Brazilian Journal of Cardiovascular Surgery 29.3 by Revista Brasileira de Cirurgia Cardiovascular

29.3 JULY/SEPTEMBER 2014

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR | BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY

VOL. 29 Nยบ 3 JULY/SEPTEMBER 2014

Agende esta data e garanta sua presença no SBCCV 2015

Educação Médica

26a 28 de março de 2015

frente às novas tecnologias

S BCC V

CONGRESSO DA SOCIEDADE BRASILEIRA

DE CIRURGIA CARDIOVASCULAR

5º Simpósio de Enfermagem em Cirurgia Cardiovascular 5º Simpósio de Fisioterapia em Cirurgia Cardiovascular 4º Congresso Acadêmico em Cirurgia Cardiovascular

26 a 28 de março de 2015 • Curitiba • Paraná • Brasil

www.sbccv.org.br

www.facebook.com/SBCCV

Você tem quatro bons motivos para participar deste evento: 1 PROGRAMA Através de palestras, mesas redondas e cursos avançados vamos discutir, debater e compartilhar experiências sobre a atualização profissional frente às novas tecnologias.

2 HANDS ON Uma estratégia de ensino-aprendizagem, que permite a interação entre o expert e os cirurgiões que desejam dominar novas tecnologias de comprovada eficácia, mas com baixas taxas de adoção, e os novos procedimentos com um domínio ainda restrito, mas em fase de expansão na prática clínica.

PROMOÇÃO Sociedade Brasileira de Cirurgia Cardiovascular

anúncio sbccv 2015.indd 1

3 PALESTRANTES A programação, como de hábito, vai reunir especialistas de reconhecido mérito acadêmico, destacando presenças nacionais e internacionais.

ORGANIZAÇÃO

(51) 3061.2959 inscricoes@abev.com.br www.abev.com.br

4 TEMAS LIVRES Uma oportunidade de divulgar e compartilhar a sua produção científica e ensaio clínico inovador através da discussão de temas importantes para os cirurgiões cardiovasculares. Partilhe sua experiência e contribua para o avanço da nossa especialidade médica.

AGÊNCIA OFICIAL

(21) 2142 9315 sbccv@blumar.com.br www.blumar.com.br

29/08/14 13:47

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

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

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

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: 1,2,3 2014, 29: 1 [supl]

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

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

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

Impact Factor: 0.632

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY Rev Bras Cir Cardiovasc, (São José do Rio Preto, SP - Brazil) jul/sep - 2014;29(3) 299-472

CONTENTS/SUMÁRIO

EDITORIAIS/EDITORIALS

BJCVS in PubMed Central RBCCV no PubMed Central Domingo M. Braile.................................................................................................................................................................................. I

ORIGINAL ARTICLES/ARTIGOS ORIGINAIS 1554 Acute kidney injury based on KDIGO (Kidney Disease Improving Global Outcomes) criteria in patients with elevated baseline serum creatinine undergoing cardiac surgery Lesão renal aguda baseada nos critérios KDIGO (Kidney Disease: Improving Global Outcomes) em pacientes com creatinina sérica elevada submetidos à cirurgia cardíaca Maurício Nassau Machado, Marcelo Arruda Nakazone, Lilia Nigro Maia.........................................................................................299 1555 Chronic stress and coping among cardiac surgeons: a single center study Estresse crônico e enfrentamento entre os cirurgiões cardíacos: um estudo de centro único Kyriakos Spiliopoulos, Laura Gansera, Hans Christian Weiland, Tibor Schuster, Walter Eichinger, Brigitte Gansera......................308 1556 Late outcome analysis of the Braile Biomédica® pericardial valve in the aortic position Avaliação dos resultados tardios da bioprótese de pericárdio bovino Braile Biomédica® em posição aórtica Lisandro Gonçalves Azeredo, Elinthon Tavares Veronese, José Augusto Duncan Santiago, Carlos Manuel de Almeida Brandão, Pablo Maria Alberto Pomerantzeff, Fabio Biscegli Jatene.............................................................................................................................316 1557 Pediatric and congenital heart transplant: twenty-year experience in a tertiary Brazilian Hospital Experiência de 20 anos com transplante cardíaco pediátrico e em portadores de cardiopatias congênitas Leonardo Augusto Miana, Estela Azeka, Luiz Fernando Canêo, Aída Luisa Turquetto, Carla Tanamati, Juliano Gomes Penha, Alexandre Cauduro, Marcelo Biscegli Jatene........................................................................................................................................................322 1558 Clinical evaluation of the Spiral Pump® after improvements to the original project in patients submitted to cardiac surgeries with cardiopulmonary bypass Avaliação clínica da bomba espiral (Spiral Pump®) após aperfeiçoamentos introduzidos ao projeto original em pacientes submetidos a cirurgias cardíacas com circulação extracorpórea Jarbas Jakson Dinkhuysen, Aron Jose Pazin de Andrade, Juliana Leme, Cibele Silva, Claudia Sanches Medina, Cristiane Célia Pereira, José Francisco Biscegli........................................................................................................................................................................330 1559 Idiopathic dilated cardiomyopathy: computerized anatomic study of relashionship between septal and free left ventricle wall Cardiomiopatia dilatada idiopática: estudo anatômico computadorizado da relação entre o septo e a parede livre do ventrículo esquerdo Paulo Sérgio Juliani, Éder França da Costa, Aristides Tadeu Correia, Rosangela Monteiro, Fabio Biscegli Jatene...........................338 1560 Addition of long-distance heart procurement promotes changes in heart transplant waiting list status Incorporação da captação à distância promove mudanças na situação dos receptores em fila para transplante cardíaco Fernando Antibas Atik, Carolina Fatima Couto, Freddy Ponce Tirado, Camila Scatolin Moraes, Renato Bueno Chaves, Nubia W. Vieira, João Gabbardo Reis..............................................................................................................................................................................344

1561 Psychological assessment of patients undergoing cardiac transplant in a teaching hospital (2004 to 2012) Avaliação psicológica de pacientes submetidos a transplante cardíaco em hospital de ensino (2004 a 2012) Sara dos Santos Cunha, Maria Cristina de Oliveira Santos Miyazaki, Daniel Fernando Villafanha, Randolfo dos Santos Junior, Neide Aparecida Micelli Domingos...............................................................................................................................................................350 1562 Evaluation of peripheral muscle strength of patients undergoing elective cardiac surgery: a longitudinal study Avaliação da força muscular periférica de pacientes submetidos à cirurgia cardíaca eletiva: estudo longitudinal Kelli Maria Souza Santos, Manoel Luiz de Cerqueira Neto, Vitor Oliveira Carvalho, Valter Joviniano de Santana Filho, Walderi Monteiro da Silva Junior, Amaro Afrânio Araújo Filho, Telma Cristina Fontes Cerqueira, Lucas de Assis Pereira Cacau................355 1563 Does Homeostasis Model Assessment of Insulin Resistance have a predictive value for post-coronary artery bypass grafting surgery outcomes? O Modelo de Avaliação da Homeostase da Resistência à Insulina tem valor preditivo para os resultados após a cirurgia de revascularização miocárdica? Ebuzer Aydin, Mehmet Ozkokeli.........................................................................................................................................................360 1564 Comparison of superior septal approach with left atriotomy in mitral valve surgery Comparação da abordagem septal superior com atriotomia esquerda em cirurgia valvar mitral Ebuzer Aydin, Akin Arslan, Mehmet Ozkokeli....................................................................................................................................367 1565 Benefit from using recycling red blood cells in cardiovascular surgery Benefício do uso de recuperadores de hemácias em cirurgias cardiovasculares Mariah Steinbach, Mauricio H. Z. Centenaro, Rui M. S. Almeida......................................................................................................374 REVIEW ARTICLES/ARTIGOS DE REVISÃO 1566 Results of heart transplantation in the urgent recipient - who should be transplanted? Resultados do transplante cardíaco no paciente urgente - quem deve ser transplantado? David Prieto, Pedro Correia, Pedro Antunes, Manuel Batista, Manuel J. Antunes..............................................................................379 1567 Fetal cardiac interventions: an update of therapeutic options Intervenções cardíacas fetais: atualização de opções terapêuticas Shi-Min Yuan.......................................................................................................................................................................................388 1568 Indication of endovascular treatment of type B aortic dissection - Literature review Indicação do tratamento endovascular na dissecção de aorta do tipo B - Revisão da literatura João Jackson Duarte, José Carlos Dorsa Vieira Pontes, Ricardo Adala Benfatti, Adriana Lugo Ferrachini, Walter Kegham Karakhanian, Álvaro Razuk Filho..............................................................................................................................................................................396 1569 Cardiomyopathy induced by artificial cardiac pacing: myth or reality sustained by evidence? Miocardiopatia dilatada induzida por estimulação cardíaca artificial: mito ou realidade sustentada pelas evidências? Andrés Di Leoni Ferrari, Aníbal Pires Borges, Luciano Cabral Albuquerque, Carolina Pelzer Sussenbach, Priscila Raupp da Rosa, Ricardo Medeiros Piantá, Mario Wiehe, Marco Antônio Goldani.......................................................................................................402 1570 Postperfusion lung syndrome: physiopathology and therapeutic options Síndrome pós-perfusão pulmonar: fisiopatologia e opções terapêuticas Shi-Min Yuan.......................................................................................................................................................................................414 SPECIAL ARTICLES/ARTIGOS ESPECIAIS 1571 Sonocubic fine: new three-dimensional ultrasound software to the screening of congenital heart diseases Sonocubic fine: novo software de ultrassonografia tridimensional para o rastreamento das doenças cardíacas congênitas Edward Araujo Júnior, Luciane Alves da Rocha, Luciano Marcondes Machado Nardozza................................................................426 1572 Modes of induced cardiac arrest: hyperkalemia and hypocalcemia - Literature review Modalidades de parada cardíaca induzida: hipercalemia e hipocalcemia - revisão de literatura Marcos Aurélio Barboza de Oliveira, Antônio Carlos Brandi, Carlos Alberto dos Santos, Paulo Henrique Husseini Botelho, José Luis Lasso Cortez, Domingo Marcolino Braile...........................................................................................................................................432

1573 Direct intramyocardial transthoracic transplantation of bone marrow mononuclear cells for non-ischemic dilated cardiomyopathy: INTRACELL, a prospective randomized controlled trial Ensaio clínico prospectivo randomizado sobre terapia com células mononucleares da medula óssea para cardiomiopatia dilatada idiopática: INTRACELL Roberto T. Sant'Anna, James Fracasso, Felipe H. Valle, Iran Castro, Nance B. Nardi, João Ricardo M. Sant'Anna, Ivo Abrahão Nesralla, Renato Abdala Karam Kalil.................................................................................................................................................................437 1574 Congenital cardiac disease in childhood x socioeconomic conditions: a relationship to be considered in public health? Cardiopatia congênita na infância x condições socioeconômicas: uma relação a ser considerada na saúde pública? Thayanny Lopes do Vale Barros, Marly de Jesus Sá Dias, Rachel Vilela de Abreu Haickel Nina......................................................448 HOW TO DO IT/COMO EU FAÇO 1575 Avoiding pitfalls of intraoperative peripheral endovascular surgery with the aid of OsiriX: expanding the use of virtual fluoroscopy Como evitar armadilhas do intraoperatório em cirurgia endovascular periférica com o auxílio do OsiriX: ampliando o uso da fluoroscopia virtual Giovani José Dal Poggetto Molinari, Andréia Marques de Oliveira Dalbem, Ana Terezinha Guillaumon.........................................455 1576 New technique "Right Anterior Small Thoracotomy (RAST operation)" for beating heart grafting of the right internal thoracic artery to the posterior descending artery to the posterior descending artery in a third redo CABG patient. A novel coronary technique. Nova técnica "Pequena toracotomia anterior direita (operação RAST)“ para enxerto da artéria torácica interna direita para a artéria descendente posterior com o coração batendo em paciente de terceira RM. Uma técnica coronária nova. Maximo Guida, Gustavo Guida, Giuseppina Pecora, Estefania De Garate.........................................................................................459 LETTERS TO THE EDITOR/CARTAS AO EDITOR 1577 Psychological assessment before heart transplantation: more hope to candidates in Brazil? Reinaldo B. Bestetti..............................................................................................................................................................................463

Reviewers BJCVS 29.3/Revisores RBCCV 29.3.................................................................................................................................464

Impresso no Brasil Printed in Brazil

Graphic design and layout: Heber Janes Ferreira

Editorial

BJCVS in PubMed Central RBCCV no PubMed Central

Domingo M. Braile1 DOI: 10.5935/1678-9741.20140108

fter waiting for almost two years, on July 10th I received an email from PubMed Central (PMC) stating that the Brazilian Journal of Cardiovascular Surgery (BJCVS) had been approved in the first phase of indexing process in this important database. We are now in the second stage, which consists of the analysis and quality control of the data of our journal. For this, GN1, our partner since 2005, has made, along with our Editorial Board, the adaptation of three editions (28.4, 29.1 and 29.2) to the standard required by the PMC, which consists of marking files in the XML language and images of high standard of resolution, among other requirements. The files were sent for evaluation in early September. This phase of the process should not be as long as the first; thus, we expect that soon we can give more good news for our readers. I want to take the time to reinforce the words of the Editorial of the volume 27.4[1]. The PMC is an online repository with open access publications in the area of health. However, it is quite picky about the pattern of indexed publications. Therefore, I ask that authors to follow the standards of the journal (http://www.rbccv.org.br/page/6), especially with regard to the quality of the images (Table 1). Thus, we can streamline the submission process and providing “Ahead of Print” manuscripts approved, with benefits for all.

Table 1. Specifications of PubMed Central for images and graphics[1]. Type LineArt (images with linear lines, usually graphical text)

Format TIF or JPEG

Resolution 900 to 1200dpi Width: 2700px

Halftone (images, usually photographs)

TIF or JPEG

300dpi Width: 900px

Combo (mixture of graphic and image)

TIF or JPEG

500 to 900dpi Width: 2700px

have similar opinion and conduct movements to change this situation, for example, the San Francisco Declaration on Research Assessment (DORA), which pointed out the shortcomings of the IF as research assessment tool. These limitations include: a) the distribution of the citation within journals is highly skewed; B) it includes a variety of articles, such as primary research and review; C) the IF of a journal can be manipulated by the editorial policy; and D) data used to calculate the IF are not transparent or publicly available[2]. The newsletter “SciELO in Perspective” published an article in August by Prof. Ernesto Spinack entitled “What “alternative metrics” or “altmetrics” can give us?”, which addresses the role of these new ways of assessing the influence of scientific study beyond the traditional ways of measuring the citations. Spinack analyzed four articles of the Spanish journal “El Profesional de la Información” that focused on demonstrating that there are several “classes” of impacts, in addition to the bibliometric because science has implications in various fields of society. He also analyzed the lack of quantitative studies of the use of social media, from the most restricted to the scientific area, and as RaseacheGate and Mendeley, besides the best known, such as Facebook and Twitter. Spinack concluded that altimetry is still in the experimental stage, having to solve problems of standardization and coverage and recalls that classic bibliometrics and scientometrics took about 20 years of theoretical discussions by eminent experts to reach a consensus based and tools and interpretations. But as the most famous indicator, the IF is still surrounded by suspicion and resistance[3].

Impact Factor Thomson Reuters announced, in late July, the Impact Factor (IF) relative to 2013 Unfortunately, BJCVS had a decrease from 0.809 to 0.632. Of course, this reduction made me upset, but there is one aspect that helps explain this decline: we have sought to reduce the self-citation, which is an item that Thomson Reuters focuses enough and can even lead to a periodic be deleted if it is abusing of this artifice. Clearly, it is important that our articles are cited by Brazilian authors, but we must seek to produce increasingly accurate scientific quality material, so that international authors also cite us to publish their studies in other refereed journals. I again emphasize my point of view that, although important, the IF cannot be considered, especially for the Coordination for the Improvement of Higher Education Personnel (Capes) and other development agencies, as the only parameter for their appraisals. Many publishers around the world

Rev Bras Cir Cardiovasc | Braz J Cardiovasc Surg

“Does homeostasis model assessment insulin resistance have a predictive value for post-coronary artery bypass grafting surgery outcomes?” (page 360). I emphasize the importance of CME to update knowledge and that BJCVS is open to criticism and suggestions to improve this system. Finally, we appreciate the support of the Brazilian Society of Cardiovascular Surgery (BSCVS) and our advertisers, without whom it would not have been possible to achieve our current level of quality.

I believe it is also important to use these assessments of access to sites of journals, even though it might not be reflected in quotes. If a journal is very accessible, it shows its importance within the scientific field and within its specialty. This is the case of BJCVS, which when added its sites (www. rbccv.org.br, www.bjcvs.org and www.scielo.br/rbccv) it had over 1.9 million visitors in 2013. Therefore, despite our IF have reduced the number of hits it reveals our great scope, reflected in submissions of manuscripts from around the world. Only in this issue, we are publishing articles from Germany, China, Portugal, Turkey, and Venezuela. And the trend is that this number may grow even more, since when our site is accessed, it already appears in the English version, which is a way to attract more readers and articles! I also emphasize that BJCVS is available as APP (application), both the iOS (iPhone, iPAD) as the Android system (Samsung, Motorola, Sony, and others). To download the app, simply enter the App Store on iOS, or Google Play on Android. We are making improvements to the system to make it more responsive and easy to use.

My warmest regards,

Editor-in-chief BJCVS E-mail: domingo@braile.com.br 1

REFERENCES

CME

1. Braile DM. Renovação: processo contínuo na RBCCV. Rev Bras Cir Cardiovasc. 2012;27(4):I-II.

The following articles are available for testing for Continuing Medical Education (CME) in this issue: “Acute kidney injury based on KDIGO (Kidney Disease Improving Global Outcomes) criteria in patients with elevated baseline serum creatinine undergoing cardiac surgery” (page 299), “Late outcome analysis of the Braile Biomédica® pericardial valve in the aortic position” (page 316), “Evaluation of peripheral muscle strength of patients undergoing elective cardiac surgery: a longitudinal study” (page 355) and

2. The San Francisco Declaration on Research Assessment (DORA) [Acesso 31 Ago 2014]. Disponível em: http://am.ascb.org/dora 3. Spinak E. O que podem nos fornecer as “métricas alternativas” ou altimetrias. SciELO em Perspectiva. [viewed 29 Aug 2014]. Available from: http://blog.scielo.org/blog/2014/08/07/o-quepodem-nos-fornecer-as-metricas-alternativas-ou-altimetrias/

Rev Bras Cir Cardiovasc | Braz J Cardiovasc Surg

Rev Bras Cir Cardiovasc 2014;29(3):299-307

Machado MN,ORIGINAL et al. - Acute ARTICLE kidney injury based on KDIGO (Kidney Disease Improving Global Outcomes) criteria in patients with elevated baseline serum creatinine undergoing cardiac surgery

Acute kidney injury based on KDIGO (Kidney Disease Improving Global Outcomes) criteria in patients with elevated baseline serum creatinine undergoing cardiac surgery Lesão renal aguda baseada nos critérios KDIGO (Kidney Disease: Improving Global Outcomes) em pacientes com creatinina sérica elevada submetidos à cirurgia cardíaca

Maurício Nassau Machado1, MD, PhD, Marcelo Arruda Nakazone1, MD, Lilia Nigro Maia1, MD, PhD DOI 10.5935/1678-9741.20140049

RBCCV 44205-1554

Abstract Introduction: Preoperatively elevated serum creatinine (SCr) is considered an independent risk factor for morbidity and mortality after cardiac surgery. The aim of this study was to apply the Kidney Disease Improving Global Outcomes classification for acute kidney injury in a population of patients with preoperatively elevated serum creatinine who underwent cardiac surgery (coronary artery bypass grafting or cardiac valve surgery) and to evaluate the acute worsening of renal function as a predictor of 30-day mortality. Methods: This was a single-center retrospective study that included patients from the Postoperative Cardiac Surgery Intensive Care Unit of the Hospital de Base, São José do Rio Preto Medical School. Demographics, type of surgery, laboratory data and pre, peri and postoperative data were obtained from a prospectively collected database. From January 2003 to June 2013, 2,878 patients underwent cardiac surgery, either coronary artery bypass grafting or cardiac valve surgery, at the Hospital de Base of São José do Rio Preto Medical School. Out of those, 918 showed elevated preoperative serum creatinine, with SCr > 1.30 mg/dL for men and > 1.00 mg/dL for women. Five hundred and forty nine patients (60%) undergoing coronary artery bypass grafting and 369 patients (40%) undergoing cardiac valve surgery. A Multivariate Cox Proportional Hazard Model (stepwise) was used to assess the relationship between AKI and mortality at 30 days.

