratory pressure Ml Milliliters MR Myocardium revascularization PRE Preoperative period RV Residual volume

pré-operatório e Grupo II - 35 pacientes de ambos os gêneros, que receberam apenas orientação de rotina da enfermaria no

Descritores: Cirurgia Torácica. Fisioterapia (Especialidade). Exercícios Respiratórios.

INTRODUCTION

Observing the fact that they are common pulmonary complications of CABG with CPB was justified to carry out this research, there is great importance in properly carrying out evaluations, guidelines and breathing exercises in the period before surgery, and addition, observe the influence and duration of physical therapy assistance in the preoperative period and also its behavior in the postoperative period.

The cardiac surgery was always clothed with great interest, curiosity, and in some moments, mysticism, and fact understandable when we analyzed the noble importance of this component for the proper functioning of the human body[1]. In recent decades the frequency of surgical procedures has progressively increased, among them the myocardial revascularization (MR). Cardiovascular diseases are a serious public health problem in Brazil[2]. In individuals over 70 years old it is estimated an incidence of 70% of coronary artery disease. As the age is a determinant of coronary atherosclerosis, a growing number of elderly people will be subjected to MR and/or other therapeutic methods[3,4]. The main risk factors that contribute to cardiac diseases are: smoking, high levels of low-density lipoprotein cholesterol (LDL-cholesterol), low level of high-density lipoprotein cholesterol (HDL-cholesterol), diabetes mellitus, systemic hypertension, family history, lifestyle, obesity, sedentary lifestyle and alcohol intake as factors related to atherosclerosis and its clinical manifestations[4,5]. The coronary artery bypass graft surgery (CABG) procedure is indicated for the treatment of ischemic heart disease that is manifested clinically by angina and acute myocardial infarction. The CABG surgery creates a new route for the blood flow and, is used for making a diversion of blood to the portions of the coronary artery distal to the obstructive atherosclerotic involvement[1,5]. With the advancements in care of physical therapy in the preoperative period, surgical techniques, cardiopulmonary bypass (CPB), techniques for myocardial protection, anesthesia and intensive care in the post-operative period, there was a decrease in morbidity and mortality of MR which caused the surgical indication in groups of patients increasingly complex[6,7].

Objective To demonstrate the importance of the role of physical therapy in the preoperative period of cardiac surgery with extracorporeal circulation, in relation to the respiratory muscle strength, pulmonary volumes and duration of hospital stay after surgery. METHODS We performed a prospective clinical study, simple blind, in the period from July 2009 to September 2011 in the ward of cardiac and thoracic surgery at Hospital das Clínicas da Universidade Estadual Paulista (UNESP), Botucatu-SP. We evaluated 70 patients of both gender, age ranging from 40 to 75 years, undergoing CABG with use of CPB, randomized by means of a computerized software (STATTREK) and delivered in a sealed envelope to the physical therapist responsible for primary health care, subdividing into two groups: - Group I (GI) - Thirty-five patients, undergoing physiotherapeutic intervention, performed under supervision, once a day, during the period that preceded the surgery. The protocol consisted of breathing exercises (breathing in time, deep breathing followed by prolonged expiration, sustained maximal inspiration with apnea of 6 seconds, and diaphragmatic breathing associated with the mobilization of the upper limbs) and breathing exercises with threshold - IMT® (Thresh-

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old - IMT® Inspiratory Muscle Trainer, HealthscanProducts Inc.) at an intensity of 40% of the initial MIP with three sets of ten repetitions, respecting two-minute intervals between each series. - Group II (GII) - thirty-five patients who did not undergo the physical therapy protocol during the preoperative period, receiving only guidelines ward routine. We included patients of both sexes, aged 40-75 years with coronary artery disease admitted for cardiac surgery with cardiopulmonary bypass (CPB) MR, who agreed to participate in the study. We excluded patients who require the use of intra-aortic balloon, carrying pulmonary pathology, musculoskeletal impairment and severe neurological surgery performed without CPB, emergency surgery, homodynamic instability, and any event that threatens the integrity of patient or the fidelity of the measures analyzed.

adjust the training load (40% MIP) using the Threshold - IMT® (Threshold - IMT® inspiratory Muscle Trainer, HealthscanProducts Inc.). A small hole about one millimeter (mm) was performed to prevent occlusion of the glottis and influence of the buccinator muscles during MIP maneuver[9]. Mark Wright 8 display with 35 mm (FERRARIS) in PRE moments, 3PO and 5PO were used to prevent lung volumes. The minute volume was obtained with the patient breathing for a minute for a mouth connected to the spirometer. Tidal volume was obtained indirectly by the relationship between the respiratory rate and minute volume (MV/FR), the two volumes measured in milliliters (ml) and respiratory rate was measured in cycles per minute (cpm) and obtained by direct observation of respiratory cycles during the evaluation of the minute volume[7]. Procedures/treatment Patients allocated to the GI protocol underwent preoperative physiotherapy consisting of breathing exercises (breathing in time, deep breath and then exhaling long, sustained maximal inspiration with a 6-second apnea, diaphragmatic breathing associated with mobilization of the upper limb, with three series out of ten for each breathing exercise) and breathing exercises with the device Threshold - IMT®. We conducted three sets of ten repetitions with an interval of two minutes each repetition, once a day for every day of hospitalization in the PRE, with a load of 40% of the initial MIP, obtained by manovacuometry[8-10]. The GII patients received only guidelines ward routine before surgery, but postoperatively, both groups performed physical therapy as needed by staff physiotherapy service.

Delimitation All patients were evaluated by the same evaluator (preoperative period - PRE), third postoperative (3PO) and fifth postoperative days (5PO), as well as received physiotherapeutical treatment, according to their needs in the postoperative period by physical therapy team in the hospital and only Group I received physiotherapy in the preoperative period. The variables evaluated were: body mass index (BMI) criterion for obesity was a BMI ≥ 30 kg/m², smoking (patients who smoke or have smoked up to 30 days before surgery and for former smokers those with a prior history, 30 days ago) as well as the time of surgery, CPB, anoxia, IOT (defined by the sum between the anesthesia time and the time that the patient remained with the endotracheal tube in the intensive care unit - ICU), VM (IOT time defined by the time of ventilator disconnection (when the patient was placed in spontaneous ventilation in the T-tube), ICU stay (when the patient arrived in the intensive care unit until discharged to the ward bed) and length of stay in the OP (obtained from the time that the patient arrived in the ICU of the Cardio chest until the time of discharge.) All these data were obtained by means of the daily developments of medical and nursing staff. The assessment of respiratory muscle strength was obtained by measurement of inspiratory pressure (MIP) and maximal voluntary expiratory (MEP) in the preoperative period (PRE), 3PO and 5PO using analog manometer Commercial Medical® brand spread over -120 to 120 cmH2O equipped with adapter buccal and nasal forceps according to the technique described by Nephew et al. (2008). The MIP measurement was performed from residual volume, and MEP was obtained from total lung capacity. Three measurements were taken technically satisfactory, and if there were more than 20% difference between the measurements, a fourth and even fifth measurement would be performed, being always considered the highest value obtained. The MIP was performed for evaluation of inspiratory muscle strength in three different stages of the study (Pre, 3PO and 5PO), as well as to

Statistical Analysis The sample should be made ​​with at least 26 patients who were randomly divided into two study groups (with physical therapy preoperatively and control patients who did not receive preoperative physiotherapy). We considered the level of significance of 5% and a test power in the order of 80% for a minimum difference in the order of two. The comparison between the groups for age and body mass index (BMI) was performed by Wilcoxon test for independent samples. The smoking variable was analyzed using Goldman to compare proportions within and among multinomial populations. The perfusion, anoxia, mechanical ventilation, anesthesia, surgery, ICU and postoperative hospital stay were obtained in minutes and analyzed by Student’s t test or the nonparametric Mann-Whitney test. MIP, MEP, TV, MV and FR were assessed by Friedman tests for comparison of the moments in each group and Mann Whitney test to compare groups at each time, adopting a significance level of 5% probability of rejecting null hypothesis. This study was approved by the Research Ethics Committee of Universidade Estadual Paulista (UNESP)/Faculty of

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Medicine of Botucatu (registration number 236/2009, protocol 3223) and all patients signed an informed consent form.

Between the GI and GII, no significant difference regarding the proportion of ex-smokers, smokers and nonsmokers, in other words, the groups were homogeneous as demonstrated below (Table 2).

RESULTS

Maximum Inspiratory Pressure (MIP) The mean values ​​the for maximum inspiratory pressures evaluated in the preoperative period and 3PO showed no significant difference between groups (P=0.276 and 0.065; respectively), however, we observed greater inspiratory muscle strength for GI in relation to GII in 5PO (P=0.001) (Figure 2).

Seventy patients were divided into two groups, Group I composed of 35 patients (12 female and 23 male) and Group II, with 35 patients (six female and 29 male), as illustrated in Figure 1. No significant difference was noticed between groups for the variables age (GI 58.9±9.53 years and GII 61.4±8.43 years; P=0.26) and body mass index (GI 26.8±3.96 kg/m2 and G II 26±3.86 kg/m2) (Table 1). The groups were homogenous concerning presence of active smoking, ex-smokers and nonsmokers, as illustrated in Table 2.

Maximum Expiratory Pressure (MEP) The mean value for the maximum expiratory pressure obtained in the preoperative period for GI was 110 (120/50 cmH2O) and 110 cmH2O (120/80 cmH2O) for GII, not presenting significant difference between groups (P=0.704). However, the values r​​ eferring MEP measured in the 5PO showed significant difference between groups (P=0.001), as illustrated in Figure 3.

Table 1. Patient characteristics regarding age and BMI. Features Age (years) BMI (kg/m2)

Group I (n = 10), Group II (n=10) Mean/SD Mean/SD 58.9±9,53 61.4±8.43 27.08±3.96 26±3.86

Wilcoxon P-value 0.26 0.10

Minute Volume (MV) The analysis of the minute volume variable is presented in Figure 4. The values ​​the MV obtained in the preoperative period presented significant difference between groups (GI:

BMI: body mass index; Wilcoxon test. * P<0.05

Fig. 1 - Characterization of groups by gender.

Table 2. Number and proportion of patients in each group according to the presence of active smoking, ex-smokers and nonsmokers. Groups Group I (physio) Group Il (no physio) Amount

ex-smokers 9 (0.26) aA 14 (0.40) aA 23 (0.33)

Smoking active smoking 11 (0.31) aA 6 (.17) aA 17 (0.24)

nonsmokers 15 (0.43) aA 15 (0.43) aA 30 (0.43)

Amount 35 (1.00) 35 (1.00) 70 (1.00)

Two proportions followed by the same lowercase letter do not differ in groups (rows). Two proportions followed by the same capital letter do not differ in the types of smoking (P>0.05). Goldman test to compare proportions between and within populations multinomina.

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Fig. 3 - Median for maximum expiratory pressure (MEP) variable at different times of the operation in the different groups. Friedman test for comparison of moments in each group and Mann Whitney test to compare the groups at each time, *P<0.05.

Fig. 2 - Median maximum inspiratory pressure (MIP) variable in different moments of the operation of each group analyzed (with and without physical therapy preoperatively). Friedman test for comparison of moments in each group and Mann Whitney test to compare the groups at each time, *P<0.05.

Fig. 4 - Median minute volume (VM ) variable at different times of the operation of each group analyzed. Friedman test for comparison of the moments in each group and the Mann Whitney test for comparison between groups at any time, *P<0.05.

Fig. 5 - Median tidal volume variable at different times for the group treated with preoperative physiotherapy and without physical therapy preoperatively. Friedman test for comparison of moments in each group and Mann Whitney test to compare the groups at each time, *P<0.05.

Table 3. Values for the infusion time, anoxia, mechanical ventilation, anesthesia, surgery, ICU stay and hospital stay after surgery for preoperative, 3PO and 5PO. Groups Group I (physio) Group II (no physio) P-value

Perfusion(1) Anoxia(1) 80 min (160-35) 70 min (150-40) 0,255

35 min (88-20) 40 min (94-14) 0,506

Time on Mechanical Ventilation(1) 855 min (1685-490) 870 min (1780-390) 0,874

Variables Time Anesthesia(2) Surgery time(2) 300,29 min ± 70,37 291,20 min ± 63,19 0,572

246,86 min ± 68,64 227,86 min ± 60,89 0,225

ICU time(1) 2630 min (2880-2100) 2590 min (2780-855) 0,152

Length of Stay PO(1) 8460 min (10080-6730) 9970 min (19580-6730) 0,001*

Values are shown as mean ± standard deviation or median (minimum and maximum values). (1) Mann and Whitney (2) Student's t test. *Significant difference between groups (P <0.05). ICU: intensive care unit; PO: postoperative

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In the present study, we observed no significant difference between the subjects of Group I and Group II as the characteristics (age, BMI, smoking and number of co morbidities), which suggests that the study subjects in both groups were homogeneous. In the study by Leguisamo et al.[9], with 86 patients undergoing CABG, divided into two groups: the intervention group (44 patients) who were assessed and received physiotherapeutic guidance at least 15 days before surgery. The control group received routine care on the day of hospitalization. The average MIP between groups showed neither significant difference in the preoperative period nor in the 1PO and 6PO. In the present study it was observed that there was no significant difference between groups to measure MIP in the preoperative period, but now in times of 3PO and 5PO significant difference between groups was found. Similarly, no significant difference in the amount of MEP preoperatively in the 3PO and between groups. However in 5PO, there was significant difference between the groups with the best values​​ of the group that performed physical therapy before surgery. Barros et al.[11] evaluated the MIP and MEP in the preoperative period, the first day after surgery and in 38 patients undergoing CABG with CPB who were divided into two groups: 23 patients in group I (respiratory muscle training) and 15 in group II (control). Group I received conventional physiotherapy over respiratory muscle training and Group II the conventional physiotherapy. The authors found that the values ​​obtained for MIP and MEP in hospital discharge were higher in group I. There was no decrease in maximal respiratory pressures, transdiaphragmatic pressure and diaphragm pressure, indicating weakness of respiratory muscle strength[12,13]. Agreeing with the authors cited above, we observed in the present study, after cardiac surgery, MIP values ​​in GI and GII which decreased in 3PO, however the value of MIP in 5PO increase was observed for GI values ​​compared to those in PRE and 3PO since the GII values ​​remained stable in 3PO. The authors noted the drop in MEP in 3PO in both groups, however, in 5PO MEP has increased in GI. Regarding PRE and 3PO in GII no return value was observed in PRE. Arcêncio et al.[12] conducted a study with 30 patients, aged 50 years-old and candidates for CABG and / or heart valve, dividing into two groups. Intervention group comprised 15 patients who underwent at least a two weeks inspiratory muscle training using incentive spirometry (“Threshold - IMT®) with 40% charge of the MIP and control group with 15 patients who received only general guidelines. The authors compared the spirometric values ​​before and after training and showed no significant difference in the values ​​of MIP and MEP[14]. Elias et al.[15] studied 42 patients aged 18 to 75 years-old with coronary artery disease, in the pre-and postoperative period, divided into two groups. Intervention group received TMR with Threshold - IMT® and control group received only guidelines. The TMR both pre and post-operative period consisted of three

Fig. 6 - Median variable respiratory rate at different times of the operation of each group analyzed (with and without physical therapy preoperatively). Friedman test for comparison of moments in each group and Mann Whitney test to compare the groups at each time, *P<0.05.

10,110 ml and GII: 12,660 ml; P=0.001). However, these values ​​have not showed significative difference in the 3PO and 5PO (P=0.585 and P=0.329; respectively). Tidal Volume Figure 5 illustrates the analysis of variable volume obtained in the PRE, 3PO and 5PO. Upon PRE, a significant difference between groups was detected (GI: 607 ml and GII: 769 ml, P=0.003), but these values ​​were not significantly different for the 3PO and 5 PO (P=0.059 and P=0.549; respectively). Respiratory rate (RR) The median refers to the respiratory rate obtained preoperatively for GI and GII showed no significant difference (16 cpm and 18 cpm, respectively, P=0.602). Likewise, the measurements were made in the 5PO 3PO and showed no significant difference between groups (P=0.090 and P=0.886, respectively), as shown in Figure 6. Infusion time, anoxia, mechanical ventilation, anesthesia, surgery, ICU stay and hospital stay after surgery. Variables infusion time, anoxia, mechanical ventilation, anesthesia, surgery and ICU stay did not significantly differ between groups, however, significant difference was observed for the length of stay variable in the postoperative period (P=0.001), as shown in Table 3. DISCUSSION Studies by Feltrim et al.[10] show that performing preoperative physiotherapy is more effective in reducing respiratory complications in patients with moderate or higher risk than those whose risk was low.

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sets of 10 inspiratory exercises once a day for three consecutive days. It was observed that after cardiac surgery there was a significant reduction in MIP and MEP in both groups. Morsch et al.[13] conducted a study to evaluate 108 patients undergoing elective CABG surgery from April 2006 to February 2007 (preoperatively and postoperatively). The average values ​​of MIP in the preoperative period were significantly decreased compared to 6 days after the surgery (P<0.001). The authors also observed a significant decrease in the values ​​of MEP obtained on the 6th postoperative day compared to the preoperative period (P<0.001). Patients with respiratory muscle weakness have higher risk of postoperative pulmonary complications. The respiratory muscle training in the pre-operative may prevent pulmonary complications in patients undergoing thoracic surgery [16]. There may be a reduction of all lung volumes resulting from factors such as diaphragmatic dysfunction, pain, absence of deep breaths, pulmonary changes and ribcage. The functional residual capacity (FRC) decreases because of the reduction of both the residual volume (RV) and expiratory reserve volume. The ventilation is affected by VC reduction by approximately 20%, and the increase in FR[22-24]. The sum of these factors cause changes in the mechanics of respiration, which leads to a shallow breathing pattern of decreased lung volume[13]. Patients undergoing CABG develop mostly PO pulmonary dysfunction with a significant reduction in lung volumes, impairments in respiratory function, decreased lung compliance and increased work of breathing. The reduction in lung volumes and capacities contributes to changes in gas exchange, resulting in hypoxemia[17]. In this study, the VM showed significant difference regarding the groups I and II in the preoperative period but not significant between groups in 3PO. Likewise, the mean value of the VM for the GI 5PO, there was no significant difference in the GII. The mean value of VC in PRE in GI was significant, as the mean value of the VC in GII patients, however in GI and GII we observed in 5PO and 3PO that there was no significant difference. It was observed in GI at different times that the increase of VM will be very likely due to increased FR, since the current VC remained without many changes between different times. Barros et al.[11] demonstrated a significant decrease in lung volumes in patients undergoing cardiac surgery in the postoperative period. Carvalho et al.[18] observed a decrease in the values ​​of minute volume and tidal volume measured on the 2nd postoperative day, however, these values ​​showed gradual improvement returning to the values o​​ btained at baseline (preoperative period) at the time of hospital discharge. In a study, Guizilini et al.[19] evaluated 30 patients with a mean age of 56 years and divided into two groups, group A (n=15) without CPB and group B (n=15) with CPB. All patients underwent pulmonary function. In both groups, there was a decrease in FVC until the fifth postoperative day (P<0.05).

Regarding the respiratory rate in the present study, we can verify that there was an increase in both groups, with a higher peak on the 3rd postoperative day and decreased on the 6th postoperative day, but the respiratory rate did not return to the preoperative values, Carvalho et al.[18] already mentioned above that they concluded in their studies that the mean respiratory frequency had a significant increase between pre and 2nd PO, 3rd PO, decreasing on the 4th postoperative day and increased again on the 5th postoperative day and decreased in hospital discharge, but patients did not return to the preoperative values. According to the results obtained in this study, we can affirm that there was no significant difference between the groups regarding the time variables: anesthesia, surgery, perfusion, anoxia, mechanical ventilation, intubation. This suggests that the groups were quite homogeneous. As for the time of postoperative hospital stay, there was a decrease of approximately 25 hours, comparing patients who underwent physical therapy before surgery with patients who did not. In contrast to the findings of this study, Patman et al.[20] performed a randomized study of 236 patients to evaluate the effects of physical therapy interventions performed early versus only started after extubation in patients undergoing cardiac surgery and no significant differences were found in the time of intubation, ICU stay and length of hospital stay between the groups. However, Celli et al.[21] conducted a study with 172 patients and showed a decrease in length of hospital stay in the group that had received guidelines breathing exercises (9.6±3.2 days) compared to the control group (13±5 days). Corroborating these findings, as well as those obtained in the present study, Leguisamo et al.[9] performed a prospective study to evaluate the effectiveness of a physiotherapy program start in the preoperative period in reducing the length of hospital stay and showed a significant reduction in length of hospital stay for the intervention group compared to the control group (P<0.05). These data suggest that physical therapy initiated before surgery can improve conditions of patients, reestablishing early respiratory pressures, reducing the length of stay and decreased hospital costs for the period of hospitalization. Limitation of the study The major limitation was the short period of time that patients received preoperative physiotherapy; however, we understand that physiotherapeutic treatment had a relevance even in a short period, so the study may add knowledge of response to therapy performed during intraoperative CABG surgery. Not performing spirometry can be mentioned as a limitation on the analysis of ventilation parameters, however, due to the conditions offered by our service, we could not perform this evaluation. On the other hand, the results showed that even with limited time monitoring in the preoperative period and respiratory

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variables obtained only by respirometry and manometry in physical therapy in the preoperative period, proved to be beneficial for patients undergoing surgery CABG. We understand that the results may open up new avenues of future research related to the role of physiotherapy in preoperative myocardial revascularization, in addition, further studies should be conducted using tools such as spirometry, to assess and quantify the volume and lung capacity more accurately.

fisioterapia no pré-operatório de cirurgia cardíaca. Fisioter Especial. 2008;3(2):16-22. 9. Leguisamo CP, KaliI RAK, Furlani AP. A efetividade de uma proposta fisioterapêutica pré-operatória para cirurgia de revascularização do miocárdio. Ver Bras Cir Cardiovasc. 2005;20(2):134-41. 10. Feltrim MIZ, Jatene FB, Bernardo WM. Em pacientes de alto risco, submetidos à revascularização do miocárdio, a fisioterapia respiratória pré-operatória previne as complicações pulmonares? Rev. Assoc. Med. Bras. 2007;53(1):8-9.

CONCLUSIONS

11. Barros GF, Santos CS, Granado FB, Costa PT, Límaco RP, Gardenghi G. Treinamento muscular respiratório na revascularização do miocárdio. Rev Bras Cir Cardiovasc. 2010;25(4):483-90.

The physical therapy has an important role in the preoperative period, restoring greater readiness ventilatory parameters of patients undergoing coronary artery bypass grafting with cardiopulmonary bypass, resulting in a decrease in length of hospital stay after surgery.

12. Arcencio L, Souza MD, Bortolin BS, Fernandes ACM, Rodrigues AJ, Evora PRB. Cuidados pré e pós-operatórios em cirurgia cardiotorácica: uma abordagem fisioterapêutica. Rev Bras Cir Cardiovasc. 2008;23(3):400-10. 13. Morsch KT, Leguisamo CP, Camargo MD, Coronel CC, Mattos W, Ortiz LDN, et al. Perfil ventilatório dos pacientes submetidos à cirurgia de revascularização do miocárdio. Rev Bras Cir Cardiovasc 2009;24(2):180-7.

Authors’ roles & responsibilities MTS Main author GNG Co-author MAMS Co-author

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18. Carvalho JBR, Ferreira DLMP, Antunes LCO, Carvalho SM, Silva MAM. Evolução das pressões e volumes pulmonares na cirurgia cardíaca. Salusvita. 2003;22(1):85-111.

5. Polanczyk CA. Fatores de risco cardiovascular no Brasil: os próximos 50 anos. Arq Bras Cardiol. 2005;84(3):199-201.

19. Guizilini S, Gomes WJ, Faresin SM, Bolzan DW, Alves FA, Catani R, et al. Avaliação da função pulmonar em pacientes submetidos à cirurgia de revascularização do miocárdio com e sem circulação extracorpórea. Rev Bras Cir Cardiovasc. 2005;20(3):310-6.

6. Cavalheiro LV, Chiavegato LD. Avaliação pré-operatória do paciente cardiopata. In: Regenga MM. Fisioterapia em cardiologia. Da Unidade de Terapia Intensiva à reabilitação. São Paulo: Roca; 2000. p.21-9.

20. Patman S, Sanderson D, Blackmore M. Physiotherapy following cardiac surgery: is it necessary during the intubation period? Aust J Physiother. 2001;47(1):7-16.

7. Hulzebos EH, Helders PJ, Favié NJ, De Bie RA, Brutel de la Riviere A, Van Meeteren NL. Preoperative intensive inspiratory muscle training to prevent postoperative pulmonary complications in high-risk patients undergoing CABG surgery: a randomized clinical trial. JAMA. 2006;296(15):1851-7. 8. Sobrinho MT, Fonseca L, Alves DLM, Silva MAM. Atuação da

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21. Celli BR, Rodriguez KS, Snider GL. A controlled trial of intermittent positive pressure breathing, incentive spirometry, and deep breathing exercises in preventing pulmonary complications after abdominal surgery. Am Rev Respir Dis. 1984;130(1):12-5. .

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Sobral MLP, etORIGINAL al. - Improvement in cardioplegic perfusion technique in single ARTICLE aortic clamping - initial results

Improvement in cardioplegic perfusion technique in single aortic clamping - initial results Aperfeiçoamento em técnica de perfusão cardioplégica no pinçamento único de aorta - resultados iniciais

Marcelo Luiz Peixoto Sobral1, PhD; Sérgio Francisco dos Santos Júnior2; Juliano Cavalcante de Sá3; Anderson da Silva Terrazas4; Daniel Francisco de Mendonça Trompieri1; Thierry Araújo Nunes de Sousa1; Gilmar Geraldo dos Santos5, PhD; Noedir Antonio Groppo Stolf6, MsC, PhD DOI: 10.5935/1678-9741.20140026

RBCCV 44205-1544

Abstract Introduction: The most common method used for myocardial protection is administering cardioplegic solution in the coronary circulation. Nevertheless, protection may be achieved by intermittent perfusion of the coronary system with patient’s own blood. The intermittent perfusion may be performed by multiple sequences of clamping and opening of the aortic clamp or due single clamping and accessory cannulation of the aortic root as in the improved technique proposed in this study, reperfusion without the need for multiple clamping of the aorta. Objective: To evaluate the clinical outcome and the occurrence of neurological events in in-hospital patients submitted to myocardial revascularization surgery with the “improved technique” of intermittent perfusion of the aortic root with single clamping. Methods: This is a prospective, cross-sectional, observational study that describes a myocardial management technique that consists of intermittent perfusion of the aortic root with single clamping in which 50 patients (mean age 58.5±7.19 years old) have been submitted to the myocardial revasculrization surgery under the proposed technique. Clinical and laboratory variables, pre- and post-surgery, have been assessed. Results: The mean peak level of post-surgery CKMB was 51.64±27.10 U/L in the second post-surgery and of troponin I was 3.35±4.39 ng/ml in the fourth post-surgery, within normal

limits. No deaths have occurred and one patient presented mild neurological disorder. Hemodynamic monitoring has not indicated any changes. Conclusion: The myocardial revascularization surgery by perfusion with the improved technique with intermittent aortic root with single clamping proved to be safe, enabling satisfactory clinical results.

Real e Benemérita Associação Portuguesa de São Paulo, São Paulo, SP, Brazil. 2 Santa Casa de Itabuna (SCMI), Itabuna, BA, Brazil. 3 Hospital Santa Izabel, Salvador, BA, Brazil. 4 Hospital Universitário Francisca Mendes (UFAM), Manaus, AM, Brazil. 5 Instituto do Coração da Faculdade de Medicina da Universidade de São Paulo INCOR/FMUSP, São Paulo, SP, Brazil. 6 Instituto do Coração da Faculdade de Medicina da Universidade Dde São Paulo (FMUSP), São Paulo, SP, Brazil. Real e Benemérita Associação Portuguesa de São Paulo, São Paulo, SP, Brazil.