Results: Out of the 918 patients studied, 391 (43%) had postoperative AKI: 318 (35%) had Kidney Disease Improving Global Outcomes stage 1, 27 (2.9%) had Kidney Disease Improving Global Outcomes stage 2, and 46 (5.0%) had Kidney Disease Improving Global Outcomes stage 3. Patients in every stage of acute kidney injury showed progressive increase in EuroSCORE values, 30-day mortality ratescardiopulmonary bypass duration, and intensive care length of stay. Among patients classified as Kidney Disease Improving Global Outcomes stage 3, 76% required dialysis with a 30-day mortality of 66%. The Cox proportional hazards model showed that the hazard ratio for 30-day mortality was 4.8 for Kidney Disease Improving Global Outcomes stage 1 patients, 13.5 for Kidney Disease Improving Global Outcomes stage 2 patients, and 20.8 for Kidney Disease Improving Global Outcomes stage 3 patients (P<0.001 for all). Subgroup analyses (coronary artery bypass grafting and cardiac valve surgery) had similar results. Conclusion: In this population, acute kidney injury based on the Kidney Disease Improving Global Outcomes criteria was a powerful predictor of 30-day mortality in patients with elevated preoperative serum creatinine who underwent cardiac surgery (coronary artery bypass grafting or cardiac valve surgery).

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

Correspondence address: Maurício Nassau Machado Hospital de Base de São José do Rio Preto Av. Brigadeiro Faria Lima, 5544 – 5° andar – Unidade Coronária (UCor) São José do Rio Preto, SP, Brazil Zip code: 15090-000 E-mail: maunmac@gmail.com

Descriptors: Acute Kidney Injury. Creatinine. Cardiovascular Surgical Procedures. Hospital Mortality.

This study was carried out in the Cardiac Intensive Care Unit from Hospital de Base, São José do Rio Preto Medical School, São José do Rio Preto, SP, Brazil.

Article received on November 11th, 2013 Article accepted on February 3rd, 2014

No financial support.

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Machado MN, et al. - Acute kidney injury based on KDIGO (Kidney Disease Improving Global Outcomes) criteria in patients with elevated baseline serum creatinine undergoing cardiac surgery

junho de 2013. Destes, 918 indivíduos apresentavam creatinina sérica alterada no pré-operatório (CrS > 1.30 mg/dL para homens e > 1.00 mg/dL para mulheres), compreendendo 549 pacientes (60%) submetidos à revascularização miocárdica e 369 pacientes (40%) submetidos à cirurgia valvar. O modelo de riscos proporcionais de Cox foi utilizado para avaliar a relação entre lesão renal aguda e mortalidade em 30 dias. Resultados: Nesta casuística, 391 pacientes (43%) apresentaram lesão renal aguda no pós-operatório, sendo 318 (35%) Kidney Disease Improving Global Outcomes estágio 1, 27 (2,9%) Kidney Disease Improving Global Outcomes estágio 2 e 46 (5,0%) Kidney Disease Improving Global Outcomes estágio 3. EuroSCORE, mortalidade em 30 dias, tempo de circulação extracorpórea e permanência em ambiente de terapia intensiva aumentaram progressivamente em todos os estágios. Dentre os pacientes classificados como Kidney Disease Improving Global Outcomes 3, 76% necessitaram diálise com mortalidade em 30 dias de 66%. A análise de Cox evidenciou razão de risco para óbito em 30 dias de 4,8 para pacientes Kidney Disease Improving Global Outcomes estágio 1, 13,5 para pacientes Kidney Disease Improving Global Outcomes estágio 2 e 20,8 para pacientes com Kidney Disease Improving Global Outcomes estágio 3 (P<0,001 para todos). Análise dos subgrupos (revascularização miocárdica e cirurgia valvar) obteve resultados semelhantes. Conclusão: Lesão renal aguda pelos critérios Kidney Disease Improving Global Outcomes destaca-se como excelente preditor de óbito em 30 dias em indivíduos submetidos à revascularização miocárdica ou cirurgia valvar que apresentam creatinina sérica pré-operatória alterada.

Abbreviations, acronyms & symbols ADQI AKI AKIN CABG CPB CVS eGFR HR KDIGO OR RIFLE SCr

Acute Dialysis Quality Initiative Acute Kidney Injury Acute Kidney Injury Network Coronary Artery Bypass Grafting Cardiopulmonary Bypass Cardiac Valve Surgery Estimated Glomerular Filtration Rate Hazard Ratio Kidney Disease Improving Global Outcomes Odds Ratio Risk, Injury, Failure, Loss and End-stage Kidney Disease Serum creatinine

Resumo Introdução: Creatinina sérica (CSr) elevada no período pré-operatório é considerada um fator de risco independente para morbidade e mortalidade em cirurgia cardíaca. Avaliar o impacto da lesão renal aguda pelos critérios Kidney Disease Improving Global Outcomes como preditor de mortalidade em 30 dias em pacientes submetidos à revascularização miocárdica ou cirurgia valvar com creatinina sérica pré-operatória elevada. Métodos: Este foi um estudo retrospectivo de centro único que incluiu pacientes da Unidade de Cuidados Intensivos em Pós-operatório de Cirurgia Cardíaca do Hospital de Base, Faculdade de Medicina de São José do Rio Preto. Dados demográficos, tipos de cirurgia, dados laboratoriais e informações pré, peri e pós-operatórias foram obtidos a partir de uma coleta prospectiva de banco de dados. Foram considerados 2878 pacientes consecutivamente submetidos à revascularização miocárdica ou cirurgia valvar no período de janeiro de 2003 a

Descritores: Lesão Renal Aguda. Creatinina. Procedimentos Cirúrgicos Cardiovasculares. Mortalidade Hospitalar.

INTRODUCTION

ADQI group)[8-10]. More recently, the AKI study group “Kidney Disease: Improving Global Outcomes (KDIGO)” proposed a modified definition, combining the differences between the RIFLE and AKIN definitions[11] (Table 1). The aim of this study was to apply the criteria for AKI based on the KDIGO classification in a population of patients with preoperative SCr above normal limits after cardiac surgery [coronary artery bypass grafting (CABG) or cardiac valve surgery (CVS)] and to evaluate acute worsening of renal function as a predictor of risk of 30-day mortality.

As the population ages, more patients with renal dysfunction are being referred for cardiac surgery[1]. Elevated serum creatinine (SCr) preoperatively is considered an independent risk factor for morbidity and mortality after cardiac surgery[2,3], with the overall risk of death for patients with creatinine ≥ 1.5 mg/dL ranging from 5% to 30%. Postoperatively, small changes in SCr, however small they may be, are also associated with a significant reduction in survival[4,5]. Elevated SCr may be associated with increased morbidity and mortality even when its change does not meet the criteria for acute kidney injury (AKI)[6]. Several consensus definitions have been developed to provide uniform criteria for AKI diagnosis. In 2004, the “Acute Dialysis Quality Initiative (ADQI)” group proposed consensus guidelines and evidence-based treatment and prevention of AKI, which were later called the RIFLE criteria (Risk, Injury, Failure, Loss and End-stage Kidney Disease)[7]. The modification of these criteria was subsequently proposed by the “Acute Kidney Injury Network" (AKIN, which included the

METHODS Patient selection This was a single-center study. We carried out a retrospective evaluation in patients from the Cardiac Surgery Intensive Care Unit at a Brazilian Medical School Center. Demographics, type of surgery, laboratory data and information of pre, peri and postoperative periods were obtained from a prospectively collected database of 2,878 patients who were older than 18

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years and had undergone isolated CABG (1,786) or CVS (1,092) from January 2003 to June 2013. We excluded 51 patients with incomplete data, 23 dialysis patients and 1,886 patients with preoperative SCr within normal limits (Men – SCr ≤ 1.30 mg/dL / Women – SCr ≤ 1.00 mg/dL). After applying the exclusion criteria, 918 patients were analyzed [549 (60%) underwent CABG and 369 (40%) underwent CVS] (Figure 1). This study was approved by the local Research Ethics (CAAE: 5974/2008). Because of its observational nature, informed consent was waived. This research fully adheres to Resolution 466/2012 of the National Health Council (CNS).

Stage 3: 3.0 or more multiplied by baseline; increase in SCr ≥ 4.0 mg/dL; or beginning of renal replacement therapy regardless of a previous KDIGO stage. Data Analysis The criteria for AKI were applied in 918 patients in the first seven postoperative days. Due to lack of data on urinary output, only SCr was used to determine the categories of AKI. According to the changes in SCr, the patients were classified as no AKI (KDIGO 0) and AKI stages 1, 2 or 3, based on the KDIGO criteria. Glomerular filtration rate (eGFR) was estimated by the Cockcroft-Gault[12] equation. The risk of postoperative death was assessed by EuroSCORE[13,14], in the absence of a specific tool for our population.

Serum Creatinine Measurement The Jaffe colorimetric method (ADVIATM 1650, Bayer, Germany) was used to measure SCr concentration. The reference value for adults is 0.6 to 1.3 mg/dL for men and 0.6 to 1.0 mg/dL for women.

Statistical Analysis Variables are presented as absolute numbers and percentages or median and interquartile ranges (25th and 75th percentile) when applicable. Continuous variables were compared using the nonparametric Mann-Whitney or Kruskal-Wallis tests, and the chi-square or Fisher’s exact test was used to compare categorical variables.

Stages of AKI based on KDIGO Classification[11] Stage 1: Increase in SCr ≥ 0.3 mg/dL (in 48 hours) or 1.5 to 1.9 multiplied by baseline (in 7 days); Stage 2: 2.0 to 2.9 multiplied by baseline SCr;

Table 1. Classification and staging for RIFLE, AKIN, and KDIGO criteria. Class Risk

RIFLE SCr or GFR Increased Scr x 1.5 or GFR decrease > 25% (within 7 days)

Stage 1

AKIN SCr Increase in SCr ≥ 0.3 mg/dL or ≥ 150% to 200% (1.5- to 2-fold) from baseline (within 48 hours)

Stage 1

KDIGO SCr Increase in SCr by ≥ 0.3 mg/dL within 48 hours or increase in SCr 1.5 to 1.9 times baseline which is known or presumed to have occurred within the prior 7 days

Injury

Increased Scr x 2.0 or GFR decrease > 50%

Increase in SCr to more than 200% to 300% (> 2- to 3-fold) from baseline

Increase in SCr to 2.0 to 2.9 times baseline

Failure

Increased Scr x 3.0 or GFR decrease > 75% or SCr ≥ 4.0 mg/dL or acute increase ≥ 0.5 mg/dL

Increase in SCr to 3.0 times baseline or increase in SCr to ≥ 4.0 mg/dL or initiation of renal replacement therapy

Loss

Persistent acute renal failure = complete loss of kidney function > 4 weeks

Increase in SCr to more than 300% (> 3-fold) from baseline or SCr ≥ 4.0 mg/dL with an acute increase of at least 0.5 mg/dL or initiation of renal replacement therapy

End Stage Kidney Disease

End stage of kidney disease (> 3 months)

Modified from Bellomo et al.[7], Mehta et al.[8] and Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group[11]

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Fig. 1 - Study flow chart showing patients underwent cardiac surgery and staging for acute kidney injury (AKI) based on the KDIGO criteria. CABG - coronary artery bypass grafting; CVS - cardiac valve surgery; PO postoperative day

Univariate and multivariate Cox proportional hazards models (stepwise) were used to determine the association between AKI and 30-day mortality. The model was adjusted for age (years), gender (reference – female gender), type of surgery (reference – CVS), body mass index (kg/m²), diabetes mellitus (reference – non-diabetic), left ventricular function (reference – preserved left ventricular ejection fraction), cardiopulmonary bypass (CPB) times (min) and AKI (reference – KDIGO 0). The adjusted Hazard Ratio (HR) and 95% confidence intervals (95% CI) were calculated for the predictors. Cumulative survival graphics were built to demonstrate the AKI impact as a predictor of 30-day mortality. P values<0.05 were considered statistically significant (two-tailed). The data were analyzed using the IBM SPSS Statistical Package v.20 (IBM Corporation, Armonk, NY).

Of the 918 patients studied, 391 (43%) developed AKI: 318 (35%) stage 1, 27 (2.9%) stage 2 and 46 (5.0%) stage 3 (Table 3). Fewer patients in stage 2 may be because the indication for dialysis automatically classifies the patient in stage 3. Any degree of AKI was associated with a significant increase in overall mortality at 30 days compared with patients with no AKI (Table 4). In univariate analysis, the hazard ratio for death at 30 days was 5.4 for patients with KDIGO stage 1, 16.8 for patients with KDIGO stage 2 and 27.2 for patients with KDIGO stage 3 (P<0.001 for all). Patients with AKI had higher EuroSCORE scores, but there was no difference in the percentage of patients at low, intermediate and high risk among the groups (Table 5). The 30-day mortality rate increased progressively in all KDIGO stages (Table 4). Time on CPB and intensive care length of stay also increased (Table 5). The proportion of patients who required mechanical ventilation for more than 24 hours after surgery increased from 6.3% for patients with KDIGO 0 to 67% among those with KDIGO 3 (Table 5). Of the patients with KDIGO 3, 76% required dialysis with a 30-day mortality rate of 66%. However, patients treated with dialysis were more severely ill, as demonstrated by the EuroSCORE calculated preoperatively [4 (2-6) vs. 8 (5-10)], P<0.001.

RESULTS Baseline characteristics of the patients are shown in Table 2. Median age was 61 years and 52% of the patients were male. Twenty-seven percent of the patients had preoperative eGFR above 60 mL/min. SCr measured in the immediate postoperative period was slightly lower than the preoperative SCr suggesting hemodilution during surgery (Table 3).

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Table 2. Baseline characteristics of patients who underwent cardiac surgery.

Type of surgery Coronary artery bypass grafting Cardiac valve surgery Multiple cardiac valve surgery Cardiac valve surgery during active infective endocarditis Age (years) Male gender Weight (kg) Height (m) Body mass index (kg/m2) Diabetes Mellitus Left Ventricular Systolic Dysfunction (moderate/severe) Intra-aortic balloon pump Reoperation Additive EuroScore Low risk (< 3) Intermediate risk (3 to 5) High risk (5) Cardiopulmonary bypass Total cardiopulmonary bypass time (min) < 90 min 90 - 120 min > 120 min Total number of grafts Total Intensive Care length of stay

All Patients (n = 918) Median (Q1 – Q3) or N (%) 549 (60) 369 (40) 156 (42) 38 (10) 61 (52 - 68) 477 (52) 70 (61 - 80) 1.63 (1.56 – 1.70) 26 (23 - 29) 248 (27) 203 (22) 43 (7.8) 134 (15) 4 (2 - 6) 248 (27) 402 (44) 268 (29) 781 (85) 94 (79 - 114) 312 (40) 308 (40) 161 (20) 3 (2 - 3) 3 (2 - 6)

Q1= percentile 25; Q3= percentile 75; N= number of individuals

Table 3. Renal function of patients who underwent cardiac surgery. All Patients (n = 918) Median (Q1 – Q3) or N (%) 1.40 (1.20 – 1.60) 49 (39 - 60) 17 (20) 231 (25) 603 (66) 67 (70)

Preoperative SCr (mg/dL) Preoperative eGFR (mL/min) eGFR ≥ 90 mL/min eGFR 60 – 89 mL/min eGFR 30 – 59 mL/min eGFR ≤ 29 mL/min Serum creatinine (mg/dL) Immediate postoperative day 1st Postoperative day 2nd Postoperative day* AKI in the first 7 days postoperatively KDIGO Stage 0 KDIGO Stage 1 KDIGO Stage 2 KDIGO Stage 3 RRT in the first 7 days postoperatively

1.30 (1.10 - 1.60) 1.50 (1.20 - 1.90) 1.30 (1.0 - 1.80) 391 (43) 527 (57) 318 (35) 27 (2.9) 46 (5.0) 35 (3.8)

Q1 - percentile 25; Q3 - percentile 75; SCr - serum creatinine; eGFR - estimated glomerular filtration rate; RRT - renal replacement therapy. *There was no determination of SCr on 2nd postoperative day for 34 patients

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Table 4. Postoperative complications of patients who underwent cardiac surgery. All Patients (n = 918) N (%) 73 (8.0) 97 (11) 27 (2.9) 86 (9.4) 79 (8.6) 135 (17) 30 (3.3) 42 (4.6) 96 (10) 15 (2.8) 46 (14) 10 (37) 25 (54)

Readmission to the intensive care unit from the ward Prolonged intensive care length of stay (> 14 days) Bleeding requiring surgical reintervention New atrial fibrillation Postoperative reintubation (within the first 7 days) Mechanical ventilation > 24 hours Mediastinitis Type I neurological injury 30-day mortality KDIGO Stage 0 KDIGO Stage 1 KDIGO Stage 2 KDIGO Stage 3 Q1 - percentile 25; Q3 - percentile 75; N - number of individuals

Table 5. Demographic data of patients who underwent cardiac surgery based on the KDIGO criteria. KDIGO 1 KDIGO 2 KDIGO 3 KDIGO 0 N = 318 N = 27 N = 46 N = 527 Median (Q1 – Q3) Median (Q1 – Q3) Median (Q1 – Q3) P-value Median (Q1 – Q3) or N (%) or N (%) or N (%) or N (%) Coronary artery bypass grafting 319 (61) 190 (60) 16 (59) 24 (52) 0.745 Cardiac valve surgery 128 (40) 11 (41) 22 (48) 208 (39) Multiple CVS 81 (15) 60 (19) 5 (19) 10 (22) 0.533 CVS during active IE 21 (4.0) 9 (2.8) 1 (3.7) 7 (15) 0.006 Age (years) 60 (51 - 67) 63 (55 - 59) 64 (58 - 70) 66 (56 - 73) <0.001 Male gender 250 (47) 185 (58) 13 (48) 29 (63) 0.009 Weight (kg) 70 (61 - 79) 71 (62 - 80) 70 (65 - 82) 69 (57 - 83) 0.444 Height (m) 1.62 (1.55 – 1.69) 1.64 (1.57 – 1.70) 1.62 (1.52 – 1.68) 1.66 (1.60 – 1.72) 0.049 Body mass index (kg/m2) 26 (24 - 30) 27 (24 - 29) 28 (24 - 32) 25 (22 - 29) 0.150 Diabetes Mellitus 127 (24) 103 (32) 9 (33) 9 (20) 0.032 LVSD (moderate/severe) 118 (22) 71 (22) 6 (22) 8 (17) 0.890 Intra-aortic balloon pump 18 (3.4) 19 (6.0) 3 (11) 3 (6.5) 0.081 Preoperative SCr (mg/dL) 1.40 (1.20 - 1.60) 1.50 (1.30 - 1.80) 1.40 (1.20 - 1.40) 1.65 (1.40 - 2.10) <0.001 Preoperative eGFR (mL/min) 51 (42 - 63) 47 (38 - 58) 53 (45 - 65) 39 (28 - 52) <0.001 Reoperation 63 (12) 52 (16) 5 (19) 14 (30) 0.004 Additive EuroSCORE 4 (2 - 5) 4 (2 - 6) 5 (2 - 7) 7 (4 - 9) <0.001 Low risk (< 3) 187 (35) 115 (36) 8 (30) 22 (48) Intermediate risk (3 to 5) 218 (41) 126 (40) 8 (30) 18 (39) 0.190 High risk (5) 122 (23) 77 (24) 11 (41) 6 (13) CPB 422 (80) 293 (92) 25 (93) 41 (89) <0.001 Total CPB time (min) 90 (76 - 109) 100 (84 - 116) 100 (76 - 122) 110 (90 - 145) <0.001 < 90 min 190 (36) 106 (33) 12 (44) 16 (35) 90 - 120 min 170 (32) 109 (34) 9 (33) 18 (39) 0.658 > 120 min 74 (14) 61 (19) 4 (15) 8 (17) Total ICU length of stay 2 (2 - 4) 3 (2 - 8) 4 (2 - 12) 8 (3 - 19) <0.001 Mechanical ventilation > 24 hours 33 (6.3) 60 (19) 11 (41) 31 (67) <0.001 CVS - cardiac valve surgery; IE - infective endocarditis; LVSD - left ventricular systolic dysfunction; SCr - serum creatinine; eGFR - estimated glomerular filtration rate; CPB - cardiopulmonary bypass; ICU - intensive care unit

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Table 6. Cox proportional hazard model considering all patients who underwent cardiac surgery for predictors of 30-day mortality. HR (CI 95%) 1.03 (1.01 - 1.05) 0.63 (0.42 – 0.95) 1.01 (1.01 – 1.02) Reference 4.76 (2.55 – 8.88) 13.54 (5.77 – 31.78) 20.81 (10.14 – 42.69)

Age (years) Male gender Total cardiopulmonary bypass time (min) KDIGO Stage 0 KDIGO Stage 1 KDIGO Stage 2 KDIGO Stage 3

P-value 0.007 0.028 < 0.001 < 0.001 < 0.001 < 0.001

HR - Hazard Ratio; CI - confidence interval

Cox regression analysis In a multivariate analysis, age (years), CPB time (minutes) and AKI (KDIGO 1-3) were independent predictors of 30-day mortality, with KDIGO stage 3 being the strongest predictor. Male gender had a reduced risk of death at 30 days (Table 6, Figure 2). Subgroup analysis (CABG and CVS) demonstrated similar results, except for reduced risk of death among male patients who underwent CABG (data not shown).