Real e Benemérita Associação Portuguesa de Beneficência de São Paulo Rua Maestro Cardim, 769, Bloco 5, 2º SS, Sala 30 – Paraíso - São Paulo, SP, Brazil - Zip code 01323-900 E-mail: mlpsobral@uol.com.br

Descriptors: Anastomosis, surgical. Thoracic Surgery. Cardiopulmonary Bypass. Myocardial Reperfusion Injury. Resumo Introdução: O método mais comumente utilizado para a proteção miocárdica é o de administrar-se solução cardioplégica na circulação coronária. Entretanto, a proteção pode ser alcançada através da perfusão intermitente do sistema coronariano com sangue do próprio paciente, que é realizada por meio de múltiplas sequências de pinçamento e abertura do clamp aórtico ou por meio do pinçamento único e canulação acessória da raiz aórtica. Objetivo: Avaliar o desfecho clínico e a ocorrência de eventos neurológicos no período intra-hospitalar dos pacientes submetidos à cirurgia de revascularização do miocárdio com a técnica proposta aqui neste estudo.

1

This study was carried out at Real e Benemérita Associação Portuguesa de Beneficência de São Paulo, São Paulo, SP, Brazil. No financial support.

Correspondence address: Marcelo Luiz Peixoto Sobral

Article received on July 7th, 2013 Article accepted on November 17th, 2013

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média 58,5±7.19 anos) submetidos à cirurgia de revascularização do miocárdio sob a técnica proposta. Foram avaliadas variáveis clínicas e laboratoriais pré e pós-operatórias. Resultados: O nível médio de pico da CKMB pós-operatória foi de 51,64±27,10 U/L no segundo pós-operatório e da troponina I foi de 3,35±4,39 ng/ml no quarto pós-operatório, e estiveram dentro do limite da normalidade. Não foi observado nenhum óbito e um paciente evoluiu com alteração neurológica leve. A monitorização hemodinâmica não revelou alterações. Conclusão: A cirurgia de revascularização do miocárdio com a técnica aperfeiçoada de perfusão intermitente da raiz da aorta com pinçamento único mostrou-se como método seguro, possibilitando resultados clínicos satisfatórios nos pacientes estudados.

Abbreviations, acronyms & symbols CVA AMI ACE CPB CABG COPD ICU LVEF

Cerebrovascular accident Acute Myocardial Infarction inhibitor Angiotensin Converting Enzyme Cardiopulmonary bypass Coronary artery bypass grafting Chronic Obstructive Pulmonary Disease Intensive Care Unit Left ventricular ejection fraction

Métodos: Descreve-se uma técnica de proteção miocárdica no uso do pinçamento único de aorta que consiste na canulação acessória da raiz aórtica com sistema aperfeiçoado para perfusão coronária intermitente, foi realizado estudo observacional transversal prospectivo onde foram estudados 50 pacientes (idade

Descritores: Anastomose Cirúrgica. Cirurgia Torácica. Circulação Extracorpórea. Isquemia Miocárdica.

INTRODUCTION

The aim of this study is to assess the clinical outcome and the occurrence of neurological events in hospital stay of patients undergoing CABG with improved technique of intermittent perfusion of the aortic root with a single clamping.

Coronary artery bypass graft (CABG) is a surgical procedure well standardized in the world today, with survival rates at one year around 97%, remaining at 81% even after ten years postoperatively[1]. The development of techniques of myocardial protection during aortic clamping is largely responsible for these good results. Myocardial protection can be achieved with the use of methods of transient ischemia, myocardial or atrial infusion of cardioplegic solution into the coronary circulation. The choice of method to be used generally depends on the behavior of the service and experience of the surgeon[2]. In an adjuvant way, a current study reports that the technique of remote ischemic preconditioning reduced the amount of release of cardiac enzymes in patients undergoing myocardial revascularization, although no difference in length of hospital stay and creatinine values ​​were reported. This technique has its efficacy independent of myocardial protection technique[3]. Hong et al.[4] conclude that the remote ischemic preconditioning with remote ischemic postconditioning of upper limb does not improve clinical outcomes in patients undergoing cardiovascular surgery. However, performing multiple clamping of the ascending aorta during surgery with intermittent infusion may have the unintended effect of higher incidence of neurological events due to the manipulation of atheromatous plaques in this region. A single aortic clamping should be preferred in order to reduce these events[5].

METHODS This is a cross-sectional observational study in which 50 patients with heart failure and indication of surgery for coronary artery bypass grafting with cardiopulmonary bypass (CPB) underwent the procedure according to regular schedule and surgery by the same surgeon between August 2010 and June 2012. Preoperative information (age, gender, diabetes mellitus II, hypertension, dyslipidemia, previous stroke, previous MI, history of smoking and alcohol consumption, COPD, CRF, ARF, LVEF and current medications) were compiled and analyzed. Intraoperative (duration of each distal anastomosis, CPB flow during each reperfusion, MAP during infusion of the aortic root, time of each reperfusion and proximal anastomosis, number of distal and proximal anastomoses, CPB and anoxia, minimum temperature during CPB, using or not of the centrifugal pump during CPB or if the CPB disconnection was in sinus rhythm or ventricular fibrillation, as well as the HR, MAP, minimum and maximum temperature, diuresis, inotropic support and IABP) and postoperative in-hospital period (neurological deficit, duration of ICU and hospital stay, and perioperative as ECG changes, urea, creatinine, creatine kinase and troponin I).

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We also obtained radiographic, echocardiographic, and cardiac catheterization data. Patients were recruited only after signing Written Informed Consent (IC), in accordance with Resolution 196/96 of the National Health Council. The study was approved by the Research Ethics Committee at Real e Benemérita Associação Portuguesa Beneficência de São Paulo under the protocol number 659-10.

imal anastomoses, mean arterial pressure of aortic root and CPB flow during periods of reperfusion of the aortic root, time of each reperfusion, CPB time, anoxia and minimum temperature reached during surgery. After the allotted time the surgery was completed as usual. Patients were monitored until discharge as the postoperative routine laboratory tests and evolution of clinical and hemodynamic parameters. We propose a standard two basic positions, which begin after the clamping performed once proximally to the insertion of the arterial cannula in the ascending aorta. Position 1 for perfusion and reperfusion of the aortic root (Figure 1) where there is a direct connection between the arterial cannula and the intravascular space existing between the clamped region and the aortic valve apparatus that shall be competent, otherwise there would be excessive extravasation of blood into the left ventricular cavity, reducing the inflow of blood to the coronary ostia and distending the left ventricle. In this position 1, the connections should still be positioned so that the pressure is measured in the aortic root in order to ensure there is no method bias so that, during CPB with clamping and stopped heart, at this site there is no increase in pressure-induced vasopressors administered by an anesthesiologist or perfusionist, which could determine misinterpretations. It should also pay attention to the proper flow offered at CPB, which in this case requires no preference between roller pump or centrifugal pump. Position 2 is the one that should be used when the time of anoxia during anastomosis, both distal and proximal, at which point “B” is closed to the side via and open to the aspirator used when necessary (Figure 2).

Inclusion criteria The study included patients of both genders with indication for CABG surgery performed with cardiopulmonary bypass, aged up to 70 years. Exclusion criteria The study excluded patients who had undergone surgery without cardiopulmonary bypass with moderate or severe aortic failure on echocardiography or aortography, with clinical evidence of previous cerebrovascular disease, clinical or ultrasound evidence of carotid system disease and concomitant surgery for aortic valve failure. Surgical strategy The approach to the heart was median longitudinal transsternal sternotomy , inverted “T” pericardiectomy, preparation for CPB, full heparinization (3mg/kg), arterial cannulation of the ascending aorta, cavoatrial cannulation and number 14 catheter insertion in the ascending aorta for connection of airway suction and infusion, entry into cardiopulmonary perfusion (conventional membrane oxygenation), clamping of the ascending aorta, making of the distal and proximal anastomoses, in this sequence, separated by a period of reperfusion of the aortic root performed by a catheter installed in the ascending aorta, the same used for aspiration of the aorta and left cavities being connected to the output side of the aortic perfusion cannula that supplied blood to reperfusion and additional via of the same side output provided flow through the newly anastomosed graft. When the distal anastomoses were performed, the coronary with more severe lesion or those which may revascularize greater myocardial injury territory, provided that it was not the anterior descending coronary artery so that there was risk of excessive traction of the graft of the left internal thoracic artery (in the cases of other distal anastomoses in the left coronary). Reperfusion blood of an average of three minutes was performed after each anastomosis. This method aims to provide distal blood flow to coronary obstruction through the newly anastomosed graft using cannula connection between the aorta and the graft itself. Using standard monitoring equipment and surgical procedure, variables were assessed during surgery such as aspect of the ascending aorta for the presence of palpable plates calcium, ischemia time during performing the distal and prox-

Fig. 1 - We propose a standard of two basic positions, which begin after the clamping is performed once proximally to the insertion of the arterial cannula in the ascending aorta for perfusion and reperfusion of the aortic root

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A third situation is still illustrated (Figure 3), which is initially important, of a cardioplegic solution backup because if we need to use it, it is ready requiring only release the cardioplegia via and clamp and the route of the aspirator before “Y” bifurcation of the vias. In this situation the “B” point should be in the position of Figure 2.

The “C” point is fundamental to the technique because it must provide at least two routes, because during reperfusion, one or more of them should be connected to the newly anastomosed grafts, which will ensure muscle myocardial perfusion distally to the coronary lesion, since the antegrade flow by ostia may be limited by significant injuries. It is important to make sure that the “C” point is open during reperfusion. Thus, the technique of myocardial protection is describes when using the single aortic clamping accessory which consists of cannulation of the aortic root with improved support for intermittent coronary perfusion system. Statistical Analysis The data of the continuous and parametric variables were expressed as mean ± standard deviation. Patients’ characteristics Most of the patients had one or more co-morbidities such as diabetes mellitus, hypertension, dyslipidemia, smoking, COPD (Chronic Obstructive Pulmonary Disease), prior AMI (Acute Myocardial Infarction), among others (Table 1).

Table 1. Patient's characteristics.

Fig. 2 - It should be used during the anoxia time during anastomosis, both distal and proximal, in which the point “B” is closed to the side via and opened to the aspirator which is used according to the need

Fig. 3 - The third situation is shown, which initially is important, of back up cardioplegic solution, because if we need to use it, it is ready, requiring only releasing the cardioplegic via and clamping the aspirator via before the “Y” bifurcation of the routes. In this situation the “B” point should be in the position of Figure 2

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Preoperative variables Age (years) Gender (M/F) Diabetes Mellitus II Systemic Arterial Hypertension Dyslipidemia Previous Stroke Previous AMI Smoking COPD CRF ARF Alcoholism Calcium in the aorta on X-ray Left Ventricular Ejection fraction (LVEF) Good (>50%) Regular (30-50%) Poor (<30%) Drugs B-blocker ACEI Nitrate AAS Diuretic Clexane Clopidogrel Insulin Antiarrhythmic Oral hypoglycemic Statins Calcium channel blockers

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N 58.5 ± 7.19 37/13 20 48 34 1 27 34 2 1 9 4 6 39 5 35 31 29 36 11 2 10 2 1 11 29 4

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RESULTS

Table 3. Perioperative variables Perioperative variables ECG changes in the pre ► postoperative 0 Plaque of calcium in the ascending aorta 4 Surgical complications 0 Preoperative urea 37.16 ± 12.47 Postoperative urea 50.50 ± 13.80 Preoperative creatinine 1.19 ± 0.24 Postoperative creatinine 1.32 ± 0.30 Mean increase of creatinine in the pre ► postoperative 0.14 ± 0.25 Peak of postoperative CK-MB (U/L) 2º PO 51.64 ± 27.10 Peak of postoperative troponin I (ng/ml) 4º PO 3.35 ± 4.39

Of the 50 patients 37 were male and 13 were female with a mean age of 58.5 ± 19.7 years. LVEF was normal in 39 patients, good in six, and poor in five of them. Regarding the optimization of preoperative medical treatment there was great heterogeneity, where 36 patients were under use of aspirin (Salicilic Acid), 35 beta-blockers and statins 29. 31 were under use of ACE inhibitors (Inhibitor of Angiotensin Converting Enzyme) and only two were insulin dependent (Table 1). In four patients plaques the ascending aorta were identified on palpation. All patients underwent a single aortic clamping during the entire procedure, having been required additional manipulation of the “clamp” for any reason. The average time for completion of each distal anastomosis was 9.20±1.15 minutes and during reperfusions of the aortic root the mean CPB flow was 3316.92±443.26 ml/min while the average MAP during reperfusions was 67.85±10.86 mmHg. The time of each reperfusion averaged 3.56±0.62 minutes. To perform the proximal anastomoses were required on average 5.56±1.44 minutes. The number of distal anastomoses was on average 2.56±0.57 per patient and proximal 1.44±0.50, and the mean CPB and anoxia times of 51.66±12.21 and 31.28±8.65 minutes respectively. The minimum temperature during surgery was on average 33.90±0.65 (Table 2). The electrocardiograms did not suffer changes different from those that may be present preoperatively and bleeding was within acceptable parameters (below 1ml/Kg/h in the early hours). There was no renal failure after CPB. The mean peak level of postoperative CK-MB was 51.64±27.10 UL in the second postoperative day and troponin I was 3.35±4.39 ng/ml on the fourth postoperative day (Table 3). Mild cognitive impairment was observed in one patient and hemodynamic monitoring revealed no changes during hospitalization, which was within the usual service standards (Table 4). No deaths were observed.

Table 4 - Intra- and postoperative variables Intra- and postoperative variables Minimum heart rate (bpm) Maximum heart rate (bpm) Minimal MAP (mmhg) Maximum MAP (mmhg) Minimum temperature (ºC) Maximum temperature (ºC) Diuresis (ml/kg/h) in 24hs Use of tridil Use of dobutamine Use of IAB Neurological deficit type I Neurological deficit type II Length of ICU (h) Length of hospital stay (days)

DISCUSSION The risk factor most important for intraoperative low cardiac output postoperatively is prolonged time of myocardial ischemia facing the effectiveness of the method used for myocardial protection[6]. Many techniques for handling myocardium during CABG are used and there is little safe evidence that a method is superior to another or that the same method is suitable in all circumstances[7]. It is known that there may be a reduction of postoperative left ventricular function even without evidence of myocardial necrosis, in the case of myocardial protection is inappropriate. Conventionally, this situation is called “myocardial stunning”, or that is, a stunned myocardium[8,9]. The arguments in favor of non-cardioplegic methods include greater simplicity and, in the case of intermittent aortic cross-clamping, the proven ability of the myocardium to withstand short periods of ischemia, interspersed with periods of physiological reperfusion, without necrosis or loss of function[10,11]. In our study we found that with single clamping, with average short time of each anastomosis, either distal 9.20±1.15 minutes or proximal 5.56 ± 1.44 minutes, and always interspersed with blood reperfusion of the aorta 3.56±0.62 minutes.

Table 2. Intraoperative variables Intraoperative variables Time of each distal anastomosis (min.) CPB flow during each reperfusion (ml/min.) MAP during root perfusion (mmHg) Time of each reperfusion (min.) Time of each proximal anastomosis (min.) Number of distal anastomoses Number of proximal anastomoses CPB time (min) ANOXIA time (min) Minimum temperature during CPB (°C) Use of centrifugal pump Sinus CPB output PV CPB output

72.46 ± 13.00 100.48 ± 15.31 66.84 ± 8.70 97.98 ± 7.36 35.18 ± 0.55 36.71 ± 0.44 1.32 ± 0.38 43 9 0 1 0 56.08 ± 34.57 8.63 ± 2.74

9.20 ± 1.15 3316 ± 443.26 67.85 ± 10.86 3.56 ± 0.62 5.56 ± 1.44 2.56 ± 0.57 1.44 ± 0.50 51.66 ± 12.21 31.28 ± 8.65 33.90 ± 0.65 45 28 22

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It was found that brief periods of myocardial ischemia with perfusion intervals did not cause progressive depletion of high energy phosphates. This fact has a protective effect of myocardial preconditioning and proves that the injury produced by repeated clamping is not cumulative, but rather, it seems to increase myocardial tolerance to subsequent periods of ischemia[12-14]. This induction of tolerance to ischemia has been termed ischemic preconditioning (IPC)[12]. These data are confirmed in our study by myocardial markers CK-MB and troponin I within normal limits, as well as the echocardiographic control postoperatively. The incidence of perioperative cerebrovascular accident (CVA) in the on-pump CABG ranges from 1.5% to 5.2% in prospective studies and from 0.8% to 3.2% in retrospective[3] vascular studies. The present study found only one case of mild cognitive impairment. The single most common cause of postoperative stroke is embolization of atherothrombotic debris from the aortic arch. Furthermore, only 45% of stroke after CABG are identified on the first day after surgery, while 55% of them occur after the normal recovery from anesthesia and are attributed to atrial fibrillation (AF), low cardiac output or hypercoagulable states resulting from tissue injury[15]. Risk factors for intraoperative stroke are CPB time, manipulation of the ascending aorta and arrhythmias[4]. The proposal of the authors was to present method of intermittent infusion to minimize the risk of multiple aortic clamping, as in patients with presence of atheromatous plaques in the ascending aorta may be increased incidence of strokes. In our study, we did not observe any occurrence of adverse neurological event. The incidence of perioperative myocardial infarction in CABG ranges from 2 to 15%[16], and this variation can be explained by the absence of a gold standard test in the specific situation of infarction after coronary revascularization. In addition, electrocardiographic changes and elevation of cardiac enzymes in the postoperative period, even in patients without myocardial ischemia may occur[17,18]. International criteria for the diagnosis of MI after cardiac surgery is a new Q wave and CK-MB level > 3 times the reference value, new bundle branch block and level of CKMB > 3 times the reference value or level of serum CK-MB > 8 times the reference value even in the absence of new Q[19] wave. Several authors have reported different cutoff points and different levels of sensitivity and specificity for troponin values as diagnostic of perioperative AMI. Using the same enzymatic method Martinez et al.[20] found a diagnostic cutoff for troponin I in values of > 12ng/ ml 10hrs after removal of the aortic clamp; Bonnefoy et al.[21] values of> 10ng/ml; Alyanakian et al.[22] values of > 15ng/ mL; Gensini et al.[23] > 9.2 ng/ml after 12hrs and Sadony et al.[24] > 11.6 ng/ml after 24 hours of removal of aortic clamp. In the present investigation we found agreement with the studies described above, regarding the markers of myocardial ischemia and electrocardiographic changes.

All patients in our study underwent surgery with cardiopulmonary bypass. Various data available in the literature indicate advantage of CABG technique without cardiopulmonary bypass in selected[25] cases, however, although controversial in some points the “ROOBY” study showed no difference between the results of neuropsychological outcomes between CABG with and without CPB[26]. Intermittent perfusion of the aortic root is performed by some services as a method of myocardial protection and, although not standardized, it has been demonstrated reproducible given the simplicity of the method that requires skill and dexterity to saving time during the primary surgical time and familiarity with connections alternating aortic perfusion, the graft and simultaneous measurement of pressure in the aortic root and ascending aortic aspiration during anoxia. The intention to provide better nutrient supply to the myocardium during intermittent infusions by this method has the benefits known and defended by adherents to the classic “intermittent aortic cross-clamping” with the additional benefit of minimal manipulation of the aorta, whereas only one clamping and unclamping of the aorta occurs, the last at the end of the proximal anastomoses. Ko at al.[27], in 15 years of follow-up, observed that the overall mortality rate of patients undergoing CABG fell from 2.5% to 1.8%. In our study, despite the low number of patients studied, there were no deaths. CONCLUSION Coronary artery bypass grafting with the technique of intermittent perfusion of the aortic root with a single clamping proved to be safe, enabling satisfactory clinical and neurological outcomes in the patients studied.

Authors’ roles & responsibilities MLPS SFSJ JCS AST DFMT TANS GGS NAGS

Main Author Help in bibliographical survey and review of the study Help in tabulating the data and monitoring of patients Help in the data tabulation Help in the monitoring of patients in the perioperative period Help in perioperative monitoring of patients Article review Article review

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11. Fernandes PMP, Jatene FB, Gentil AF, Coelho FF, Kwasnicka K, Stolf NAG, et al. Influência do Pré-Condicionamento Isquêmico na Proteção Miocárdica em Revascularização do Miocárdio com Pinçamento Intermitente da Aorta. Análise de Íons e Gasometria. Arq Bras Cardiol. 2001;77(4):311-7.

24. Sadony V, Korber M, Albes G, Podtschaske V, Etgen T, Trösken T, et al. Cardiac troponin I plasma levels for diagnosis and quantitation of perioperative myocardial damage in patients undergoing coronary artery bypass surgery. Eur J Cardiothorac Surg. 1998;13(1):57-65.

12. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124-36.

25.Cantero MA, Almeida RMS, Galhardo R. Análise dos resultados imediatos da cirurgia de revascularização do miocárdio com e sem circulação extracorpórea. Rev Bras Cir Cardiovasc.2012;27(1):38-44.

13. Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet. 1993;342(8866):276-7.

26. Shroyer AL, Grover FL, Hattler B, Collins JF, McDonald GO, Kozora E, et al. On-pump versus off-pump coronary artery bypass surgery. N Engl J Med. 2009;361(19):1827-37.

14. Jenkins DP, Pugsley WB, Alkhulaifi AM, Kemp M, Hooper J, Yellon DM. Ischemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery. Heart. 1997;77(4):314-8.

27. Ko W, Tranbaugh R, Marmur JD, Supino PG, Borer JS. Myocardial Revascularization in New York State: Variations in the PCI-to-CABG Ratio and Their Implications. J Am Heart Assoc. 2012;1(2): e001446.

15. Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for

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Almeida BL, et al. - Left subclavian artery stenting: an option for the treatment ORIGINAL ARTICLE of the coronary-subclavian steal syndrome

Left subclavian artery stenting: an option for the treatment of the coronary-subclavian steal syndrome Angioplastia com stent de artéria subclávia esquerda: uma opção no tratamento da síndrome do roubo coronário-subclávio

Bruno Lorenção de Almeida1, MD; Antonio Massamitsu Kambara1, MD; Fabio Henrique Rossi1, MD; Samuel Martins Moreira1, MD; Eduardo Silva Jordao de Oliveira1, MD; Frederico Augusto de Carvalho Linhares Filho1, MD; Patrick Bastos Metzger1, MD; Aldo Zampieri Passalacqua1, MD

DOI: 10.5935/1678-9741.20140031

RBCCV 44205-1545

Abstract Introduction: The subclavian steal syndrome is characterized by the vertebral artery flow inversion, due to a stenotic lesion in the origin of the subclavian artery. The Coronary-subclavian Steal Syndrome is a variation of the Subclavian Steal Syndrome and is characterized by inversion of flow in the Internal Thracic artery that has been used as conduct in a myocardial revascularization. Its diagnosis must be suspected in patients with difference in pulse and arterial pressure in the upper limbs, that present with angina pectoris and that have done a myocardial revascularization. Its treatment must be a surgical bypass or a transluminal angioplasty. Objective: The objective is to show the left subclavian artery stenting as a safe and effective method to treat the coronary-subclavian steal syndrome. Methods: Historical prospective, non-randomized trial, through revision of the hospital records of the patients treated with the stenting of the left subclavian artery, from January 2006 to September 2012. Results: In the mentioned period, 4.291 miocardial revascularizations were performed with the use of the left mammary artery, and 16 patients were identified to have the Coronary-subclavian steal syndrome. All of them were submitted to endovascular treat-

ment. The success rate was 100%; two patients experienced minor complications; none of them presented with major complications. Eleven of the 16 patients had ultrassonographic documentation of patent stent for at least one year; two patients lost follow up and other two died. Conclusion: The stenting of the left subclavian artery is a good option for the treatment of the Coronary-subclavian Steal Syndrome, with high level of technical and clinical success.

Instituto Dante Pazzanese de Cardiologia (IDPC), São Paulo, SP, Brazil.

Instituto Dante Pazzanese de Cardiologia Av. Dr. Dante Pazzanese, 500 - Vila Mariana - São Paulo, SP, Brazil – Zip code: 04012-180 E-mail: brunolorencao@gmail.com

1

Descriptors: Angioplasty. Peripheral Arterial Disease. Coronary Disease. Subclavian Artery. Coronary-Subclavian Steal Syndrome. Resumo Introdução: A síndrome do roubo de subclávia caracteriza-se por inversão de fluxo na artéria vertebral, decorrente de lesão estenótica na origem da artéria subclávia. A síndrome do roubo coronário-subclávio é uma variante da síndrome do roubo de subclávia e caracteriza-se por inversão de fluxo na artéria torácica interna que foi usada como conduto na revascularização do miocárdio. Seu diagnóstico deve ser suspeitado em pacientes com diferença de pulso ou pressão em membros superiores que

Work carried out at the Instituto Dante Pazzanese de Cardiologia (IDPC), São Paulo, SP, Brazil. No financial support. Correspondence address: Bruno Lorenção de Almeida

Article received on May 5th, 2013 Article accepted on August 19th, 2013

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Resultados: Foram realizadas neste período, 4.291 revascularizações miocárdicas com uso de torácica interna esquerda, sendo identificados 16 pacientes portadores da síndrome do roubo coronário-subclávio. Todos foram submetidos a tratamento endovascular. O índice de sucesso terapêutico foi de 100%; dois pacientes experimentaram complicações menores; nenhum apresentou complicações maiores. Do total, 11 pacientes apresentavam documentação ultrassonográfica de stent pérvio por pelo menos um ano; dois pacientes perderam seguimento e outros dois foram a óbito. Conclusão: A angioplastia com stent da artéria subclávia esquerda é uma boa opção para o tratamento da Síndrome do roubo coronário-subclávio, com altas taxas de sucesso técnico.

Abbreviations, acronyms & symbols ASA CSSS SSS

acetylsalicylic acid Coronary-subclavian steal syndrome Subclavian Steal Syndrome

apresentem quadro anginoso e com histórico de revascularização miocárdica. Seu tratamento pode ser realizado através de bypass cirúrgico ou por meio de angioplastia transluminal percutânea. Objetivo: O objetivo deste artigo é mostrar a angioplastia com stent da artéria subclávia esquerda como um tratamento efetivo e seguro da síndrome do roubo coronário-subclávio. Métodos: Estudo prospectivo histórico, não randomizado, através da revisão de prontuários dos pacientes submetidos a angioplastia de artéria subclávia, no período de Janeiro de 2006 a Setembro de 2012.

Descritores: Angioplastia. Doença Arterial Periférica. Doença das Coronárias. Artéria Subclávia. Síndrome do Roubo Coronário-Subclávio.

INTRODUCTION

wire of the same diameter, to give support to the stent (Figure 1). This approach allows several attempts of recanalization, whether proximal or distal to the lesion and appropriate angiographic control (Figure 2). Balloon expandable stents were used in the majority of the cases; only one selfexpandable stent was used. The sizes varied form 7 to 10 mm in diameter and 25 to 60 mm in length. The material selection was made by visual angiographic analysis and was based on the nominal diameter of the target vessel, diameter proximal and distal to the lesion and the extension of it (Figure 3). Only one of the four cases of occlusion demanded pre dilatation (Figure 4), due to the difficulty of moving the balloon expandable stent through the lesion.