The reasons why small changes in SCr correlated with increased hospital mortality are not entirely clear. Possible explanations include the adverse effects of decreased renal function, such as volume overload, anemia, uremia, acidosis, electrolyte disturbances, and increased risk of infections[11,15]. Visual analysis of the survival curves graph of our study showed a continuous decrease of survival in patients who developed AKI, with a higher risk of death within the first week postoperatively (Figure 2). Preoperative renal dysfunction is known as a postoperative risk predictor; however, in tools such as EuroSCORE[13,14], InsCor[16], and Parsonnet[17], preoperative renal dysfunction is considered a risk factor only in cases of advanced kidney disease (SCr>2.00 or 2.26 mg/dL) or in patients on dialysis. In its update published in 2012, called EuroSCORE II[3], assessment of renal function was included by calculating the eGFR, with values below 85 mL/min being a risk factor. Estimates of preoperative renal function based on eGFR show that over 75% of patients undergoing CABG have an eGFR below 90 mL/min[18], highlighting the importance and high prevalence of renal dysfunction in patients undergoing heart surgery. Furthermore, these patients are older and have more comorbidities, such as cerebrovascular disease, peripheral artery disease, chronic obstructive pulmonary disease and diabetes mellitus[18]. Several studies have shown that slight changes in renal function have a significant impact on short and long term outcomes in patients undergoing cardiac surgery[5,19-23]. Other studies suggest that intraoperative factors such as CPB times are important contributors to postoperative renal dysfunction[24-26], as observed in our study (OR 1.01 - 95% CI 1.01 to 1.02, P value<0.001 - data not shown), but others have not demonstrated this direct relationship[27,28]. The use of off-pump CABG was also tested in preoperative renal dysfunction with contradictory results[18,29,30]. Many publications have reported preoperative renal dysfunction as a risk predictor for morbidity and postoperative mortality. Kumar et al.[31] identified class III obesity (BMI > 40 kg/m²) as an independent predictor of AKI after on-pump CABG, and Brown et al.[32] found high rates of readmission within 30 days after cardiac surgery in patients who developed

Fig. 2 - Overall survival curves of patients who underwent cardiac surgery, according to the KDIGO criteria.

DISCUSSION In our study, AKI after CABG or CVS was found to be common and associated with high rates of prolonged intensive care length of stay, morbidity and mortality. This study also demonstrated the importance of KDIGO AKI criteria as a powerful predictor of 30-day mortality in patients with preoperative SCr above normal limits. We found a higher risk of death in those with poor renal function as well as those who required dialysis; however, even slight increases in SCr postoperatively (KDIGO stage 1) were associated with a significant increase in mortality.

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AKI. Zakeri et al.[22] evaluated patients with mild to moderate impaired renal function (SCr < 2.26 mg/dL) who underwent CABG. Operative mortality was higher in this group of patients as well as the need for dialysis and occurrence of stroke postoperatively. Both the measurement of SCr as well as eGFR (< 60 mL/min) were independent predictors of hospital mortality and in a 3-year follow-up. Cooper et al.[33] evaluated more than 483,000 patients using the American Society of Thoracic Surgeons database. Seventy-eight percent of patients had some degree of preoperative (CrCl < 90 mL/min) renal dysfunction. Mortality was inversely proportional to the renal function. In an adjusted model, the eGFR was one of the strongest predictors of morbidity and hospital mortality.

2. Miceli A, Bruno VD, Capoun R, Romeo F, Angelini GD, Caputo M. Occult renal dysfunction: a mortality and morbidity risk factor in coronary artery bypass grafting surgery. J Thorac Cardiovasc Surg. 2011;141(3):771-6. 3. Nashef SA, Roques F, Sharples LD, Nilsson J, Smith C, Goldstone AR, et al. EuroSCORE II. Eur J Cardiothorac Surg. 2012;41(4):734-44. 4. Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P, et al. Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol. 2004;15(6):1597-605. 5. Lassnigg A, Schmid ER, Hiesmayr M, Falk C, Druml W, Bauer P, et al. Impact of minimal increases in serum creatinine on outcome in patients after cardiothoracic surgery: do we have to revise current definitions of acute renal failure? Crit Care Med. 2008;36(4):1129-37.

Study limitations Our study has several limitations. First, these data originated from a single center. Although data were collected prospectively, the analysis was performed retrospectively. There was no determination of cause of death, which did not allow us to differentiate between cardiovascular death and death from all causes. Several known and unknown confounding variables could theoretically have influenced the observed mortality rates. Despite the use of multivariate models for control and adjustment of some of these variables, the possibility of the presence of other unknown confounders cannot be ruled out.

6. Tolpin DA, Collard CD, Lee VV, Virani SS, Allison PM, Elayda MA, et al. Subclinical changes in serum creatinine and mortality after coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2012;143(3):682-688. 7. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis Quality Initiative workgroup. Acute renal failure definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204-12.

CONCLUSION The development of AKI, based on KDIGO criteria, correlated with increased morbidity and was a robust predictor of 30-day mortality in patients with preoperative baseline SCr above normal limits undergoing coronary artery bypass grafting or cardiac valve surgery.

8. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al; Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11(2):R31. 9. Levin A, Warnock DG, Mehta RL, Kellum JA, Shah SV, Molitoris BA, et al; Acute Kidney Injury Network Working Group. Improving outcomes from acute kidney injury: report of an initiative. Am J Kidney Dis. 2007;50(1):1-4.

Authorsâ&#x20AC;&#x2122; roles & responsibilities MNM MAN LNM

Design of the project; data collection; statistical analysis; discussion of results; manuscript writing Discussion of results; manuscript writing, article review Discussion of results; manuscript writing, article review

10. Molitoris BA, Levin A, Warnock DG, Joannidis M, Mehta RL, Kellum JA, et al; Acute Kidney Injury Network. Improving outcomes from acute kidney injury. J Am Soc Nephrol. 2007;18(7):1992-4. 11. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2:1-138.

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13. Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg. 1999;16(1):9-13.

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15. Hoste EA, Kellum JA. Acute renal failure in the critically ill: impact on morbidity and mortality. Contrib Nephrol. 2004;144:1-11. 16. Mejía OA, Lisboa LA, Puig LB, Moreira LF, Dallan LA, Pomerantzeff PM, et al. InsCor: a simple and accurate method for risk assessment in heart surgery. Arq Bras Cardiol. 2013;100(3):246-54.

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19. Devbhandari MP, Duncan AJ, Grayson AD, Fabri BM, Keenan DJ, Bridgewater B, et al. Effect of risk-adjusted, non-dialysisdependent renal dysfunction on mortality and morbidity following coronary artery bypass surgery: a multi-centre study. Eur J Cardiothorac Surg. 2006;29(6):964-70.

29. Sajja LR, Mannam G, Chakravarthi RM, Sompalli S, Naidu SK, Somaraju B, et al. Coronary artery bypass grafting with or without cardiopulmonary bypass in patients with preoperative non-dialysis dependent renal insufficiency: a randomized study. J Thorac Cardiovasc Surg. 2007;133(2):378-88.

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21. Simon C, Luciani R, Capuano F, Miceli A, Roscitano A, Tonelli E, et al. Mild and moderate renal dysfunction: impact on shortterm outcome. Eur J Cardiothoracic Surg. 2007;32(2):286-90. 22. Zakeri R, Freemantle N, Barnett V, Lipkin GW, Bonser RS, Graham TR, et al. Relation between mild renal dysfunction and outcomes after coronary artery bypass grafting. Circulation. 2005;112(9 Suppl):I270-5.

31. Kumar AB, Bridget Zimmerman M, Suneja M. Obesity and post-cardiopulmonary bypass-associated acute kidney injury: a single-center retrospective analysis. J Cardiothorac Vasc Anesth. 2014;28(3):551-6. 32. Brown JR, Parikh CR, Ross CS, Kramer RS, Magnus PC, Chaisson K, et al; Northern New England Cardiovascular Disease Study Group. Impact of perioperative acute kidney injury as a severity index for thirty-day readmission after cardiac surgery. Ann Thorac Surg. 2014;97(1):111-7.

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Spiliopoulos K, et al. - Chronic stress and coping among cardiac surgeons: ORIGINAL ARTICLE a single center study

Chronic stress and coping among cardiac surgeons: a single center study Estresse crônico e enfrentamento entre os cirurgiões cardíacos: um estudo de centro único

Kyriakos Spiliopoulos1, MD; Laura Gansera2; Hans Christian Weiland2, MD; Tibor Schuster3, MD; Walter Eichinger2, MD, PhD; Brigitte Gansera2, MD, PhD

DOI: 10.5935/1678-9741.20140083

RBCCV 44205-1555

Abstract Introduction: Cardiac surgeons stress may impair their quality of life and professional practice. Objective: To assess perceived chronic stress and coping strategies among cardiac surgeons. Methods: Twenty-two cardiac surgeons answered two self -assessment questionnaires, the Trier Inventory for Chronic Stress and the German SGV for coping strategies. Results: Participants mean age was 40±14.1 years and 13 were male; eight were senior physicians and 14 were residents. Mean values for the Trier Inventory for Chronic Stress were within the normal range. Unexperienced physicians had significantly higher levels of dissatisfaction at work, lack of social recognition, and isolation (P<0.05). Coping strategies such as play down, distraction from situation, and substitutional satisfaction were also significantly more frequent among unexperienced surgeons. “Negative” stress-coping strategies occur more often in experienced than in younger colleagues (P=0.029). Female surgeons felt more exposed to overwork (P=0.04) and social stress (P=0.03).

Conclusion: Cardiac surgeons show a tendency to high perception of chronic stress phenomena and vulnerability for negative coping strategies.

Department of Cardiovascular Surgery, Clinic Bogenhausen, Munich, Germany Department of Thoracic and Cardiovascular Surgery, University of Thessaly, Larissa, Greece (Lecturer). 2 Department of Cardiovascular Surgery, Clinic Bogenhausen, Munich, Germany. 3 Institute for Medical Statistics and Epidemiology, Technical University Munich, Germany.

Correspondence address: Kyriakos Spiliopoulos Department of Cardiovascular Surgery, Klinikum Muenchen-Bogenhausen, Englschalkinger Str. 77, D-81925 Munich, Germany. E-mail: spiliopoulos@med.uth.gr

Descriptors: Stress, Psychological. Cardiac Surgical Procedures. Case Studies. Resumo Introdução: O estresse em cirurgiões cardíacos pode prejudicar sua qualidade de vida e prática profissional. Objetivo: Avaliar a percepção de estresse crônico e as estratégias de enfrentamento entre os cirurgiões cardíacos. Métodos: Vinte e dois cirurgiões cardíacos responderam a dois questionários de autoavaliação, o Inventário de Trier sobre estresse crônico (Trier Inventory for Chronic Stress - TICS) e o German SVF sobre estratégias de enfrentamento do estresse. Resultados: Os participantes tinham idade média de 40±14,1 anos; sendo 13 do sexo masculino. Oito participantes eram mé-

This study was carried out at Department of Cardiovascular Surgery, Clinic Bogenhausen, Munich, Germany.

Article received on November 12th, 2013 Article accepted on June 22nd, 2014

No financial support.

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tes entre os cirurgiões inexperientes. Estratégias "negativas" de enfrentamento do estresse ocorrem mais frequentemente em cirurgiões experientes do que em colegas mais jovens (P=0,029). As cirurgiãs sentem-se mais expostas ao excesso de trabalho (P=0,04) e estresse social (P=0,03). Conclusão: Cirurgiões cardíacos mostram tendência para alta percepção de fenômenos de estresse crônico e vulnerabilidade para estratégias de enfrentamento negativas.

Abbreviations, acronyms & symbols TICS

Trier inventory for chronic stress

dicos seniores e 14 eram residentes. Os valores médios do Inventário de Trier sobre Estresse Crônico estavam dentro da faixa normal. Médicos inexperientes tinham níveis significativamente mais elevados de insatisfação no trabalho, isolamento e falta de reconhecimento social (P<0,05). As estratégias de enfrentamento, como minimização, distração da situação e satisfação substituta, também foram significativamente mais frequen-

Descritores: Estresse Psicológico. Procedimentos Cirúrgicos Cardíacos. Estudos de Casos.

INTRODUCTION

work, and emotional burden in this particular group of physicians. The aims of this single-center pilot-study were to compare chronic stress experience and coping strategies among cardiac surgeons with those of an age-matched representative sample and to analyze the impact of different factors such as gender and position (head of department, senior physician, resident) on stress experience and coping.

In recent years the constantly changing working conditions in hospitals, mainly determined by rising numbers of patient numbers and shorter stays[1], have increased psychosocial stress and its consequences among hospital doctors[2]. In particular, surgeons appear to suffer high levels of stress, as described by many authors[3-5]. This is specially true for a post in cardiac surgery usually characterized by overtime, sleep deprivation, delays in payment, limited control and loss of autonomy, feelings of isolation, and lack of time for research activities, all of which may place physicians at particular risk of having to cope with an imbalance between their personal and professional life. Serious manifestations of chronic stress among surgeons include depression, anxiety, divorce or broken relationships, mistakes at work and thoughts about giving up their profession as well as symptoms of burnout, such as emotional exhaustion, depersonalization, and low personal accomplishment[6]. In the last 20 years, the inconsistent and fragile coherence between acute stress and measurable variables of health and illness paved the way for the development of research i on the topic of chronic occupational stress. Nevertheless, as of 2003 there were no methods in the German language to evaluate chronic stress comprehensively and validly. The Trier Inventory for Chronic Stress (TICS) represents a standardized instrument to measure chronic stress. It consists of a self-assessment questionnaire validating different kinds of chronic stress, and it measures primarily experiences of specific sources of work load[7]. On the other hand, the German multidimensional stress-coping inventory (SVF) measures the trait aspects of coping with everyday stress[8,9]. A detailed description of both assessment tools is given in the method-section. Given the fact, that there is a lack of evidence-based data analyzing stress-experience and coping strategies specifically in the cardiac surgeon population, the present series set out to assess, for the first time, stress-factors, satisfaction at

METHODS Study Sample The study population consisted of 22 cardiac surgeons, from a single center, with different positions and experience. Due to the small size of the group, the survey should be treated as a pilot study. All participants signed informed consent forms and, in accordance with German law, approval from a medical ethics review board was not required. All surgeons worked on a regular basis, 5 days and 40 hours per week, excluding "on call" services. Measures Psychosocial stress at work was assessed by two anonymous well-established and standardized written questionnaires used to measure perceived chronic stress, TICS and coping strategies (German SVF). The TICS standardized questionnaire consists of 57 Items and 10 scales for a differentiated diagnosis of various facets of perceived chronic stress. Participants had to report the frequency of specific stress situations experienced within the last 3 months. The 10 scales include: overwork, social trashing, pressure to succeed, lack of work satisfaction, excessive demands at work, lack of social recognition, social stress, social isolation, chronic worrying, and total value of chronicle stress. Overwork, social stress, and pressure to succeed are related to stress resulting from high demand at work whereas lack of work satisfaction, excessive demand at work, lack of

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social recognition, social trashing, and social isolation detect stress-phenomena arising from a lack of satisfaction of one’s needs. Furthermore, TICS contains a scale for chronic worrying as well as a 12-Item-screening-scale, providing the full extent of perceived stress. The assessment achieves good profile reliability[7] and all scales fit the ordinal Rasch-model. Validated instruments were used to make measurements in accordance with the demand-control and effort-reward imbalance models. Internal consistency ranged between 0.84 and 0.91 (Cronbach‘s Alpha) and split-half reliability between 0.78 and 0.89 (m: 0.83, Rasch). Reliability of all scales was sufficiently high (Cronbach’s Alpha between 0.84 and 0.91; m: 0.87). For each item, the frequency of experience in the last 3 months had to be indicated on a 5-point rating scale, ranging from “never” to “very often”. The German SVF questionnaire was used to assess coping. It comprises 19 scales for different types of reactions to an unspecified range of situations that impair, adversely affect, irritate or disturb the emotional equilibrium or balance of the subject. Each scale consists of six items that are answered using a 5-point scale, according to the probability of that reaction. The coping mechanism scales of the SVF are depicted in Table 1. Items are rated on a scale of 1 to 5: never, hardly, potentially, probably, most likely. Total negative and positive coping strategies are measured after summarizing the values of scales 1-10 or 13 to 18, according to the test-developers` instructions. The reliability of all scales was sufficiently high (median Cronbach‘s Alpha was 0.8 for test-retest reliability by the authors). Validity has been tested by intercorrelations between subscales, correlations with a variety of questionnaires and specification of different stress-

ful situations, confirming the relationship between coping and personality described by Watson & Hubbard[10]. Statistical methods Statistical analyses were performed using 95% confidence intervals and the Mann-Whitney-U Test. The level of significance was set at P<0.05. Due to the limited sample size and in order to avoid being overconservative in our evaluation, Bonferroni correction of P-values was not performed. However, all statistical comparisons were thoroughly reported enabling an informal correction of P-values by the reader. With this approach, we followed a practical solution as proposed by Saville[11] to consider multiple testing. In addition the results were compared to an age-matched representative sample, using available normal values (T-scale; mean=50 and SD=10) for the SVF and TICS in German volunteers with regard to gender for the age range of 20 to 64 years. RESULTS Twenty two professionals answered the questionnaires, corresponding to the total sample size. Among the participants, the mean age was 40±14.1 years, ranging from 26 to 60 years; 59% (n=13) were male and 41% (n=9), female. Concerning position and professional qualification, 36.4% (n=8) were specialists (6 males), including the head of the department, and 63.6% (n=14) were residents (7 males). Figure 1 shows that the surveyed cardiac surgeons, when compared to the age-matched population, presented mean

Table 1. Coping mechanism scales of the SVF. Coping mechanism Play down Compare with others Guilt defence Distraction from situation Substitutional satisfaction Ego boost Situational control Reaction control Positive self-instruction Need for social support Avoidance Flight tendency Social retreat Rumination Resignation Self-pity Self –accusation Aggression Self-medication/ use of drugs

Response I tell myself, “It is not that bad” I tell myself, “Others couldn’t take it the way I do” I tell myself, “I am not to blame” I try to concentrate on something else I treat myself by buying something nice I think about my success in other situations I make a plan how to solve the problem I try to keep my behaviour under control I tell myself not to give up I try to talk to someone about the problem I start to avoid this kind of situation I only want to get out of this I prefer to be by myself I think about it over and over I tend to give up I ask myself “why me?” I tell myself, “After all it’s my fault” I get enraged I‘ll have a few beers, glass of wine…

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values and 95% confidence intervals for TICS and SVF mostly within the normal range. The only marginal outlier (but still with a mean value within the normal range) refers to the item measuring lack of social recognition. With regard to the level of professional experience, the analysis revealed that inexperienced surgeons showed significantly higher levels (P< 0.05) of dissatisfaction at work and lack of social recognition and isolation (TICS). Coping strategies (SVF), such as play down, distraction from situation, and substitutional satisfaction were also significantly more frequent in this group (Figure 2). On the other hand, their experienced counterparts presented higher, but non-significant, values for pressure to succeed, overwork, self accusation, and

social stress as well as for coping strategies such as flight tendency, guilt defence, social retreat, self-pity and self-accusation, ego boost, resignation and aggression (Figure 2). In terms of coping, â&#x20AC;&#x153;negativeâ&#x20AC;&#x153; strategies were more present in experienced than in younger colleagues (P=0.029); (Figure 2). Concerning the impact of gender, female surgeons felt significantly more exposed to overwork (P=0.04) and social stress (P=0.03); (Figure 3). Interestingly, although all of our female surgeons (2 senior physicians and 7 residents) felt more exposed to overwork, isolated gender-specific comparisons among residents showed significantly higher values for male residents regarding overwork (P=0.002), social stress (P=0.001) and play-down strategies (P=0.04).