The subclavian steal syndrome (SSS) is characterized by the vertebral artery flow inversion, due to a stenotic lesion in the origin of the subclavian artery. The Coronary-subclavian Steal Syndrome is a variation of the SSS and is characterized by inversion of flow in the Internal Mammary artery that has been used as conduct in a myocardial revascularization, leading to miocardial infarction. Its diagnosis must be suspected in patients with difference in pulse and arterial pressure in the upper limbs, that present with angina pectoris and that have done a myocardial revascularization. Its treatment must be a surgical bypass or, after the rise of the minimal invasive techniques, a transluminal angioplasty. Objective The objective of this article is to show the left subclavian artery stenting as a safe and effective method to treat the Coronary-subclavian Steal Syndrome. METHODS Retrospective, non-randomized trial, through revision of the hospital records of the patients treated with the stenting of the left subclavian artery, from January 2006 to September 2012. Epidemiological and clinical data were assessed, as well as technique and materials used in the procedure. The study was approved by the ethics commission. The procedures were performed after local anesthesia and positioning of a valvulated sheath in the common right femoral artery and in the left brachial artery, by the Seldinger technique. After systemic heparin, the lesion was crossed with a 0.035’’ hydrophilic guidewire, and then it was exchanged by a stiff

Fig. 1 - Filling of the left subclavian artery by retrograde flow of the left internal mammary artery

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Fig. 2 - Proximal and distal access to the lesion access and facilitating overtaking angiographic control

Fig. 4 - Filling anterograde left subclavian artery and the proximal third of the left internal thoracic artery

The monitoring was carried out on an outpatient basis and by performing ultrasound duplex color of the left subclavian artery. Routinely the patient returned to the Endovascular clinic in a week for initial evaluation of pulse and pressure measurement in the upper limbs. Then we continued monitoring in the sector of origin. RESULTS Four thousand two hundred and ninety one coronary artery bypasses were performed in this period with the use of the left internal mammary artery angioplasty and 69 angioplasties of the subclavian artery in this Institute, identifying 16 patients with the Coronary-subclavian steal syndrome (CSSS). All of them underwent endovascular treatment. The mean age of patients was 67.2 (53-81 years), sevenfemales and nine males. Table 1 shows the distribution of risk factors among patients treated. The clinical presentation leading to diagnosis of CSSS varied, and three patients presented with acute myocardial ischemia and in the other 12, the diagnosis was made by coronary angiography after provocative test positive for ischemia. In only one case the diagnosis was made after coronary angiography prior to percutaneous valve replacement (Table 2). Of the 16 patients included, 13 had stenoses and three had occlusions, in all cases in the proximal left subclavian artery. The therapeutic success rate was 100%, with the criterion of antegrade flow in the internal mammary through digital angiography. Two patients experienced minor complications, being a minor hematoma and pseudoaneurysm that did not require

Fig. 3 - Balloon Expandable stent being released by brachial access

All patients were receiving antiplatelet therapy with acetylsalicylic acid (ASA) at the time of diagnosis, in doses ranging from 75 to 325 mg/day. In addition, Clopidogrel was started 75 mg/day orally, or 300 mg loading dose in the morning of the procedure, maintaining the dual antiplatelet therapy for 30 days.

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surgical correction. No patient had major complications. Upon examination of the medical records, 11 patients had sonographic documentation of stent patency for at least one year; two patients lost follow-up and two died. One of infection and sepsis in diabetic foot and other unknown cause. In all cases there was clinical improvement of symptoms after the procedure.

vian-subclavian, carotid-subclavian, axillary- axillary grafts, subclavian- carotid transposition or even transposition of the internal mammary artery. Potential complications include fistula of the thoracic duct, Horner’s syndrome, supraclavicular nerve injury (eg N. Phrenic and recurrent laryngeal) and decompensation of preexisting atherosclerotic disease in the supra-aortic trunks, thereby leading to ischemic or neurological symptoms[7,8]. In the cases presented, there were two minor complications and no major complications, besides the therapeutic and clinical success of 100%. The technical literature reports success of more than 80%, with rates of complications from 3 to 6% and high patency up to ten years of follow-up[5,7,9,10]. None of the patients experienced vertebrobasilar acute neurological symptoms due to reverse flow in vertebral artery, which protects cerebral circulation leading to embolic events fragments plate to the upper member. The forward flow is restored gradually from 20 seconds to 30 minutes, probably due systems of cerebral selfregulation by decreasing vascular resistance[3,8]. There are reports in the literature of internal mammary artery blockage and aspiration of blood through the brachial catheter during the procedure, to avoid potential embolization to coronary territory, especially when it is noted an antegrade flow in the internal mammary - a variant of the CSSS[3,10]. However, in the patients presented, this technique was not used, without any harm to the result. The choice of balloon expandable stents rather than selfexpandable in most cases is due to its greater radial strength and greater accuracy in delivery. However, in very tight lesions or occlusions when it perceives a certain resistance in the positioning of the stent, may be necessary pre-dilation to facilitate their passage and to prevent it from deforming over the balloon. In the cases presented, only one required a pre-dilatation. One should remember that the label of the balloon- expandable stents available on the market today does not include its use in the supra -aortic area. The use of these stents in this region is due to the excellent results in case series. In most services is not routine an angiographic study of aortic arch and supra-aortic trunks prior to Coronary artery bypass[7,11]. Thus, the physical examination of the upper limbs is necessary, so you can detect any change in pulse/pressure or supraclavicular souffle before surgery[5,12]. In contrast, in revascularized patients presenting with acute or insidious myocardial ischemia, we must always remember the CSSS as a possible etiology. In fact, the development of this syndrome in less than a year after myocardial revascularization suggests the presence of subclavian steal syndrome not diagnosed by the time of surgery[5].

Table 1. Demographical Characteristics of the analyzed patients. n Age Male Female Systemic Hypertension Diabetes Mellitus Dyslipidemia Smoking • Former smokers Chronic Renal Insufficiency*

16 67.2 (53-83 years) 9 (56.2%) 7 (43.7%) 16 (100%) 7 (43.7%) 13 (81.2%) 5 (31.2%) 7 (43.7%) 1 (6.2%)

*Non dialysis chronic renal insufficiency patient, being treated after adequate renal preparation Table 2. Clinical characteristics of the patients. Acute Myocardial Infarction Angina/Positive provocative test Others*

3 (18.7%) 12 (75%) 1 (6.2%)

*Asymptomatic patient; diagnosis in the coronary angiography previous to valve replacement surgery

DISCUSSION With an incidence between 0.5% and 2% of patients undergoing coronary artery bypass grafting[1], the CSSS was initially described by Hargola / Valle and Tyras / Barner in the 70s, concurrently with the beginning of the use of the internal mammary artery as a conduit artery[2]. The use of this artery is widely accepted because of its high long-term patency rate and low atherosclerosis, being used in most Coronary artery bypasses[3 -6]. The incidence of this syndrome was 0.3% in our study, being equivalent to that found in the literature. All cases diagnosed underwent endovascular treatment. The left subclavian artery is the branch of the aortic arch most affected by atherosclerosis[7], which is the main cause of the syndrome. This also explains why the vast majority of cases in the literature CSSS occur on the left side, not being different in the cases presented. Other causes include Takayasu arteritis, actinic arteritis and giant cell arteritis[1]. The occlusion of the proximal subclavian artery causes flow reversal in arteries downstream (vertebral and internal mammary), leading to several vertebral- basilary symptoms (dizziness, nystagmus, nausea) and myocardial ischemia[2]. Conventional surgical revascularization procedures have good long-term patency[7], but contain a risk of morbidity of 4-11% and a mortality rate of up to 5%. Options include subcla-

CONCLUSION Angioplasty and stenting of the left subclavian artery is a good option for the treatment of coronary subclavian steal

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syndrome, with high rates of technical and clinical success. Besides, does not preclude surgical treatment, in the case of more than one unsuccessfull endovascular attempt.

5. Westerband A, Rodriguez JA, Ramaiah VG, Dietrich EB. Endovascular therapy in prevention and management of coronarysubclavian steal. J Vasc Surg .2003;38(4):699-704 6. Dinkhuysen JJ, Souza LCB, Fichino MZS, Chaccur P, Arnoni AS, Piegas LS, et al. Anastomose mamária-coronária: análise de 2923 casos. Rev Bras Cir Cardiovasc. 1987;2(1):7-21.

Authors’ roles & responsibilities BLA Author AMK Coauthor, scientific reviewer FHR Coauthor, scientific reviewer SMM Coauthor, scientific reviewer ESJO Coauthor, data collection FACLF Coauthor, data collection PBM Coauthor, statistical analysis AZP Coauthor, statistical analysis

7. Costa SM, Fitzsimmons PJ, Terry E, Scott RC. Coronary-subclavian steal: case series and review of diagnostic and therapeutic strategies: three case reports. Angiology. 2007;58(2):242-8. 8. Martinez R, Rodriguez-Lopez J Torruella L, Ray L, LopezGalarza L, Diethrich EB. Stenting for occlusion of the subclavian arteries. Technical aspects and follow-up results. Tex Heart Inst J. 1997;24(1):23-7.

REFERENCES

9. Van Noord BA, Lin AH, Cavendish JJ. Rates of symptom reoccurrence after endovascular therapy in subclavian artery stenosis and prevalence of subclavian artery stenosis prior to coronary artery bypass grafting. Vascular Health Risk Manag. 2007;3(5):759-62.

1. Tariq S, Tuladhar S, Wingfield E, Poblete H. Coronary subclavian steal syndrome unamenable do angioplasty successfully managed with subclavian-subclavian bypass. Case Report Vasc Med. 2012;2012:784231.

10. Nishio A, Takami T, Ichinose T, Masamura S, Hara M, Shimada K, et al. Percutaneous transluminal angioplasty and stent placement for subclavian steal syndrome with concomitant anterograde flow in the left internal mammary artery graft for coronary artery bypass. Neurol Med Chir (Tokyo). 2003;43(10):488-92.

2. Chokyu I, Terada T, Matsuda Y, Okumura H, Shintani A, Nakamura Y, et al. Stenting for left subclavian artery stenosis before and after coronary artery bypass grafting using the internal mammary artery: a report of three cases. Interv Neuroradiol. 2008;14(2):209-14.

11. Fergus T, Pacanowski JP Jr, Fasseas P, Nanjundappa A, Habeeb Ahmed M, Dieter RS. Coronary-subclavian steal: presentation and management: Two case reports. Angiology. 2007;58(3):372-5.

3. Kneale BJ, Irvine AT, Coltart DJ. Coronary subclavian steal syndrome following coronary bypass surgery. Postgrad Med J. 1996;72(848):358-60.

12. Munk PS, Larsen AI, Fjetland L, Nilsen DWT. Acute occlusion of the left subclavian artery causing a non-ST-elevation myocardial infarction with subacute lung edema due to a coronary subclavian steal syndrome--a case report. Int J Cardiol. 2006;108(1):139-41.

4. Miiller JC, Candemil PC, Loures JMGR, Zucco FM, Belz WE, Loures NGR, et al. Síndrome do roubo coronário-subclávio: relato de caso e revisão de literatura. J Vasc Bras. 2012;11(2):166-70.

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Peres MB, et al. - EvolutionARTICLE of weight and height of children with congenital ORIGINAL heart disease undergoing surgical treatment

Evolution of weight and height of children with congenital heart disease undergoing surgical treatment Evolução pondero-estatural de crianças com cardiopatias congênitas submetidas a tratamento cirúrgico

Murilo Bertazzo Peres1, Ulisses Alexandre Croti2, MD, PhD; Moacir Fernandes de Godoy2, MD, PhD; Carlos Henrique De Marchi2, MD, PhD; Sírio Hassem Sobrinho2, MD, PhD; Lilian Beani2, MD, PhD; Airton Camacho Moscardini2 MD, PhD; Domingo Marcolino Braile2, MD, PhD

DOI: 10.5935/1678-9741.20140036

RBCCV 44205-1546

Abstract Objective: To evaluate the height and weight development of children with congenital heart disease undergoing surgery with the goal of determining when they reach the threshold of normal development and whether there are differences between patients with developmental pattern below the level of normality preoperatively (z-score<-2 for the analyzed parameter) in comparison to the total group of cardiac patients. Methods: We prospectively followed up 27 children undergoing operation into five time periods: preoperatively and at four subsequent outpatient appointments: 1st month, 3rd month, 6th month and 12th month after hospital discharge. The anthropometric parameters used were median z-score (MZ), weight (WAZ), height (HAZ), subscapular skinfold (SSFAZ), upper arm circumference (UAC) and triceps skinfold (TSFAZ). The evolution assessment of the parameters was performed by analysis of variance and comparison with the general normal population from unpaired t test, both in the total group of cardiac patients, and in subgroups with preoperative parameters below the normal level (Zm<-2 ).

Results: In the total group there was no significant evolution of MZ of all parameters. WAZ was statistically lower than the normal population until the 1st month of follow-up (P=0.028); HAZ only preoperatively (P=0.044), SSFAZ in the first month (P=0.015) and at 12th month (P=0.038), UAC and TSFAZ were always statistically equal to the general population. In patients whose development was below the level of normality, there were important variation of WAZ (P=0.002), HAZ (P=0.001) and UAC (P=0.031) after the operation, and the WAZ was lower than the normal population until the 3rd month (P=0.015); HAZ and UAC, until the first month (P=0.024 and P=0.039 respectively), SSFAZ, up to the 12th month (P=0.005), the TSFAZ only preoperatively (P=0.011). Conclusion: The operation promoted the return to normalcy for those with heart disease in general within up to three months, but for the group of patients below normal developmental pattern of the return occurred within 12 months.

1-Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil. 2-Faculdade de Medicina de São José do Rio Preto, Hospital de Base (FUNFARME / FAMERP), São José do Rio Preto, SP, Brazil.

5544 Brigadeiro Faria Lima Avenue, room 7 São José do Rio Preto, SP, Brasil CEP 15090-000 E-mail: uacroti@uol.com.br; uacroti@cardiol.br

Work carried out at Hospital de Base – School of Medicine of São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brasil.

The study received financial support from the Scientific Initiation Scholarship Program (BIC2009/2010) at the School of Medicine of São José do Rio Preto (FAMERP) Article received on June 6th, 2013 Artigo approved on Setempter 14th, 2013

Descriptors: Congenital heart disease. Child Development. Growth. Operation. Anthropometry.

Correspondence adressaddress: Ulisses Alexandre Croti.

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mês e 12º mês após a alta hospitalar. Os parâmetros antropométricos usados foram a média do z-score (Zm) do peso (ZmP/I), da altura (ZmA/I), prega cutânea subescapular (ZmPCS/I), perímetro braquial (ZmPB/I) e prega cutânea tricipital (ZmPCT/I). A avaliação da evolução dos parâmetros foi feita pela análise de variância e a comparação com a população geral normal pelo teste t não pareado, tanto no grupo total dos cardiopatas, quanto nos subgrupos com parâmetros pré-operatórios abaixo do patamar da normalidade (Zm<-2). Resultados: No grupo total não houve evolução significativa dos Zm de todos os parâmetros. O ZmP/I foi estatisticamente menor que da população normal até o 1º mês de seguimento (P=0,028); o ZmA/I, somente no pré operatório (P=0,044); o ZmPCS/I, no o 1º mês (P=0,015) e no 12º mês (P=0,038); o ZmPB/I e o ZmPCT/I sempre foram estatisticamente iguais ao da população geral. Nos pacientes com desenvolvimento abaixo do limiar da normalidade houve variação importante do ZmP/I (P=0,002), do ZmA/I (P=0,001) e do ZmPB/I (P=0,031) após a operação, sendo que o ZmP/I foi menor que da população normal até o 3º mês (P=0,015); o ZmA/I e o ZmPB/I, até o 1º mês (P=0,024 e P=0,039 respectivamente); o ZmPCS/I, até o 12º mês (P=0,005); o ZmPCT/I, somente no pré-operatório (P=0,011). Conclusão: A operação promoveu o retorno à normalidade para os cardiopatas em geral dentro de até três meses, porém para o grupo de pacientes abaixo do padrão normal de desenvolvimento o retorno ocorreu em até 12 meses.

Abbreviations, acronyms & symbols IVC IAC CoA SD AVSD WHO PDA SUS HAZ TSFAZ MZ-score WAZ BPAZ SSFAZ TSFAZ

interventricular communication interatrial communication coarctation of the aorta Standard Deviation (partial) atrioventricular septal defect World Health Organization patent ductus arteriosus Unified Health System Height/Age Z-score triceps skinfold/age Z-score Median Z-scores Weight/age Z-scores brachial perimeter/age Z-score subscapular skinfold/age Z-score triceps skinfold/age TOF cyanotic tetralogy of Fallot

Resumo Objetivo: Avaliar a evolução pôndero-estatural de crianças com cardiopatias congênitas submetidas a tratamento cirúrgico com intuito de determinar quando atingem o limiar de desenvolvimento normal e se há diferenças entre pacientes com padrão de desenvolvimento abaixo do patamar da normalidade no pré-operatório (z-score<-2 para o parâmetro analisado) em relação ao grupo total de cardiopatas. Métodos: Acompanhamento prospectivamente de 27 crianças submetidas à operação em cinco períodos: pré-operatório e em quatro subsequentes retornos ambulatoriais: 1º mês, 3º mês, 6º

Descritores: Cardiopatia Congênita. Desenvolvimento Infantil. Crescimento. Cirurgia. Antropometria.

INTRODUCTION

Divergences about how these children can develop after surgery prompted us to evaluate the weight-height evolution in order to determine when they reach the threshold of normal development and whether there are differences between patients with standard development below the level of normality in the preoperative period (z-score <-2 for the parameter analyzed) compared to the total group of cardiac patients.

The prevalence of congenital heart disease is approximately 6/1000 live births, the most common severe congenital anomaly and having important implications in mortality in the first year of life[1,2]. In our environment, Guitti estimated a prevalence of 5.4 / 1,000 live births, with interventricular communication (IVC) as the most common injury found[3]. Congenital heart defects usually cause changes in development, mainly in height and weight, which when measured are shown below the normal mean for age[4-8]. These changes are usually multifactorial and may be from both cardiac and extra-cardiac causes[8-10]. The advancement of corrective surgeries had great impact on the improvement of growth and weight gain in these patients[11-14], but it always dependent on factors such as the severity of the initial underdevelopment, the presence or absence of cyanosis, the hemodynamic status, pre-natal causes and fundamentally the type of disease[12-20].

METHODS From October 2009 to June 2011, 27 children with congenital heart disease admitted to perform corrective surgery were studied in the Department of Pediatric Cardiovascular Surgery, School of Medicine of São José do Rio Preto, Hospital de Base (FAMERP), São Paulo, Brazil. The study was approved by the Research Ethics Committee of the Institution (Opinion No. 181/2009 and Protocol 3088/2009).

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The mean age was 27.6 months, ranging 3-115 months with a standard deviation of 26.7 months and a median of 20.1 months. Twelve were male (44.4%). The diagnosis in 17 children was acyanogenic disease, seven with interatrial communication (IAC), five with atrial septal defect (ASD), one with partial ventricular septal defect (PVSD), two with patent ductus arteriosus (PDA) and two with coarctation of the aorta (coarctation). The other 10 children had tetralogy of Fallot (TOF). The study included children whose families accepted the Informed Consent for outpatient follow-up period of at least one year. We excluded premature patients, and patients with genetic syndromes or noncardiac causes of malnutrition. Weight, height, subscapular skinfold, brachial perimeter and triceps skinfold were measured in the preoperative periods and in four subsequent outpatient care moments: 1st month, 3rd month, 6th, month and 12th month after hospital discharge. Weight was measured with properly calibrated pediatric scales[21-23]. The measures were determined with the aid of a pediatric digital scale (Filizola®), with a maximum of 15 kg and 5g division. We also used a caliper of Sanny ® brand precision of tenths of a millimeter, a measuring tape in millimeters and a children’s anthropometer to obtain height measurement [21-23]. The subscapular skinfold was determined obliquely to the longitudinal axis of the body, following the guidance of ribs two inches below the inferior angle of the scapula[23]. The brachial perimeter was obtained as the measurement of the circumference at the middle third of the arm[23]. The triceps skinfold was measured on the posterior side of the arm, at the midpoint between the upper lateral edge of the acromion and the inferior border of the olecranon. The measurement was carried out following the longitudinal axis of the member[23]. All children were measured by the same person, with the same instruments and the same environment, in other words, in the Cardiopediatrics Outpatient of Hospital de Base. Each measurement was repeated three times and the mean value found was considered for the study[21-23]. The z-scores were calculated in relation to age, and for weight/age (WAZ), height/age (HAZ), brachial perimeter/age (BPAZ), subscapular skinfold/age (SSFAZ), triceps skinfold/ age (TSFAZ), based on the WHO Anthro program of the World Health Organization (WHO)[24,25]. Based on the WHO growth curves, we considered z-scores values -2 or less, for any parameter used, as being below the normal standard of weight and height[24,25] development. Statistical analysis was performed with the aid of Stats Direct Statistical Software Version 1.9.15. Values of ​​ continuous variables were expressed as means and standard deviation (SD). We used analysis of variance to perform the comparison of the evolution of the values of ​​ the mean z-scores (MZ) over this period, for all anthropometric parameters (WAZ, HAZ,

BPAZ, SSFAZ, TSFAZ), and Dunnett’s post-test analysis in case of detection of statistically significant difference. The unpaired two-tailed Student’s t test was performed to compare the values ​​of MZ in each follow-up period with the normal general population, which was considered as a z-score of 0 and SD of 2. These tests were applied specifically in the total group of patients with cardiac disesases and in the subgroups of cardiac patients below the normal development pattern in the preoperative period according to the anthropometric parameter analyzed (in subgroups of patients with z-score below -2 in the preoperative period to the parameter analysed). It was assumed a 5% alpha error with significance level of P≤0.05. The representation has been demonstrated with the aid of Box plot graphs. RESULTS All measurements were taken in 27 children in the preoperative period, but there were some flaws during the follow-up, and only 14 of them were evaluated in the 1st month, 16 in the 3rd month, 18 in the 6th month and 16 in the 12th month. The was no statistical significance in WAZ for the analysis of variance over the study period for the total group of cardiac patients (P=0.081). For the group with the WAZ below the normal pattern of development related to the preoperative analysis of variance demonstrated statistical significance (P=0.002), and the post-test analysis demonstrated statistical difference in WAZ during the preoperative period with WAZ of the 6th month (P=0.011) and 12th month (P=0.006). The WAZ of the total group of cardiac patients was significantly lower than the general population’s only in the preoperative period (P=0.008) and during the 1st month (P=0.028). The WAZ in the group below the normal pattern of development was lower than the general population’s only in the preoperative period (P<0.001) in the 1st month (P=0.001) in the 3rd month (P=0.015), and in the 6th month (P=0.047) of the follow-up period. Figures 1 and 2 demonstrate the evolution of the WAZ for the total group of cardiac patients and for the group of cardiac patients with WAZ in the preoperative period below normal developmental pattern. In HAZ there was no statistical significance in the analysis of variance over the study period for the total group of cardiac patients (P=0.182). For children with HAZ in the preoperative period below normal development pattern the analysis of variance demonstrated statistical significance (P=0.001), and the post-test analysis showed statistical difference in HAZ in the preoperative period with HAZ of the 3rd month (P = 0.040), the 6th month (P=0.007) and the 12th month (P<0.001).

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the preoperative period compared to those from the 6th month (P= 0.045) and 12th month (P= 0.031). The BPAZ of the total group of cardiac patients was not significantly lower than the general population’s in any period. The BPAZ in the group below the normal pattern of development was lower than the general population’s only in the preoperative period (P= 0.058) and in the 1st month (P=0.036). Figures 5 and 6 show the evolution of BPAZ for the total group of patients with cardiac problems and for the group of cardiac patients below the normal pattern of development. The SSFAZ showed no statistical significance in the analysis of variance for the total group of cardiac patients (P=0.514). For children with SSFAZ in the preoperative period below normal developmental pattern, the analysis of variance also did not show statistical significance (P=0.101).

Fig. 1 - Evolution of median z-scores for weight/age (WAZ) in the group of cardiac patients. Analysis of variance with P=0.081. (*) The WAZ was significantly lower when compared with the general population’s in the preoperative period and the first month

Fig. 3 - Evolution of z-scores for height/age (HAZ) in the group of cardiac patients. Analysis of variance with P=0.182. (*) HAZ was significantly lower when compared with the general population’s in the preoperative period

Fig. 2 - Evolution of median z-scores for weight/age (WAZ) in cardiac patients with WAZ in the pre-operative period which was below the normal developmental pattern. Analysis of variance with P=0.002. (*) The WAZ was significantly lower when compared with the general population’s in the preoperative period, in the first, third and sixth months

The HAZ of the total group of cardiac patients was significantly lower than the general population’s only in the preoperative period (P=0.044). The HAZ in the group below the normal pattern of development was lower than the general population’s in the preoperative period (P=0.028) in the 1st month (P=0.024) during the follow-up. Figures 3 and 4 demonstrate the evolution of HAZ for the total group of patients with cardiac complications and for the group of cardiac patients with HAZ in the preoperative period below normal developmental pattern. There was no statistical significance for the BPAZ in the analysis of variance for the total group of cardiac patients (P=0.266). For children with BPZ in the preoperative period below normal development pattern, the analysis of variance demonstrated statistical significance (P=0.031), and the posttest analysis demonstrated statistical difference in BPAZ in

Fig. 4 - Evolution of z-scores for height/age (HAZ) in cardiac patients with HAZ in the preoperative period which was below the normal pattern of development. Analysis of variance with P=0.001. (*) HAZ was significantly lower when compared with the general population’s in the preoperative period and in the first month

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Fig. 5 - Evolution of z-scores for brachial perimeter/age (BPAZ) in the group of cardiac patients. Analysis of variance with P=0.266. There was no difference compared with the general population

Fig. 7 - Evolution of z-scores for the subscapular skinfold/age (SSFAZ) in the group of cardiac patients. Analysis of variance with P=0.514. (*) The SSFAZ was significantly lower when compared with the general population’s in the preoperative period, in the first and last months of monitoring

Fig. 6 - Evolution of z-scores for brachial perimeter/age (BPAZ) in cardiac patients with BPAZ in the preoperative period which was below the normal pattern of development. Analysis of variance with P=0.031. (*) The BPAZ was significantly lower when compared with the general population’s in the preoperative period and the in first month

Fig. 8 - Evolution of z-scores for the subscapular skinfold/age (SSFAZ) in cardiac patients with SSFAZ in the preoperative period that was below the normal pattern of development. Analysis of variance with P=0.101. (*) The SSFAZ was significantly lower when compared with the general population’s in the preoperative period and in all follow-up months

The SSFAZ of the total group of cardiac patients was significantly lower than the general population’s in the preoperative period (P<0.001) in the 1st month (P=0.015) and in the 12th month (P=0.038). The SSFAZ in the group below the normal pattern of development was lower than the general population’s in the preoperative period (P<0.001) in the 1st month (P=0.066) the 3rd month (P=0.004) the 6th month (P=0.038) and in the 12th month (P=0.005). Figures 7 and 8 show the evolution of SSFAZ for the total group of patients with cardiac diseases and for the group with cardiac patients below the normal pattern of development. There was no statistical significance in TSFAZ in the analysis of variance for the total group of cardiac patients (P=0.819). For children with TSFAZ in the preoperative period below normal development pattern, the analysis of variance did not show statistical significance (P=0.054).