Fig. 1 - Mean values and 95% confidence intervals for TICS and SVF (all surgeons).

Fig. 2 - Mean values and 95% confidence intervals for TICS and SVF (senior physicians versus residents).

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Fig. 3 - Mean values and 95% confidence intervals for TICS and SVF (females versus males).

1 Compare with others 2 Play down 3 Guilt defense 4 Distraction from situation 5 Substitutional satisfaction 6 Ego boost 7 Situational control 8 Reaction control 9 Positive self- instruction 10 Need for social support 11 Avoidance

Item (Fig. 1 to Fig. 3)

12 Flight tendency 13 Social retreat 14 Rumination 15 Resignation 16 Self-pity 17 Self-accusation 18 Aggression 19 Self- medication/ use of drugs 20 Total of positive coping strategies 21 Total of negative positive coping strategies 22 Overwork

23 24 25 26 27 28 29 30 31

Social trashing Pressure to succed Lack of work satisfaction Excessive demands at work Lack of social recognition Social stress Social isolation Chronic worrying Total value for chronicle stress

and coping mechanisms among cardiac surgeons, and the second one, beside a series performed by Mikalauskas et al.[14] on the incidence of burnout syndrome, to focus on this specific surgical specialty. Cardiac surgery, characterized by special attributes of surgical practice along with the rigors and length of training for this profession, seems to attract individuals of a particular character and determination as indicated by the relatively high mean age of 40 years of our study population, despite 64% being residents. In addition, the specialty still poses barriers to women, which was confirmed by the lower percentage of women in our series (41%) the finding with only two female out of eight specialists. Cardiac surgeons work hard, deal regularly with matters of life and death, and make substantial personal sacrifices in

DISCUSSION Although several studies have dealt with coping strategies in the context of health, their main focus has been surgical patientsâ&#x20AC;&#x2122; reactions and, specifically for cardiac surgery, patients undergoing heart transplantation[12,13]. There are few reports analyzing psychological implications, especially in healthcare professionals of surgical specialties. In recent years, occupational stress among medical doctors has become the subject of extensive investigation since it is a determinant factor of physical and mental disorders that force these professionals to take leaves of absence from their work. To our knowledge, the present study represents the first published attempt to assess directly perceived chronic stress

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favor of their professional practice, making them prone to burnout syndrome. Studies including either surgeons from several surgical subspecialties and/or graduates report that the incidence of burnout syndrome ranges from 30% to 38%[15-19], while Mikaulskas et al.[14] stated that in their cardiac surgical collective more than half (62%) of the respondents met the criteria for being burned out, with 19.3%, 25.9%, and 42.3% experiencing high emotional exhaustion, high depersonalization, and low personal accomplishment at work, respectively. Similary, in a large study published by Campbell et al.[16] surveying 582 surgeons from the University of Michigan, 32% showed high levels of emotional exhaustion, 13% increased levels of depersonalization, and 4% presented evidence of a low sense of personal accomplishment, while an Australian study of 126 surgeons, carried out by Benson et al.[20], indicated that burnout levels were significantly higher for surgeons than for the normal population, with 67.6% of the sample approaching high burnout levels. All of these findings confirm that a substantial number of colleagues in surgical specialties are struggling with a high level of personal and professional distress and that among cardiac surgeons appear to be even more susceptible to burnout. Further analysis of the aforementioned studies[16,20] showed that younger surgeons were more vulnerable to developing burnout syndrome than their older counterparts. These data, although gathered from general surgeons, concur with ours, in which younger colleagues felt exposed to chronic stress phenomena more frequently, in particular to dissatisfaction at work, lack of social recognition, and social isolation. Younger surgeons reported significantly higher burnout levels, regardless of their career status. Concerning the role of various factors in predicting occupational chronic stress and subsequent burnout syndrome, it is noteworthy to mention the main findings of a prospective study performed by the Buddeberg-Fischer et al.[21] in a cohort of Swiss medical school graduates, who where followed throughout their professional career, beginning in 2001. In their fourth and eighth years after graduation, 443 physicians reported on their workplace conditions, the experienced effort-reward imbalance, the professional and emotional support received as well as their personal characteristics. The mean chronic stress (TICS-SCSS) of the study-sample was significantly higher (P<0.001) compared to an age-matched representative population. In the prediction of chronic stress, workplace effort-reward imbalance as well as over-commitment turned out to be the most important risk factors, while stress protective factors were high satisfaction with career support, sense of coherence, and occupational self-efficacy. However, in the prediction of chronic stress, gender had no significant moderator effect, a finding which is in contrast to our results of gender specific differences in the historically male- dominated discipline of cardiac surgery. In particular, male residents showed significant higher values

concerning overwork (P=0.002), social stress (P=0.001) and play- down strategies (P=0.04) than their young female colleagues, whereas all female surgeons (senior physicians and residents) felt more exposed to overwork (P=0.04) and social stress (P=0.03). These findings suggest that experienced female surgeons suffer from the incompatibilities between their professional career and family, children, household etc., whereas experienced male surgeons are more frequently stressed by isolated job-related factors, such as pressure to succeed and overwork. The only other available study in cardiac surgeons constructed by Mikalauskas et al.[14] did not include female surgeons, thus all information about gender differences is derived from general series in populations of all specialties. A prospective study from Johns Hopkins University including more than 1300 male physicians, documented that the prevalence of clinically significant depression was 12.8%[22], while in the analysis of 4500 female physicians in the Women Physicians' Healthstudy, the prevalence of depression was 19.4%[23]. Regarding coping strategies among cardiac surgeons, there is a substantial lack of evidence in the literature. Despite suggestions that, in general, negative stress-coping responses decrease with experience[24,25], most of the studies assessed only intraoperative stress and not the entire chronic occupational stress of surgeons. The negative correlation of experience and negative coping-strategies was documented among others surgeons in an investigation of â&#x20AC;&#x153;burnoutâ&#x20AC;? among American surgeons[16]. The study showed younger surgeons to be more susceptible to burnout and negative stress coping-mechanisms. The results of our study compare favorably to this report in terms of dissatisfaction at work, lack of social recognition and isolation (TICS), but are contrary in terms of coping strategies, where experienced surgeons showed higher values for negative coping compared to the unexperienced ones. These discrepancies in the results may be caused by the relatively small sample size of our series. To sum up, we did not have a solid explanation for this observation and this finding should be considered as tentative. Finally the findings of our study imply that stress management strategies are particularly important in the prevention of professional burnout in cardiac surgeons. This will further help them to improve their technical skills, decision-making time and trust with subsequent improvement in the quality of the provided health care. Interventions aiming at reducing psychosocial stress at work should consist of both an organizational and a health policy level approach. Limitations of the study The small number of surgeons, involved in the investigation might be regarded as a substantial limitation. Nevertheless, explanatory power of both questionnaires is sufficiently proven for each item or scale in terms of individual deviation from the normal range.

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A second caveat concerns the generalizability of our results, as health care systems differ across countries.

6. Klein J, Grosse Frie K, Blum K, von dem Knesebeck O. Psychosocial stress at work and perceived quality of care among clinicians in surgery. BMC Health Serv Res. 2011;11:109.

CONCLUSION

7. Schulz P, Schlotz W, Becker P. Trierer Inventar zur Erfassung von chronischem Streß (TICS): Skalenkonstruktion, teststatistische Überprüfung und Validierung der Skala Arbeitsüberlastung. Diagnostica. 1999;45(1):8-19.

Although most values were within the normal range, cardiac surgeons tend to a high level of perceived stress phenomena and vulnerability for negative coping strategies. In particular, dissatisfaction at work, social isolation, and a lack of social recognition were more frequent among residents. On the other hand, senior physicians showed higher values for pressure to succeed and negative coping strategies, such as resignation and aggression. It is a matter of concern that especially young cardiac surgeons report feeling stressed early in their professional career. Actions have to be taken in order to reduce stress levels, mainly through the re-establishment of reciprocity between perceived effort invested and rewards received, in the form of career opportunities and acceptance of personal capacities including emotional support.

8. Janke W, Erdmann G, Kallus W. Der StressverarbeitungsFragebogen (The coping questionnaire).Verlag für Psychologie; 1985. 9. Ising M,Weyers P,Janke W, Erdmann G. Untersuchung zu den Gütekriterien des SVF78 von Janke und Erdmann, eine Kurzform des Stressverarbeitungfragebogens SVF 120. Zeitschrift für differentielle und diagnostische Psychologie. 2001;4:279-90. 10. Watson D, Hubbard B. Adaptional style and dispositional structure: coping in the context of the five-factor model. J Pers. 1996;64:737-74. 11. Saville DJ. Multiple comparison procedures: the practical solution. The American Statistician. 1990;44:174-80. 12. Pfeifer PM, Ruschel PP, Bordignon S. Coping strategies after heart transplantation: psychological implications. Rev Bras Cir Cardiovasc. 2013;28(1):61-8.

Authors’ roles & responsibilities KS LG HCW TS WE BG

Main author, drafting of the paper Data collection, drafting of the paper Data collection, drafting of the paper Data collection, statistical analysis Co-author, drafting of the paper, data collection Senior author

13. Allman E, Berry D, Nasir L. Depression and coping in heart failure patients: a review of the literature. J Cardiovasc Nurs. 2009;24(2):106-17. 14. Mikalauskas A, Širvinskas E, Marchertienė I, Macas A, Samalavičius R, Kinduris Š, et al. Burnout among Lithuanian cardiac surgeons and cardiac anesthesiologists. Medicina (Kaunas). 2012;48(9):478-84. 15. Bertges Yost W, Eshelman A, Raoufi M, Abouljoud MS. A national study of burnout among American transplant surgeons. Transplant Proc. 2005;37(2):1399-401.

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20. Benson S, Truskett PG, Findlay B. The relationship between burnout and emotional intelligence. Australian surgeons and surgical trainees. ANZ J Surg. 2007;77(suppl 1): A79.

23. Frank E, McMurray JE, Linzer M, Elon L. Career satisfaction of US women physicians: results from the Women Physiciansâ&#x20AC;&#x2122; Health Study. Society of General Internal Medicine Career Satisfaction Study Group. Arch Intern Med. 1999;159(13):1417-26.

21. Buddeberg-Fischer B, Klaghofer R, Abel T, Buddeberg C. Junior physiciansâ&#x20AC;&#x2122; workplace experiences in clinical fields in German-speaking Switzerland. Swiss Med Wkly. 2005;135(12):19-26.

24. Kikuchi K, Okuyama K, Yamamoto A, Hara T, Hara T. Intraoperative stress for surgeons and assistants. J Ophthalmic Nurs Technol. 1995;14(2):68-70, 72-3.

22. Ford DE, Mead LA, Chang PP, Cooper-Patrick L, Wang NY, Klag MJ. Depression is a risk factor for coronary artery disease in men: the precursors study. Arch Intern Med. 1998;158(13):1422-6.

25. Yamamoto A, Hara T, Kikuchi K, Hara T, Fujiwara T. Intraoperative stress experienced by surgeons and assistants. Ophthalmic Surg Lasers. 1999;30(1):27-30.

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Azeredo LG, etORIGINAL al. - Late outcome analysis of the Braile Biomédica® pericardial ARTICLE valve in the aortic positiony

Late outcome analysis of the Braile Biomédica® pericardial valve in the aortic position Avaliação dos resultados tardios da bioprótese de pericárdio bovino Braile Biomédica® em posição aórtica

Lisandro Gonçalves Azeredo1, MD; Elinthon Tavares Veronese2, MD; José Augusto Duncan Santiago2, MD; Carlos Manuel de Almeida Brandão2, MD, PhD; Pablo Maria Alberto Pomerantzeff2, MD, PhD; Fabio Biscegli Jatene2, MD, MsC, PhD

DOI 10.5935/1678-9741.20140081

RBCCV 44205-1556

Abstract Objective: Aortic valve replacement with Braile bovine pericardial prosthesis has been routinely done at the Heart Institute of the Universidade de São Paulo Medical School since 2006. The objective of this study is to analyze the results of Braile Biomédica® aortic bioprosthesis in patients with aortic valve disease. Methods: We retrospectively evaluated 196 patients with aortic valve disease submitted to aortic valve replacement with Braile Biomédica® bovine pericardial prosthesis, between 2006 and 2010. Mean age was 59.41±16.34 years and 67.3% were male. Before surgery, 73.4% of patients were in NYHA functional class III or IV. Results: Hospital mortality was 8.16% (16 patients). Linearized rates of mortality, endocarditis, reintervention, and structural dysfunction were 1.065%, 0.91%, 0.68% and 0.075% patients/year, respectively. Actuarial survival was 90.59±2.56% in 88 months. Freedom from reintervention, endocarditis and structural dysfunction was respectively 91.38±2.79%, 89.84±2.92% and 98.57±0.72% in 88 months.

Conclusion: The Braile Biomédica® pericardial aortic valve prosthesis demonstrated actuarial survival and durability similar to that described in the literature, but further follow up is required to assess the incidence of prosthetic valve endocarditis and structural dysfunction in the future.

Hopital Evangélico de Cachoeiro de Itapemirim, Cachoeiro de Itapemirim, ES, Brazil. 2 Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo InCor-HCFMUSP, São Paulo, SP, Brazil. This study was carried out at Instituto do Coração (Heart Institute) of Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo InCor-HCFMUSP, São Paulo, SP, Brazil.

Correspondence Address: Lisandro Gonçalves Azeredo Instituto do Coração (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Av. Enéas Carvalho Aguiar, 44 - Cerqueira César, São Paulo, SP, Brazil Zip code: 05403-000 E-mail:lisandro.azeredo@hotmail.com

Descriptors: Heart Valve Prosthesis Implantation. Aortic Valve. Survival Analysis. Resumo Objetivo: A troca valvar aórtica por substitutos biológicos de pericárdio bovino Braile é realizada rotineiramente no Instituto do Coração da Faculdade de Medicina da USP desde 2006. O objetivo deste estudo é analisar os resultados da utilização da prótese aórtica Braile Biomédica® em pacientes com doença valvar aórtica. Métodos: Foram analisados, retrospectivamente, 196 pacientes portadores de valvopatia aórtica submetidos à troca valvar aórtica por prótese biológica de pericárdio bovino Braile Biomé-

Article received on March 17th, 2014 Article accepted on June 22nd, 2014

No financial support.

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pacientes/ano, respectivamente. A sobrevida actuarial foi de 90,59±2,56% em 88 meses. A curva livre de reoperação, endocardite e disfunção estrutural foi respectivamente de 91,38±2,79%, 89,84±2,92% e 98,57±0,72% em 88 meses. Conclusão: O implante da prótese aórtica de pericárdio bovino Braile Biomédica® demonstrou sobrevida e durabilidade compatível com a literatura, porém maior seguimento é necessário para avaliar a incidência de endocardite e disfunção estrutural no futuro.

Abbreviations, acronyms & symbols NYHA

New York Heart Association

dica® entre 2006 e 2010. A idade média foi de 59,41±16,34 anos e 67,3% eram do sexo masculino. No pré-operatório, 73,4% dos pacientes estavam em classe funcional III ou IV. Resultados: A mortalidade hospitalar foi 8,16% (16 pacientes). As taxas linearizadas de óbito, endocardite, reoperação e disfunção estrutural foram de 1,065%, 0,91%, 0,68% e 0,075%

Descritores: Implante de Prótese de Valva Cardíaca. Valva Aórtica. Análise de Sobrevida.

INTRODUCTION

surgeries were performed by the Heart Valve Surgical Team of the InCOR-FMUSP, excluding prosthetic endocarditis. Patients with previous cardiac surgery, native valve endocarditis, and mitral repair procedures were included in the analysis group. The Heart Institute Scientific Committee and the Ethics Committee of the of the University of São Paulo Medical School (FMUSP) approved the paper, with number 0453/07. Age ranged from 16 to 85 years-old, mean of 59.41±16.41years. One hundred thirty two (67.3%) patients were male, and 64 (32.7%) were female. Mortality rate of the analyzed group, predicted by EuroSCORE II[8] was 3.48±3.99% (ranging from 0.56 to 26.48%; median = 2.025%). All patients were submitted to traditional surgery by median sternotomy, cardiopulmonary bypass with moderate hypothermia (28°C), aortic cannulation, and single or double venous cannulation, in cases of mitral valve involvement. Anterograde, intermittent, cold blood cardioplegic myocardial protection was performed. Aortic opening was carried out by inverted “J” aortotomy and the left atrium was opened by conventional left atriotomy. The original Braile Biomédica® sizers were used to measure the aortic annulus. Prosthetic suture in the aortic annulus was made with or without Polyester Fiber (Mersilene® or Ethibond®2-0), with pledgets at surgeon’s discretion. Main etiology of surgical aortic replacement was degenerative in 104 cases (53.1%), followed by structural dysfunction of bioprosthesis in 42 cases (21.4%), rheumatic disease in 29 (14.8%), infective endocarditis in 9 (4.6%), bicuspid aortic valve in 10 (5.1%) and other causes in 2 (1%). Regarding prosthesis size, the prosthesis labeled number 19 by the manufacturer was used in 3 patients (1.5%), number 21 in 37 (18.9%), number 23 in 90 (45.9%), number 25 in 55 (28.1%) and number 27 in 11 (5.6%).

Bovine pericardial bioprostheses have been used for aortic valve replacement since the early 70’s, when first generation of bioprostheses became commercially available. Description[1], clinical use, and initial results have been known since then. A variety of models and materials have been introduced for everyday use and evaluated for long-term use[2,3]. The choice of which prosthesis to use – biological or mechanic – was not associated to a significant improvement in survival[4,5]. However, in terms of freedom from reintervention during a 20-year follow-up, bioprostheses were inferior compared to mechanical prostheses[5]. The is no consense in literature regarding long-term results of bioprosthesis, which vary not only by age group, anatomic implant position or materials used, but also by unique manufacturing and preservation techniques used by each manufacturer. In the Heart Institute of the Universidade de São Paulo (InCOR – FMUSP) the first bovine pericardial bioprosthesis to be used was the Fisics-InCOR prosthesis[6] in 1984. Pomerantzeff et al.[7] published the results of 15-years of experience with 2607 of those prostheses. In 2001, the Braile Biomédica® bovine pericardial bioprosthesis started to be used at InCOR-FMUSP, but its everyday use began only in 2006. The aim of this paper is to analyze the initial experience with Braile Biomédica® bovine pericardial bioprosthesis, from 2006 to 2011, concerning survival and freedom from endocarditis, structural dysfunction, and reintervention. METHODS This study was observational and retrospective, using a historic cohort, from April 2006 to December 2010. In that period, 196 elective consecutive aortic bioprosthesis implant

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Associated procedures were performed in 33 patients (16.8%), 25 (12.7%) of them being mitral reconstruction and 8 (4.1%), mitral comissurotomies. In regards to functional status (NYHA), 26 (13.3%) patients were in functional class IV, 118 (60.2%) in functional class III, 48 (24.5%) in functional class II and 4 (2.0%) in functional class I. Follow-ups were carried out by physician’s consultations at the InCOR-FMUSP, registered in the institutional electronic medical chart (sI3) or by phone interviews. Mean follow-up time was 40.29±17.05 months, and 22 patients (11.2%) failed to follow up. The results were reported according to the Akins et al.[9] definitions in the Guidelines for reporting mortality and morbidity after cardiac valve interventions. The GraphPad Prism6 (GraphPad Software, Inc. La Jolla, CA) software was used for the statistical analysis. Continuous data were presented as mean ± standard deviation, categorical variables as percentages (%) and exact Fisher test for comparison between groups. Survival, freedom from reintervention, endocarditis or structural dysfunction were obtained by the Kaplan-Meier estimator.

The linearized event rates of reoperation, death, infective endocarditis and structural dysfunction are reported in Table 3. There was neither hemolysis nor non-structural dysfunction on this series. Actuarial survival in 88 months was 90.59±2.56% (Figure 1). Freedom from reintervention curve (Figure 2), infective endocarditis and structural dysfunction (Figure 3) was 91.38±2.79%, 89.84±2.92% and 98.57±0.72% in 88 months, respectively.

Table 1. Subgroups in hospital mortality. Subgroups Mortality (%) Functional Status (NYHA) I, II and III 6.47 IV 19.23 Number of prior interventions First surgery 8.45 One or more 7.40 Associated procedures Isolated aortic replacement 7.36 Aortic replacement and mitral procedure 12.12 Age group <65 years 2.83 ≥65 years 14.4 Ejection Fraction >50% 5.88 ≤50% 13.33

RESULTS In-hospital mortality was 8.16% (16 patients). The causa mortis was cardiogenic shock in 6 patients (37.5%), pulmonary sepsis in 8 patients (50%), renal failure in 1 patient (6.25%), and hepatic failure in 1 patient (6.25%) with hepatitis C. Patients younger than 65 years-old had 2.83% mortality (3 out of 106), while patients 65 or older had 14.4% mortality (13 out of 90). Mortality rates for the 54 reoperation cases was 7.40% whereas, while among first surgery patients, it was 8.45%. Mortality, analyzed according to the pre-operative functional status of the patient, was 0% for NYHA I, 6.25% for NYHA II, 6.78% for NYHA III and 19.23% for NYHA IV (Table 1). According to the procedure, isolated aortic valve replacement had the lowest mortality rate at 7.36% (12 out of 163), and the associated procedures –mitral reconstruction or comissurotomy – presented a 12.12% mortality rate (4 out of 33). In the follow-up, there were 12 prosthesis-related deaths and 11 non-related deaths. The most common prosthesis-related death was infective endocarditis, in 10 cases, followed by one case of stroke and one unclarified death. For the 10 cases of infective endocarditis that culminated in death, initial infection was recognized in 5 cases: one erysipelas, one pulmonary infection, and 3 urinary infections. For the 11 non-related deaths, the main cause of death was pulmonary infection in 3 cases, followed by cardiac failure and urinary infection, both with two cases. There was one case each of abdominal sepsis, acute intestinal obstruction, pulmonary cancer, and trauma (Table 2).

P 0.433 1.00 0.482 0.0036 0.0931

Table 2. Late mortality causes. Related Deaths Infective endocarditis Stroke Unclarified Non-Related Deaths Pulmonary infection Cardiac failure Urinary infection Abdominal sepsis Acute abdominal obstruction Pulmonary cancer Trauma Total

10 1 1 3 2 2 1 1 1 1 23

Table 3. Linearized event rates (late outcome). Event Reintervention Death Endocarditis Structural dysfunction

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% Patients/Year 0.68 1.065 0.91 0.075

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Fig. 2 - Kaplan-Meier freedom from reintervention curve after 88 months of aortic valve prosthetic implantation.

Fig. 1 - Kaplan-Meier survival curve after 88 months of aortic valve prosthetic implantation.

Fig. 3 - Kaplan-Meier curves, freedom from endocarditis and from structural valve dysfunction after 88 months of aortic valve prosthetic implantation.

DISCUSSION

of mechanical prosthesis. As a national reference center, there is a major concern about adequate control of anticoagulation in patients coming from other regions, leading to a greater use of bioprostheses. In-hospital mortality was 8.16%, compared to national reports of 8%[13] mortality for general cardiac surgery and from 7.0 to 15.0% for aortic valve replacement[14,15], not adjusted. Being a tertiary center with great experience in bioprosthesis implantation[6,7] and in reoperations[16,17], there is a high incidence of previous cardiac surgeries, historically rising – from 1980 to 1999, 22.8% were reoperations[16] and, from 2006 to 2010, 27.5% were reoperations. This incidence is only

There is few data about longevity of Brazilian bioprosthesis in comparison with other[10], and as for the Braile Biomédica® prosthesis, there are no data that show their use in an everyday basis, evaluating its performance in a consecutive group of patients that include reoperations, endocarditis and associated surgeries[11,12]. In the analyzed group, mean age was 59 years. For the most part, in the Brazilian Public Health Care System, indication of bioprosthesis in young patients is due to the inability to follow adequate medical control of anticoagulation, ruling out the use

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comparable to Bacco et al.[15], that, with 25.6% incidence of reoperations, found 15% in-hospital mortality for aortic valve replacement. Despite mortality higher than data from the United States and the United Kingdom[18,19], it is worth mentioning the need of pairing mortality to surgical risk[8,9,20] and of internal validation of the risk score models. In Canada, Forcillo et al.[21], analyzing Carpentier-Edwards bovine pericardial bioprosthesis in aortic position, found actuarial survival of 78±2% at 5 years, lower than the 90.59±2.63% actuarial survival at 5 years found by us. EuroSCORE II[8] mortality estimate was 3.48±3.99% and our actual mortality was 8.16%. At a concomitant period, from October 2008 to July 2009, Lisboa et al.[22] demonstrated inadequate calibration of EuroSCORE II at InCOR-FMUSP, and found better calibration of additive and logistic EuroSCORE and InsCor, a locally developed risk model. Indeed, the poorly calibrated EuroSCORE II to predict mortality in the group of patients evaluated reinforces the need for implementation, and widespread use of a Brazilian risk model. In-hospital mortality for redo operations is considered higher than first operations[8,17], with 2.87 odds ratio (95% CI 2.03 – 4.05)[23]. However, interestingly we noted similar in-hospital mortality rates between redo’s and first surgeries, 7.40% and 8.40%, respectively. In a previous historical cohort at the same institution, Brandão et al.[17] found 8.7% mortality for cardiac reoperations. The reasons for improvement are not enterily clear, but the technique standardization by Pomerantzeff et al.[16] led to progressive improvement of outcomes as well as training of a specific team, which was responsible for over 95% of the redo operations at the institution. In agreement with the literature[8,17,23,24], our series showed mortality rates increasing according to the functional status. Associated procedures also showed higher mortality rates, but without statistical significance. Age group and anatomic prosthetic position are the main determinant factors of calcific bioprosthesis dysfunction, with greater longevity found in the elderly with aortic prosthesis[25]. However, rising numbers of bioprosthesis implantation in younger patients, due to contra indications of oral anticoagulation or the impossibility of adequately controlling anticoagulation, have given rise to a concern about degeneration resistance of biologic prosthesis in younger patients. To ilustrate, the only case of structural dysfunction of the cohort occurred 37 months after implantation, in a 44-year-old patient, who did not receive a mechanical prosthesis because his social condition precluded adequate anticoagulation control. We found freedom from structural dysfunction of 98.57±0.70% at 5 years, comparable to the Carpentier-Edwards prosthesis[21] at 98±0.2% and superior to the St Jude Biocor[15] at 89.2±3.5%, and a linearized rate of 0.075% patients-year. Using Braile Biomédica® prosthesis, we found freedom from infective endocarditis at 5 years of 89.85±2.94%, while Carpentier-Edwards prosthesis[21] was 98±0.3%, the difference

is partially due to the economic and social differences between the health care systems where both prostheses were analyzed (Brazil and Canada). The present study has as limitations the retrospective cohort of a single center, with a limited number of cases and insufficient power to rare events. CONCLUSION Braile Biomédica® bovine pericardial prosthesis in aortic position led to similar durability and survival to that reported in the international literature. Further follow-up is required to evaluate future incidence of infective endocarditis and structural dysfunction. Authors’ roles & responsibilities LGA ETV JADS CMAB PMAP FBJ

Analysis and/or interpretation of data, statistical analysis, study conception and design, drafting of the manuscript and critical review of the content Analysis and/or interpretation of data Analysis and/or interpretation of data Analysis and/or interpretation of data, statistical analysis, study conception and design, drafting of the manuscript and critical review of the content Analysis and/or interpretation of data, final approval of the manuscript, study conception and design, drafting of the manuscript and critical review of the content Final approval of the manuscript

REFERENCES 1. Ionescu MI, Pakrashi BC, Holden MP, Mary DA, Wooler GH. Results of aortic valve replacement with frame-supported fascia lata and pericardial grafts. J Thorac Cardiovasc Surg. 1972;64(3):340-53. 2. Braile DM, Ardito RV, Greco OT, Lorga AM. IMC bovine pericardial valve: 11 years. J Cardiac Surg. 1991;6(4 Suppl):580-8. 3. Cosgrove DM, Lytle BW, Taylor PC, Camacho MT, Stewart RW, McCarthy PM, et al. The Carpentier-Edwards pericardial aortic valve. Ten-year results. J Thorac Cardiovasc Surg. 1995;110(3):651-62. 4. Almeida AS, Picon PD, Wender OCB. Resultados de pacientes submetidos à cirurgia de substituição valvar aórtica usando próteses mecânicas ou biológicas. Rev Bras Cir Cardiovasc. 2011;26(3):326-37. 5. Rahimtoola SH. The year in valvular heart disease. J Am Coll Cardiol. 2010;55(16):1729-42.

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6. Pomerantzeff PM, Zerbini EJ, Verginelli G, Jatene AD. Valve replacement in the Heart Institute, University of Sao Paulo, Brazil. Ann Thorac Surg. 1989;48(3 Suppl):S41-4.

Tarasoutchi F, Grinberg M, et al. Reoperações valvares: experiência do InCor-FMUSP. Rev Bras Cir Cardiovasc. 1991;6(3):182-9.

7. Pomerantzeff PM, Brandao CM, Cauduro P, Puig LB, Grinberg M, Tarasoutchi F, et al. Fisics-Incor bovine pericardial bioprostheses: 15 year results. Heart Surg Forum. 1998;1(2):130-5.

17. Brandão CMA, Pomerantzeff PMA, Souza LR, Tarasoutchi F, Grimberg M, Oliveira SA. Fatores de risco para mortalidade hospitalar nas reoperações valvares. Rev Bras Cir Cardiovasc. 2002;17(3):236-41.

8. Nashef SA, Roques F, Sharples LD, Nilsson J, Smith C, Goldstone AR, Lockowandt U. EuroSCORE II. Eur J Cardiothorac Surg. 2012;41(4):734-44.

18. Altintas G, Diken AI, Hanedan O, Yurdakok O, Ozyalcin S, Kucuker SA, Ozatik MA. The Sorin Freedom SOLO stentless tissue valve: early outcomes after aortic valve replacement. Tex Heart Inst J. 2013;40(1):50-5.

9. Akins CW, Miller DC, Turina MI, Kouchoukos NT, Blackstone EH, Grunkemeier GL, et al. Guidelines for reporting mortality and morbidity after cardiac valve interventions. Eur J Cardiothorac Surg. 2008;33(4):523-8.

19. Beholz S, Repossini A, Livi U, Schepens M, El Gabry M, Matschke K, et al. The Freedom SOLO valve for aortic valve replacement: clinical and hemodynamic results from a prospective multicenter trial. J Heart Valve Dis. 2010;19(1):115-23.

10. Gomes WJ. Qualidade das próteses valvares. Estamos tratando bem nossos pacientes no Sistema Único de Saúde? Rev Bras Cir Cardiovasc. 2011;26(3):VIII.

20. Braile DM, Monteiro R, Brandau R, Jatene FB. Risk prediction models: are they really necessary? Arq Bras Cardiol. 2010;95(6):677-8.

11. Braile DM, Leal JCF, Godoy MF, Braile MCV, Paula Neto A. Substituição valvar aórtica por bioprótese de pericárdio bovino: 12 anos de experiência. Rev Bras Cir Cardiovasc. 2003;18(3):217-20.

21. Forcillo J, Pellerin M, Perrault LP, Cartier R, Bouchard D, Demers P, Carrier M. Carpentier-Edwards pericardial valve in the aortic position: 25-years experience. Ann Thorac Surg. 2013;96(2):486-93.

12. Brick AV, Miana AA, Colen EA, Passos PHC, Borges Â, Jorge PC, et al. Seguimento de 9 anos da bioprótese valvular cardíaca de pericárdio bovino IMC-Biomédica: estudo multicêntrico. Rev Bras Cir Cardiovasc 1987;2(3):189-99.

22. Lisboa LA, Mejia OA, Moreira LF, Dallan LA, Pomerantzeff PM, Dallan LR, et al. EuroSCORE II and the importance of a local model, InsCor and the future SP-SCORE. Rev Bras Cir Cardiovasc. 2014;29(1):1-8.

13. Gomes WJ, Mendonça JT, Braile DM. Cardiovascular surgery outcomes opportunity to rediscuss medical and cardiological care in the Brazilian public health system. Rev Bras Cir Cardiovasc. 2007;22(4):III-VI.

23. Mejía OAV, Lisboa LAF, Puig LB, Moreira LFP, Dallan LAO, Pomerantzeff PMA, et al. InsCor: Um método simples e acurado para avaliação do risco em cirurgia cardíaca. Arq Bras Cardiol. 2013;100(3):246-54.

14. Farias FR, da Costa FD, Balbi Filho EM, Fornazari Dde F, Collatusso C, Ferreira AD, et al. Aortic valve replacement with the Cardioprotese Premium bovine pericardium bioprosthesis: four-year clinical results. Interact Cardiovasc Thorac Surg. 2012;15(2):229-34.

24. Rizzoli G, Bottio T, De Perini L, Scalia D, Thiene G, Casarotto D. Multivariate analysis of survival after malfunctioning biological and mechanical prosthesis replacement. Ann Thorac Surg. 1998;66(6 Suppl):S88-94.

15. Bacco FW, Sant’anna JRM, Sant’anna RT, Prates PR, Kalil RAK, Nesralla IA. St Jude Medical-Biocor bovine pericardial bioprosthesis: long-term survival. Rev Bras Cir Cardiovasc. 2005;20(4):423-31.

25. Banbury MK, Cosgrove DM 3rd, White JA, Blackstone EH, Frater RW, Okies JE. Age and valve size effect on the longterm durability of the Carpentier-Edwards aortic pericardial bioprosthesis. Ann Thorac Surg. 2001;72(3):753-7.

16. Pomerantzeff PMA, Yochitomi Y, Fabri HA, Cardoso LF,

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Miana LA, etORIGINAL al. - Pediatric and congenital heart transplant: twenty-year ARTICLE experience in a tertiary Brazilian Hospital

Pediatric and congenital heart transplant: twenty-year experience in a tertiary Brazilian Hospital Experiência de 20 anos com transplante cardíaco pediátrico e em portadores de cardiopatias congênitas

Leonardo Augusto Miana1, MD PhD; Estela Azeka2, MD PhD; Luiz Fernando Canêo2, MD PhD; Aída Luisa Turquetto2; Carla Tanamati2, MD PhD; Juliano Gomes Penha2, MD; Alexandre Cauduro2, MD; Marcelo Biscegli Jatene2, MD, MsC, PhD

DOI 10.5935/1678-9741.20140106

RBCCV 44205-1557

Abstract Introduction: Cardiac transplantation remains the gold standard for end-stage cardiomyopathies and congenital heart defects in pediatric patients. Objective: This study aims to report on 20 years of experience since the first case and evaluate our results. Methods: We conducted a retrospective analysis of the database and outpatient follow-up. Between October 1992 and April 2012, 109 patients underwent 114 transplants. 51.8% of them being female. The age of patients ranged from 12 days to 21 years with a mean of 8.8+5.7 years and a median of 5.2 years. The underlying diagnosis was dilated cardiomyopathy in 61.5%, congenital heart disease in 26.6% and restrictive cardiomyopathy in 11.9%. All patients above 17 years old had congenital heart disease. Results: Survival rate at 30 days, 1, 5, 10, 15, and 20 years were 90.4%, 81.3%, 70.9%, 60.5%, 44.4% and 26.7%, respectively. Mean cold ischemic time was 187.9 minutes and it did not correlate with mortality (P>0.05). Infectious complications and rejection episodes were the most common complications

(P<0.0001), occurring, respectively, in 66% and 57.4% of the survivors after 10 years. There was no incidence of graft vascular disease and lymphoproliferative disease at year one, but they affected, respectively, 7.4% and 11% of patients within 10 years. Conclusion: Twenty-year pediatric heart transplant results at our institution were quite satisfactory and complication rates were acceptable.

InCor-Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo HCFMUSP, São Paulo, SP, Brazil. INC. Faculdade de Medicina, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil. 2 InCor-Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo HCFMUSP, São Paulo, SP, Brazil.

Correspondence Address: Leonardo Augusto Miana Instituto do Coração da Faculdade de Medicina da Universidade de São Paulo Pediatric Cardiac Surgery Unit Av. Dr. Enéas de Carvalho Aguiar, 44, Bloco 2, 2° Andar, Cerqueira Cesar, São Paulo, SP, Brazil. Zip code: 05403-900 E-mail: leonardomiana@gmail.com

Descriptors: Heart Transplantation. Heart Defects, Congenital. Cardiomyopathies. Tissue Donors. Donor Selection. Graft Rejection. Cold Ischemia. Resumo Introdução: O transplante cardíaco tem sido o tratamento de escolha para pacientes pediátricos portadores de miocardiopatias e portadores de cardiopatias congênitas em fase final da doença. Objetivo: Relatar a experiência de 20 anos do serviço e avaliar seus resultados.

Work carried out at Institute do Coração(Heart Institute - InCor) of Hospital das Clínicas, University of São Paulo Medical School, São Paulo, Brazil. No financial support.

Article received on December 11th, 2013 Article accepted on July 10th, 2014

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de 90,4%, 81,3%, 70,9%, 60,5%, 44,4 e 26,7%, respectivamente. O tempo médio de isquemia do órgão transplantado foi de 187,9 minutos e não teve correlação com a mortalidade (P>0,05). Intercorrências infecciosas e rejeição foram as complicações mais incidentes (P<0,0001), atingindo 66 e 57,4% dos sobreviventes após 10 anos. A incidência de doença vascular do enxerto e doença linfoproliferativa foi zero no primeiro ano e atingiu, respectivamente, 7,4 e 11% dos pacientes em 10 anos. Conclusão: O Transplante Cardíaco neste grupo de pacientes pediátricos e portadores de cardiopatias congênitas pôde oferecer resultados satisfatórios, com uma taxa de complicações aceitável ao longo do seguimento.

Abbreviations, acronyms & symbols GVD HTx NYHA

Graft vascular disease Heart transplantation New York Heart Association

Métodos: Estudo retrospectivo por meio de análise do banco de dados. Entre outubro de 1992 e abril de 2012, 109 pacientes foram submetidos a 114 transplantes. 51,8% eram do sexo feminino. A idade dos pacientes variou de 12 dias a 21 anos, com média de 8,8+5,7 anos e mediana de 5,2 anos. O diagnóstico de base dos pacientes foi de miocardiopatia dilatada em 61,5%, cardiopatias congênitas em 26,6% e miocardiopatia restritiva em 11,9%. Todos os pacientes entre 17 e 21 anos eram portadores de cardiopatias congênitas. Resultados: A sobrevida em 30 dias, 1, 5, 10, 15 e 20 anos foi

Descritores: Transplante de Coração. Cardiopatias Congênitas. Cardiomiopatias. Doadores de Tecidos. Seleção do Doador. Rejeição de Enxerto. Isquemia Fria.