Fig. 9 - Evolution of z-scores for triceps skinfold/age (TSFAZ) in the group of cardiac patients. Analysis of variance with P=0.819. There was no difference with the general population

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In the groups of patients with heart diseases below normal development pattern in the preoperative period, those with z-score below -2, there was significant variation in weight, height and brachial parameter, indicating that corrective surgery was of utmost importance for rapid weight and height recovery. Weight and height proved to be good parameters for the analysis of evolution in the total group of cardiac patients, with recovery in the 3rd and 1st month respectively, becoming statistically similar to the general population. The same occurred with the group of patients with below normal developmental pattern in the preoperative period for weight and height, with recovery in the 12th and 3rd month. Therefore, the weight and height seem to be the best parameters for routine outpatient follow-up. The TSFAZ and BPAZ in the total group of cardiac patients were not lower than the general population’s for the time periods examined, in other words, they were always within the normal range, showing that these parameters may not be useful in people with heart disease in general as the analysis tool of weight-height development, since they require a serious initial commitment for being altered. In the groups of cardiac patients below normal developmental pattern in the preoperative period for the same parameters, the tricips skinfold was normalized in the 1st month and the brachial perimeter in the 3rd month, showing that these parameters may be useful for the follow-up of severely malnourished children, and especially BPAZ, which showed statistically significant variation and indicated to be a parameter of rapid improvement after corrective cardiac surgery. The SSFAZ in the total group of cardiac patients showed recovery from the 3rd month of the follow-up period, however, it is probably not a very reliable parameter because the difficulty of its measurement may cause measurement errors, which may explain what happened in the 12th month, with a drop of recovery over the general population. Moreover, in the group with heart disease patients’ below normal developmental pattern in the preoperative period for subscapular skinfold, the measure remained below the general population throughout the follow-up, indicating that it is probably a parameter of delayed recovery in malnourished patients and, therefore it is necessary a longer follow-up to analyze the recovery to the normal parameters. Numerous studies show that after surgery, children with heart disease benefit from the recovery to its normal state of development within one year[11-15], which is in agreement with our findings. Vaidynathan et al.[14] also found similar results to ours, with significant increase in WAZ from the 3rd month of the follow-up period. However, few studies include the perimeter and skinfolds to assess the development, and Silva VM et al.[4] positively correlated with subscapular skinfold with weight and height percentile values with age, confirming our findings that this

Fig. 10 - Evolution of z-scores for triceps skinfold/age (TSFAZ) in cardiac patients with TSFAZ in the preoperative period which was below the normal pattern of development. Analysis of variance with P=0.054. (*) The TSFAZ was significantly lower when compared with the general population’s only in the preoperative period

The TSFAZ of the total group of cardiac patients was not significantly lower than the general population’s in the analyzed periods. It was lower in the group below the normal pattern of development than the general population’s in the preoperative period (P=0.011), as can be seen in Figures 9 and 10. DISCUSSION As already mentioned by several authors, patients with congenital heart disease have a deficit in weight and height development[4-6,8,17]. The low energy intake, hypermetabolism[8,9] and cell hypoxia[9] are factors that decrease the availability of energy and hamper the adoption of a proper diet for these children, contributing to their developmental delay [10,15]. Hemodynamic factors such as cyanosis, hypertension and heart failure are implicated in the worsening of the energy expenditure, leading to a growth disorder[7,14,15,17,20]. The pulmonary hypertension seems to be the most relevant, to increase oxygen consumption by the right ventricle, which can often be hypertrophic or dilated by volume overload [7,15,17,20]. Factors restricting growth potential are also implicated in growth retardation of cardiac patients, such as low birth weight, small for gestational age and associated genetic syndromes [7,11,17]. In the total group of cardiac patients, the present study found no significant variation of MZ for all parameters analyzed during the first 12 months after the operation, which can be evidenced by analysis of variance. This may indicate that these parameters require outpatient treatment longer than a year to demonstrate significant variation in this specific group of patients, and also suggest that the sample was insufficient or small for the proposed study.

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anthropometric measurement may be useful in monitoring children with heart disease to assess the degree of malnutrition, despite its technical difficulties. Besides not presenting good energy reserves, heart diseases also provides a low-calorie-and-fat[10] contribution, which favors the involvement of subcutaneous reserves in the measured location. This study demonstrated that children most severely malnourished in the preoperative period received the most benefits from the operation, increasing their weight and height parameters within the first year, which is consistent with the literature. However, this recovery is slower than in individuals in general, precisely because of the degree of malnutrition in the preoperative period[13-16].

REFERENCES 1. Hoffman JIE, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39(12):1890-900. 2. Rivera IR, Silva MAM, Fernandes JMG, Thomaz ACP, Soriano CFR, Souza MGB. Cardiopatia congênita no recém-nascido: da solicitação do pediatra à avaliação do cardiologista. Arq Bras Cardiol. 2007;89(1):6-10. 3. Guitti JCS. Aspectos epidemiológicos das cardiopatias congênitas em Londrina, Paraná. Arq Bras Cardiol. 2000;74(5):395-9. 4. Silva VM, Lopes MVO, Araujo TL. Evaluation of the growth percentiles of children with congenital heart disease. Rev. Latinoam Enferm. 2007;15(2):298-303.

Major limitations of the study This was a prospective study that required regular monitoring of children and all of them were treated by the Unified Health System (SUS) in a tertiary referral center serving a wide geographic area. Therefore we faced some limiting factors such as economic hardship and distance to attend the follow-up appointments. Thus, the number of patients was not constant in the follow-up months, which was partly offset by appropriate statistical analysis. The hemodynamic or clinical variables such as pulmonary hypertension or degree of preoperative cyanosis were not considered, which are constantly mentioned in the literature as an aggravating factor in height and weight recovery[7,15,17]. Birth weight was also not assessed, which is known as an aggravating factor in height and weight development[6,7,14], however premature infants were excluded.

5. Tefuarani N, Hawker R, Vince J, Sleigh A, Williams GM. Surgical programme at Royal Alexandra Hospital, Sidney, for Papua New Guinea children with congenital heart disease, 1978-1994. J Paediatr Child Health. 2002;38(2):178-82. 6. Amorim LFP, Pires CAB, Lana AMAL, Campos AS, Aguiar RALP, Tibúrcio JD, et al. Apresentação das cardiopatias congênitas diagnosticadas ao nascimento: análise de 29.770 recém-nascido. J Pediatr. 2008;84(1):83-90. 7. Levy RJ, Rosenthal A, Miettinen OS, Nadas AS. Determinants of growth in patients with ventricular septal defect. Circulation. 1978;57(4):793-7. 8. Menon G, Poskitt EM. Why does congenital heart disease cause failure to thrive? Arch Dis Child. 1985;60(12):1134-9. 9. Weintraub RG, Menahem S. Growth and congenital heart disease. J Paediatr Child Health. 1993;29(2):95-8.

CONCLUSION Children with congenital heart disease undergoing operation return to normal height and weight evolution within 3 months, and those that are below the normal developmental pattern in the preoperative period receive the most benefits, returning to normal evoluiton within 12 months.

10. Vieira TCL, Trigo M, Alonso RR, Ribeiro RHC, Cardoso MRA, Cardoso ACA, et al. Avaliação do consumo alimentar de crianças de 0 a 24 meses com cardiopatia congênita. Arq Bras Cardiol. 2007;89(4):219-24. 11. Bravo-Valenzuela NJM, Passarelli MLB, Coates MV, Nascimento LFC. Recuperação pôndero-estatural em crianças com síndrome de Down e cardiopatia congênita. Rev Bras Cir Cardiovasc. 2011;26(1):61-8. 12. Cheung MM, Davis AM, Wilkinson JL, Weintraub RG. Long term somatic growth after repair of tetralogy of Fallot: evidence for restoration of genetic growth potential. Heart. 2003;89(11):1340-3.

Authors’ roles & responsibilities

13. Schuurmans FM, Pulles-Heintzberger CF, Gerver WJ, Kester AD, Forget PP. Long-term growth of children with congenital heart disease: a retrospective study. Acta Paediatr. 1998;87(12):1250-5.

MBP Autor principal UAC Coautor MFG Coautor CHM Coautor SHS Coautor LB Coautor ACM Coautor DMB Coautor

14. Vaidynathan B, Nair SB, Sundaram KR, Babu UK, Shivaprakasha K, Rao SG, et al. Malnutrition in children with congenital heart disease (CHD) determinants and short term impact of corrective intervention. Indian Pediatr. 2008;45(7):541-6.

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15. Tokel K, Azak E, Ayabakan C, Varan B, Aşlamaci SA, Mercan S. Somatic growth after corrective surgery for congenital heart disease. Turk J Pediatr. 2010;52(1):58-67.

crianças portadoras de cardiopatia congênita com shunt esquerdadireita: importância da presença de hipertensão pulmonar. Arq Bras Cardiol. 1995;65(5):403-7.

16. Manso PH, Carmona F, Jácomo AD, Bettiol H, Barbieri MA, Carlotti AP. Growth after ventricular septal defect repair: does defect size matter? A 10-year experience. Acta Paediatr. 2010;99(9):1356-60.

21. Vannucchi H, Unamuno MRL, Marchini JS. Avaliação do estado nutricional. Medicina (Ribeirão Preto). 1996;29(1):5-18.

17. Varan B, Tokel K, Yilmaz G. Malnutrition and growth failure in cyanotic and acyanotic congenital heart disease with and without pulmonary hypertension. Arch Dis Child. 1999;81(1):49-52.

23. Frisancho AR. Anthropometric standards for the assessment of growth and nutritional status. 1. ed. Ann Arbor: University of Michigan Press; 1990.

18. Pinheiro DGM, Pinheiro CHJ, Marinho MJF. Comprometimento do desenvolvimento pondo-estatural em crianças portadoras de cardiopatias congênitas com shunt cianogênico. Rev Bras Promoç Saúde. 2008;21(2):98-102.

24. WHO. Multicentre Growth Reference Study Group. WHO Child Growth Standards: Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass indexfor-age: Methods and development. Geneva: World Health Organization; 2006.

22. Marcondes E. Pediatria Básica. 9. ed. São Paulo: Sarvier; 2002.

19. Huber J, Peres VC, Santos TJ, Beltrão LF, Baumont AC, Cañedo AD, et al. Cardiopatias congênitas em um serviço de referência: evolução clínica e doenças associadas. Arq Bras Cardiol. 2010;94(3):333-8.

25. WHO. Multicentre Growth Reference Study Group. WHO Child Growth Standards: Head circumference-for-age, arm circumference-for-age, triceps skinfold-for-age and subscapular skinfold-for-age: Methods and development. Geneva: World Health Organization; 2007.

20. Leite HP, Carvalho ACC, Fisberg M. O estado nutricional de

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Oliveira MAB,SPECIAL et al. - TheARTICLE calcium paradox - What should we have to fear?

The calcium paradox - What should we have to fear? Paradoxo do cálcio - o que temos a temer?

Marcos Aurélio Barboza de Oliveira1, MD; Antônio Carlos Brandi2, MD; Carlos Alberto dos Santos2, MD; Paulo Henrique Husseni Botelho2, MD; José Luís Lasso Cortez3, MD; Gilberto Goissis4, PhD; Domingo Marcolino Braile5, MD, PhD DOI: 10.5935/1678-9741.20140054

RBCCV 44205-1547

Abstract The calcium paradox was first mentioned in 1966 by Zimmerman et al. Thereafter gained great interest from the scientific community due to the fact of the absence of calcium ions in heart muscle cells produce damage similar to ischemiareperfusion. Although not all known mechanisms involved in cellular injury in the calcium paradox intercellular connection maintained only by nexus seems to have a key role in cellular fragmentation. The addition of small concentrations of calcium, calcium channel blockers, and hyponatraemia hypothermia are important to prevent any cellular damage during reperfusion solutions with physiological concentration of calcium.

Resumo O paradoxo do cálcio foi pela primeira vez citado em 1966 por Zimmerman et al. A partir daí, ganhou grande interesse por parte da comunidade científica internacional devido ao fato da ausência do íon cálcio produzir na célula muscular cardíaca dano semelhante à lesão de isquemia-reperfusão. Apesar de não serem conhecidos todos os mecanismos envolvidos no processo da lesão celular no paradoxo do cálcio, a conexão intercelular mantida somente pelo nexus parece ter papel chave na fragmentação celular. A adição de pequenas concentrações de cálcio, bloqueadores de canal de cálcio, hiponatremia ou hipotermia são importantes para evitar que haja lesão celular no momento da reperfusão com soluções com concentração fisiológica de cálcio.

Descriptors: Heart Arrest, induced. Myocardial Ischemia. Calcium.

Descritores: Parada Cardíaca Induzida. Isquemia Miocárdica. Cálcio.

INTRODUCTION

Unlike what would be expected, the complete absence of calcium not only caused the cardiac arrest, but also altered the cell membranes of cardiac myocytes, culminating in the reperfusion phase with their necrosis, explaining the term “paradox”[1]. In the following years many researchers have studied possible physiological mechanisms of paradox, culminating

In 1960 Zimmerman et al.[1,2] described massive lysis of cardiomyocytes after administration of cardioplegia solution without calcium followed by reperfusion with saline solution with calcium physiological concentration in isolated rat heart. This event was called “calcium paradox”.

Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brasil; Centro Universitário de Votuporanga (UNIFEV), Santa Casa Votuporanga, Votuporanga, SP, Brazil. 2 Hospital de Base São José do Rio Preto. São José do Rio Preto, SP, Brazil. 3 Santa Casa Votuporanga, Votuporanga, SP, Brazil. 4 Braile Biomédiaca, Indústria Comércio e Representações, São José so Rio Preto, SP, Brazil. 5 Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil.

Marcos Aurélio Barboza de Oliveira Avenida República do Líbano, 2700, casa 80 - São José do Rio Preto, SP, Brazil - Zip code: 15092-440 E-mail: m_aurelio@sbccv.org.br

1

This study was carried out at São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, SP, Brazil. No financial support.

Correspondence address:

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Article received on November 24th, 2013 Article accepted on February 13rd, 2014

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ical strain), etc.. All these conditions cause injury to the myocardium even in the absence of extracellular calcium[18-22]. Another mechanism accepted is that calcium comes into the cell in a massive way, causing damage and cell death[23].

Abbreviations, acronyms & symbols DNP Dinitrophenol ADP Adenosine diphosphate ATP Adenosine triphosphate LV Left ventricle

Structural cellular changes The first description of structural changes in myocyte perfused in calcium-free medium was performed by Muir et al.[16], who observed changes in glycocalyx and intercalated disks of myocytes in isolated rat hearts. Intercalated disks are complex structures divided into several regions, the major one being occupied by adherens fascia. These are the places of greatest tension between the cells at the time of myocardial contraction. Desmosomal junctions, called macula adherens, are present and serve to unite the cells. Nexus or gap junctions are focal points of intimate cell contact, being local with electrical signaling between cells[24]. Muir et al.[16] noted that cardiac myocytes which underwent perfusion showed no calcium from 30 minutes of clear separation in regions of the fascia adherens and macula adherens, while the nexus remained intact (Figure 1). Ashraf[13] and Yates & Dhalla[25] observed similar changes in 10 to 15 minutes of exposure to the same environment. Shorter periodes of 3-5 minutes generally do not cause physical separation in the ultrastructure of the intercalated discs[23].

with a significant amount of studies on the subject, many being presented in 1983 at the IX World Congress of the Society for Heart Research, held in London[3]. In this event was compiled much of what we knew at the time about the lack of calcium in cardioplegic solution, the extensive myocardial damage that this solution causes and alternative ways for developing a safe hypocalcemic cardioplegia[4-6]. After nearly 50 years of the discovery of this paradox, this study aims to discuss some harmful effects of calcium paradox in the heart, considering its importance, molecular mechanisms, cellular ultrastructural changes, additive protective or harmful effect when placed in combination with other solutions and some ways to avoid it. Importance of calcium paradox In the 1980s, the calcium metabolism in the heart has been extensively studied. At that time, there was consensus on the consequences of the succession of a medium without calcium followed by another filled of it to heart muscle cells, which rapidly internalizes this ion, leading it to lysis and heart failure. This phenomenon is similar to reperfusion injury[7]. Another key aspect is the understanding of mechanisms involved, as cardioplegic solutions should not cause cellular damage. Hypocalcemic cardioplegic solutions are effective to induce cardiac arrest[8]. However, substances that interrupt or mitigate undesirable side effects must be present to prevent ventricular dysfunction after cardiopulmonary bypass [7] . Studies on metabolic pathways that promote or disrupt the process[9,10], as well as their relationship to heart failure[11,12] have been published, which we will discuss briefly below.

Fig. 1 - Electron micrograph of rat heart after 12 minutes of perfusion without calcium at 37oC. The intercalated disks are separated in the regions of the fascia adherens (FA), but are still interconnected by the nexus joints (N). The outer layer of the sarcolemma (OL) or glycocalyx is detached from the plasma membrane of the myocytes. Reproduced from Ganote et al., 1985[23]

Causal mechanism Several hypotheses were formulated to explain the calcium paradox as increased permeability of calcium in the sarcolemma[13], the glycocalyx[14] and separation of intercalated discs[15,16], but no further clarified the whole mechanism of the calcium paradox. It is also possible that intracellular hypercalcemia is not the primary cause of the calcium paradox. Its increase may occur as a result of damage to sarcolemma accompanied by an entry of moderate amount of calcium to structurally altered[17] cells. Isolated absence of calcium can cause cell damage, but its deleterious effect is potentiated in media with anoxia, caffeine, 2,4-dinitrophenol (DNF), ventricular balloon (mechan-

The calcium-free medium increases the amount of intracellular sodium both in cultured myocytes and in isolated heart. Moving to a medium rich in calcium, this ion rapidly enters cells via antiporter pump Na+/Ca+2, working on a reverse way. The similarities end here, as there is contraction of myocytes in culture, but not cytolysis, whereas in the isolated heart we found mass lysis of the cells. This phenomenon was described as intolerance to calcium[26-28].

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Lysis at the time the myocyte contacts reperfusion solution rich in calcium after sensitization in medium without this ion occurs because these cells have intermediate disc only connecting to one another, and there is their avulsion during contraction with exposure of the intracellular medium of each of them explaining the massive cell death of them[16]. Another change that occurs during infusion without calcium is the detachment of glycocalyx, which is usually a focal shift that is not seen until 10 to 15 minutes after infusion of the solution without calcium. Frank et al.[29,30] have shown that despite the detachment of the external layer of glycocalyx, there is an inner membrane that is adhered on the cell membrane. Ashaf et al.[13] and Frank et al.[29] observed aggregation and anomalous rearrangement of the constituent molecules of the cell membrane when placed in calcium free medium, so that there is irreversible cell damage due to altered membrane permeability. The molecular mechanisms of these changes are not yet known. Phase of re-entry of calcium into the cell After 10-15 minutes in medium deprived of calcium, the myocyte is sensitized, and the separation of the intercalated discs between cells is established[23]. The sarcomeres of each cell condense into a single band of contraction. The fascia adherens remain connected to sarcomeres, but are completely separate from the membranes of adjacent cells. Regions of intercalated discs, located between the areas of fascia adherens become fragmented and allow the mitochondria to go into the intercellular space [31]. Ganote et al.[19] mention that hypothermia prevents lysis of the fascia adherens and therefore cytolysis. The contractions of the sarcomere and cell necrosis are identical to those observed in other types of injury as catecholamine necrosis and ischemia/reperfusion injury. However, it should be emphasized that the cellular ultrastructure when in medium without calcium differs from all previous separation of the intermediate disks and the presence of a single central shrink band[23].

calcium permeability. However, Nayler et al. [17] using 2 mM calcium instead of magnesium in the private period of calcium showed that despite a detachment of the glycocalyx, there was no increase in membrane permeability to calcium and Slade et al.[33] have also observed that myocytes placed in buffer medium without calcium also lose glycocalyx, without, however, observing a change from the influx of calcium ion. With the use of neuraminidase there is complete separation of the glycocalyx of myocytes with increased cell permeability to calcium. To explain this phenomenon, Ganote et al.[23] postulate that in this case the membrane glycoproteins would also be damaged, losing control of the calcium flow. ATP Ruigrok et al.[34] showed that the massive release of enzymes which occurs during reperfusion of calcium is dependent on energy. This conclusion is based on experiments that consumed the intracellular ATP from myocyte with anoxic perfusion or the inclusion of this cell in medium without glucose. The non-cardiac cells did not release enzymes during phase of normal calcium after 5 minutes of perfusion without calcium due to depletion of ATP[34]. Calcium channel blockers Baker & Hearse[35] observed that the effect of calcium channel blockers is best demonstrated when there is low extracellular calcium concentration during reperfusion. Under these conditions, calcium entry occurs preferentially through the slow channels of the membrane. The limitation of this entry enables the recovery from injury of intercalated discs and sarcolemma. In solutions with physiological concentration of calcium in the reperfusion solution, the calcium channel blockers offer little protection to the paradox, suggesting that more than one route is important for the entry of calcium into the cell[36].

Traces of calcium Rebeyka et al.[32] found in CPB model that dog hearts perfused with cold cardioplegic solution without calcium showed a worse recovery of ventricular function and greater area of​​ necrosis than those in which the solution was only 70 Οmol/L calcium, showing that even small concentrations of calcium are sufficient to protect the heart of calcium paradox. Glycocalyx The separation of the external layer of the cell membrane glycocalyx from myocyte occurs after exposure of the cell to calcium-poor medium[23]. Frank et al.[14] believed that this separation would be responsible for the increase in the membrane

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Sodium Dhalla et al.[37] showed that when the concentration of sodium is reduced to 35 mm in phase without calcium, the magnitude of tissue damage is reduced during reperfusion with calcium. This is due to the low concentration of sodium, which slows the entry of calcium into the membrane by antiport pump Na+/Ca+2, facilitating intracellular ionic rebalancing and preventing contracture that would lead to cell death[37]. During the period without calcium, low sodium concentration reduces the transmembrane gradient and delays the calcium efflux and sodium influx. This would slow down the removal of both intracellular calcium and the cell damage caused by the absence of this ion. In the period with normal calcium low sodium would also be beneficial because it reduces calcium influx via antiporter pump Na+/Ca+2, working in a reverse way. The slow elimination of calcium when the

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cell is without it and slower internalization during reperfusion provides the cell conditions to reestablish its ionic balance before any structural damage[37]. Hypothermia Hypothermia protects the myocyte from calcium paradox[38,39]. It prevents the separation of the intercalated disc and detachment the glycocalyx[40]. In addition, it reduces the Na+/Ca+2, and may decrease the loss of Ca+2 ions in calcium-free perfusion time[41]. The ideal temperature found for myocardial protection of calcium paradox was 22oC[42-44].

Fig. 2 - Electron micrograph of rat heart after 5 minutes in calciumfree perfusion, followed by 15 minutes with the addition of DNP at the first perfusate. The sarcomeres are contracted herein, pulling the fascia adherens (FA) and causing damage to the cell membrane of the myocyte in the nexus area. The cytosol is exteriorized in the form of blebs (B) in the intercellular region. Reproduced from Ganote et al., 1985[23]

Mechanical injury Ganote et al.[20] states that when isolated rat hearts are placed in anoxia in medium with physiological concentration of calcium, the distension of the volumetric balloon in the left ventricle (LV) occurs with a small increase resulting from enzymatic cell lysis, but the LV distension is difficult. When the medium is free of calcium and normoxia, distension is easy and enzyme release is also small. However when we have anoxia and calcium-free medium, there is massive release of cellular enzymes. This is because anoxic hearts can withstand the wall tension that the balloon prints due to the intercalated disks were incomplete. The cavity is distended by elongation of the sarcomeres, with their lesion. In calcium-free medium and normoxia, the muscle fibers are now relaxed and the voltage produced by the balloon is not sufficient to cause avulsion of weakened intercalated disks. But when anoxia and medium without calcium are superimposed, the cell maintains the stiffness of the sarcomeres to the fragility of the intercalated disks. The pressure of the inflated balloon adversely affects directly the region, causing release of intracellular enzymes[20].

Caffeine Caffeine causes the sarcolemma calcium release but not in mitochondria[46]. Thus, intracellular calcium increases slightly, but without its overhead[31]. The persistent contraction produced by caffeine is dependent on calcium and in its absence there is support for only 20 to 30 seconds, followed by relaxation[18]. Hearts perfused with solution containing caffeine, but without calcium at 22oC do not manifest increased enzymes, but those kept at 37oC have similar injury to the calcium paradox[18]. Whereas the increase in intracellular calcium concentration is not significant because there was no reperfusion with calcium, it is unlikely that the lesion is originally from poisoning by calcium, but by direct action of ventricular contraction on sarcolemma[18]. CONCLUSION

Dinitrophenol The dinitrophenol (DNP) is a fat-soluble weak acid that acts as protonophore (translocator protons) entering the mitochondria positively charged and leaves it negatively charged, creating electron transport out of the mitochondria, preventing the conversion of ADP to ATP[45]. It also causes rapid ventricular contraction both in hearts which underwent calcium-free medium as in those with normal concentration of this ion. However, those in medium without calcium causes massive cell lysis[22] (Figure 2). This observation is consistent with the hypothesis that contraction physically separates the cells, causing cell lysis in those in free-calcium medium. The DNP alone causes contraction of cells, and it is not necessary to add calcium to the medium. Intracellular calcium present in mitochondria and sarcolemma would not be sufficient to generate environment that simulates medium with normal calcium[22].

We should fear the phenomenon known as “calcium paradox” because it irreversibly damages the membrane of the myocyte, causing extrusion of cellular contents. However, despite its biomolecular mechanisms are not fully understood, measures such as hypothermia, hyponatremia, and the presence of traces of calcium in the perfusion solution decreases the risk of this injury, enabling the recovery of ventricular function after induced cardiac arrest.

Authors’ roles & responsibilities MABO Main Author ACB Help in bibliographic survey and translated articles CAS Help in literature review and translation of articles PHHB Help in correcting the manuscript JLLC Help in correcting the manuscript GG Co-supervisor DMB Advisor

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Silva AKF, et al.SPECIAL - Cardiac risk stratification in cardiac rehabilitation programs: ARTICLE a review of protocols

Cardiac risk stratification in cardiac rehabilitation programs: a review of protocols Estratificação de risco cardíaco em programas de reabilitação cardíaca: revisão de protocolos

Anne Kastelianne França da Silva¹, MD; Marianne Penachini da Costa de Rezende Barbosa¹, MD; Aline Fernanda Barbosa Bernardo¹, MD; Franciele Marques Vanderlei¹, MD, PhD; Francis Lopes Pacagnelli², MD, PhD; Luiz Carlos Marques Vanderlei¹, MD, PhD

DOI: 10.5935/1678-9741.20140067

RBCCV 44205-1548

Abstract Objective: Gather and describe general characteristics of different protocols of risk stratification for cardiac patients undergoing exercise. Methods: We conducted searches in LILACS, IBECS, MEDLINE, Cochrane Library, and SciELO electronic databases, using the following descriptors: Cardiovascular Disease, Rehabilitation Centers, Practice Guideline, Exercise and Risk Stratification in the past 20 years. Results: Were selected eight studies addressing methods of risk stratification in patients undergoing exercise. Conclusion: None of the methods described could cover every situation the patient can be subjected to; however, they are essential to exercise prescription.

Resumo Objetivo: Reunir e descrever características gerais dos diferentes protocolos de estratificação de risco existentes para cardiopatas submetidos ao exercício. Métodos: Realizou-se busca nas bases eletrônicas LILACS, IBECS, MEDLINE, Biblioteca Cochrane, SciELO, por meio dos descritores: Doenças cardiovasculares, Centros de Reabilitação, Guia de Prática Clínica, Exercício e Estratificação de Risco e a palavra-chave “Risk Stratification”, nos últimos 20 anos. Resultados: Foram selecionados oito trabalhos abordando métodos de estratificação de risco em indivíduos submetidos a exercício. Conclusão: Nenhum dos métodos descritos conseguiu abranger todas as situações de risco a que o paciente está sujeito, porém eles são fundamentais para prescrição do exercício.

Descriptors: Cardiovascular Diseases. Rehabilitation Centers. Practice Guideline. Exercise. Risk Assessment.

Descritores: Doenças Cardiovasculares. Centros de Reabilitação. Guia de Prática Clínica. Exercício. Medição de Risco.

years-old[3] and ischemic heart disease, strokes, hypertension and other heart diseases are responsible for 16 million deaths annually[4]. This scenario points to the need for effective low-cost interventions of a preventive nature to reduce cardiovascular events and improve survival in patients with CVD[5]. In this

INTRODUCTION Cardiovascular diseases (CVD) are currently the leading cause of mortality worldwide, generating significant economic costs to the health system[1,2]. In Brazil, they are responsible for about 20% of all deaths in individuals over 30

Faculdade de Ciências e Tecnologia of Universidade Estadual Paulista Júlio de Mesquita Filho - FCT / UNESP, Department of Physical Therapy, Presidente Prudente, SP, Brazil. 2 Universidade do Oeste Paulista - UNOESTE, Department of Physical Therapy, Presidente Prudente, SP, Brazil.

Rua Roberto Simonsen, 305- Presidente Prudente – SP – Brazil Zip code: 19060-900

Correspondence address: Anne Kastelianne França da Silva Faculdade de Ciências e Tecnologia da Universidade Estadual Paulista Júlio de Mesquita Filho (FCT/UNESP), Departamento de Fisioterapia

No financial support.

1

Work carried out at Faculdade de Ciências e Tecnologia of Universidade aulista Júlio de Mesquita Filho (FCT/UNESP), Presidente Prudente, SP, Brazil.

Article received on February 23th, 2014 Article accepted on April 21st, 2014

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behaviors and interventions in physical exercise programs for cardiac patients.

Abbreviations, acronyms & symbols AACVPR ACSM AHA BSC CR CVD HRF METs SFC

American Association of Cardiovascular and Pulmonary Rehabilitation American College of Sports Medicine American Heart Association Brazilian Society of Cardiology Cardiac rehabilitation Cardiovascular diseases Heart rate frequency Metabolic equivalent Société Française de Cardiologie

METHODS Search strategy This study was constructed from a survey of data found in existing literature. We conducted a literature search to update ourselves on methods for cardiac risk stratification in patients undergoing exercise, without language restrictions. The articles selected were obtained through a literature search conducted in December 2013 in the following online databases: LILACS, IBECS, MEDLINE, the Cochrane Library and SciELO, covering the last 20 years, i.e. from January 1993 to December 2013. For this research cross-references were made of the following keywords in English (MeSH - Medical Subject Headings): Cardiovascular Diseases, Rehabilitation Centers, and Exercise Practice Guideline. The keyword “Risk Stratification” was also included because of its extreme relevance to the topic under focus.

context, programs for cardiac rehabilitation (CR) emerge as a major tool because studies show that the practice of physical exercise safely improves aerobic capacity, cardiovascular function, and quality of life of cardiac patients[6,7]. In addition, regular physical exercise may, among other effects, promote benefits of a psychological nature, improve levels of adherence to pharmacological therapy[8], control risk factors, contribute to the reduction in mortality and improve symptoms of CVD[9], reducing clinical manifestations such as acute myocardial infarction, cardiac arrest or sudden death[10] and favorably influencing surgical outcomes[11]. However, to obtain the beneficial effects and ensure safety during physical exercises it is essential that it be prescribed correctly. To prescribe the appropriate exercise intensity for each individual it is first necessary to know the patient’s level of risk, and for this purpose cardiac risk stratification becomes critical. Cardiac risk stratification means careful evaluation of the clinical and functional status of the patient, starting with clinical history and physical, laboratory and ancillary tests, in order to classify the subject individually in a risk range (low, moderate, and high)[12]. This procedure provides indications for the appropriate targeting of the patient throughout the rehabilitation process, and the identification of risk levels, making it an integral part of the management of patients during and after an acute myocardial event[13]. In recent years, different protocols for cardiac risk stratification for participation in exercise programs were developed and validated by several national and international entities, such as multivariate analyzes, which have provided clinicians and researchers with a wide range of information and, consequently, a reduction in the probability of acute cardiovascular events occuring while performing an exercise program[12,14]. Despite the importance of this process of risk stratification in physical exercise programs for cardiac patients, to our knowledge there are no publications that gather information and describe the characteristics of different protocols. Thus, this study aimed to gather information and describe the general characteristics of different existing risk stratification protocols, which may assist researchers and clinicians in targeting safer

Selection of studies For this review, we initially carried out the screening of titles related to the topic in question. This selection was based first on titles that addressed the main idea: cardiovascular rehabilitation, cardiovascular diseases, physical training, safety in physical training for cardiac patients, cardiovascular events, cardiac risk, and methods of cardiac risk stratification; then, on titles that focused on activities to combat sedentary lifestyle. At the end of the search, repeated titles were removed, since they were held in various databases. Then, a detailed reading of the article abstracts was undertaken to select only those that dealt exclusively with CR and the methods used for cardiac risk stratification for performing exercise. Having excluded abstracts that did not deal with the issue, the full texts were evaluated and those did not meet the exclusion criteria were included in the final results of the search. In addition, all references to the studies selected were reviewed to supplement the search. A single evaluator, under the supervision of a senior reviewer, undertook all stages of the search. Inclusion criteria The inclusion criteria were the following: a) studies published in all languages; b) the latest update of the stratification method, when updates occur periodically; c) articles published in the past 20 years; and d) works that specifically addressed strategies for cardiac risk assessment in cardiac patients undergoing exercise. Exclusion Criteria The exclusion criteria were the following: a) studies that did not mention the need for risk stratification in individuals

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practicing CR; b) authors who quoted in their work methods previously published by other entities; c) works in which risk assessment only covered risk factors for CVD; d) publications that dealt only with the prescription of exercise without describing a method for risk stratification; e) those articles that did not contain all the information found in the abstract; and f) full articles that were impossible to obtain for analysis after direct contact with the author or co-author.

Protocol of the American College of Sports Medicine[14] The guidelines of the American College of Sports Medicine (ACSM) for assessment and prescription of exertion were drawn up taking into account the participation of any person in an exercise program[14]. Thus, the main feature of the criteria for risk stratification of this entity is its simplicity (Chart 2). The presence of features in a higher risk class determines the range of risk and intensity of the training of each individual. Moreover, according to the guidelines, the presence of a negative risk factor (high serum HDL cholesterol) eliminates a positive risk factor so that an individual being rated in the moderate risk by having three positive risk factors may be reclassified in the low risk range if high serum HDL cholesterol is present. This highlights the importance of investigating laboratory tests, clinical and family history, and conducting physical assessments to determine the range of appropriate risk for each individual. ACSM does not delimit the period in which the individual must be reassessed. However, the use of this protocol alone requires extreme caution in patients with heart disease whose clinical condition has become unstable[14].

Analysis of Data Data were described according to the methods of risk stratification performed, references used for the development of the protocol, the clinical condition of the patient, the population addressed, and summary of the test protocol. RESULTS Eight methods of risk stratification were extracted from the databases searched. The general characteristics of the protocols found can be seen in Chart 1.

Chart 1. General characteristics of the methods of risk stratification. Protocol ACSM (2007) SBC (2013)

AHA (2001) PASHKOW (1993) AACVPR (2007)

SFC (2002) SEC (2000) SEC (2000)

General Characteristics Targeted at any individual who wants to perform an exercise program. Uses the presence of risk factors, signs and symptoms of cardiovascular, metabolic, and respiratory diseases as risk selection criteria. it does not discuss results of additional tests for stratification. Targeted at those who have suffered AMI and it uses the maximal exercise test as a primary method of risk stratification. It also uses the presence of signs and symptoms of congestive heart failure in high-risk individuals. It considers as high risk those individuals with functional capacity = 5 METs and EF = 35%. Extensive method that uses mainly symptoms or the presence of heart disease, risk factors, and exercise testing for risk selection. It considers as high risk those individuals with functional capacity <6 METs and EF ≤ 30%. Targeted at those who have suffered AMI. It uses results of complementary tests to stratify risk. It considers as high risk for events those individuals with functional capacity ≤ 4.5 METs. It does not use EF as criteria. It uses the maximal exercise test as the primary method of risk stratification (presence of symptoms during stress or recovery test). Their absence may inappropriately categorize the individual. Targeted at those who have suffered AMI. It considers as high risk those individuals with functional capacity <5 METs and EF <40%. Targeted at those who have suffered AMI based mainly on clinical history and maximal exercise test. It considers at high-risk individuals with functional capacity <5 METs and EF <30%. Designed for individuals who have suffered AMI. It uses clinical data and tests such as echocardiography and exercise testing to define risk groups. It considers as high risk those individuals with functional capacity <5 METs and EF <35%. Designed for individuals who have suffered AMI and wish to participate in sports activities. It evaluates VO2max associated with age to designate METs value in low-risk individuals. It considers as high risk those individuals with EF <50%.

Classification Low, moderate and High Risk. Low, moderate and High Risk. Risk Classes (A, B, C and D). Low, moderate and High Risk. Low, moderate and High Risk. Low, moderate and High Risk. Low, moderate and High Risk. Low and High Risk.

SBC: Brazilian Society of Cardiology; ACSM: American College of Sports Medicine; AHA: American Heart Association; AACVPR: American Association of Cardiovascular and Pulmonary Rehabilitation; SFC: French Society of Cardiology; SEC: Spanish Society of Cardiology; METs: Metabolic Equivalent; EF: Ejection Fraction; CHF: Congestive Heart Failure; AMI : Acute Myocardial Infarction; VO2 Max: Maximum Oxygen Consumption

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Chart 2. ACSM criteria for risk stratification of events during the year.

The AHA guidelines provide recommendations for the monitoring and supervision of participants and/or patients as well as for possible restriction of activities[16]. Unlike previous guidelines, AHA classifies individuals into risk classes (A, B, C and D), and within the B and C classes there are further criteria that determine the clinical characteristics and the presence of symptoms that characterize the evolution of Congestive Heart Failure, pinpointed by the “Functional Classification of the New York Heart Association.” If the individual chooses not to undergo a stress test, he should follow the guidelines described in Class B. Individuals classified in Class A (Chart 4A) have no restrictions except for basic advice, with supervision and monitoring during exercise deemed unnecessary. It is suggested that people classified as Class A-2 and, in particular, class A-3 undergo a medical examination and possibly an exercise stress test under medical supervision before starting vigorous exercise[16].

Low Risk • Men under 45 years of age and women under age 55 who are asymptomatic and do not meet more than a threshold of major risk (Positive factors - family history, cigarette smoking, hypertension, hypercholesterolemia, impaired fasting glucose, obesity, sedentary lifestyle. Negative factors - high serum HDL cholesterol). Moderate Risk • Men aged 45 years or older, women aged 55 or more; or those who satisfy the threshold for two or more major risk factors described above. High Risk • Individuals with one or more signs and symptoms (pain; discomfort in the chest, neck, jaw or arms; breathlessness at rest or on rapid exertion; dizziness or syncope, orthopnea or paroxysmal nocturnal dyspnea; edema of the ankles, palpitations or tachycardia intermittent claudication; known heart murmur; excessive fatigue; breathlessness in daily activities) or cardiovascular disease (heart disease, cerebrovascular, peripheral vascular), lung disease (chronic obstructive pulmonary disease, asthma, interstitial lung disease, cystic fibrosis) or known metabolic disease (diabetes mellitus, thyroid disorders, kidney or liver disease).

Chart 3. SBC criteria for risk stratification of events during the year. Low Risk • Functional Capacity = 7 METs. • Absence of myocardial ischemia at rest or stress test with less than 6 METs intensity. • Left ventricular EF = 50%. • Absence of significant ventricular ectopy after the third day after AMI. • Adequate blood pressure response to stress. • Ability to self-monitor the intensity with which one exercises

Thus, the objective of this protocol is to identify the need to refer an individual at increased risk for a medical evaluation and possibly undergo an exercise test. The ACSM itself recognizes the guidelines of the AACVPR and the AHA and recommends that heart patients be stratified based on the criteria of those institutions[14]. Protocol of the Brazilian Society of Cardiology[15] The protocol of the Brazilian Society of Cardiology (BSC) is mainly based on results obtained with the maximal exercise test. According to BSC, it is essential to carry out the progressive maximal exercise test to identify myocardial ischemia, ventricular dysfunction, cardiac arrhythmias and atrioventricular conduction disorders. Based on the results obtained in the supplementary examination patients should be stratified to start a cardiac rehabilitation program[15]. Chart 3 shows the criteria used by BSC for risk stratification. According to BSC, patients referred to as low risk should be reassessed every year, whereas patients with moderate and high risk should be reassessed earlier, that is, every six months or whenever any clinical modification occurs[15]. The presence of any of the characteristics listed in the moderate or high classifications is sufficient for classification of patients in that category.

Moderate Risk • Presence of myocardial ischemia. • ST depression = 2 mm segment. • Reversible abnormalities during exercise, myocardial scintigraphy with thallium. • Left ventricular EF = 35-49%. • Absence of complex ventricular ectopy. • No drop in blood pressure during exercise. High Risk • Recurring angina with ischemic changes in ST segment beyond 24 hours after hospital admission. • Signs and symptoms of congestive heart failure. • Left ventricular EF = 35%. • Complex ventricular ectopy (multifocal premature ventricular contractions, ventricular tachycardia, R on T phenomenon, ventricular fibrillation). • Functional Capacity = 5 METs in angina limited exertion test, ST segment depression or inadequate blood pressure response. • Decreased or failure to increase systolic blood pressure during exercise. • Persistent ischemic changes in ST and/or angina during exercise.

Protocol of the American Heart Association[16] The American Heart Association (AHA) developed a more extensive system of risk classification for the medical release of cardiac patients, described in Chart 4A and 4B.

METs: metabolic equivalent; EF: ejection fraction; AMI: Acute Myocardial Infarction

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Chart 4A. AHA criteria for risk stratification of events during exercise in healthy individuals (class A) and low risk (class B).

Chart 4B. AHA criteria for risk stratification of events during exercise in individuals with moderate to high risk (class C) and activity restriction (class D).

Class A This classification includes: • A1: Children, adolescents, men < 45 years old, and women < 55 years old who have no symptoms or known presence of heart disease or major coronary risk factors. • A2: Men ≥ 45 years old and women ≥ 55 years old who have no symptoms or known presence of heart disease and with < 2 major cardiovascular risk factors. • A3: Men ≥ 45 years old and women ≥ 55 years old who have no symptoms or known presence of heart disease and with ≥ 2 major cardiovascular risk factors.

Class C This classification includes individuals with any of the following diagnoses: • C1: CAD with the clinical characteristics outlined below. • C2: Valvular heart disease, excluding severe valvular stenosis or regurgitation with the clinical characteristics outlined below. • C3: Congenital heart disease; risk stratification for patients with congenital heart disease should be guided by the 27th Bethesda Conference recommendations*. • C4: Cardiomyopathy: EF 30%; includes stable patients with heart failure with the clinical characteristics outlined below, excluding hypertrophic cardiomyopathy or recent myocarditis. • C5: Complex ventricular arrhythmias not well controlled.

Class B This classification includes individuals with any of the following diagnoses: • B1: CAD (MI, CABG, PTCA, angina pectoris, abnormal exercise test, and abnormal coronary angiograms) whose condition is stable and who have the clinical characteristics outlined below. • B2: Valvular heart disease, excluding severe valvular stenosis or regurgitation with the clinical characteristics outlined below. • B3: Congenital heart disease; risk stratification for patients with congenital heart disease should be guided by the 27th Bethesda Conference recommendations*. • B4: Cardiomyopathy: EF ≤ 30%; includes stable patients with heart failure with clinical characteristics as outlined below, excluding hypertrophic cardiomyopathy or recent myocarditis. • B5: Exercise test abnormalities that do not meet any of the high risk criteria outlined in class C below.

Clinical characteristics (any of the following): 1. NYHA class 3 or 4. 2. Exercise test results • Exercise capacity 6 of METs • Angina or ischemic ST depression at a workload of 6 METs • Fall in systolic blood pressure below resting levels during exercise • Nonsustained ventricular tachycardia with exercise 3. Previous episode of primary cardiac arrest (ie, cardiac arrest that did not occur in the presence of an acute myocardial infarction or during a cardiac procedure). 4. A medical problem that the physician believes may be lifethreatening. Class D This classification includes individuals with any of the following: • D1: Unstable ischemia. • D2: Severe and symptomatic valvular stenosis or regurgitation. • D3: Congenital heart disease; criteria for risk that would prohibit exercise conditioning in patients with congenital heart disease should be guided by the 27th Bethesda Conference recommendations*. • D4: Heart failure that is not compensated. • D5: Uncontrolled arrhythmias. • D6: Other medical conditions that could be aggravated by exercise.

Clinical characteristics (must include all of the following) Clinical characteristics according to additional tests. They should check all the clinical features present. 1. New York Heart Association class 1 or 2 2. Exercise capacity ≤ 6 METs 3. No evidence of congestive heart failure 4. No evidence of myocardial ischemia or angina at rest or on the exercise test at or below 6 METs 5. Appropriate rise in systolic blood pressure during exercise 6. Absence of sustained or nonsustained ventricular tachycardia at rest or with exercise 7. Ability to satisfactorily self-monitor intensity of activity

*Fuster V, Gotto AM, Libby P, Loscalzo J, McGill HC. 27th Bethesda Conference: Matching the intensity of risk factor management with the hazard for coronary disease events. J Am Coll Cardiol 1996;27(5):964-76.

*Fuster V, Gotto AM, Libby P. 27th Bethesda Conference: Matching the intensity of risk factor management with the hazard for coronary disease events. J Am Coll Cardiol 1996;27:964-76.

CAD: Coronary Artery Disease; EF: Ejection Fraction; NYHA: New York Heart Association; METs: Metabolic Equivalent

EF: ejection fraction; CAD: Coronary Artery Disease; MI: Myocardial Infarction; CABG: coronary artery bypass graft; PTCA: Percutaneous Transluminal Coronary; METs: Metabolic Equivalent

12th session, always accompanied by the monitoring of blood pressure and electrocardiogram[16]. After successfully completing a series of supervised exercise sessions in Class C, the patient may be reclassified to Class B, provided that it is safe to undertake that activity with the prescribed intensity and that he has demonstrated

For those assigned to either Class B (Chart 4A) or C (Chart 4B), the guideline recommends that activities be individualized and prescribed by qualified persons. In addition, initial medical supervision is considered useful until such time when the individual can perform his or her activities safely and without supervision, usually between the 6th and

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the capacity for self-monitoring. No activity for the purpose of training is recommended for those classified in Class D (Chart 4B), but daily activities are prescribed, so that the individual may be gradually restored to Class C[16]. It should be recognized that the AHA guidelines do not take into account co-morbidities (for example, type 1 diabetes, morbid obesity, severe lung disease or debilitating neurological or orthopedic conditions) that could result in modification of recommendations for monitoring and supervision during exercise training[14].

Chart 5. Criteria defined by Pashkow for risk stratification of events during the year. Low Risk • After uncomplicated coronary revascularization • ≥ 7.5 METs 3 weeks after an ischemic event • No ischemia, left ventricular dysfunction or significant arrhythmia Moderate Risk • ≤ 7.5 METs 3 weeks after an ischemic event • Angina or 1 - to 2- mm ST segment depression with exercise • Perfusion or wall motion abnormalities with stress • History of congestive heart failure • More than mild but less than severe left ventricular dysfunction • Late potentials present on signal-averaged electrocardiogram • Nonsustained venricular arrhythmia • Inability to self-monitor exercise or comply with exercise prescription

Protocol designed by Frederic J. Pashkow[13] In 1993, Pashkow developed a model for risk stratification based on the orientation of important guidelines at the time as well as new means of risk identification. He summarized them in three levels: low, moderate and high risk; considered by him to be extremely useful for the planning of the program[13]. His model is aimed at those who have suffered cardiac events such as myocardial infarction[13] and it uses important features of ancillary exams, such as the progressive exercise test, electrocardiogram, and echocardiogram. The author argues that risk stratification should be a continuous process within or outside a rehabilitation program, since it evaluates the evolution of risk of each individual and determines the prognosis of any patient after an acute myocardial infarction. Moreover, the process of stratification makes it possible to identify individuals at risk of death or reinfarction and those who require only conventional therapy to achieve a good prognosis, such as those considered low risk[13]. The low, moderate and high risk levels suggested by Pashkow are described in Chart 5. The presence of a feature in the highest risk range classifies the individual in that category.

High Risk • Severe left ventricular dysfunction • ≤ 4.5 METs 3 weeks after cardiac event • Exercise-induced hypotension (≥ 15 mmHg) • Exercise-induced ischemia > 2-mm ST segment depression • Ischemia induced at lows levels of exercise • Persistence of ischemia after exercise • Sustained ventricular arrhythmia spontaneous or induced METs: Metabolic Equivalent

For individuals classified as low-risk for participating in exercise, the guideline recommends that direct supervision of the exercise should occur for at least 6-18 workouts or 30 days after the event or post-procedure. For those with moderate risk, direct supervision should occur for at least 12 to 24 sessions or 60 days after the event or post-procedure, and high-risk patients should be monitored for at least 18 to 36 exercise sessions or 90 days after the event or post-procedure[12].

Protocol of the American Association of Cardiovascular and Pulmonary Rehabilitation[12] The guideline of the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) uses variables common to those established models and allows for categorization in simple classes of risk, divided into: low, moderate, and high risk for participating in exercises. The low-risk patients do not exhibit any of the characteristics mentioned. Patients at greatest risk have any one of the characteristics mentioned. Those who do not fit into any classification are considered moderate risk[12]. This guidance is based primarily on the findings of an exercise test. It states that those who do not undergo the test before entering the program or those with undiagnosed exercise testing may be categorized inadequately using these criteria, and it suggests that these patients should be treated more cautiously with regard to risk stratification and that they should be monitored with a more conservative methodology for the prescription of exercise[12]. Chart 6 describes the definitions of low, moderate and high risk suggested by the AACVPR guideline.

Protocol of the Société Française de Cardiologie[17] The Société Française de Cardiologie (SFC) adapted the recommendations on exercise prescription of the European Society of Cardiology and the AACVPR in preparing its method of risk stratification[17]. This model is based on the patient's history and clinical examination and, systematically, on the stress test and echocardiogram[17]. This protocol recommends that after the initial assessment, the patient may be included in one of three risk categories described in Chart 7. However, the SFC suggests as an initial and temporary contraindication those who present: pericardial effusion, phlebitis, thrombus in the left ventricle or decompensated heart failure[17]. According to the SFC, patients with low or intermediate risk are able to start a classical training program, the structure of which is currently based primarily on the training heart rate frequency (HRF) determined during the stress test[18].

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Chart 6. AACVPR criteria for risk stratification in patients with low, moderate and high risk of events during the year. Low Risk • Absence of complex ventricular dysrhythmia during exercise testing and recovery • Absence of angina or other significant symptoms (e.g., unusual shortness of breath, light-headedness, or dizziness heart rate and systolic blood pressure with increasing workloads and recovery) • Presence of normal hemodynamics during exercise testing and recovery (i.e., appropriate increases and decreases in heart rate and systolic blood pressure with increasing workloads and recovery) • Functional capacity ≥ 7 METs Nonexercise testing findings • EF ≥ 50% at rest • Uncomplicated MI or revascularization procedure • Absence of complicated ventricular arrhythmias at rest • Absence of CHF • Absence of signs or symptoms of post-event or post-procedure ischemia • Absence of clinical depression Nonexercise testing findings • EF ≥ 50% at rest • Uncomplicated MI or revascularization procedure • Absence of complicated ventricular arrhythmias at rest • Absence of CHF • Absence of signs or symptoms of post-event or post-procedure ischemia • Absence of clinical depression Moderate Risk • Presence of angina or other significant symptoms (e.g., unusual shortness of breath, light headedness, or dizziness occurring only at high levels of exertion [ <7METs]) • Mild to moderate level of silent ischemia during exercise testing or recovery (ST-segment depression < 2 mm from baseline) • Function capacity < 5 METs Nonexercise testing findings: • EF = 40% to 49% at rest High Risk • Presence of complex ventricular arrhythmias during exercise testing or recovery • Presence of angina or other significant symptoms (e.g., unusual shortness of breath, light-headedness, or dizziness at low levels of exertion [≥ 5 METs] or during recovery) • High level of silent ischemia (ST-segment depression ≥ 2 mm from baseline) during exercise testing or recovery • Presence of abnormal hemodynamics with exercise testing (i.e., chronotropic incompetence or flat or decreasing systolic BP with increasing workloads) or recovery (i.e., severe postexercise hypotension) Nonexercise testing findings: • EF < 40% at rest • History of cardiac arrest or sudden death • Complex dysrhythmias at rest • Complicated MI or revascularization procedure • Presence of CHF • Presence of signs or symptoms of postevent or postprocedure ischemia • Presence of clinical depression METs : Metabolic Equivalent; EF: Ejection Fraction; MI: Myocardial Infarction; CHF: Congestive Heart Failure; BP: Blood Pressure

Protocol of the Sociedad Española de Cardiología[19,20] The Spanish Society of Cardiology (ESC) published two papers in 2000, entitled: Guides to clinical practice in cardiovascular prevention and cardiac rehabilitation[19] and Guides to clinical practice in physical activity of the cardiac patient[20], which addressed the practice of physical activity in individuals who have suffered AMI. The guide provides recommendations for risk stratification of these individuals using criteria such as

High-risk patients, combined with indicators of poor prognosis (low ejection fraction, early and severe ischemia, serious ventricular arrhythmias) are patients for whom training poses greater risks, but, on the other hand, gains are high in terms of quality of life. The prescription of exercise is more cautious here, and it usually begins with mild sessions and a higher level of monitoring during the first days, allowing for adaptation and subsequent resistance training[18].

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clinical assessment and examinations, including echocardiography and stress testing. Although the guidelines are similar, there are differences in the stratification of risk. The article entitled “Guides to clinical practice in cardiovascular prevention and cardiac rehabilitation”[19] suggests that the main indication for CR is ischemic heart disease in its different aspects, but it is expandable to all CVD and should also be applied to healthy subjects presenting risk factors. The guide reports that a program of secondary prevention should always be associated with CR in order to favor control of risk factors, improve quality of life, and reduce mortality and morbidity in this population[19]. The guide stratifies cardiac patients in three risk categories (Chart 8A) and calls for supervised programs for individuals of medium and high risk, with controlled heart failure, and those with psychological manifestations such as depression. Those classified as low risk for cardiac events during exercise can be admitted to a supervised program if they present the conditions mentioned[19].

The article entitled “Guides to clinical practice concerning the physical activity of cardiac patients”[20] makes general recommendations regarding the practice of sports for cardiac patients. The guide stresses that before starting any physical activity, whether of a sporting nature or not, cardiac individuals should be evaluated as to their personal and family medical history as well as sports activities they have engaged in and should undergo physical assessments, including a 12-lead resting electrocardiogram and stress test to at least submaximal[20]. The guide recommends avoiding exercise in patients with unstable angina, heart failure and aortic aneurysm or severe ventricular pseudoaneurysm. It stratifies individuals into two risk classes[20]. Chart 8B refers to the risk stratification for patients undertaking sports. Some similarities with Chart 8A can be noticed: both advise that individuals should be considered low risk when presenting ejection fraction >50%, absence of arrhythmias and ischemia, and clinical hospital outcome without complications. However, when the stratification refers to cardiac patients with high risk, most of the characteristics of a group considered “moderate” are added to the criteria that describe a high-risk population, allocating to this risk range all those individuals who would be considered as moderate risk or high risk in the previous guide. It is still recommended that patients at low risk should be assessed annually and they may play sports with low to moderate dynamic and static component. Those at high risk should be reassessed every six months and they are free to

Chart 7. SFC criteria for risk stratification of events during the year. Low Risk • Hospital clinical evolution without complications (without recurrent ischemia, heart failure or severe ventricular arrhythmia). • Good functional capacity (>6 METs) three weeks or more after the acute phase. • Systolic function of the left ventricle preserved. • Absence of myocardial ischemia at rest or during exercise. • Absence of serious ventricular arrhythmias at rest or during exercise.

Chart 8A. ESC criteria for risk stratification of events during the year to participate in a cardiac rehabilitation program.

Moderate Risk • Moderate functional capacity (5-6 METs) three weeks or more after the acute phase, high ischemic threshold. • Moderately impaired systolic function of the left ventricle. • Moderate residual myocardial ischemia and/or depression of the ST <2 mm segment in the stress test or reversible myocardial ischemia during echocardiography or isotopic explorations. • Mild ventricular arrhythmias (Lown class I or II) at rest or during exercise.

Low Risk • Hospital clinical evolution without complications • Functional capacity >7 METs • Absence of ischemia • EF >50% • Absence of severe ventricular arrhythmias Moderate Risk • Occurrence of Angina • Abnormalities reversible with thallium stress • Functional capacity between 5-7 METs • EF 35-49%

High Risk • Evolution of hospital clinical complications (heart failure, cardiogenic shock and/or severe ventricular arrhythmia). • Survivors of sudden death. • Low functional capacity (<5 METs) three weeks or more after the acute phase. • Severely impaired left ventricular function (EF <30%). • Residual myocardial ischemia (severe incapacitating exertion angina, low ischemic threshold and/or ST-segment depression >2 mm on the electrocardiogram in exercise). • Complex ventricular arrhythmias (Lown Class III, IV, and V) at rest from exercise.