INTRODUCTION

METHODS

Despite recent advances in stem cells research and breakthroughs in the diagnosis and clinical management of heart failure (HF), heart transplantation (HTx) is still considered the best therapeutic strategy to increase survival and improve symptoms in end-stage HF patients[1]. In children, the occurrence of conventionally untreatable congenital heart disease and severe cardiomyopathy may be indications for this procedure. However, HTx in the pediatric population still faces greater difficulties than in adults due to greater scarcity of donors or technical difficulties imposed by some congenital malformations[2]. Recently, Jacobs et al.[2] reported their experience with just over 100 pediatric HTx and found that the presence of congenital heart disease did not increase mortality compared with cardiomyopathies. However, heterotaxy and reoperations in patients with congenital heart disease, decrease the chances of survival. In Brazil, the first HTx in a newborn was performed at our institution in November 1992[3]. In April 2012, our team of Pediatric and Congenital Heart Surgery held its hundredth HTx, consolidating its position as the largest and most active center outside Europe and North America[4]. We have several publications in this area, from 1996, when we published our initial experience[3,5-8], to our two most recent studies, one addressing the results of HTx in patients with cardiogenic shock[9] and another in patients with rejection and cyclosporine intolerance[10]. At the moment, a reflection on these 20 years of experience is important for the cardiology and cardiac surgery communities, especially in Brazil, to show our current status and which aspects are in need to more attention and improvement.

This study was conducted hrough retrospective analysis of our database after approval by the Ethics in Research Committee of our institution. Regarding infections, the database of the Committee on Infection Control was used. Patients Between October 1992 and April 2012, 109 pediatric and congenital heart patients underwent 114 HTx, with five re-transplants. The age of patients ranged from 12 days to 21 years (mean=8.8±5.7 years, median 5.2 years). Among the 109 patients, 11 were between zero and one year of life (10.1%), 71 were between one and 10 years-old (65.1%), and 27 were older than 10 at the time of operation (24.8%). Two patients above 17 years old with congenital heart disease were included in this sample. The distribution of patients according to age and diagnosis is shown in Figure 1. Primary diagnosis varied from cardiomyopathy in 80 patients (73.4%) and congenital heart disease in 29 (26.6%). Among those with congenital heart disease, 10 patients had single-ventricle physiology (Table 1), 23 (79.3%) had undergone to previous surgery prior to HTx hospitalization, one (3.5%) patient with Ebstein’s anomaly had undergone surgical correction and developed acute ventricular dysfunction being subjected to urgent HTx after circulatory support. Five had not been submitted to any previous surgical procedure (17.2%). Donor age ranged from 8 months to 52 years (mean = 13.8+10.5 years, median=11 years). The average weight of donors was 39.8±23 kg, while recipient mean body weight was 20±13.9 kg. The average weight mismatch between donor and recipient was 2.1±0.7. Gender distribution was mostly homogeneous (51.8% female). The number of HTx per year ranged between 1 and 18 procedures (average=6 HTx/per year). There has been an upward trend in the number of cases in recent years. Follow-up was conducted through personal contact during out-patient consultations and/or consultation using the electronic medical record or phone calls.

Objective This study aims to report our experience and evaluate our results.

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Fig. 1 - Age distribution between congenital heart disease and cardiomyopathy.

superior vena cava using a graft or the donor innominate vein itself. Myocardial protection was achieved by using cold crystalloid antegrade Roe’s solution[11], at the time of organ harvesting. This formula has been used since the first procedure in 1992 until the present day. When the predicted ischemic time was longer than three hours, it was decided to repeat cardioplegia before beginning the anastomosis.

Table 1. Diagnosis and previous surgical approach in patients with congenital heart disease. Diagnosis

Previous surgical approach AV block + pacemaker yes DORV yes Ebstein’s anomaly yes HLHS no PA IVS yes TA yes Single ventricle yes CCTGA yes VSD yes Uhl’s Anomaly no Mitral insufficiency + AV block yes Truncus arteriosus yes Tetralogy of Fallot yes ASD + restrictive cardiomyopathy no TGA + Senning yes IAS aneurysm and mitral valve prolapse no Total

N 4 4 3 2 2 2 2 2 1 1 1 1 1 1 1 1 29

Immunosuppression protocol The immunosuppression protocol for patients who have negative prospective crossmatch is based on continuous infusion of perioperative cyclosporine (infusion starts 6 hours before implant), corticosteroids associated with human immunoglobulin and rabbit antithymocyte globulin. For those with positive prospective crossmatch, plasmapheresis was also performed, 5 sessions on alternate days, in addition to other cytolytic and immunosuppressive drugs and the immunomodulators already mentioned[12]. Statistical analysis Descriptive data were presented in mean ± standard deviation. To evaluate the survival of pediatric heart transplant in 20 years the actuarial survival Kaplan Meier method was used. To assess the impact of diagnosis and age on survival, the Cox proportional regression was used. The statistical software program used was the Statistical Package for Social Sciences for Windows, v. 11.5 (SPSS Inc, Chicago, IL). It was adopted as significant a P-value of less than 0.05.

Surgical technique The surgical technique employed involved bicaval and aortic cannulation for extracorporeal circulation with moderate hypothermia (30oC). Bicaval anastomosis was performed in most cases. When hypoplastic left heart was present, innominate artery cannulation was performed and periods of deep hypothermic selective cerebral perfusion for aortic arch reconstruction were used. When there was previous surgery involving the pulmonary arteries (PA’s), as in Glenn or Fontan operations, it was necessary to carry out reconstruction of the PA’s through different techniques. The presence of persistent left superior vena cava demanded that it be connected with the right

RESULTS Survival The 30-day survival was 90.4%. Survival at one, five, ten, fifteen and twenty years was 81.3%, 70.9%, 60.5%, 44.4% and

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26.7%, respectively (Figure 2). Mean follow-up was 8 years. Median survival of patients after HTx was 11.07 years (9.33 to 12.8, CI 95%) and the median was 11.57 years (7.72 to 15.42, CI 95%). The Cox proportional regression analysis of the impact of age on survival revealed no statistical significance (P=0.198). In the same manner, the diagnosis of congenital heart disease was not a predictor of poor survival during follow-up (P=0.126). Survival curves of patients with congenital heart disease and cardiomyopathies are shown in Figure 3.

disease in the first two years after HTx. However, after 15 years of follow up, there was an incidence of 7.4% and 20.2%, respectively. Of the patients affected by GVD, two of them underwent stent implantation in the affected coronary artery. One showed good results; however, coronary artery bypass grafting was indicated in the second case due to persistent myocardial ischemia. Another two of the GVD patients underwent re-transplantation and the other two are currently listed. Lymphoproliferative disease affected eight patients over the 20-year follow-up. Three had pulmonary lesions, two had abdominal location, and three had polyadenopathy. Four patients (50%) died, and the deaths of two of them were related to lymphoproliferative disease. The remaining four patients had disease regression and show good progress. Figure 4 shows the curves of incidence of major complications. Five patients had undergone re-transplantation, two due to GVD and three because of graft rejection.

Complications Infectious complications and rejection episodes were the most common complications during follow-up. We observed an average of three rejection episodes per patient over the 20 years of follow-up. As it can be seen in Figure 4, after 20 years of follow-up, almost all patients had at least one episode of infection and/or rejection. There was a statistically significant difference (P<0.0001) compared to the incidence of other complications, such as graft vascular disease (GVD) and lymphoproliferative disease. There was no occurrence of GVD and lymphoproliferative

Causes of death The causes of mortality varied over time and data are detailed in Table 2.

Fig. 2 - Actuarial Survival graph including all patients submitted to heart transplant. 30-day survival=90.5%; 1 year=81.3%; 5 years=70.9%; 10 years=60.5%; 15 years=44.4%; 20 years=26.7%; patients at risk: time zero=109, 30 days= 97, 1 year=77, 5 years=44, 10 years=19, 15 years=9, 20 years=4

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Fig. 3 - Comparative graph between survival with Congenital Heart and Cardiomyopathy after Heart Transplant. P=0.13 with Cox proportional regression analysis.

Fig. 4 - Graph illustrating incidence of complications during Heart Transplant follow-up. GVD= Graft Vascular Disease; n= number of patients at risk P>0.05 when comparing infection versus rejection; P<0.0001 when compared Infection versus GVD;Â P<0.0001 when comparing infection versus Lymphoproliferative Disease; P<0.0001 when comparing rejection versus GVD; P<0.0001 when comparing rejection versus Lymphoproliferative Disease; P>0.05 when comparing GVD versus Lymphoproliferative Disease

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Table 2. Causes of death according to the time of HTx follow-up. Time of Follow-up

MODS (%)

Rejection (%)

Infection (%)

Sudden Death (%)

GVD (%)

0-30 d 30 d-1 y 1 y -5 y 5y-10 y >10 y Total (%)

1(16.6) 4(66.8) 1(16.6) 6(15)

6(60) 3(30) 1(10) 10(25)

1(10) 5(50) 1(10) 1(10) 2(20) 10(25)

1(16.7) 2(33.3) 3(50)

1(33.4) 2(66.6) 3(7.5)

6(15)

Lynphoproliferative Disease (%) 1(50) 1(50) 2(5)

Primary Graft Disfunction (%) 2(100)

PTE (%)

1(100) 2(5)

1(2.5)

d=days; y=years; MOD=Multiple organ disfunction; GVD=graft vascular disease; PTE=pulmonary thromboembolism

Cold ischemic time Mean organ’s cold ischemic time was 187.9+72.3 minutes. Cold ischemic time was less than 60 minutes in 10 cases (8.8%), between 61 and 120 minutes in 31.6% of the cases (36 cases), 121 to 180 minutes in 25.4% (29 patients), 181 to 240 minutes in 17 (14.9%), 241 to 300 minutes in 16 cases (14%) and above 301 minutes in 5.3% of cases (6 HTx). However, in this study, the ischemic time had no direct correlation with mortality (P=0.23).

enormous contributions of Bailey et al.[13] who transplanted a baboon heart in small Fae, stricken with hypoplastic left heart syndrome, who later became known worldwide as baby Fae. Extracorporeal circulation and myocardial protection Despite the constant development of cardiovascular surgery, few changes have occurred in our protocol over the twenty years. Myocardial protection remains identical and has been working well, since we observed less than 2% of deaths related to primary graft dysfunction, despite an often extended cold ischemic time. Extracorporeal circulation has evolved considerably in the interim, accompanied by HTx, with the incorporation of monitoring line pressures and association of modified ultrafiltration for patients below 30 kg. The protocol of moderate hypothermia has been kept.

Geographical origin of receivers and donors The geographical origin of receptors in Brazil was very diverse, covering 18 states and the Federal District. Nevertheless, the uptake of organs occurred almost entirely in the state of São Paulo, with 93% of the cases. The rest (7%) of the donors were located in other states, namely: Santa Catarina, Rio de Janeiro, Minas Gerais, Goiás, and the Federal District. There was an offer of 621 organs in these 20 years, 68% from individuals aged 16-20 years (422 donors), 17% aged 11-15 years (106 donors), 8% aged 6-11 years (50 donors), and 7% aged 0-5 years (43 donors). However, most potential donors were rejected due to weight mismatch or hemodynamic instability.

Cold ischemic time In our series, cold ischemic time was on average three hours and it did not correlate with mortality. The influence of ischemic time in post-HTx mortality finds considerable controversy in the literature. While some authors corroborate our findings[14], others believe that ischemic time is an independent predictor of mortality after HTx[2]. Even with our policy of preference for uptake within the state itself (93% of the time), in 19% of the cases, the ischemic time was longer than 4 hours. Longer ischemic times were caused mostly by logistical problems in transportation, since it is a big state and mobility some times may be difficult, and technical difficulties related to the implant, such as in re-operations and anatomical challenges related to congenital hearts, with the need to reconstruct the venous drainage and/or the pulmonary arteries.

Circulatory support The use of circulatory support in this series was observed in only three patients in whom extracorporeal membrane oxygenation (ECMO) was used. These patients were in severe cardiogenic shock. Hospital discharge was possible for one of them after transplantation. Multiple organ failure was the cause of death of the other two. DISCUSSION

Re-transplantation A recent North American study in pediatric HTx with more than 4000 cases attributed increased mortality to re-transplantation[15], although Jacobs et al.[2] and Kanter et al.[14] have shown to be possible to obtain results superimposed to the first intervention. We had a low incidence of re-transplantation (4.4%); however, the survival of these

The first pediatric heart transplant was performed in Brazil more than 20 years ago, and it was only possible thanks to a two-year preparation based in Loma Linda protocols. This preparation was made through an important expertise transfer, accompanied by visits from our team to the Californian hospital. Loma Linda was the birthplace of pediatric HTx, since the

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patients did not differ from patients undergoing primary Tx, corroborating these authors[2,12].

to control infection in these immuno-compromised patients need to be more efficient as they may have a positive impact on survival. In this series of patients, infections were responsible for 25% of mortality.

Circulatory Support The outcome of patients not listed as priority in our institution was similar to that reported recently by North American researchers, who analyzed the outcome of pediatric patients listed for HTx[15]. However, our mortality rate in the priority list was high, as we already demonstrated in 2008, when we studied patients with cardiogenic shock[9]. This is due to the obvious severity of the disease and donor shortage for pediatric patients, especially, when HTx needs to be performed on an emergency basis. The use of circulatory support could help reduce mortality in this setting[2,16,17]. In this series, ECMO was used in three cases and only one was discharged after transplantation. In view of this, our institution has been working vigorously to increase circulatory support results and usage. Another approach to improve the supply of organs is pediatric HTx in ABO incompatibility system, which has already been successfully performed in patients under one year, with results similar to the ABO compatible HTx[2,18]. It is known that the indication for circulatory support as bridge to transplantation in the pediatric population has been increasing and reached a quarter of cases currently on the ISHLT report[19].

Graft vascular disease In this series, the incidence of this complication was 7.4% in 10 years of follow-up. The increase in BNP, in addition to its already known relationship with rejection, seems to be associated with the occurrence of GVD[7]. In our department, we have made aggressive attempts to perform coronary angiography and/or coronary angiotomography to have and early diagnosis. Lymphoproliferative disease The occurrence of lymphoproliferative disease, especially in children, may be related to soroconversion of the Epstein-Barr virus post-HTx. However, the exact incidence of this disease is unknown, ranging from 2 to 20%[8]. Our treatment protocol consists in the reduction of the immunosuppressive therapy and, in selected cases, the use of monoclonal anti-CD 20 antibody (rituximab). This complication can be lethal. In eight patients in our study, mortality was 25%, with all of those deaths being directly related to the complication. Survival As far as the known severity and complexity of these patients, data show that we can expect satisfactory results in the medium and long-term follow-up of children who are submitted to HTx in our institution. Most studies show that despite a higher immediate mortality, the survival of patients below one year is better[2,19]. This did not occur in our series, in which survival did not vary with age. We attribute this to the small number of infants (11 cases). The 30-day mortality in our center was satisfactory and comparable to that reported recently by North-American researchers[2]. Most importantly, that study reported a high incidence of hypoplastic left heart, unlike our experience. In our hospital, it was possible to transplant only two HLHS patients. Late survival at 15 years is around 50% in international records. Our data show a slightly lower survival rate (44.4%); however, with median survival around 11 years, close to the international results[19].

Immunosuppression and Rejection The immunosuppressive regimen has evolved over time, especially with the advent of monoclonal antibodies and plasmapheresis. However, our protocol basically consists of the use of calcineurin inhibitor and cytostatic. The initial calcineurin inhibitor is cyclosporine, and in patients with refractory or late rejection and adverse effects to cyclosporine, tacrolimus was used as salvage therapy. Rejection was responsible for 25% of deaths. The diagnosis of rejection is performed by clinical evaluation with noninvasive methods such as clinical symptoms of irritability, fatigue, heart failure, arrhythmias, electrocardiographic and echocardiographic changes. Gallium 67 scintigraphy and BNP (brain natriuretic peptide) have been useful in contributing to confirm the diagnosis[7]. The endomyocardial biopsy is the gold standard for diagnosis. At the beginning of the experiment, the protocol consisted of performing it only in cases refractory to treatment. More recently, the protocol has been more invasive and biopsy is routinely done in the first and second months of follow-up, and at the time of suspected rejection and/or control treatment.

CONCLUSION Our results reinforce the therapeutic success of heart transplantation for the treatment of these patients in our country.

Infection Our infection rate was significant with a predominance of bacterial infections and sepsis with pulmonary involvement, which reflects the findings in most services. However, policies

ACKNOWLEDGEMENTS The authors are very thankfull to Marisa Siqueira and P창mela Garcia for their collaboration during data collection.

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Aiello VD. Desordem linfoproliferativa pós-transplante em paciente pediátrico. Arq Bras Cardiol. 2006;87:108-11.

Authors’ roles & responsibilities LAM EA LFC ALT CT JGP AC MBJ

Data analysis, preparation of the manuscript and final approval Data collection and analysis and preparation of the manuscript Data collection and analysis Data collection and preparation of the manuscript Data collection and analysis Data collection and analysis Data collection and analysis Data analysis and preparation of the manuscript

9. Jatene MB, Miana LA, Pessoa AJ, Riso A, Azeka E, Tanamati C, et al. Transplante cardíaco pediátrico em vigência de choque cardiogênico refratário: análise crítica da viabilidade, aplicabilidade e resultados. Arq Bras Cardiol. 2008;90(5):360-4. 10. Branco KC, Azeka E, Trindade E, Galas FR, Hajjar LA, Benvenuti L, et al. The impact of tacrolimus as rescue therapy in children using a double immunosuppressive regimen after heart transplantation. Transplant Proc. 2012;44(8):2483-5. 11. Roe BB, Hutchinson JC, Fishman NH, Ullyot DJ, Smith DL. Myocardial protection with cold, ischemic, potassium-inducd cardioplegia. J Thorac Cardiovasc Surg. 1977;73(3):366-74. 12. Asante-Korang A, Jacobs JP, Ringewald J, Carapellucci J, Rosenberg K, McKenna D, et al. Management of children undergoing cardiac transplantation with high Panel Reactive Antibodies. Cardiol Young. 2011;21 Suppl 2:124-32.

REFERENCES 1. Kaushal S, Jacobs JP, Gossett JG, Steele A, Steele P, Davis CR, et al. Innovation in basic science: stem cells and their role in the treatment of paediatric cardiac failure--opportunities and challenges. Cardiol Young. 2009;19 Suppl 2:74-84.

13. Bailey LL. The evolution of infant heart transplantation. J Heart Lung Transplant. 2009;28(12):1241-5.

2. Jacobs JP, Asante-Korang A, O’Brien SM, Chai PJ, Dadlani GH, Rodriguez-Fazzi GL et al. Lessons learned from 119 consecutive cardiac transplants for pediatric and congenital heart disease. Ann Thorac Surg. 2011;91(4):1248-54.

14. Kanter KR, Vincent RN, Berg AM, Mahle WT, Forbess JM, Kirshbom PM. Cardiac retransplantation in children. Ann Thorac Surg. 2004;78(2):644-9. 15. Feingold B, Park SY, Comer DM, Moore CG, Webber SA, Bryce CL. Outcomes after listing with a requirement for a prospective crossmatch in pediatric heart transplantation. J Heart Lung Transplant. 2013;32(1):56-62.

3. Barbero-Marcial M, Azeka E, Camargo PR, Jatene MB, Riso AA, Auler Jr JOC, et al. Características do transplante cardíaco neonatal e infantil. Rev Bras Cir Cardiovasc. 1996;11(2): 60-6. 4. Hertz MI. The Registry of the International Society for Heart and Lung Transplantation. Introduction to the 2012 annual reports: new leadership, same vision. J Heart Lung Transplant. 2012;31(10):1045-51.

16. Urban M, Pirk J, Dorazilova Z, Netuka I. How does successful bridging with ventricular assist device affect cardiac transplantation outcome? Interact Cardiovasc Thorac Surg. 2011;13(4):405-9. 17. Morales DL, Almond CS, Jaquiss RD, Rosenthal DN, Naftel DC, Massicotte MP, et al. Bridging children of all sizes to cardiac transplantation: the initial multicenter North American experience with the Berlin Heart EXCOR ventricular assist device. J Heart Lung Transplant. 2011;30(1):1-8.

5. Azeka E, Barbero-Marcial M, Jatene M, Camargo PR, Auler JO, Atik E, et al. Heart transplantation in neonates and children. Intermediate-term results. Arq Bras Cardiol. 2000;74(3):197-208. 6. Azeka E, Marcial MB, Jatene M, Auler JO Jr, Ramires JA. Eight-year experience of pediatric heart transplantation: clinical outcome using non-invasive methods for the evaluation of acute rejection. Pediatr Transplant. 2002:6(3):208-13.