High Risk • Reinfarction. Hospital CHF • ST segment depression of >2 mm with HR <135 bpm • Functional capacity <5 METs with or without ST-segment depression • EF <35% • Hypotensive response to stress • Malignant ventricular arrhythmias METs: Metabolic Equivalent; EF: Ejection Fraction; CHF: Congestive Heart Failure

METs: Metabolic Equivalent; EF: Ejection Fraction

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Chart 8B. ESC criteria for risk stratification of events during the year for participants in sports activities.

In addition to these entities, Pashkow developed a method of stratification aimed at those with episodes of myocardial infarction, based on current guidelines at the time and on new means of identifying risks and he summed it up into low, medium, and high risk[12]. Most protocols use additional tests as reference, among which the ergometric test can be considered as a well-established methodology for risk stratification of cardiac patients[21]. For cardiac risk stratification the metabolic equivalent (METs) obtained from the ergometric test is indicated in many of the protocols as one of the main references for determining the risk level of each individual. The METs is a unit used to quantify the intensity of physical activity and energy expenditure caused by it[12]. The objective of stratifying cardiac risk goes beyond the classification of the individual’s risk as it also allows the clinician to direct the therapeutic approach, to establish the level of monitoring and the appropriate dose of exercise (intensity, duration, etc.). Therefore, it is very important to implement risk stratification both for those who want to start a program of self-directed physical activity and for those who enter programs with exercises for primary or secondary prevention. Among the protocols found for cardiac risk stratification with the exception of ACSM, all the protocols use the findings of the stress test as the main reference to stratify an individual safely, before starting exercise training, making this an extremely important tool in a CR program. Those using data from stress testing determine that the individual at greatest risk is one that presents a METs value lower than 5 METs during the test, and moderate values ​​between 5 and 7.5 METs, enabling greater safety when choosing any of protocols, since there is no exaggerated disproportion in them. However, only the ACSM protocol uses comorbidities such as type 1 diabetes, morbid obesity, severe pulmonary disease, and neurological conditions as stratifying criteria, which are important for planning the training as well as for a better view of the patient’s condition and response to exercise. SFC and AACVPR are the only ones that address the factor of “cardiac arrest” as a criterion to determine wheter a patient is at high risk for cardiac events during exercise, a very relevant factor when seeking to admit an individual safely into a rehabilitation program. The SEC issued two stratification methods for cardiac patients, one for those who underwent CR and another for those who wish to practice sports competitively[19,20]. Like other entities it stratifies risks based on clinical findings and laboratory tests such as echocardiogram and stress test. For those individuals who wish to practice sports activities the criteria are more stringent when establishing the ranges of risk, because it involves a much more intense activity than that performed in a CR center. Of all the methods mentioned here, only the ACSM is not directly aimed at patients suffering from a cardiovascular

Low Risk • Systolic function normal at rest (EF greater than 50%). • Normal tolerance to exercise. - Patients under 50 years old: greater than 35 ml/min kg (10 METs) VO2max - Patients between 50 and 59 years old: greater than 31 ml/min kg (9 METs) VO2max - Patients between 60 and 69 years old: greater than 28 ml/min kg (8 METs) VO2max - Patients over 70 years old: VO2max greater than 24 ml/min kg (7 METs) • Absence of exercise-induced ischemia. • Absence of exercise-induced arrhythmias. • Absence of coronary stenosis or greater than 50%, indicating good coronary revascularization. Moderate Risk Does not mention High Risk • Depressed systolic function at rest (EF less than 50%). • Evidence of exercise-induced ischemia. • Evidence of exercise-induced arrhythmias. • Coronary lesions exceeding 50% stenotis. EF: Ejection Fraction; VO2max: Maximum Oxygen Consumption; METs: Metabolic Equivalent

participate in low intensity sports. For those patients who have had a heart attack or bypass surgery recently, it is advised to join a CR program before starting any sports activity. Finally, the guide points out that patients with ischemic heart disease should not compete, and are only free to practice sports to stay healthy[20]. CONCLUSION The criteria for risk stratification for events during exercise or physical activity are derived from multivariate research considering factors associated with the increased risk of morbidity and mortality in general. The main protocols for cardiac risk stratification for participation in physical exercise programs that are currently available are organized by the following entities: the American College of Sports Medicine (ACSM), the Brazilian Society of Cardiology (SBC), the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR), the American Heart Association (AHA), the Société Française de Cardiologie (SFC) and the Spanish Society of Cardiology (SEC). These entities regularly publish reviews of their guidelines for assessment and prescription of exertion, trying to establish standards for the assessment and prescription of exertion, including the recommendations for risk stratification of patients who wish to begin a rehabilitation program.

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disorder, which can make its use less safe when applied to this population. In particular, the AHA protocol is further subdivided into four risk classes, those considered healthy, those at low-risk, those at moderate to high risk, and those for whom physical training is not recommended. The other protocols classify individuals as low, moderate, and high risk. We may note another difference between protocols regarding to how up-todate they are, given that the oldest protocol dates from 1993 and the most recent from 2013. When assessing whether the AACVPR and AHA guidelines are really valid when predicting complications during exercise, Paul-Labrador et al.[22] found that neither were effective in assigning patients with complications to high-risk groups demonstrated by the low positive predictive values (5-7% variation) and low sensitivities (17-42% variation). However, the authors noted that these results might not be a specific failure of the guidelines, but might rather be due to the combination of an absence of potential predictors of risk and the low occurrence of serious complications in their study. On the other hand, Zoghbi et al.[23], when evaluating the proposed AACVPR protocol in 1999 associated with noncardiac comorbidities[24], such as diabetes mellitus, chronic obstructive pulmonary disease, cerebrovascular disease, and peripheral arterial disease, among others, observed that cardiac events were best predicted when both classifications were combined, suggesting that in order to appreciate more fully the overall complexity of the disease among patients practicing CR, risk stratification should be supplemented not only with the inclusion of cardiac risk factors, as suggested in current guidelines, but also with an evaluation of non-cardiac comorbidities[25]. When stratifying the cardiac risk patients attending 65 CR centers by using the SFC protocol , Pavy et al.[26] were unable to correctly predict the risk of complications during physical training. The same occurred with Vongvanich et al.[27] when they used the AACVPR protocol. The authors attribute this result to the low frequency of serious complications during the trainings conducted. We are not aware of studies evaluating other protocols (ACSM, SBC, and Pashkow SEC). Finally, based on the studies cited above, although risk stratification remains necessary at the beginning of a rehabilitation program, the occurrence of a major cardiovascular event seems to be difficult to predict in most cases[22-27]. Several guidelines allow risk stratification, but the criteria are derived from factors associated with an increased risk of morbidity and mortality in the general population[12]. Thus, it is not clear whether the overall risk and the risk during exercise training are similar[26]. Finally, to prescribe the appropriate exercise intensity within a CR program, it is necessary to know beforehand the level of risk that each individual faces. This stratification of

cardiac risk associated with the assessment of non-cardiac comorbidities and cardiac risk factors for CVD is absolutely paramount because that way it is possible to establish the level of monitoring and the appropriate dose of exercise and consequently, it is essential for the start of a safe and effective CR program. Authors’ roles & responsibilities AKFS

MPCRB AFBB FMV

FLP LCMV

Analysis and/or interpretation of data; final approval of the manuscript; conception and design of the study; implementation of operations and/or experiments; writing of the manuscript or revising it critically for content Analysis and/ or interpretation of data; implementation of operations and/or experiments; writing of the manuscript or revising it critically for content Analysis and/or interpretation of data; implementation of operations and/or experiments; writing of the manuscript or revising it critically for content Analysis and/or interpretation of data; conception and design of the study; implementation of operations and/or experiments; writing of the manuscript or revising it critically for content Analysis and/or interpretation of data; conception and design of the study; implementation of operations and/or experiments; writing of the manuscript or revising it critically for content Analysis and/or interpretation of data; final approval of the manuscript; conception and design of the study; implementation of operations and/or experiments; writing of the manuscript or revising it critically for content

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22. Paul-Labrador MJ, Vongvanich P, Merz CN. Risk stratification for exercise training in cardiac patients: do the proposed guidelines work? J Cardiopulm Rehabil. 1999;19(2):118-25.

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26. Pavy B, Iliou MC, Meurin P, Tabet JY, Corone S. Safety of exercise training for cardiac patients: results of the French registry of complications during cardiac rehabilitation. Arch Intern Med. 2006;166(21):2329-34.

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27. Vongvanich P, Paul-Labrador MJ, Merz CNB. Safety of medically supervised exercise in a cardiac rehabilitation center. Am J Cardiol. 1996;77(15):1383-5.

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Carvalho FilhoREVIEW EB, et al. ARTICLE - Vacuum-assisted drainage in cardiopulmonary bypass: advantages and disadvantages

Vacuum-assisted drainage in cardiopulmonary bypass: advantages and disadvantages Sistema a vácuo na circulação extracorpórea: vantagens e desvantagens

Élio Barreto de Carvalho Filho1, Fernando Augusto de Lima Marson1, MD; Loredana Nilkenes Gomes da Costa1, Nilson Antunes1, PhD DOI: 10.5935/1678-9741.20140029

RBCCV 44205-1549

Abstract Systematic review of vacuum assisted drainage in cardiopulmonary bypass, demonstrating its advantages and disadvantages, by case reports and evidence about its effects on microcirculation. We conducted a systematic search on the period 1997-2012, in the databases PubMed, Medline, Lilacs and SciELO. Of the 70 selected articles, 26 were included in the review. Although the vacuum assisted drainage has significant potential for complications and requires appropriate technology and professionalism, prevailed in literature reviewed the concept that vacuum assisted drainage contributed in reducing the rate of transfusions, hemodilutions, better operative field, no significant increase in hemolysis, reduced complications surgical, use of lower prime and of smaller diameter cannulas.

Resumo Revisão sistemática sobre drenagem assistida a vácuo na circulação extracorpórea, demonstrando seus benefícios, desvantagens, por relatos de casos e evidências sobre seus efeitos na microcirculação. Realizou-se pesquisa sistemática, no período de 1997-2012, nas bases de dados do PubMed-Medline, Lilacs e SciELO. Termos: “circulação extracorpórea”, “vácuo”, “drenagem”, “cirurgia cardíaca” e suas correspondentes traduções, em condições variadas. Dos 70 artigos selecionados, 26 foram incluídos na revisão. Embora a drenagem assistida a vácuo possua potencial significante de complicações e exija tecnologia e profissionalismo respectivo adequado, prevaleceu na literatura revisada o conceito de que a drenagem assistida a vácuo contribuiu na redução no índice de transfusões, hemodiluições, melhor campo operatório, não aumento de hemólise significativa, redução de complicações pós-cirúrgicas, uso de menor prime e uso de cânulas de menor calibre.

Descriptors: Cardiopulmonary Bypass. Review. Thoracic Surgery.

Descritores: Circulação Extracorpórea. Revisão. Cirurgia Torácica.

The CPB circuit has two reservoirs, and the venous reservoir receives blood from the venous drainage and the cardiotomy reservoir receives blood from the operative field, recovered by aspiration. In addition, it has oxygenator coupled to a heat exchanger. Between the oxygenator and the arterial cannula an arterial line filter is installed. Some equipments are used according to the method of the team, as the pre-by-

INTRODUCTION Cardiopulmonary bypass (CPB) is a set of machines, devices, tubes and techniques that temporarily replace the pump and ventilatory functions of the heart and lungs, respectively, while these organs are excluded from the circulation by surgical event[1].

Faculdade de Ciências Médicas da Universidade Estadual de Campinas (FCM-Unicamp), Campinas, SP, Brazil.

Correspondence address: Fernando Augusto de Lima Marson Unicamp - Universidade Estadual de Campinas Tessália Vieira de Camargo, 126 - Cidade Universitária “Zeferino Vaz” Campinas, SP, Brazil - Zip code: 13083-887

1

This study was carried out at Hospital das Clínicas da Faculdade de Ciências Médicas da Universidade Estadual de Campinas (HC-FCM-Unicamp), Campinas, SP, Brazil.

E-mail: fernandolimamarson@hotmail.com Article received on April 6th, 2013 Article accepted on September 2nd, 2013

No financial support.

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Carvalho Filho EB, et al. - Vacuum-assisted drainage in cardiopulmonary bypass: advantages and disadvantages

After this step, the process of selecting studies for examining titles and abstracts was initiated. The first inclusion criterion used was identification of relevant studies, whereas those in which the drainage system was the main subject of the article (Table 1). At this moment, all studies that only cited vacuum as a method used in surgeries and/or described events were excluded.

Abbreviations, acronyms and symbols CPB VAD TNP CVP

cardiopulmonary bypass vacuum assisted drainage topical negative pressure central venous pressure

pass filter, cardioplegia system as well as the use of the vacuum system. The use of vacuum-assisted drainage system (VAD) emerged in an attempt to reduce the deleterious effects of hemodilution and with the advent of minimally invasive surgery has gained prominence, in addition to be used in heart[2-5] surgeries. The vacuum technique consisted of using negative pressure in the venous reservoir, allowing the active drainage vein, eliminating the principles of gravity and siphoning[6]. This way it is possible to shorten the circuit, reducing the prime volume, hemodilution and possibly the incidence of blood transfusion[2-5]. The systematic review aimed to examine the use of VAD in CPB citing its advantages and disadvantages through case reports and evidence about its effects on microcirculation.

Summary of Data 47 articles were found using the keywords, in the first search in the PubMed-Medline and 23 articles in SciELO-Lilacs. Through analysis of the abstracts included in this phase, we defined as criteria for recovery of full articles: case report, systematic reviews, meta-analyzes, randomized controlled trials, whose results dealt with the direct effect of the use of vacuum in the patient (positively or negative). The review was concluded with the reading of 27 full articles. The 27 studies analyzed were divided into three groups: (I) reported cases with the use of vacuum drainage (n=3); (II) use of vacuum in surgical processes and their influence on hemodynamic (n=5); (III) use of vacuum pump procedures and their evaluation (n=19). In group I, there were three case reports, two of which describe methods that were successful and one with accident using the vacuum technique. Shin et al.[7] used the vacuum drainage in surgery for tumor in the right atrium. At the end of the procedure the technique was assessed as effective, allowing the removal of the tumor in a safe and simple way. Similarly, Fukuda et al.[8] describe the surgery of the tricuspid valve in a patient with severe congestion caused by insufficient heart valve with calcified tissue. At the end of the study, the authors report a successful procedure citing that hemolysis caused by the method was insignificant and the patient remained stable postoperatively, with minimal bleeding and improvement in edema of the lungs and kidneys. Gregory et al.[9] in a case report, mentioned massive air embolism in patient who underwent the Fontan operation. The problem occurred in the venous reservoir pressurization caused by suction pad that blocked the air flow from within the reservoir. Therefore they recommend the deep knowledge of the perfusionist on the material used in order to avoid this type of accident. In group II, five studies using vacuum as treatment of surgical wounds and/or abscess have been described. Petzina et al.[10] in their study showed that the use of vacuum system generated immediate reduction in cardiac output and systolic volume, as well as the left ventricular end-diastolic volume. Kadohama et al.[11] in a case report, also demonstrated the efficacy of using vacuum to post sternotomy, even in pediatric patients, as well as Anne et al.[12] who mentioned the efficiency of the vacuum in wound closure in mediastinum. Lindstedt et al.[13] showed the benefits of vacuum treatment on myocardial microcirculation.

METHODS Systematic research was performed, including articles published in Portuguese and English, in the period 1997 to 2012. The reference search was performed in the databases of the following databases: PubMed-Medline (http://www.ncbi.nlm. nih.gov/pubmed), Lilacs (http://lilacs.bvsalud.org/), SciELO (http://www.scielo.org/php/index.php)using the keywords:“bypass”, “vacuum”, “drain”, “heart surgery” and its corresponding translations and synonyms, in varied conditions. The reviews on the subject and reference lists of included articles were consulted in search of new items for inclusion in this study.

Table 1. Overview of randomized studies that examined the use of vacuum assisted drainage. Characteristics Reduction in transfusion Reduction in hemodilutions Better operative field Non-significant hemolysis Reduction in postoperative complications Lower prime volume Smaller cannulas diameter High risk Limitations Air Embolism

Number of studies (references) 7 [8-12,18,21] 7 [9,12,18,20,22] 2 [9,24] 7 [10,18,19,20,22,26] 2 [10,18] [10-12,17,18,20,21] 7 4 [11,18,20,24] 2 [13,34] 3 [12,17,19] 5 [11,13,16,18,19]

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Finally, Chen et al.[14] demonstrated that a vacuum assist to aid in wound scarring can be used for its benefits such as to restore the integrity of the basement membrane, reducing the endothelial space and edema, blood vessel patency, increasing their diameter and capillary volume and stimulate angiogenesis. In group III were analyzed the following characteristics: blood transfusion, hemodilution, surgical field, hemolysis, postoperative complications, prime volume, size of the cannulas used, air embolism, limitations and risks of the technique.

Another reported benefit was the improvement in visualization of the operative field with the reduction of blood, resulting in greater security and convenience to the procedure[6,24]. The limiting venous drainage promotes more congested surgical field and imposes difficulties in viewing by the surgeon. The possibility of using smaller diameter tubes is another important factor[17,18,20,24]. This possibility is explained because the vacuum system improves the flow rate through the cannula, allowing greater flow. With this, one can use smaller caliber of venous cannulas, which improves visualization during surgery, without compromising venous drainage. It also allows cannulation of smaller vessels. The vacuum drainage is closely related to minimally invasive surgeries advocating small surgical incisions and optimization of the operative field. However, due to the benefits this type of drainage can be used in normal infusions, provided that safety measures are taken: (i) the use of own modern equipment, (ii) the use of filters and (iii) knowledge of the technique by the perfusionist[29]. Only two authors considered the type of drainage analyzed as being at high risk[29,30], being a procedure with high probability of accidents due to the rapid rate at which the volume changes in the reservoir. Even with such statement, the studies conclude that the procedure is effective and safe, because even with the condition of rapid change in volume in the reservoir, the experience in the described cases confirms the viability of an efficient procedure together with technical mastery. Davila et al.[30] stated that the procedure has risk because the technique is different from the usually practiced, forcing the perfusionist to have knowledge of the system. In a vacuum pump system, the system must be built to allow alternatives in cases of accidents. In the specific situation of use of negative pressure, blood circulation methods and depressurization of the tanks must be designed to provide safe procedure. Exemplifying the fact, Davila et al.[30] demonstrated that simple change in the valve position of the circuit assembly can generate pressurization system, preventing or hindering the correction of the accident. In our survey, air embolism was reported in five studies[17,18,22,29,31] showing that the venous vacuum assistance produced almost 10 times more embolism in the arterial line compared to the gravitational line, despite the use of suitable equipment. The aforementioned embolism refers to the production of microbubbles in the fluid due turbulence produced during the passage through a narrow tubing under a high pressure. The same studies show that only by comparing the length of the methods of vacuum and gravity, in a situation of air into the venous line circuit by the venous line, the vacuum allows more volume of air into the system. This suggests potential danger, especially

DISCUSSION The development of research in CPB has helped to clarify doubts of some procedures, often for non-scientific reasons, but from experience in the surgical routine. This systematic review shows that the use of a vacuum drainage system can be effective, safe, providing new techniques to be performed. Analyzing three case reports found (group I), we observed that in one case there was an accident with massive air embolism. Gregory et al.[9] reported that the accident was not caused solely by the vacuum system used, but suction pad not suitable for the procedure, which generated the pressurization system. Replacing the suction pad for another that could maintain and facilitate the flow of air with the environment, the procedure has become safe. Thus, the author calls attention to the materials used in the procedure, which can cause accidents when unknown by professionals. On analysis, it was observed that 79% (n=15) of the authors consider that the technique of vacuum assist provides benefit to the procedure and/or patient. The reduction in the number of transfusions[5,6,15-19] contributes to not overload in blood banks. The reduction occurs by improving venous drainage and, consequently, no need for volume increase in the venous reservoir to maintain levels of security against ingress of air into the system. The lower use of blood products contributes to reduction of postoperative[16,20] complications, and the technique offers reduced total prime[5,16-21] reducing hemodilution[5,6,18-21] and maintaining hematocrit and hemoglobin levels at acceptable levels. There was disagreement with respect to generation of hemolysis by the use of a vacuum. Most authors[16,18,20,22-25] considers that hemolysis caused in procedures with negative pressure procedures were similar to hemolysis in gravitational drainage. However, when comparing vacuum drainage with drainage by centrifugal pump, Cirri et al.[26] showed that the vacuum drainage causes higher degree of hemolysis, according conclusions confirmed by Gregoretti et al.[27]. However, Lau et al.[28] and Shin et al.[24] disagree, showing similar levels of hemolysis.

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in the use of prime reduced, as with lowered volume levels in the reservoir the turbulence generated in CPB can allow air embolism. The other authors cited confirm the possibility of embolism, however claim to be controllable the risks of this involvement, since the perfusionist has knowledge of the applied technique, knowing the limitations and risks involved. Even with increased chances of accidents, Carrier et al.[32] and Murai et al.[25] argue that the use of vacuum does not increase the chance of neurological and general complications, confirming the theory that the risks can be controlled. In addition to the risks mentioned above, some limitations on vacuum technique are taking into account by some authors as Colangelo et al.[22], who reported the technique as costly, while mentioning the procedure using centrifugal pump to perform the drainage. However, the statement becomes fragile. Ii is of global knowledge that there are other methods of lower cost for the procedure, such as: (i) use of the monitor to control the vacuum from the vacuum system installed in operating rooms, (ii) vacuum pumps and (iii) roller pump. Another limitation is cited by Taketani et al.[5], affirming that the vacuum procedure presents instability due to imprecise control of negative pressure. However, this limitation is overcome when using valves or monitors that control levels of negative pressure. The survey also included studies that deal with the influence of vacuum in hemodynamic parameters, especially on the microcirculation. Currently, there is little knowlegement about the effects of the vacuum in the microcirculation, a place that really cares perfusionists, because in this area it is difficult to achieve blood perfusion. There are studies reporting the effectiveness of vacuum treatment[10-12] as that detailed by Gustafsson et al.[33] on surgical wounds such as post sternotomy mediastinitis. The mechanism by which the topical negative pressure (TNP) promotes wound healing is by stimulating blood flow in the periphery of the wound and skeletal muscle. The mechanical stress and pressure gradient through the tissue cause increased blood volume in the area. Both mechanical stress or increased blood flow are known to stimulate endothelial proliferation, capillary budding and angiogenesis[34]. Seeking to use knowledge of TNP for improved myocardial microcirculation, Lindstedt et al.[13] performed a study with 6 pigs simulating myocardial ischemia by occluding the left posterior descending artery and using the TNP as a way to improve the microcirculation. The results proved that the use of 50 mmHg of topical negative pressure stimulated a 25 mm depth perfusion in the skeletal muscle and there was a doubling of the blood flow in the myocardium detected using Laser Doppler. Petzina et al.[10] performed a sternotomy in 6 pigs and treated the surgical wound using vacuum, and demonstrat-

ed that the use of negative pressure reduced cardiac output and stroke volume of the animals undergoing the surgical process. This procedure would be used in patients with deep sternal infections that have ischemic heart failure. Concomitant to this, Chen et al.[14] show the effects of the vacuum in the microcirculation. The author studied wounds in rabbits, analyzing the speed of capillary blood flow, as well as its size, capillary density, the structure of the endothelium and the healing process. The best rated pressure level was -10 kPa, which achieved maximum speed of blood in the capillaries in 4 minutes and remained with this flow for a longer time. After the completion of the wounds on the rabbits’ ears, it was observed in the tissue: turgid mitochondria, membrane-targeting, large endothelial spaces, few cell junctions and many pinocytic vesicles. After 2 minutes of use of vacuum, the capillaries become more round, the endothelium cubic and the basal membrane were almost completely recovered. In 10 minutes, the capillaries become elliptical and dilated. In 30 minutes capillary sprouts emerged as villous processes, meaning angiogenesis. In 2 hours new vessels were found, the endothelial spaces have been reduced and cell junctions were firmer. In 24 hours we observed reduction in pinocytic vesicles. In the control group, in 3 days was still observed fragmented cell membrane and diverse cell membrane. We attribute to these facts the increased blood volume caused by stimulation of negative pressure gradient, favoring membrane integrity, resulting in reduced permeability, which consequently will reduce edema formation and thus heal the site quickly. Transposing this study for the cardiopulmonary bypass, even in different conditions, we think that the use of vacuum can benefit the microcirculation, promoting better tissue perfusion and minimizing interstitial edema caused by inflammation and by changing flow regime generated by cardiopulmonary bypass. A study that still needs to be performed. Munster et al.[35] reported the perfusion procedure with the aid of vacuum in 54 patients. The system described in the study is similar to that normally used in cardiopulmonary bypass with addition of negative pressure monitor, disposable pressure transducer and “Y” connector to attach the tank to the vacuum source. The relief valve of the venous reservoir already composed the system and therefore it did not have to be added. By using this system, the author claims to have enabled the heart to be always empty, as well as allowed the use of smaller cannulas facilitating the surgical procedure. Other factors were reported as the maintainability of patient’s central venous pressure (CVP) close to zero, reducing the addition of 250 ml of prime fluid on average and no haemolysis was observed postoperatively. With these data, Munster et al.[35] reiterate the authors previously cited of some benefits of using negative pressure in CPB, adding that the procedure used is low cost and benefits the patient during the infusion, by reducing the patient’s

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CVP, thereby improving venous drainage and reducing preload momentarily until the CPB. The effect of better venous drainage allows the perfusionist maneuvers, depending on the hematocrit (greater than 25%) and hemoconcentration. This procedure can reduce the excess liquid, even reducing – after CPB – the preload on the myocardium, as well as reducing the formation of edema in the patient, resulting in significant improvement in clinical outcome.

extracorpórea e necessidade de hemotransfusão: experiência de serviço. Rev Bras Cir Cardiovasc. 2011;26(1):122-7. 7. Shin H, Mori M, Matayoshi T, Suzuki R, Yozu R. Resection of giant right atrial lymphoma using vacuum-assisted cardiopulmonary bypass without snaring the inferior vena cava. Ann Thorac Cardiovasc Surg. 2004;10(4):249-51. 8. Fukuda W, Aoki C, Daitoku K, Fukuda I. Vacuum-assisted venous drainage in tricuspid valve re-replacement. Interact Cardiovasc Thoracic Surg. 2011;13(1)101-3.

CONCLUSION

9. Gregory SM, Kussman BD, Wagner JW, Boyle SL, Howe RJ, Pigula FA et al. Massive Air Embolism in a Fontan patient. J Extracorp Technol. 2011;43(2):79-83.

In conclusion, although the VAVD has significant potential for complications and requires technology and appropriate professionalism, it prevailed in the reviewed literature the concept that the VAVD contributed in reducing the rate of transfusions, hemodilutions, better operative field, no significant increase in hemolysis, reduced postoperative complications, smaller use of prime and smaller cannulas diameter.

10. Petzina R, Ugander M, Gustafsson L, Engblom H, Sjögren J, Hetzer R, et al. Hemodynamic effects of vacuum-assisted closure therapy in cardiac surgery: Assessment using magnetic resonance imaging. J Thorac Cardiovasc Surg. 2007;133(5):1154-62. 11. Kadohama T, Akasaka N, Nagamine A, Nakanishi K, Kiyokawa K, Goh K, et al. Vacuum-assisted closure for pediatric postsernotomy mediastinitis: are low negative pressures sufficient? An Thorac Surg. 2008;85(3):1094-6.

Authors’ roles & responsibilities EBCF Data Survey, review of articles and textual construction FALM Reviewer LNGC Reviewer IN Reviewer and author responsible for publishing

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Biocompatibility of Ricinus communis polymer with addition of calcium carbonate compared to titanium. Experimental study in guinea pigs. Biocompatibilidade do polímero de óleo de mamona com acréscimo de carbonato de cálcio comparado ao titânio. Estudo experimental em cobaias.

Yorgos Luiz Santos De Salles Graça1; Ana Cristina Opolski1, MD; Barbara Evelin Gonçalves Barboza1, MD; Bruna Olandoski Erbano1, MD; Caroline Cantalejo Mazzaro1, MD; Flávia Caroline Klostermann1, MD; Enéas Eduardo Sucharski1, MD; Luiz Fernando Kubrusly2, MD, PhD

DOI: 10.5935/1678-9741.20140030

RBCCV 44205-1550

Abstract Objective: The aim of the present investigation was to determine whether the difference in inflammatory tissue reaction between the Riccinus communis (castor) polymer with calcium carbonate and the titanium implant is statistically significant. Methods: Thirty-two Cavia porcellus were allocated into four groups of eight animals each. We implanted the two types of materials in the retroperitoneal space of all the animals. They were euthanized at 7, 20, 30 and 40 days after surgery, and an histological study of the samples was conducted. Results: All implants showed characteristics of chronic inflammation regardless of the material and timepoint of evaluation. There was no statistically significant difference between Pm+CaCO3 and Ti with regard to the presence of granulation tissue, tissue congestion, histiocytes, lymphocytes, neutrophils, giant cells, and fibrosis (P> 0.05).

Conclusion: The castor oil polymer plus calcium carbonate implant was not statistically different from the titanium implant regarding inflammatory tissue reaction.

1

Research Center of the Instituto Denton Cooley de Pesquisas (Denton Cooley Research Institute); Faculdade Evangélica do Paraná; Hospital Vita Education and Research Institute, Curitiba, PR, Brazil.

Rua Alferes Ângelo Sampaio 1896 – Batel - Curitiba, PR, Brazil Zip code: 80420160 E-mail: yorgoslssg@hotmail.com

Universidade Federal do Paraná, Instituto do Coração (InCor) - Hospital Vita, Curitiba, PR, Brazil.

This work was carried out at Denton Cooley Research Institute; Faculdade Evangélica do Paraná; Hospital Vita-InCor Education and Research Institute. No financial support.

Descriptors: Bioprosthesis materials. Heart, artificial Guinea pigs. Implants, Experimental. Ricinus communis. Boiocompatible. Inflammation. Resumo Objetivo: Determinar se a reação tecidual do implante retroperitoneal do polímero de óleo de mamona com acréscimo de carbonato de cálcio (Pm+CaCO3) é significativa, por meio de análise histopatológica, tendo como controle o implante de titânio não tratado (Ti). Métodos: Estudo experimental, intervencionista e randomi-

2

Correspondence address: Yorgos Luiz Santos de Salles Graça Instituto do Coração (InCor)

Article received on March 11th, 2013 Article accepted on January 13th, 2014

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vas dicotômicas, para análise da diferença entre o Pm+CaCO3 e o Ti em cada momento de avaliação foi usado o teste binomial. Considerando os materiais separadamente, a comparação dos quatro grupos foi feita utilizandose o teste exato de Fisher. Valores de P<0,05 indicaram significância estatística. Resultados: Todos os implantes apresentaram características de inflamação crônica, independente do material e do momento de avaliação. Não houve diferença estatisticamente significativa entre o Pm+CaCO3 e o Ti considerando a presença de tecido de granulação, congestão tecidual, histiócitos, linfócitos, neutrófilos, células gigantes e fibrose (P>0,05). Conclusão: Não foi encontrada diferença significativa entre a reação tecidual do Pm+CaCO3 e a do Ti.

Abbreviations, acronyms & symbols CaCO3 Calcium carbonate CAD Circulatory assist device CO2 Carbon dioxide COBEA Brazilian College of Animal Experimentation CHF Congestive heart failure HE Hematoxilin-eosin Pm Castor oil polymer Pm+CaCO3 Castor oil polymer with added calcium carbonate PVP-I Polyvinylpirrolidone-iodine solution Ti Titanium

zado com 32 cobaias. Os animais foram separados em quatro grupos iguais e eutanasiados com 7, 20, 30 e 40 dias após o ato cirúrgico. Foram confeccionadas lâminas em hematoxilina-eosina e em tricrômio de Masson. Em relação a variáveis qualitati-

Descritores: Implante de Prótese. Coração Artificial. Cobaias. Implantes Experimentais. Ricinus communis. Biocompatível. Inflamação.

Castor oil is a plant product extracted from the beans of Ricinus communis, which is found in tropical and subtropical areas. The oil is a viscous liquid obtained by hot or cold pressing of the seeds or by solvent extraction[8]. The studies on the use of castor oil and its by-products for polyurethane synthesis started in the late 1940’s with the preparation of polyurethane films for surface coating[9]. The first reports of the use of polyurethanes in medical applications date back to 1959, when Mandarino and Salvatore implanted a rigid polyetherurethane foam for bone fixation in situ. Castor oil polyurethanes can be produced with a range of different characteristics, from the most flexible (e.g., elastomers) to the most rigid ones (e.g., bone cements). The Pm polymer can be prepared pure or with added calcium carbonate (CaCO3) at a range of ratios by weight between the polyol, prepolymer, and CaCO3. Adding CaCO3 to the implant increases its mechanical strength and further reduces the production costs of the material[10]. In the present study, the ratio of 1/3 polyol, 1/3 prepolymer and 1/3 CaCO3 was used according to the mechanical tests performed by the manufacturer, Poliquil (Araraquara, SP), which point to that ratio as the optimal for medical use. In biocalcification studies, both in vivo and in vitro, Pm was regarded as a useful material not only for manufacturing implants, but also for the construction of accessories and devices such as pumps and valves for extracorporeal circulation[9]. The objective of the present study was to evaluate Pm with the addition of 33% CaCO3 (Pm+CaCO3) in order to gather sufficient histological data to ascertain low inflammatory reaction in the retroperitoneal space of guinea pigs compared with the reaction produced by titanium, thereby enabling the production of an even less expensive biomaterial, which would be affordable to the Brazilian population.

INTRODUCTION Cardiovascular diseases remain as the leading cause of morbidity and mortality worldwide[1]. As life expectancy increases, the prevalence of these comorbidities is expected to become even greater. Congestive heart failure (CHF) is one of these diseases and accounts for an average of 400,000 new cases per year in the United States[2]. End-stage CHF is a clinical condition for which few therapeutic options exist. Heart transplant is still an option in advanced CHF; however, it is a limited course of action due to the small number of donors and the high surgical risk involved[2]. In view of this, developing new support measures for these patients is a necessity. This prompted the conception of a Circulatory Assist Device (CAD). These devices, which are analogous to a human heart, are today a key component of the therapeutic support for patients in cardiogenic shock or end-stage heart failure[4,5]. In 1997, we began to develop an affordable CAD for the Brazilian public health system. We conducted tests in vitro[3] and designed a device made of titanium, as is the great majority of such devices available worldwide. Experimental studies in vivo with sheep were performed and proved the efficacy of the device. In 2011, Kubrusly et al.[6] initiated studies with a biocompatible material of national origin for the prospective production of a lower-cost device‒this marked the beginning of the studies on the use of castor oil polymer (Pm) in the production of CADs. This polymer is formed by the reaction, in equal amounts by weight, between a polyol (OH) and a castor oil prepolymer[7]. In keeping with our primary objective, which is to develop a Brazilian-made device suited to the resources of our country, we are at the stage of replacing costly mechanical parts for national-hence, less expensive-materials.

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Operative technique Following anesthesia, each animal was placed in the prone position and its hair was removed with scissors, bilaterally, along the dorsum. Subsequently, surgical field antisepsis was performed using a polyvinylpirrolidone-iodine solution (PVP-I) (Figure 1A). Local anesthesia was administered with 2% lidocaine diluted in normal saline. A 2-cm incision was subsequently made at 2 cm from the vertebral axis, to the right, in the region between the iliac crest and the last rib. The epithelium, the subcutaneous tissue and the fascia were penetrated, and the muscle layer was reached. This layer was carefully opened and the virtual retroperitoneal space was accessed, where the Pm+CaCO3 disc was implanted (Figure 1B). The procedure was repeated on the left side; however, the Ti disc was implanted this time (Figure 1C). The deep and superficial incision planes were sutured with nylon 30[14] in a running fashion (Figure 1D).

METHODS This experimental, randomized interventional study was developed by the Denton Cooley Institute at the Histology and Cell Biology Laboratories, the Animal Colony, and the Clinical and Surgical Experimentation Laboratory of the Faculdade Evangélica do Paraná. Ethical issues The present study was submitted to the Research Ethics Committee of the Sociedade Evangélica Beneficente de Curitiba and approved under Technical Opinion 4277/11. This study was conducted in conformity with Law 6638 of May 8th, 1979-Regulations for the Didactic and Scientific Practice of Animal Vivisection. The standards established in the “Guide for the Care and Use of Laboratory Animals” (Institute of Laboratory Animal Resources, National Academy of Sciences, Washington, D.C., 1996) and the guidelines of the Brazilian College of Animal Experimentation (COBEA) were also met.

Collection of the material for histopathological study The surgical specimen was removed en bloc and immediately immersed in 10% neutral buffered formalin, where it remained for 72 hours at room temperature. After fixation, the Ti and Pm+CaCO3 discs were removed through a lateral incision and the specimens were then rinsed in water for 24 hours, routinely processed and embedded in paraffin. The material was sectioned at 6 µm and stained by the hematoxylin-eosin (HE) technique for the cellular and capillary elements, and the technique of Masson’s trichrome with Nile blue for the collagen fibers from fibrosis. The analysis was conducted using an Olympus® light microscope model DX 50. The aim of microscopy was to evaluate the inflammatory process elicited by each material, i.e., congestion, formation of granulation tissue, and peri-implant fibrosis. The inflammation characteristics were qualitatively assessed for every slide of each group, and graded as absent, mild, moderate, or marked. The analyzed cells were histiocytes, neutrophils, lymphocytes, and giant cells. Histiocytes were defined in the present histopathological study as a type of normally stationary and inactive macrophage originated in the reticuloendothelial system that can be activated on stimulation; neutrophils, polynuclear white blood cells with neutrophilic granules; lymphocytes, a type of white blood cells between 10-12 µm in diameter, having a round nucleus with condensed chromatin and scarce, faintly basophilic cytoplasm; giant cells were defined as those formed by the fusion of several distinct cells. A x10 focusing eyepiece and x40 objective were used for the microscopy study. The cell types were counted in 10 fields under the microscope in the areas involved in the inflammatory process induced by the foreign body.

Sample Thirty-two male guinea pigs (Cavia porcellus), Rodentia, Mammalia were used, with weights between 250‐300 g (mean, 289.15±17.47 g), aged between 4‐6 months, and previously healthy. The animals were obtained from the Instituto de Tecnologia do Paraná, and were raised and maintained under similar environmental and dietary conditions. The animals were randomized into four groups (A, B, C and D), with eight guinea pigs in each group. They were euthanized in a CO2 gas chamber, four animals at a time, at 7 (group A), 20 (group B), 30 (group C), and 40 (group D) days after the implant surgery[11]. Experimental setting The guinea pigs were housed in the animal colony of the Faculdade Evangélica do Paraná in compliance with the “Manual of Technical Guidelines for Animal Experimentation Colonies” of the Department of Microbiology, Biomedical Sciences Institute, Universidade de São Paulo[12]. The animals were acclimatized for seven days prior to the experiments, and were given filtered water and standard commercial chow ad libitum up to four hours before euthanasia. The operative procedures were conducted using sterile material and technique in a cooled environment at the Clinical and Surgical Experimentation Laboratory, Faculdade Evangélica do Paraná. Tramadol was administered intramuscularly at the dose of 1 mg/kg according to the analgesia protocol, with duration of 12-24 hours[12]. Anesthesia The animals were anesthetized as recommended by Radde et al.[13], using ketamine and xylazine (87 and 13 mg/kg, respectively), both administered intraperitoneally.

Preparation and source of implants The control material was Ti and Pm+CaCO3, the test mate-

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Fig. 1 - A) Operative procedure surgical field antisepsis with polyvinylpirrolidone-iodine solution (PVP-I) and marking of the site of surgical incision; B) Implantation of the Pm+CaCO3 disc on the right-side hemibody; 1C) Implantation of the Ti disc on the left-side hemibody; 1D) Suture of the superficial plane with nylon 30

rial. The Ti alloy, characterized as grade 2, was obtained from a business company in the form of cylindrical bars 5 mm in diameter. The bars were composed of 99.7% Ti; 0.009% C; 0.095 Fe; 0.0003% H; 0.0038% N, and 0.152% O2. The mechanical properties of the bar were the following: % elongation (IN) L=32; % reduction in area L= 52; ultimate tensile strength (UTS) Ksi L= 78.8, and yield tensile strength (YS) Ksi (0.2%) L= 57. The Pm and the CaCO3 were obtained from a laboratory specialized in medical grade polymers (Poliquil, Araraquara, SP, Brazil). The preparation of the castor polymer implants began with equal amounts from one vial of polyol, one vial of vegetable polyurethane resin hardener, and an equal proportion by weight of CaCO3. These components were mixed at equal ratios by weight in a beaker using a glass stirring rod for 3 min until full homogenization was achieved. The homogenate thus obtained was placed in two insulin syringes. Following full polymerization, the syringes were sectioned with a scalpel blade into 3-mm-thick cross sections; subsequently, the plastic of the syringe barrel was removed[15]. Thus, discs with

a thickness of 3 mm and a diameter of 5 mm were obtained to be implanted retroperitoneally in the guinea pigs. Disc antisepsis was performed by immersing the discs in 70% alcohol for 15 min. The Ti implants were produced by a specialized manufacturer (Neodent, Curitiba, PR, Brazil). The Ti bar was attached to the plate of an engine lathe (Tormax 20A -ROMI) and cut with the aid of a cutting fluid (Quimatic oil). Subsequently, the discs were smoothed to be rid of rough spots or irregularities resulting from the first process. The Ti implants had the same dimensions as the Pm implants and were also sterilized in 70% alcohol. Statistical analysis Regarding the dichotomous qualitative variables, the test binomial was used in the analysis of the difference between the Pm+CaCO3 and Ti implants at each timepoint. When considering the materials separately, the four groups were compared using Fisher’s exact test. Values of P<0.05 indicated statistical significance. The data were analyzed using the SPSS software version 20.0.

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RESULTS Regarding peri-implant tissue inflammation, 100% of the implants showed histological characteristics of chronic inflammation; therefore, no statistically significant difference was found between the Pm+CaCO3 and the Ti group regardless of the evaluation timepoint (P=1 across comparisons). The presence of lymphocytes, neutrophils, giant cells, and peri-implant tissue congestion was consistently not marked over time for either implant material (P=1 across comparisons). For some variables, the time effect was significant. The analysis of both Pm+CaCO3 and Ti implants showed a progressive and linear decrease in the granulation process and in the presence of histiocytes. For both materials, these factors appeared markedly in the group evaluated in the first 7 days of the study (group A) whereas they were predominantly graded as not marked in the last two groups (C and D) (P<0.05). However, there was no statistically significant difference in the behavior of these variables between the two types of material (P=1 across comparisons). Albeit also without statistical differences between the materials, peri-implant fibrosis was found to be marked in groups A and B, and not marked in groups C and D. A slight tendency was noted for the polymer implant to exhibit less fibrosis than the Ti in groups C and D, although this was not statistically significant (Figures 2 and 3).

Fig. 2B - Light microscopy – Pm+CaCO3 -associated fibrosis. Staining by Masson’s Trichrome with Nile Blue

DISCUSSION As established in the previous study in the same line of research, we maintained the methodology[6] in order to obtain materials that are low-cost, abundant in nature, and with an acceptable biocompatibility profile that would ideally replace the time-honored materials in medical practice, as these are expensive and difficult to be obtained. Fig. 3 - Analysis of the difference in marked fibrosis between groups Pm+CaCO3 and Ti according to the evaluation timepoints

The favorable characteristics of Pm were first reported by such authors as Ohara et al.[16], Carvalho et al.[17], Ignácio et al.[18], Silva[19], and Kubrusly[6], thereby opening the way to the use of this polymer in orthopedics, orthodontics, bucomaxilar surgery, neurosurgery, and cardiovascular surgery. Furthermore, the production process of Pm is very attractive, as it needs no catalysts and shows simple processability and flexibility in formulation, thereby enabling the addition of other components- in the present case, CaCO3- without interfering with the chemical reaction. The Pm material shows versatility in terms of curing temperature, with a maximum exothermic peak at 45°C and no production of post-reaction free residual monomers-an undesirable occurrence for assisted circulation devices,

Fig. 2A - Light microscopy – Titanium-associated fibrosis. Staining by Masson’s Trichrome with Nile Blue

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common among polymers, which prompted researchers to use titanium for this purpose. Dias et al.[20] conducted a study with four capuchin monkeys (Cebus apella), wherein the investigators placed a Pm implant in a bone defect previously created in the nasal dorsum of the animals; later, the histological analysis revealed no foreign body granulomas or phagocytic cells. Although no bone tissue analysis was performed in the present study, no foreign body granulomas were found on histological analysis. A study by Mastrantonio and Ramalho[15] evaluated the response of the connective tissue of mice to Pm over a period of 60 days and, again, biocompatibility results were favorable. Titanium is considered to be an inert material; authors such as Van Noort et al.[21] have extensively demonstrated its applicability in medical grade alloys since mid-20th century. Alloys of Ti have been widely used as bone substitutes, in implantable materials in the human body such as screws and plates, and are present today in reconstructive surgery as well. Likewise, Pm has been expanding its range of applications. In the present study, it was noted that the predominant type of inflammation in both study materials (Pm+CaCO3 and Ti) was chronic inflammation, i.e., predominance of monomorphonuclear cells regardless of the assessment timepoint. The initial seven-day period is directly related to the type of suture used in the surgery. Siqueira and Dantas[22] have defined this length of time as the period of deposition of hyaluronic acid and collagen, both of which are produced in an attempt to reconstitute the injured tissues. In the current study, the presence of granulation tissue and histiocytes was marked in the first seven days, albeit without statistical significance when the two types of material were compared. The lower amount of fibrosis found in groups C and D, i.e., at 30 and 40 postoperative days, diverged from the results of Costa et al.[23], who noted the formation of dense fibrous tissue surrounding the Pm implant. In the present study, as in the previous study by Kubrusly and co-workers[6], for both materials, the adjacent connective tissue showed normal histological characteristics and a tendency toward decreasing tissue reaction with increasing post-implantation timepoints. Furthermore, macro- and microscopically, no polymer structure degradation occurred when it was subjected to the body temperature ranges of the guinea pigs. This can be reinforced by the fact that the polyurethanes exhibited thermal stability up to 210°C, which demonstrates that these polymers will not undergo thermal decomposition at ambient temperature[24]. In addition to showing stability at high temperatures, Pm+CaCO3 is a Brazilian technology and represents the possibility of providing a lighter implantable device for the patient. Our CAD in study, the K-pump, made of steel, weighs 194 g. A titanium-made device with the same dimensions is estimated to weigh between 85-95 g. The weight of the Pm+CaCO3 implant will be approximately 45-55 g, which is below the average of most currently available fully

implantable CADs and suitable for pediatric patients and small-built adults. In line with the data from the study with pure Pm[6], Pm+CaCO3 also has identical biocompatibility properties to those of the Ti implant. In addition to the preserved biocompatibility, the new combination confers greater mechanical strength and a smaller proportion of polymer raw material is used in its preparation. Therefore, production costs are further reduced, since smaller amounts of polyol and prepolymer are needed to produce our CAD. This economy of 33 % in raw material affords a 10-20% reduction in the production costs of the core structure of our CAD; this represents a further step toward our goal. CONCLUSION No statistically significant difference was found between the Pm+CaCO3 and the Ti implants with respect to the induced tissue reaction in guinea pigs. ACKNOWLEDGMENTS We would like to thank the Denton Cooley Research Institute, particularly Professor Dr. Luiz Fernando Kubrusly for his support and encouragement in the present study; the Vita Research Center, which made possible the undertaking of the present study; POLIQUIL (Araraquara, SP, Brazil), particularly Mr. Antonio Carlos Rossi and Mr. Alexandre Guillen, who helped supply the castor polymer; Neodent company (Curitiba, PR, Brazil), particularly Mr. Adailton Becker, for their assistance handling and cutting the titanium pieces; Dr Ana Cristina Lira Sobral for Reading and Report of the blades of pathological analysis; Dr Marcia Olandoski for Statistical analysis; Dr Fernando Bermudez Kubrusly for his support in the present study and the Faculdade Evangélica do Paraná for the helpfulness and support throughout the study. Authors’ roles & responsibilities YLSG ACO BEGB BOE CCM FCK EES LFK

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Review of the literature; participation in the experimental surgeries; drafting of the manuscript Review of the literature; participation in the experimental surgeries; drafting of the manuscript Review of the literature; participation in the experimental surgeries; drafting of the manuscript Review of the literature; participation in the experimental surgeries; drafting of the manuscript Review of the literature; participation in the experimental surgeries; drafting of the manuscript Review of the literature; participation in the experimental surgeries; drafting of the manuscript Review of the literature; participation in the experimental surgeries; drafting of the manuscript Review of the literature; participation in the experimental surgeries; drafting of the manuscript

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Molinari GJDP, et al. - The use of virtual resources in preoperative preparation BRIEF COMMUNICATION of infrarenal aneurysms: exploring the OsiriX’s potential

The use of virtual resources in preoperative preparation of infrarenal aneurysms: exploring the OsiriX’s potential O uso de recursos virtuais na preparação pré-operatória de aneurismas infrarrenais: explorando o potencial do OsiriX

Giovani Jose Dal Poggetto Molinari1, MD; Andréia Marques de Oliveira Dalbem1, MD; Ana Terezinha Guillaumon1, PhD

DOI: 10.5935/1678-9741.20140065

RBCCV 44205-1551

Abstract Introduction: In the past few years, the increase of endovascular surgeons' interest on tomography image edition through softwares is marked specially when it concerns to its use on preoperatory study for endovascular aneurysm repair. It is presumed that the bigger the number of informations extracted from the tomography exam and its three-dimensional reconstruction, the smaller is the need of patient's exposure to contrast, as well as the its exposure and the surgical team to radiation. Concepts of image manipulation on the OsiriX software with volume reconstruction of tridimensional tomographic scans of virtual fluoroscopy were used. Methods: Through manipulation of multi-slice tomography images under three-dimensional reconstruction on software, it was able to modify values of the exam's dose-irradiated distribution. These volume reconstruction presets were saved as Virtual Fluoroscopy, reproducible upon any OsiriX platform. It was able to construct a biplanar image appearing to the patient's operatory

fluoroscopy. When compared to the intraoperatory angiography, the images were alike. Discussion: Dose-irradiated distribution data manipulation allowed to visualize as opaque bone surfaces and transparent lowdose radiation's areas (viscerae). Thus, under previously marked renal arteries, it was possible to predict it's anatomical positioning related to visualization under real fluoroscopy. Foretelling the better positioning of the C-arm through this technique enables to obtain images with the minimum influence of parallax effect. It is believed that it supports to assess the renal arteries topographic positioning on a bi-dimensional intraoperatory image. The need of frequent angiographies to localize the renal arteries is reduced, decreasing the exposure to contrast on vulnerable patients.

Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil.

Correspondence address: Giovani Jose Dal Poggetto Molinari Hospital de Clínicas da Universidade Estadual de Campinas (HC- Unicamp) Rua Vital Brasil, 251- Cidade Universitária Zeferino Vaz - Barão Geraldo Campinas, SP, Brasil – Zip code: 13083-888 E-mail: drgiovani.molinari@uol.com.br

1

Descriptores: Endovascular Procedures. Aortic Aneurysm, abdominal. Multidetector Computed Tomography. User-Computer Interface. Fluoroscopy. Pilot Projects.

This study was carried out at Hospital de Clínicas da Universidade Estadual de Campinas (HC –Unicamp), Campinas, SP, Brazil.

Article received on December 23rd, 2013 Article accepted on March 16th, 2014

No financial support.

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possível manipular valores de projeção da distribuição de dose irradiada. A esta configuração, foi atribuído o nome de Virtual Fluoroscopy, formato reprodutível em qualquer plataforma OsiriX. Com isto, obteve-se uma imagem biplanar aparentemente a uma fluoroscopia operatória do doente. Quando comparadas à angiografia e fluoroscopia intraoperatória, estas imagens revelaram-se equivalentes. Discussão: A manipulação de dados de distribuição da dose irradiada em uma superfície permite que se visualizem como opacas áreas de alto contraste (como superfícies ósseas) e como transparentes valores de baixa atenuação (partes moles). Orientados por marcações nas artérias renais, pode-se prever minuciosamente o seu posicionamento anatômico em relação à sua visualização sob fluoroscopia. Outrossim, a antecipação do correto posicionamento do aparelho de radioscopia com o uso desta técnica permite a obtenção da imagem com o mínimo de interferência do efeito parallax. Com isso, acreditamos ser possível estimar o posicionamento topográfico das artérias renais em imagem bidimensional intraoperatória. Consegue-se reduzir o número de angiografias na tentativa de se obter a melhor imagem que forneça a localização das artérias renais e do colo do aneurisma, reduzindo sobrecarga renal em pacientes vulneráveis.

Abbreviations, acronyms & symbols DICOM Digital Imaging and Communications in Medicine AAA Abdominal Aortic Aneurysm MPR Multiplanar reconstruction MIP Maximum Intensity Projection 3D Tridimensional TC Computed Tomography

Resumo Introdução: Desde os últimos anos, tem crescido o interesse dos cirurgiões vasculares com prática em cirurgia endovascular na utilização de softwares de manipulação de imagens tomográficas, principalmente quando se refere à sua utilização no reparo endovascular dos aneurismas de aorta abdominal infrarrenais. Assim, o pós-processamento das imagens tornouse uma grande ferramenta na interpretação e documentação das alterações, melhorando a produtividade e a precisão das informações, utilizando volumes cada vez menores de contraste iodado no planejamento e execução do tratamento endovascular. Da mesma forma, menor é a exposição à radiação ionizante no intraoperatório. Divulgam-se os resultados iniciais da análise da viabilidade da manipulação de imagens tomográficas no software OsiriX por meio da fluoroscopia virtual. Métodos: Através da manipulação de imagens de cortes tomográficos finos sob-reconstrução tridimensional por volume, foi

Descritores: Procedimentos Endovasculares. Aneurisma da Aorta Abdominal. Tomografia Computadorizada Multidetectores. Interface Usuário-Computador. Fluoroscopia. Projetos Piloto.

INTRODUCTION

Currently, CT is one of the most important methods for diagnosis and monitoring of vascular diseases; and its performance is due to the spatial and temporal resolutions, associated with inherent attenuation of the vascular lumen obtained by the administration of intravenous contrast. There is no type of reconstruction more effective than the other, but all have their features and directions, and often the use of more than one type suitable for the demonstration of a pathology is necessary[1]. Thinner CT sections allow the three-dimensional reconstruction reaches a level of excellence in detail and quality, using increasingly smaller volumes of iodinated contrast due to the increased speed of image capture obtained[2]. The exposure of the patient to a minimum volume of iodinated contrast is one of the concerns more present during the planning and implementation of endovascular aneurysm repair, since the incidence of contrast-induced nephropathy in vulnerable patients - patients with renal dysfunction, diabetic nephropathy, dehydration, hypotension, heart failure, octogenarians, among others - can vary from 12 50%. It is defined as a 25% increase in baseline serum creatinine and is usually transient. However, it can lead to undesirable clinical outcomes such as prolonged hospitalization, clinical

Since last few years, the interest of vascular surgeons with endovascular surgery practice has grown in the use of image manipulation software DICOM (Digital Imaging and Communications in Medicine) on computed tomography (CT), especially when referring to its use in endovascular preoperative preparation of infrarenal abdominal aortic aneurysm (AAA). With the adoption of high-resolution multislice CT scans and the increased availability of applications reconstructions equipment protocols, postprocessing of images has become a great tool that assists the interpretation and documentation of changes, improving productivity and accuracy of information. In multichannel detectors equipment, efficient transmission systems, processing and storage of data and the refined engineering enable the reduction in acquisition time and improved spatial resolution in the longitudinal axis of the images. The latter is dependent on the voxel size (the smallest unit volume point in a digital image) that is in turn defined by the slice thickness[1].