18. Saczkowskia R, Daceyb C, Bernier PL. Does ABO-incompatible and ABO-compatible neonatal heart transplant have equivalent survival? Interact Cardiovasc Thorac Surg. 2010;10(6):1026-33.

7. Sylos C, Azeka E, Kajita L, Benvenutti L, Strunz CC, Branco KC, et al. [B-type natriuretic peptide assessment in the diagnosis of rejection after pediatric heart transplant. Arq Bras Cardiol. 2009;92(3):215-26.

19. Dipchand AI, Kirk R, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, et al; International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation. Sixteenth Official Pediatric Heart Transplantation Report--2013; focus theme: age. J Heart Lung Transplant. 2013;32(10):979-88.

8. Fernandes PMP, Azeka E, Odoni V, Junqueira JJM, Bento GP,

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Dinkhuysen ORIGINAL JJ, et al. - Clinical evaluation of the Spiral Pump ® after ARTICLE improvements to the original project in patients submitted to cardiac surgeries with cardiopulmonary bypass

Clinical evaluation of the Spiral Pump® after improvements to the original project in patients submitted to cardiac surgeries with cardiopulmonary bypass Avaliação clínica da bomba espiral (Spiral Pump®) após aperfeiçoamentos introduzidos ao projeto original em pacientes submetidos a cirurgias cardíacas com circulação extracorpórea

Jarbas Jakson Dinkhuysen1, MD, PhD; Aron Jose Pazin de Andrade2, PhD; Juliana Leme2, MsC; Cibele Silva2; Claudia Sanches Medina2; Cristiane Célia Pereira2; José Francisco Biscegli2, PhD DOI 10.5935/1678-9741.20140095

RBCCV 44205-1558

Abstract Objective: The objective of this paper is to present the results from Spiral Pump clinical trial after design modifications performed at its previous project. This pump applies axial end centrifugal hydraulic effects for blood pumping during cardiopulmonary bypass for patients under cardiac surgery. Methods: This study was performed in 52 patients (51% males), between 20 to 80 (67±14.4) years old weighing 53 to 102 (71.7±12.6) kg, mostly under myocardial revascularization surgery (34.6%) and valvular surgery (32.8%). Besides the routine evaluation of the data observed in these cases, we monitored pump rotational speed, blood flow, cardiopulmonary bypass duration, urine free hemoglobin for blood cell trauma analysis (+ to 4+), lactate desidrogenase (UI/L), fibrinogen level (mg/dL) and platelet count (nº/mm3). Results: Besides maintaining appropriate blood pressure and metabolic parameters it was also observed that the Free Hemoglobin levels remained normal, with a slight increase after 90 minutes of cardiopulmonary bypass. The Lactate Dehydrogenase showed an increase, with medians varying

between 550-770 IU/L, whereas the decrease in Fibrinogen showed medians of 130-100 mg/dl. The number of platelets showed a slight decrease with the medians ranging from 240,000 to 200,000/mm3. No difficulty was observed during perfusion terminations, nor were there any immediate deaths, and all patients except one, were discharged in good condition. Conclusion: The Spiral Pump, as blood propeller during cardiopulmonary bypass, demonstrated to be reliable and safe, comprising in a good option as original and national product for this kind of application.

Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil and Instituto Dante Pazzanese de Cardiologia (IDPC), São Paulo, SP, Brazil. 2 Instituto Dante Pazzanese de Cardiologia (IDPC), São Paulo, SP, Brazil.

Correspondence adress: Jarbas Jakson Dinkhuysen R. Sampaio Viana, 75 - 2o Conjunto 209 – Paraíso, São Paulo, SP, Brazil. Zip code: 04004-000 E-mail: j.dinkhuysen@uol.com.br

Descriptors: Centrifugal Pumps. Axial Flow Pumps. Cardiopulmonary Bypass. Extracorporeal Circulation. Hemolysis. Resumo Objetivos: Apresentar resultados da aplicação da bomba espiral que emprega efeitos hidráulicos centrífugo e axial de bombeamento como elemento propulsor do circuito de circulação extracorpórea em pacientes submetidos a cirurgias cardíacas após modificações introduzidas no design do projeto original.

This study was carried out in Divisões de Bioengenharia e de Cirurgia Cardiovascular do Instituto Dante Pazzanese de Cardiologia (IDPC), São Paulo, SP, Brazil.

Article received on October 2nd, 2013 Article accepted on July 24th, 2014

No financial support.

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pressóricos e metabólicos adequados. Quanto aos marcadores de danos à crase sanguínea, as alterações estiveram proporcionais ao tempo maior de circulação extracorpórea. Os níveis de Hemoglobina Livre permaneceram com valores normais, com ligeiro aumento a partir dos 90 minutos de circulação extracorpórea. A Desidrogenase Láctica mostrou aumento, variando as medianas entre 550 a 770 UI/L enquanto o Fibrinogênio mostrou queda das medianas de 130 a 100 mg/ dl. O número de plaquetas mostrou ligeira queda das medianas variando entre 240.000 a 200.000/mm3. Não ocorreram dificuldades de saída de perfusão, não se observou óbito imediato e todos os pacientes, exceto 1, obtiveram alta hospitalar. Conclusão: A bomba espiral aplicada como bomba propulsora de sangue durante cirurgia cardíaca se mostrou confiável e segura, não causou impacto traumático à crase sanguínea importante e se constitui opção como dispositivo original, concebido em nosso meio.

Abbreviations, acronyms & symbols ACT SMR CPB ETO IDPC LD MAP SP

Activated Coagulation Time Surgical Myocardial Revascularization cardiopulmonary bypass Ethylene oxide Institute Dante Pazzanese of Cardiology Lactate Dehydrogenase Medial arterial pressure Spiral Pump

Métodos: O estudo foi realizado em 52 pacientes (51% masculinos), com idade entre 20 a 80 (67±14,4) anos, peso 53 a 102 (71,7±12,6) kg, submetidos na maioria a cirurgia de revascularização miocárdica (34,6%) e Orovalvar (32,8%). Além das avaliações rotineiras, foram registrados rotação, tempo de CEC e para análise do impacto traumático à crase sanguínea, hemoglobina livre na urina (+ a 4+), desidrogenase láctica, fibrinogênio (mg/dL) e contagem de plaquetas (nº/mm3). Resultados: Observou-se a manutenção de parâmetros

Descritores: Bombas Centrífugas. Bombas de Fluxo Axial. Ponte Cardiopulmonar. Circulação Extracorpórea. Hemólise.

INTRODUCTION

experiment protocol, number 2010/003, approved by the IDPC’s Ethics Committee for Animal Usage, and with those new results, SP was able to undergo to a new clinic evaluation phase. For this phase, new devices were assembled inside controlled environment, according to ISO 14644, ISO 8 and ISO 13485, and sterilized by ethylene oxide (ETO)[9]. As the original prototype (Figure 1A), this new model uses centrifugal and axial forces simultaneously as hydraulic principles, improving its hydrodynamic performance without increasing blood damage. This pump has in its interior a spiral conic rotor to generate pumping pressures. Axial pumping effect is produced due to double entrance threads at impeller surface, and centrifugal pumping effect occurs because of impeller conical shape. At the top of the housing, there is the inlet port and, at the bottom, the outlet port, both with 3/8-inch connections (Figure 1B). Housing base consists of a plastic disc with one stainless steel shaft that holds all internal pump components. Housing base provides total isolation between pump inside and outside. Motor torque is transmitted to spiral impeller by magnetic coupling, using two annular magnets, one inside the impeller and another fixed to the shaft of the driver motor. Preliminary studies have shown that changes in rotor design caused important changes in device performance and positive impact was noted during hemolysis tests due to the new conical shape and new rotor design, as well as making lower the pump outlet port (Figures 2 and 3)[6,7]. Previous studies, conducted in 1998, showed that the original pump performance was 3000 rpm under a pressure of 350 mmHg, and under similar pumping flow as the reference model Biopump® (BPX80, Medtronic, USA). However, it was around 2500 rpm for the same pressure with the new SP model[5,7].

The Division of Bioengineering from Instituto Dante Pazzanese de Cardiologia (IDPC) started in 1992 a research aiming to develop a blood pump for cardiopulmonary bypass (CPB), called Spiral Pump® (SP). The SP was idealized as a device to drive blood minimizing damage to blood cells during CPB[1-3], and also, providing lower cost by being produced in Brazil protected by a Patent of Invention number PI 91,022,215 from the National Institute of Industrial Property. SP uses two hydraulic pumping principles simultaneously, centrifugal and axial, provided by conically shaped rotor with threads on its surface, increasing the hydrodynamic pumping performance without increasing rates of blood cell damage such as hemolysis[4]. Between 1994 and 1999, a pilot number of devices was produced, for in vivo tests (sheep), based on an experimental protocol, approved by IDPC’s Experimental Research Ethics Committee. SP was used as a pumping device for CPB. From 1999 to 2002, clinical evaluations were performed on 43 patients during cardiac surgery with CPB[5]. After approved in clinical evaluations, the device was registered at the National Health Surveillance Agency (ANVISA) under number 10264470020. In 2007, the development of a new rotor design had started, using two entrances at the threads of the spiral impeller pumps and also, modifying the device external base, aiming to have same coupling system as other devices, allowing its use routinely in cardiac surgeries. During this improvement process, many additional in vitro and in vivo tests were performed[5-9]. A new in vivo tests were performed according to a new

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Fig. 1A - Original prototype, developed in 1992 and 1B - The new model, developed in 2007, with two thread entrances and with the modified device's external base[5,6]. Entrada=Intelet port; Cone externo=Outer spire; Fuso=Rotor; SaĂda=Outlet port; Base externa do cone=Housing base

Fig. 2A - First model and 2B - Rotor final model

Fig. 3A - Housing initial model and 3B - Housing final model with change in output port position.

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Objectives This work aims to conduct clinical evaluation with Spiral Pump (SP) during cardiopulmonary bypass (CPB), as an impeller blood pump for patients under cardiac surgery.

and, from the right atrium, with single cannula or selective of higher and lower cava to drain venous blood toward the membrane oxygenator reservoir to CO2/O2 exchange. After CPB initiation and stabilization of metabolic and perfusion parameters with esophageal temperature around 32ºC, pulmonary ventilation was stopped and the perfusionist, every 5 minutes, took balance notes from MAP, CVP, diuresis, temperature, flow and occasional events. As usual, at the beginning, middle and end of the procedure, samples for laboratory tests were collected (blood gases, A/V, K+, Na+, hematocrit, glucose) that were used as standard for possible therapeutic interventions during the procedure. The anticoagulation control during CPB were performed by measuring Activated Coagulation Time (ACT) in an activated coagulation monitor MCA2000 (Adib Jatene Foundation, Sao Paulo, Brazil), trying to keep it above 500 seconds. At the end of CPB, reversion of heparin was performed with protamine sulfate, as previously established standard. Completing the surgical procedure, the patient was taken to Postoperative Recovery Unit under mechanical ventilation, ECG monitoring and MAP, diuresis and temperature controls. In order to evaluate the interactions between SP and blood, specific investigated parameters in this study were: LDH (U/L), fibrinogen (g/L), platelet count (no/mm3), ACT (seconds) and the urinalysis tape in pre CPB (5 minutes before), every 15 minutes during the procedure and after CPB (5 minutes after infusion) in all patients in the operating room before being referred to the Postoperative Recovery Unit. For subsequent evaluation, ACT was determined for the period that preceded the CPB, during (30, 60, 90 and 120 minutes) and after anticoagulation reversing at the end of the procedure. All patients have been previously contacted by researchers in the preoperative period, according to surgery schedule, and were told about the study objectives, risks and benefits, in accordance to Informed Consent Statement signed by each participant of the Clinical Evaluation Protocol, No. 4072 of April 5, 2011, approved by IDPC´s Research Ethics Committee.

METHODS Inclusion criteria: • Indication for cardiac surgery with CPB in most myocardial revascularization and orovalvular lesions; • With or without cardioplegia; • Age between 40 and 80 years; • Male and female; • Body weight between 55 and 120 kg. Exclusion criteria: • Cardiac surgery without CPB; • Abnormalities in laboratory tests (coagulogram); • Surgery for patients with underweight (<55 kg). Study was conducted in a group of 52 patients, 27 male (52%), age of 20-80 (67.0±14.4) years, weight of 53-102 (71.7±12.6) kg. Indications for surgery were: • Surgical Myocardial Revascularization (SMR) 19 (36.5%); • Orovalvar surgery 17 (32.6%), SMR + orovalvar 11 (21.1%); • Other 2 (3.8%); • Valvar + other 1 (1.9%); • Congenital + orovalvar 1 (1.9%); • Congenital 1 (1.9%). CPB circuit components were: SP, drive module (Bioconsole 550®, Medtronic, Minneapolis, USA), flowmeter (Bioprobe® TX50, Medtronic, Minneapolis, USA), CPB machine (Macchi, Sao Paulo, Brazil), tube kit with blood filter (Nipro Medical, Sorocaba, Brazil), Vital adult membrane oxygenator (Nipro Medical, Sorocaba, Brazil) (in 18 cases) and Quadrox adult oxygenator - Softlibe Coating and adult hemoconcentrator - HPH 1000 (Maquet, Germany) (in 34 cases). All clinical evaluation procedures were performed by the same surgeon, principal investigator, and two perfusionists to maintain reliable results. Routine procedures for cardiac surgeries were used, such as general anesthesia with endotracheal intubation for pulmonary ventilation, assessment of body temperature by an esophageal thermometer, assessment of average medial arterial pressure (MAP) by catheterization of peripheral arterial line and central venous pressure (CVP) by catheterization of central vein, urinary catheterization to evaluate urinary flow and heart rate monitoring with specific monitor. The exposure of the heart was performed by median thoracotomy and, after systemic heparinization (5 mg/kg), CPB was installed by the ascending aorta or femoral artery for oxygenated blood intake from the oxygenator, pumped by the SP,

Statistical analysis Describing patient samples, attendance and percentage were used for qualitative variables and average, standard deviation, median and interquartile range for quantitative variables. Two-tailed Fisher's exact tests were made for qualitative variables and Kruskal Wallis for quantitative ones. For the variables that have association (P<0,05) in the Kruskal Wallis tests, multiple comparisons were made (2 by 2 tests), through the non parametric Turkey method, to verify which groups are different between themselves. ANOVA non-parametric tests were also performed, with time being the only factor, with n greater than or equal to 5. Charts profiles were used with 95% confidence intervals for the averages.

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RESULTS

group and 20,000/mm3 for the 0 to >120 minutes group, denoting small traumatic impact to the blood. The values of lactic dehydrogenase (VN 305UI/L) in pre CPB ranged between 238-994 (427.6±134.5) and post CPB between 380-1954 (926.7±350.1) IU/L. Fibrinogen values (VN 200-400 mg/dl) before CPB ranged between 164.2 to 403.2 (267±56.4) and after CPB between 145.5 to 439.3 (215.3±48.1) mg/dl, and Platelet (VN 150000400000/mm3) showed before CPB between 103000-307000 (209.100±64.900/mm3) and after CPB between 66000233000 (146,000 ± 43,000/m3). Figure 5 shows the Box Plot analyzing the percentage of Lactate Dehydrogenase (Chart 1), fibrinogen (Chart 2) and Platelet Count (Chart 3) for three groups of patients, a CPB group from 0 to 60 minutes, a group from 0 to 120 minutes and a group with time above 120 minutes, observing the expected results for this procedure. There were no immediate deaths, observing ICU stay ranged from 1 to 4 (average 2.4) days. One patient remained 13 and another remained 44 days for presenting postoperative complications that required intensive controls, the patients in question were diabetic and smokers, complicating the postoperative period. One death occurred on the 1st postoperative day due to bleeding by clotting disorder. Patients were discharged from 3 to 14 (average 6.5) days and only one remained for longer due to postoperative complications and for being diabetic and smoker, and was discharged on the 61st postoperative day in good condition.

Time of CPB ranged from 30 to 240 (111.2±47.7) minutes in all cases and no problem was observed during perfusion outcome. There are 12 graphs in Figure 4 with observed parameters from device clinical evaluation. First graph shows rotational speed of SP during CPB, always related to weight (body surface area) for each patient, small variations between 2000 - 2500 rpm were observed. The flow provided by SP (second graph) shows oscillations from 3.7 to 3.3 L/min with a higher standard deviation at final moments during the procedure. Considering as appropriate the MAP value of 60 mmHg during CPB, we observed that the curve oscillates right below this level with higher standard deviation at final moments during the procedure (third graph), this fact has not caused any organic damage due to the lowering of esophageal temperature near 30°C, reducing the metabolic and perfusion requirements. Urinary volume generated during CPB varied around 150 ml at first moments, decreasing around 100 ml from 30 to 150 minutes (fourth graph). Related to laboratory data, we emphasize that all time scales of the following graphs ranged from pre CPB, 0-120 minutes and post CPB. The pH values ranged close to normal values of 7.45 (fifth graph), with larger oscillation after 75 minutes until the end of the procedure. The Sodium (Na) levels (sixth graph) ranged below 139 mg/L and increased after 90 minutes of perfusion, maintaining this level until the end of the procedure, so did the Potassium (K) levels (seventh graph). As expected, the hematocrit (Ht) showed significant decrease after perfusion initiation, this is due to hemodilution imposed by oxygenator priming, usually with saline solutions, and remained around 30% until 105 minutes, increasing at the end of the procedure (eighth graph), the same occurs to hemoglobin (Hb) values (ninth graph). Blood glucose (tenth graph) varied around 130 mg/L initially to levels near 200 mg/L at final moments of CPB and considering infusion of serum glycosylated during anesthesia. ACT analysis (eleventh graph) shows adequate levels of anticoagulation during procedure, ranging from 1500 to 1800 seconds. Finally, free hemoglobin analysis from urine, which represents the mechanical trauma impact to the blood (twelfth graph), shows levels close to 0 within 90 minutes, when we observed an increase of values from 0 to 1 with increased standard deviation, common fact observed at the end of CPB. Considering the values of lactic dehydrogenase, we observed an increase of the medians ranging between 500-770 IU/L (Figure 5 and Chart 1). The levels of fibrinogen showed a decrease of medians between 130-100 mg/dl (Figure 5 and Chart 2), both proportional to higher CPB time. Related to number of platelets (Figure 5 and Chart 3), the medians ranged between 240,000/m3 for the 0 to 60 minutes of CPB

DISCUSSION During the project development, the rapid prototyping process helped to make possible the construction and assembly of different SP models in a short period of time, moreover, allowed cost reduction in the manufacture of disposable product process, to avoid costly manufacturing of different plastic injection molds. Various changes were performed to hydrodynamically test the performance curves (pressure x flow), showing that, for each prototype, changes in pumping characteristics were made, until we reach the most efficient one, that has been selected for clinical use[4,5]. While developing the design of medical products, such as blood pumps for CPB, patients can be adversely affected by the use of devices that may cause high levels of plasma free hemoglobin, especially in the postoperative period. Therefore, the project is based on consistent in vitro and in vivo tests that can generate product with good acceptance and competitiveness for clinical application[6]. Structural characteristics of a blood pump are important in determining its hydrodynamic performance and blood trauma. Often, small structural changes cause large changes to the results, as shown in this work[6].

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Fig. 4 - Chart with observed parameters during procedures.

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Fig. 5 - Box Plot with observed parameters during procedures.