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complications during hospitalization and increased hospital mortality. While the risk of nephropathy is dose-dependent, it is recommended in patients with glomerular filtration rate less than 60% that the volume of administered contrast is less than 100 ml[3]. Thus, we can assume that the greater the amount of information is extracted from the CT scan and its three-dimensional reconstruction, the less the need for contrast exposure during the intraoperative period, and the lower the exposure of the patient and the surgical team to radiation ionizing. We believe that in addition to precise measurement - such as diameters, lengths and angles[1] - and the analysis of the characteristics of the aneurysm, it is possible to get better

use of information such as topographic positioning of visceral arteries and their respective references of radioscopic viewing since the reconstruction of tomographic sections of smaller thicknesses allows the scanned virtual reproduction of the patient and his disease[4]. METHODS We disclosed herein the initial results of the analysis of the feasibility of tomographic image manipulation software (OsiriX MD) with the use of virtual fluoroscopy. This technique has practical significance with easy incorporation into routine endovascular planning. We used it as an aid in predic-

Fig. 1 - Up - ostial renal artery markings in axial projection, with auxiliary view on longitudinal section (at right). Below – At left, preoperative virtual fluoroscopy, with representation of the markings of the renal arteries, previously performed on axial slices. At right, intraoperative angiography: Please note that there is minimal interference of the parallax effect in the middle of the image

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tion of the intra luminal placement of angiographic catheters and fluoroscopy unit during endovascular aortic aneurysms repair. A number of cases from 14 studies were collected, with promising results. The steps for preparing the configuration of virtual fluoroscopy and illustrations of the technique used in two of our cases. Multichannel CT scans of patients undergoing endovascular infrarenal AAA at the Center for Highly Complex Endovascular Surgery, State University of Campinas, August to December 2013 were analyzed. We used three-dimensional multiplanar reconstruction through DICOM images manipulation software (OsiriX MD)

for analysis of aneurysms in series of images with thin 1-3 mm CT slices, intravenous iodinated contrast in arterial phase. Initially, markings on the renal arteries on axial projections were made, through the point command. This feature also signals the voxel in the image examined, so that is subsequently represented in any view, either axial or through both volume or multiplanar three-dimensional reconstruction (Figures 1 and 2). In a 3D reconstruction by volume rendering, using the pre-defined Bone CT reconstruction and Pencil, we can modify the tomographic values of windowing, CLUT (color lookup table) and shading which in turn define brightness, contrast and color range of the image (Figure 3).

Fig. 2 - Up - ostial renal artery markings in axial projection, with auxiliary view on longitudinal section (at right). Below – At left, preoperative virtual fluoroscopy, with representation of the markings of the renal arteries, previously performed on axial slices. At right, intraoperative angiography: Also note the little influence of the main body of the endoprosthesis on the angular position in the visualization of renal arteries studied (in this case, Endologix AFX endoprosthesis)

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intensity projection (MIP), which demonstrates the densest voxel (higher attenuation coefficient) - which are displayed as opaque areas of high contrast (as bone surfaces) and as transparent values of low attenuation (soft tissue). Even if in the plan above the overlay to structures that compete with the density of the aorta exists, this is a desirable effect when the aim is a three-dimensional reconstruction that simulates a simple biplane fluoroscopy in grayscale of the studied area. The ideal positioning of the fluoroscopy unit during the surgical procedure may be different than expected during the preoperative study, in that the aneurysm possibly shorten or lengthen higher than expected. However, although it is described that the angulation of the neck of the aneurysm can be changed, the angular position does not change even under the influence of the inserted guide wire or endoprosthesis itself[6]. Thus, guided by the initial markings of the renal arteries, we can minutely predict its anatomical position in relation to its visualization under fluoroscopy, as well as estimate the location of the aneurysm neck, considered the starting point for determining the intraoperative positioning of surgical arch and angiographic intraluminal catheter. Additionally, one can associate corrections of projections of anteroposterior and rotational angle of the neck, since the tortuosity of the aneurysm causes typical changes in the anatomy of the patient and are particularly challenging in the endovascular treatment. Furthermore, the anticipation of the correct positioning and centering of the fluoroscopy device using this technique allows obtaining image with minimal interference from the parallax effect (where there is a difference in the apparent position of an object when viewed under overlay planes). Thus we believe it is possible, through the virtual fluoroscopy under manipulation of DICOM images in software, estimating the topographic position of the renal arteries in intraoperative two-dimensional image (angiography and fluoroscopy). Similarly, when displaying a virtual fluoroscopy tomographically, one can reduce the number of intraoperative angiography in an attempt to obtain the best dimensional angiographic image that provides the location of the renal arteries and the aneurysm neck. The closer this angiographic reproduction to virtual view of fluoroscopy the more careful is the surgeon search for positioning the renal arteries, and the better will be the use of the aneurysm neck for fastening and sealing of the endoprosthesis, being more accurate its release while the total volume of contrast used is smaller and reducing renal overload in vulnerable patients. New ways to adapt this software has increasing by expanding its use to new tasks. Our proposal is to create familiarity of professionals and encourage demystified practice of this computer program, an essential tool in surgical planning, where more and more procedures are guided by images.

Fig. 3 - Manual configuration of the preset 3D at OsiriX MD, named as Virtual Fluoroscopy. Window width (WW - the window width) sets the number of gray scales shown and window level (WL - the window level) sets the value of the average gray scale of this width. CLUT (color look up table - lookup table of colors) defines a mechanism of the software used to transform a range of input color to another color range[5]. When represented as No-CLUT in 8-bit, it displays images in grayscale. Turning off the shading feature the effect of light is reduced (to enhance the three dimensional appearance) favoring the perception of the final image as biplanar, as it is conventional in a fluoroscopy. This configuration may be republished in any OsiriX platform

At this configuration, the name of Virtual Fluoroscopy was assigned and reprinted in other OsiriX platforms, always yielding the same two-dimensional image in a single tomographic volume, thus becoming a reproducible format. Once the series of images is subjected to a reconstruction using the software - with advance signaling of voxel through the point - this is shown in three-dimensional and multiplanar images, allowing a more detailed study of the reference point at odd angles of the human anatomy and its topography. The images were reproduced and placements achieved intraoperatively, revealing themselves equivalent (Figures 1 and 2). DISCUSSION The reconstruction volume approaches the attenuation coefficient of the voxel at a scale of color and degree of opacity (transparency) along the axes. It preserves the information of depth, and shows a better spatial distribution of structures. In a traditional reconstruction, this three-dimensional effect is enhanced by light (shading)[1]. The manipulation of these data (the dose distribution radiating to a surface) allows visualization of the maximum

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Endovascular. In: Brito CJ, ed. Cirurgia Vascular. 3rd ed. Rio de Janeiro: Revinter; 2013. p.689-736.

Authors’ roles & responsibilities GJDPM

AMOD ATG

Statistical analysis; final approval of the manuscript; conception and design of the study; implementation of operations and/or experiments; writing of the manuscript or revising it critically for its content Realization of operations and/or experiments; writing of the manuscript or revising it critically for its content Final approval of the manuscript; writing of the manuscript or revising it critically for its content

3. Ribeiro PCA, Ribeiro MJS. Meios de contraste. In: Lobato AC, org. Cirurgia Endovascular. 2nd ed. São Paulo: Instituto de Cirurgia Vascular e Endovascular de São Paulo; 2010. p.39-58. 4. Pitoulias GA, Donas KP, Schulte S, Aslanidou EA, Papadimitriou DK. Two-dimensional versus three-dimensional CT angiography in analysis of anatomical suitability for stentgraft repair of abdominal aortic aneurysms. Acta Radiol. 2011;52(3):317-23.

REFERENCES

5. Blankensteijn JD, Kool LJS. Computed Tomography. In: Cronenwett JL, Johnston KW et. al. Rutherford’s Vascular Surgery. 7th ed. Philadelphia: Elsevier Inc.; 2010. p.329-43.

1. Kuroki IR, Magalhães FV, Rizzi P, Coreixas IMH. Angiotomografia. In: Brito CJ, ed. Cirurgia Vascular: cirurgia endovascular, angiologia. 3a ed. Rio de Janeiro: Revinter; 2013. p.438-96.

6. van Keulen JW, Moll FL, van Herwaarden JA. Tips and techniques for optimal stent graft placement in angulated aneurysm necks. J Vasc Surg. 2010;52(4):1081-6.

2. Ferreira MMV, Freitas AJ, Coelho LH, Zaniolo MRM, Sá J. Aneurismas da Aorta Torácica e Toracoabdominal - Tratamento

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Soeiro AM, et al. - Intracardiac embolization of inferior vena cava filter CLINICAL-SURGICAL CORRELATION associated with right atrium perforation and cardiac tamponade

Intracardiac embolization of inferior vena cava filter associated with right atrium perforation and cardiac tamponade Embolização de filtro de veia cava associado à perfuração de átrio direito e tamponamento cardíaco

Alexandre de Matos Soeiro1, MD; Felipe Lourenço Fernandes1, MD; Rafael Plens Teixeira1, MD, MsC, PhD; Pedro Felipe Gomez Nicz1, MD, PhD; Maria Carolina Feres de Almeida Soeiro1; Carlos V. Serrano Jr.1, MD, PhD; Múcio Tavares de Oliveira Jr.1, MD, PhD

DOI: 10.5935/1678-9741.20140060

RBCCV 44205-1552

Abstract Insertion of inferior vena cava filters has been well established in literature, reducing occurrence of pulmonary embolism after an episode of deep venous thrombosis in patients with contraindication to anticoagulation. There are a small number of complications related to procedure and embolization is rare. In this context, we described a case of intracardiac embolization associated with cardiac tamponade.

Resumo A colocação percutânea de filtro de veia cava inferior é bem estabelecida em literatura, reduzindo a chance de ocorrência de tromboembolismo pulmonar após um episódio de trombose venosa profunda em pacientes com contraindicações à anticoagulação. O índice de complicações relacionadas ao procedimento é pequeno, sendo embolização evento extremamente raro. Nesse contexto, descrevemos um caso de embolização intracardíaca de filtro de veia cava inferior associada ao tamponamento cardíaco.

Descriptors: Vena Cava Filters. Vena Cava, inferior. Cardiac Tamponade.

Descritores: Veia Cava Inferior. Tamponamento Cardíaco. Filtros de Veia Cava.

INTRODUCTION

ter to prevent clots reaching the pulmonary arteries was first described in 1958 by Hunter and DeWeese[3]. From this time until the present day, the models and placement techniques have evolved considerably, however the ICVF is not free of risks, and device-related complications can occur, e.g. in situ thrombosis (0-25%), occlusion of the ICVF (2-30%), recurrence of PE (0.5-6%), filter fracture (2-10%) and vena cava filter embolization (< 1%)[4,5]. Embolization of the filter to the heart or pulmonary artery is an extremely rare complication that can lead to symptoms

The treatment of choice for prevention of pulmonary embolism (PE) secondary to deep vein thrombosis (DVT) is anticoagulation; however, some patients may have contraindications to it. Without treatment, the chance of developing PE after an episode of DVT is approximately 40%[1]. Thus, for patients with contraindications to anticoagulation, there is the option of placing an Inferior Vena Cava Filter (ICVF) in an attempt to prevent PE[2]. The idea of implementing a fil-

Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (INCOR–HCFMUSP), São Paulo, SP, Brazil.

Correspondence address: Alexandre de Matos Soeiro Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Unidade Clínica de Emergência Av. Dr. Eneas de Carvalho Aguiar, 44 - Cerqueira César - São Paulo, SP, Brazil - Zip code: 05403-900 E-mail: alexandre.soeiro@bol.com.br

1

Work carried out at the Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (INCOR–HCFMUSP), São Paulo, SP, Brazil.

Article received on December 30th, 2013 Article accepted on March 24th, 2014

No financial support.

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At entrance physical examination he was prostrated, pale and disoriented. Had a heart rate of 114 bpm, blood pressure of 108/80mmHg, weak pulse and capillary refill of less than 3 seconds. Cardiac examination showed hypophonetic and rhythmic heart sounds without murmurs. Pulmonary examination had diminished breath sounds at lung bases, a respiratory rate of 16 breaths per minute and an oxygen saturation of 94%. Extremities examination demonstrated an asymmetrical bilateral edema, that was larger in the left limb. Electrocardiogram was normal. At initial laboratory studies he had hemoglobin of 9.7 g/dL, hematocrit of 31%, leukocytes 10.360/mm3, 351.000 platelets, CK-MB 1.12 ng/mL, troponin I 0.288 ng/ mL, urea 19mg/dL, creatinine 0.86 mg/ dL,C-reactive protein (CRP) 272.22 mg/dL. As the initial hypothesis was PE, the patient underwent CT angiography of the pulmonary arteries. Instead of showing signs of PE, CT showed an ICVF dislocation. It had moved to the right atrium. There was also right-sided pleural effusion and pericardial effusion (Figure 1). Transthoracic echocardiogram showed signs of cardiac tamponade. In such way, emergent surgical pleural and pericardial drainage was performed. After the procedure, CT and echocardiogram still showed moderate pericardial effusion, now with no signs of cardiac tamponade and a foreign body into the right atrium. In this moment the patient developed an early nosocomial infection thereby delaying the withdrawal of ICVF performed by open thoracotomy. During the procedure we observed that the ICVF had perforated the free wall of the right atrium (Figure 2).

Abbreviations, acronyms & symbols PE DVT ICVF

Pulmonary embolism Deep vein thrombosis Inferior vena cava filter

ranging from hypotension, syncope, dyspnea or even cardiac arrest as the first manifestation[2,6]. The cause of embolization of the ICVF can vary greatly, and includes: placing the device in an unsuitable location, device failure and a vena cava with an enlarged diameter (>28 mm)[6]. In case of intracardiac embolization, therapeutic options involve surgical or endovascular removal or even maintenance of the vena cava filter in the same place[5], however the best treatment option is under discussion. Many authors suggested that the removal by open thoracotomy would be the best option[2]. Below we report a case of embolization of a vena cava filter in a patient treated at the Heart Institute in Sao Paulo. CASE REPORTÂ A 47-years-old male who had a history of epilepsy was admitted to our service due to dyspnea and chest pain, that was worse during inspiration. Forty-five days prior to this admission he had been submitted to a subdural hematoma surgical drainage secondary to a same height fall. Following the procedure the patient developed DVT. Since he had clinical contraindication to anticoagulation,insertion of an ICVF was performed.

Fig. 1 - Tomography with the image of a vena cava filter located in transition of right atrium and right ventricle, before (A) and after (B) pericardial drainage

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with ICVF embolization was performed by Lahey et al.[13] in 1991. In this first published report, the authors associate the displacement of ICVF to its improper placement, with no evidence of fracture. As in our case, the patient had the IVCF removed by open surgery. Differently to this first description and our case, the majority of reports in the literature with cardiac tamponade described the presence of fractured IVCF and intracardiac embolization of only parts of the filter[7-10]. Chandra et al.[8] reported there was no any well-defined correlation or factor associated with increased likelihood of intracardiac device embolization. Furthermore, the IVCF brands are variable and not necessarily associated with this complication[8,14]. Nicholson et al.[14] performed a single-center study in 2004, in which they published a series of 80 cases of patients who had IVCF placed. There were 5 cases of intracardiacembolization after filter fracture, and they were associated to two brands: BARD RECOVERY and BARD G2. Three of those patients had cardiac tamponade and one resulted in death. In all cases, the extraction was performed by open surgery[14]. Regarding the observed time between the IVCF placement and embolization, the literature is also inconclusive. Hussain et al.[11] described a case of embolization and cardiac tamponade after only four hours of filter implantation. However, the placement was performed in the subclavian vein, unlike our case. In another hand, most of the published series showed cases where embolization occurred months after the filter placement, usually associated with device fracture[7-10]. The therapeutic options in cases of cardiac embolization involve surgical removal, endovascular treatment or even conservative approach[3,7-14]. Many authors suggest that the withdrawal by open thoracotomy would be the best option[1,7,8,10-14]. Controversially, Vergara et al.[9] described a case of embolization associated with cardiac tamponade, in which the ICVF was removed percutaneously, suggesting that in selected patients, this is a plausible alternative to open surgery. In our case, we opted for open surgical removal due to association with perforation and cardiac tamponade. However, the best treatment option is still uncertain due to the rarity of cases and it should be individualized[1]. We could not find in Brazilian literature descriptions of cases of IVCF embolization associated with cardiac tamponade. This makes this case unique nationwide, inferring the clinician to consider this adverse outcome in the indication of the procedure and as a complication of its placement[2,3]. CONCLUSION

Fig. 2 - Inferior vena cava filter perforating the free wall of the right atrium Postoperatively, the patient developed septic shock, resolved after 33 days of antibiotics (Meropenem, Colistimethate, Linezolid, Fluconazole and amikacin at different times). He was discharged in good general condition, without anticoagulation due to the poor patient compliance and because the risk factor for DVT and PE, that was immobilization, had been resolved. After two months, he presented a new episode of DVT in the left medial gastrocnemius vein, at this time the anticoagulation therapy with warfarin was introduced. DISCUSSION Embolization of the IVCF to the heart or pulmonary artery is an extremely rare complication that can lead to symptoms ranging from hypotension, syncope, dyspnea or even cardiac arrest as the first manifestation[2,6]. The cause of embolization of the ICVF can vary greatly, and includes: placing the device in an unsuitable location, device failure and a vena cava with an enlarged diameter (>28 mm)[4-14]. In a series published by Ferris et al.[5], in which 324 patients had undergone to ICVF implantation, there were no cases of distal embolization. Similarly, another published case series with respect to 26 years of ICVF implants in 1731 patients at a center in the United States showed a complication rate of 0.3%, a rate of PE after the procedure of only 5.6% and no heart embolization. The first description of cardiac tamponade associated

Although embolization of the IVCF to the heart or pulmonary artery is an extremely rare complication (0.1-1.2%), clinicians should be aware of IVCF complications, in order to optimize the time-to-diagnosis and prevent further device-related complications[7,8].

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5. Athanasoulis CA, Kaufman JA, Halpern EF, Waltman AC, Geller SC, Fan CM. Inferior vena cava filters: review of 26-year singlecenter clinical experience. Radiology. 2000;216(1):54-66.

Authors’ roles & responsibilities AMS FLF RPT PFGN MCFAS CVSJ MTOJ

Analysis and interpretation of data; final approval of the manuscript; conception and design of the study; writing of the manuscript or revising it critically for its content Analysis and interpretation of data; final approval of the manuscript; writing of the manuscript or revising it critically for its content Final approval of the manuscript; writing of the manuscript or revising it critically for its content Final approval of the manuscript; conception and design of the study; writing of the manuscript or revising it critically for its content Final approval of the manuscript; conception and design of the study; writing of the manuscript or revising it critically for its content Final approval of the manuscript; conception and design of the study; writing of the manuscript or revising it critically for its content Final approval of the manuscript; conception and design of the study; writing of the manuscript or revising it critically for its content

6. Ferris EJ, McCowan TC, Carver DK, McFarland DR. Percutaneous inferior vena caval filters: follow-up of seven designs in 320 patients. Radiology. 1993;188(3):851-6. 7. Rogers NA, Nguyen L, Minniefield NE, Jessen ME, de Lemos JA. Fracture and embolization of an inferior vena cava filter strut leading to cardiac tamponade. Circulation. 2009;119(18):2535-6. 8. Chandra PA, Nwokolo C, Chuprun D, Chandra AB. Cardiac tamponade caused by fracture and migration of inferior vena cava filter. South Med J. 2008;101(11):1163-4. 9. Vergara GR, Wallace WF, Bennett KR. Spontaneous migration of an inferior vena cava filter resulting in cardiac tamponade and percutaneous filter retrieval. Catheter Cardiovasc Interv. 2007;69(2):300-2. 10. Saeed I, Garcia M, McNicholas K. Right ventricular migration of a recovery IVC filter’s fractured wire with subsequent pericardial tamponade. Cardiovasc Intervent Radiol. 2006;29(4):685-6.

REFERENCES

11. Hussain SM, McLafferty RB, Schmittling ZC, Zakaria AM, Ramsey DE, Larson JL, et al. Superior vena cava perforation and cardiac tamponade after filter placement in the superior vena cava--a case report. Vasc Endovascular Surg. 2005;39(4):367-70.

1. Sella DM, Oldenburg WA. Complications of inferior vena cava filters. Semin Vasc Surg. 2013;26(1):23-8. 2. Caplin DM, Nikolic B, Kalva SP, Ganguli S, Saad WE, Zuckerman DA; Society of Interventional Radiology Standards of Practice Committee. Quality improvement guidelines for performance of inferior vena cava filter placement for the prevention of pulmonary embolism. J Vasc Interv Radiol. 2011;22(11):1499-506.

12. Bolton JW, Aldea GS. Perforation of the heart by an inferior vena cava filter. Mil Med. 1994;159(4):360-2. 13. Lahey SJ, Meyer LP, Karchmer AW, Cronin J, Czorniak M, Maggs PR, et al. Misplaced caval filter and subsequent pericardial tamponade. Ann Thorac Surg. 1991;51(2):299-300.

3. Weinberg I, Kaufman J, Jaff MR. Inferior vena cava filters. JACC Cardiol Interv. 2013;6(6):539-47.

14. Nicholson W, Nicholson WJ, Tolerico P, Taylor B, Solomon S, Schryver T, et al. Prevalence of fracture and fragment embolization of Bard retrievable vena cava filters and clinical implications including cardiac perforation and tamponade. Arch Intern Med. 2010;170(20):1827-31.

4. Owens CA, Bui JT, Knuttinen MG, Gaba RC, Carrillo TC, Hoefling N, et al. Intracardiac migration of inferior vena cava filters: review of published data. Chest. 2009;136(3):877-87.

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Letters to the Editor/Cartas ao Editor

DOI: 10.5935/1678-9741.20140077

RBCCV 44205-1553

Comment on "Depression after CABG: A prospective study."

REFERENCES

1. Nunes JKVRS, Figueiredo Neto JA, Sousa RML, Costa VLXC, Silva FMAM, Hora AFLT, et al. Depression after CABG: a prospective study. Rev Bras Cir Cardiovasc. 2013;28(4):491-7.

Dear Editor In the December 2013 edition of the Brazilian Journal of Cardiovascular Surgery, Nunes et al.[1] reported that a high prevalence of depressive symptoms in coronary artery bypass surgery (CABG) patients group, especially on the initial six months after surgery. Results of study by Nunes et al. are particularly important not only because depression is a mortality risk factor after CABG, but tapping a serious problem worldwide - the need of addressing the supply of physicians[2]. However, we disagree how the patients were classified as depressive. There are some scales for screening depression and Beck Depression Inventory (BDI) is one of them. Current study consists of population of elderly subject which was almost half of entire study participants. In elderly, Geriatric Depression Scale is useful tool to assess the depression because of its brevity and favorable psychometric properties. However, BDI may not be suitable for screening depression in elderly people[3]. Previous history of depression or other mood disorders were not reported in the current study. Previous studies showed that depression is a risk factor for cardiovascular diseases and the coronary events are 1.64 times higher in depressed patients[4]. It is possible to conclude that depressive symptoms reported in the study by Nunes et al.[1] may be present before CABG and not related to CABG. We believe that these point needs to be considered as arguable with regards in the present study.

2. Pinton FA, Carvalho CF, Miyazaki MCOS, Godoy MF. Depression as a risk factor for early and late morbidity after coronary artery bypass surgery. Rev Bras Cir Cardiovasc. 2006;21(1):68-74. 3. Smarr KL, Keefer AL. Measures of depression and depressive symptoms: Beck Depression Inventory-II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D), Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale (HADS), and Patient Health Questionnaire-9 (PHQ-9). Arthritis Care Res (Hoboken). 2011;63(Suppl 11):S454-66. 4. Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med. 2004;66(6):802-13.

Professor Salerno is named for the highest position of the University of Miami Professor Salerno Ê nomeado para o mais alto cargo da Universidade de Miami Tomas A. Salerno, M.D., vice chair of the Miller School of Medicine’s Department of Surgery and chief of cardiothoracic surgery, was elected chair of the Faculty Senate for a oneyear term beginning June 1. Salerno, who joined the Miller School faculty in 1999, will succeed Richard Williamson, a professor at the School of Law who stepped down after five terms as chair. Linda L. Neider, professor in the School of Business Administration who initially began serving in the Senate

Umit Cintosun1, Umut Safer1 1. Department of Geriatrics, Gulhane School of Medicine. Ankara, Turkey.

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shortly after joining the UM faculty in 1979, was elected firstvice chair. Sam Terilli, a veteran media lawyer who joined the School of Communication faculty in 2003, was elected to his second term as second vice chair. Salerno, who has served in the Faculty Senate since 2008, most recently as first vice chair, said he looks forward to uniting faculty from all schools, representing their views, goals and dreams, and promoting their well-being. “I have been involved in many aspects of faculty life, and in many Senate committees, including Promotion, Personnel and General Welfare, and the Medical School Council, and have most enjoyed interacting with University scholars, and the leadership of the University and the different schools,” Salerno said. “I have been inspired by the legacies of previous Senate chairs, and in this new role, I will do my best to represent faculty, make sure that their voice is heard, and be a strong leader in these challenging times.” Neider, an expert in leadership and human resources, has served in a variety of administrative roles over the past three decades, including more than 20 years as chair of the School of Business Administration’s Department of Management, and several years as a vice dean. During her Senate service, she has chaired or been a member of a number of committees, including Academic Standards, Budget and Compensation, Student Affairs, Professional Conduct, and Women and Minorities. Terilli, who practiced media, commercial and employment law for 30 years, including 12 years as general counsel of the Miami Herald Publishing Company, is the incoming chair of the School of Communication’s Department of Journalism

Fig.1 – Professor Tomas A. Salerno

and Media Management. In the Senate, he chairs the Ad Hoc Committee on the Miller School of Medicine, and previously chaired two other Senate ad hoc committees—one on the Internal Review Board and the other on revising the rules for early evaluations of deans and other administrators. He also chaired the Administrative Services Committee, and served as a member of the Committee on Professional Conduct and as an academic counsel for faculty. Originally posted in: http://everitas.univmiami.net/2014/05/08/ faculty-senate-elects-new-leaders/

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REVIEWERS

Reviewers BJCVS/RBCCV 29.2 The Brazilian Journal of Cardiovascular Surgery/Revista Brasileira de Cirurgia Cardiovascular (BJCVS/RBCCV) is committed to ethics and always seeks to increase its scientific level. Thus, it is essential the work of reviewers. For those who reviewed the articles in this issue, my warmest thanks.

Domingo Braile Editor-in-Chief BJCVS

Alexandre C Hueb Alfredo José Rodrigues

Karlos Alexandre de Sousa Vilarinho Luis Alberto Dallan Luiz Felipe Moreira

Bruno Botelho Pinheiro

Magaly Arrais dos Santos Marcelo Arruda Nakazone Mauricio de Nassau Machado Moacir Fernandes de Godoy Moise Dalva

Carla Tanamati Carlos Marcelo Pastre Eduardo Augusto Victor Rocha Elaine Soraya Barbosa de O. Severino Enio Buffolo

Neuseli Marino Lamari Nilson Antunes

Fábio Antonio Gaiotto Fausto Miranda Junior Fernando Platania

Omar Asdrúbal Vilca Mejia Orlando Petrucci Otoni Moreira Gomes

Giovani José Dal Poggetto Molinari

Raquel Ferrari Piotto Reinaldo Bestetti Rodrigo Coelho Segalote

Henrique Murad Isabella Martins de Albuquerque

Vera Lúcia dos Santos Alves Victor Rodrigues Ribeiro Ferreira

João Carlos Leal

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ERRATUM/ERRATA DOI: 10.5935/1678-9741.20140005e

RBCCV 44205-1554

In the printed version of 29.1 issue, in the article “Use of EuroSCORE as a predictor of morbidity after cardiac surgery”, on page 12, Figures 3 e 4 were inverted. Below, the correct figures with the respective legends.

Fig. 3 – Graph of the ROC curve for RTI

Fig. 4 – Comparative Box-plot of EuroSCORE according to DDRF

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RBCCV em números 28 anos de circulação ininterrupta Fator de Impacto 0,809

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