Currently, roller pumps are used in cardiac surgery and centrifugal pumps for severe cases. The roller pump is widely used due to low cost, easy usage and simplicity, its flow is linear with slight pulsatility, but generates high negative pressure when sucking blood to the CPB circuit, which can cause major blood damages[10]. Centrifugal pumps, mostly imported, have higher costs, so they are not often used. The development of a blood pump with national technology and low cost will enable more often usage in public and private hospitals. During CPB, the flow, provided by a centrifugal pump, depends on the motor rotational speed and on the pump output pressure that depends on the pressure drop of CPB circuit and on its after load. Thus, when the peripheral resistance of the patient increases, the blood pressure will increase also, causing decrease in the pump flow. This is a self-compensatory effect that does not happen in peristaltic roller pumps. Roller pumps provide a constant flow for a fixed rotation of the motor, in other words, independent of blood pressure. So, if an increase in peripheral resistance of the patient occurs, the blood pressure will rise too much, causing risks to the patient[11]. Compression of blood between collapsed structures, heating, friction during pumping, irregular surfaces, turbulent flows, the stagnation flow and the rapid pressure variations are among the main mechanisms of trauma in these devices. Hemolysis is always a reason for conducting research for development of blood pumps, it is impossible to avoid it completely, so maintaining close to normal values found in the literature is necessary[11]. Group under study consisted of adult patients undergoing cardiac surgery with conventional CPB and SP as blood pump. In the procedures, perfusions during heart surgery were followed from pre CPB to post CPB and, in this period,

the operating data of SP, such as rotational speed, blood flow, vibration and noise were controlled and were considered satisfactory according to standards for cardiac surgery. The flow data, comparing to the theoretical flow calculated for each patient, were within our expectations and attending the needs for perfusion during surgery, demonstrating that SP is suitable for perfusion of adult patients. Physiological and laboratory parameters such as diuresis, mean arterial pressure, temperature and blood gas data were recorded. The selected as hemolysis indicators were hemoglobin and hematocrit, which were satisfactory by means of comparison with normal and expected post-perfusion values found in the literature[11]. In the case of hemoglobin, analysis over time shows that this parameter tends to fall after the first fifteen minutes of perfusion, stabilizing below the reference value and returning to normal after the end of perfusion. The same occurs with the hematocrit, which, before CPB, presents mean values very close to normal minimum value, but still shows higher than expected during perfusion and after CPB. In most cases, there was no free hemoglobin (Hb) in urine and its presence in urine was seen only in cases over 115 minutes of perfusion. Specific parameters to this study, Lactate Dehydrogenase, Platelets and Fibrinogen, have its analysis performed according to pefusion time. We noted that time has a direct influence on the increase of LDH and decreased platelets and fibrinogen, these parameters are indicators of hemolysis. But the values found are still acceptable for the post CPB, which means that the pumping system was adequate without traumatic impact. It is important to say that hemolysis mechanically caused is not only a consequence from SP usage, but is a result of a whole perfusion system that includes the pump, arterial filter, oxygenator, hemoconcentrator and plastic tubes.

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Cardiac surgery techniques and perfusion time were varied and the SP performance showed suitable for all cases relating to easy rotation/flow adjustment by the perfusionist and noise or vibration absence. The results from this study demonstrate that the perfusion system with the usage of SP showed changes for indicative parameters within acceptable values and satisfactorily under the requirements for its application in cardiac surgery, being able to be applied safely.

4. Dinkhuysen JJ. Bomba Sanguínea Espiral: concepção, desenvolvimento e aplicação clínica de projeto original [Tese de Livre Docência]. São Paulo: Faculdade de Medicina da Universidade de São Paulo, 2005. 115p. 5. Dinkhuysen JJ, Andrade A, Manrique R, Saito CSM, Leme J, Biscegli JF. Bomba Sanguínea Espiral: concepção, desenvolvimento e aplicação clínica do projeto original. Rev Bras Cir Cardiovasc. 2007;22(2):224-34. 6. Leme J. Projeto, Desenvolvimento e Ensaios In Vitro de Novo Modelo de Bomba de Sangue para Circulação Extracorpórea – Bomba Espiral [Dissertação de Mestrado]. Campinas: Faculdade de Engenharia Mecânica, Universidade Estadual de Campinas, 2010. 93p.

Authors’ roles & responsibilities JJD Author AJPA Coauthor JL Coauthor CS Coauthor CSM Coauthor CCP Coauthor JFB Coauthor

7. Leme J, Fonseca J, Bock E, Silva C, Silva BU, Santos AE, et al. A New Model of Centifugal Blood Pump for Cardiopulmonary Bypass: Design Improvement, Performance, and Hemolysis Tests. Artif Organs. 2011;35(5):443-7. 8. Silva C. Ensaios “In Vivo” e Avaliação clínica de Bomba de sangue para circulação Extracorpórea durante cirurgia cardíaca: SPIRAL PUMP [Dissertação de mestrado]. Campinas: Faculdade de Engenharia Mecânica, Universidade Estadual de Campinas, 2013. 96p.

REFERENCES 1. Pego PMF, Miura F, Higa SS, Moreira LFP, Dallan LA, Chamone DAF, et al. Hemólise em circulação extracorpórea, estudo comparativo entre bomba de rolete e bomba centrífuga. Rev Bras Cir Cardiovasc. 1989;4(3):220-4.

9. Silva C, Silva BV, Leme J, Vebelhart B, Dinkhuysen J, Biscegli JF, et al. “In vivo” evaluation of Centrifugal blood pump for Cardiopulmonary bypass - Spiral Pump. Artif Organs. 2013,37(11):954-7.

2. Tamari Y, Lee-Sensiba K, Leonard EF, Parnel V, Tortolani AJ. The effects of pressure and flow on hemolysis caused by BIO-Medicus centrifugal pumps and roller pumps. J Thorac Cardiovasc Surg. 1993; 106(6):997-1007.

10. Vieira Junior FU, Vieira RW, Antunes N, Petrucci O, Oliveira PP, Serra MMP, et al. Análise do perfil hidrodinâmico em diferentes modelos de bombas de roletes utilizadas em CEC. Rev Bras Cir Cardiovasc. 2009;24(2):188-93.

3. Andrade AJP, Biscegli J, Dinkhuysen J, Sousa JE, Ohashi Y, Hemmings S, et al. Characteristics of Blood Pump Combining the Centrifugal and Axial Pumping Principles. Artif Organs. 1996;20(6):605-12.

11. Nose Y. Design and development strategy for the Rotary Blood Pump. Artif Organs. 1998;22(6):438-46.

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Juliani PS, et al. - IdiopathicARTICLE dilated cardiomyopathy: computerized anatomic ORIGINAL study of relashionship between septal and free left ventricle wall

Idiopathic dilated cardiomyopathy: computerized anatomic study of relashionship between septal and free left ventricle wall Cardiomiopatia dilatada idiopática: estudo anatômico computadorizado da relação entre o septo e a parede livre do ventrículo esquerdo

Paulo Sérgio Juliani1, PhD; Éder França da Costa2; Aristides Tadeu Correia1, MsC; Rosangela Monteiro1, MsC, PhD; Fabio Biscegli Jatene3, MD, MsC, PhD

DOI 10.5935/1678-9741.20140063

RBCCV 44205-1559

Abstract Introduction: A feature of dilated cardiomyopathy is the deformation of ventricular cavity, which contributes to systolic dysfunction. Few studies have evaluated this deformation bearing in mind ventricular regions and segments of the ventricle, which could reveal important details of the remodeling process, supporting a better understanding of its role in functional impairment and the development of new therapeutic strategies. Objective: To evaluate if, in basal, equatorial and apical regions, increased internal transverse perimeter of left ventricle in idiopathic dilated cardiomyopathy occurs proportionally between the septal and non-septal segment. Methods: We performed an anatomical study with 28 adult hearts from human cadavers. One group consisted of 18 hearts with idiopathic dilated cardiomyopathy and another group with 10 normal hearts. After lamination and left ventricle digital image capture, in three different regions (base, equator and apex), the transversal internal perimeter of left ventricle was divided into two segments: septal and not septal. These segments were measured

by proper software. It was established an index of proportionality between these segments, called septal and non-septal segment index. Then we determined whether this index was the same in both groups. Results: Among patients with normal hearts and idiopathic dilated cardiomyopathy, the index of proportionality between the two segments (septal and non-septal) showed no significant difference in the three regions analyzed. The comparison results of the indices NSS/SS among normal and enlarged hearts were respectively: in base 1.99 versus 1.86 (P=0.46), in equator 2.22 versus 2.18 (P=0.79) and in apex 2.96 versus 3.56 (P=0.11). Conclusion: In the idiopathic dilated cardiomyopathy, the transversal dilatation of left ventricular internal perimeter occurs proportionally between the segments corresponding to the septum and free wall at the basal, equatorial and apical regions of this chamber.

Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil. 2 Veterinary Physician, private office, Florianópolis, SC, Brazil. 3 Faculdade de Medicina da Universidade de São Paulo (FMUSP); Director of InCor-Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo HCFMUSP, São Paulo, SP, Brazil.

Correspondence Address: Paulo Sérgio Juliani Instituto do Coração (InCor) of Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo Av. Enéas Carvalho Aguiar, 44 - Cerqueira César, São Paulo, SP, Brazil Zip code: 05403-000 E-mail: psjuliani@usp.br

Descriptors: Ventricular Remodeling. Cardiomyopathy, Dilated. Heart Failure.

This study was carried out in the Insituto do Coração (InCor) of Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil.

Article received on October 11th , 2013 Article accepted on March 16th, 2014

Financial support: Fundação Zerbini.

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Objetivo: Verificar se, em regiões diferentes, o aumento do perímetro transversal da câmara ventricular esquerda na cardiomiopatia dilatada idiopática ocorre de maneira proporcional entre o segmento septal e o não septal (parede livre). Métodos: Foi realizado um estudo anatômico com 28 corações adultos. Um grupo foi constituído por 18 corações com cardiomiopatia dilatada idiopática e outro grupo com 10 corações normais. Em três regiões diferentes (base, equador e ápice), o perímetro interno transversal do ventrículo esquerdo foi dividido em dois segmentos: septal e não septal. Foi criado um índice de proporcionalidade entre esses segmentos. Em seguida verificou-se se esse índice era o mesmo entre os grupos. Resultados: Entre corações normais e portadores de cardiomiopatia dilatada idiopática, o índice de proporcionalidade entre os dois segmentos (septal e não septal) não apresentou diferença significativa nas três regiões analisadas. Conclusão: Na cardiomiopatia dilatada idiopática, a dilatação transversal do septo é proporcional à dilatação da parede livre nas regiões basal, equatorial e apical da câmara ventricular esquerda.

Abbreviations, acronyms & symbols Cm Centimeters DCM dilated cardiomyopathy Dist AV-AP Distance from atrioventricular sulcus to the left ventricular apex ISFC International Society and Federation of Cardiology LV Left ventricle NSS Non-septal segment SAVE Septal anterior ventricular exclusion SPSS Statistical Package for Social Sciences SS Septal segment WHO World Health Organization

Resumo Introdução: Uma das características da cardiomiopatia dilatada idiopática é a deformação da cavidade ventricular, a qual contribui para a disfunção sistólica. Poucos trabalhos julgam importante a avaliação dessa deformação ventricular levando em consideração regiões e segmentos do ventrículo, o que pode revelar detalhes importantes do processo de remodelamento, dando suporte a um melhor entendimento do seu papel no comprometimento funcional e ao surgimento de novas estratégias terapêuticas.

Descritores: Remodelação Ventricular. Cardiomiopatia Dilatada. Cardiomiopatias. Insuficiência Cardíaca.

INTRODUCTION

wall), in order to confirm the hypothesis that dilation occurs proportionally between these segments.

Dilated cardiomyopathy (DCM) is the most common among the primary diseases of the myocardium and is featured, in special, by dilation of one or both ventricles and systolic dysfunction[1]. This is a very interesting model inside a current context of major interest in studies that correlate shape and function of the cardiac pump. The geometrical alterations due to dilation observed in DCM can cause severe functional impairment[2]. Several authors have studied the effects of these alterations in the left ventricle and developed theories that could explain the reasons for this functional impact. Through exams such as magnetic resonance, for example, verified the influence of geometrical alteration, tending to sphericity, affecting the ventricular torsion during systole or even the ventricular relaxation globally decreasing the cardiac pump performance[2-5]. However, few studies have evaluated the ventricular chambers splitting them into segments, or observing the changes in size in different places inside the chambers, thus seeking for understanding the real complexity of the geometrical changes in the ill heart. These can give support to the deepening of studies about the influence of the geometrical deformation on cardiac performance as well as the development of more accurate techniques to provide a reverse remodeling[6-8]. In this context, the aim of this study is to evaluate if, in different regions, increased transverse perimeter of left ventricular chamber in idiopathic dilated cardiomyopathy occurs proportionally between the septal and non-septal segment (free

METHODS The selection of the anatomical specimens used and the analysis of results used the current classification system, proposed by the World Health Organization (WHO) and the International Society and Federation of Cardiology (ISFC)[9]. The Commissions of Science and Ethics from The Heart Institute (Instituto do Coração (InCor)) and Ethics for Research Projects Analysis (CAPPesq from the Hospital das Clínicas staff and Faculdade de Medicina da Universidade de São Paulo) approved the studies (protocols no. 2803/06/048 and 501/06, respectively). Materials Twenty-eight adult hearts (obtained from necropsy of normal individuals or patients with dilated cardiomyopathy) fixed in 10% formaldehyde were divided into 2 groups, based on their anatomopathological reports. The first group consisted on 18 hearts with idiopathic dilated cardiomyopathy (DCM), from which 13 (72.22%) were originated from male individuals. The hearts weight ranged from 358 to 942 grams, with an average of 595.44 grams. The age ranged from 26 to 64 years old, with an average of 42.44 years old. The exclusion criteria for DCM were: ischemic coronary disease and/or LV aneurisms, congenital heart abnormalities, valve abnormalities, myocardial infiltrative disease, previous heart surgery and the previous use of pacemaker or resynchronization therapy

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and/or circulatory assist devices. The second group called NORMAL consisted of 10 cardiomyopathy-free hearts, from which 9 (90%) originated from male individuals. The age ranged from 29 to 70 years old, with an average of 51.4 years old. The weight of those hearts ranged from 212 to 338 grams, with an average of 280.4 grams. The inclusion criteria for the NORMAL group were: non-related cardiopathy causa mortis, specimens without macroscopic alterations, particularly valvulopathies, weight up to 340 grams, age between 18 and 75 years old and anatomopathological report certifying normality.

- The equatorial dot at 50% the distance from the atrioventricular sulcus to the apex - The basal dot 20% far from the atrioventricular sulcus - The apical dot 80% far from the atrioventricular sulcus Over the established dots, the transversal section of specimens was proceeded using an electric knife and the following regions were obtained: BASAL, EQUATORIAL and APICAL. Digital image capture of transversal cuts The regions originated from the sections were placed on a plain surface of a table, with its basal cut facing upward (Figure 2). The table was equipped with a steel holder to fix a digital imaging device (“Sony Cybershot” model, 3.2 megapixels) to allow the digital image capture of specimens so that those pictures could be obtained from a capture plan precisely placed perpendicularly to the surface. Next to each specimen and as tall as its basal face a centimeter ruler was placed (to be used for calibration purposes on the measurement software). Each region was identified with a small paper tag placed next to it, containing its respective identification.

Longitudinal axis measurement and specimen slicing The longitudinal axis of the heart was measured as follows: with the aid of a millimeter ribbon, a line was drawn near the posterior interventricular sulcus, starting from the atrioventricular sulcus towards the apex. Over this line three dots were marked and used as an anatomic division of the left ventricle (Figure 1):

Computerized digital imaging measurement method With these digital images, the left ventricular chamber internal perimeter was measured using the software Image Tool for Windows, version 3.00, developed by The University of Texas Health Science Center, USA, disregarding the trabecular relief. The right ventricular chamber vertices were used as a reference to delimitate and measure (in cm) the segment related to the interventricular septum (septal segment – SS), considering the remaining as non-septal segment (NSS) (Figure 2). To analyze the proportionality between segments, the value obtained by the NSS measurement was divided by the SS value in each specimen, thus obtaining the NSS/SS ratio. The values were compared between both groups, corresponding to the ventricular region analyzed (basal, equatorial and apical).

Fig. 1 - Posterior view of a heart with schematic delimitation of dots for ventricular lamination. Basal dot (20%), equatorial dot (50%), apical dot (80%). DistAV-AP = distance from atrioventricular sulcus to the left ventricular apex

Fig. 2 - From left to right: cranial view, respectively, from equatorial, apical and basal regions of the left ventricle in dilated hearts. The blue line corresponds to the non-septal segment (NSS) and the red line to the septal segment (SS).

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Statistical analysis The descriptive analyses for the quantitative data with normal distribution were performed, showing the mean values along with their respective standard deviations. The condition for normal distribution in each group was evaluated with the Shapiro-Wilk test. The Student’s t-test was used to perform comparisons between NORMAL and DCM groups. A type-I error probability (α) of 0.05 was considered in every inferential analyses. The inferential and descriptive statistical analyses were performed by using the SPSS software, version 17 (SPSS 17.0 for Windows).

lent anatomical definition among tissues, it cannot be used in some situations, such as in patients with uncompensated heart failure who do not tolerate the apnea needed for the exam and others who would eventually suffer from claustrophobia, as well as arrhythmia carriers and in those who make use of brain metal implants, pacemaker or cardioversor – defibrillator[10,11]. Therefore, for the proposed evaluation, the anatomical method was chosen, as it still presents the best way to study the left ventricular geometry[2]. The trabecular relief exclusion during ventricular chamber perimeter measurement does not change significantly the values checked[7]. Ventricular Geometry The importance of the geometrical study and its impact on the heart functioning as a pump can be demonstrated by Laplace’s law (T=P.pR, where T=tension or ventricular muscle strength, P=intracavitary pressure, P=3.1416, R=chamber radius)[12]. It clarifies the interrelationship between the ventricle shape and the forces exerted on it. Several studies have pointed out the ventricular sphericity as the main cause of lower heart performance on DCM[3,4,13], bringing a simplistic view to the existing phenomena in this pathology. With the aim of searching a better detailing of this process, the choice was to analyze the left ventricle in segments rather than considering it a spatial geometric figure. It was shown previously that each segment presents distinct behavior during the ventricular remodeling process[7].

RESULTS The null hypothesis was test taking into consideration that the proportionality between NSS and SS in each LV slice region would be the same between both groups. The mean values for the variables measured in both groups, as well as the NSS/SS ratio are displayed in Table 1. The NSS/SS ratios calculated for the normal hearts were 2 for the base, 2.2 for the equator and 3 for the apex. Therefore in the base, equator and apex, the free wall is respectively 100%, 120% and 200% bigger than the septum. Likewise, the NSS/SS ratios calculated for the dilated hearts were 1.9 for the base, 2.2 for the equator and 3.6 for the apex. Thus, in the base, equator and apex, the free wall on dilated ones is respectively 90%, 120% and 260% bigger than the septum. In the statistical analysis comparing the NSS/SS ratios in the basal, equatorial and apical regions of both groups no significant difference was found (P=0.46, P=0.79 and P=0.11, respectively). Figure 3 represents this analysis. Figure 3 shows that in the comparison analysis of the NSS/ SS ratio mean values in the three ventricular regions between NORMAL and DCM no statistically significant differences were found (P>0.05). DISCUSSION Methodology In spite of the constant technological innovations that allow higher and higher accuracy of the structure and in situ cardiac function assessment a lot of factors still bring important limitations to these methodologies, as it occurs in the cine nuclear magnetic resonance imaging that, despite providing an excel-

Fig. 3 - Comparison of mean values of the NSS/SS ratios from basal, equatorial and apical regions of the left ventricular chamber in both groups

Table 1. Descriptive results (averages) for the variables measured (cm) in both groups, as well as the NSS/SS ratio of 3 regions analyzed. VE Non-Septal Segment (NSS)

Septal Segment (SS)

NSS / SS

Normal

Averages

Basal 3.4

Equatorial 3.5

Apical 2.2

Basal 6.5

Equatorial 7.5

Apical 6.1

B 2

E 2.2

A 3

DCM

Averages

2.7

12.9

6.9

1.9

2.2

3.6

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Possible applications The surgical strategies developed so far aiming at reestablishing a “physiological geometry” in the LV do not take enough into consideration this distinct segmental behavior of the left ventricle remodeling process. The first technique performed in non-ischemic cardiopathy, developed by Batista et al.[12] based on the perception of the clinical improvement in patients submitted to aneurysmectomies and cardiomyoplasties, took into consideration the total increase in the ventricular chamber, applying Laplace’s theory, and consisted of a muscle slice removal from the LV lateral wall. Other techniques that seek to provide the geometry restructuring (Dor, SAVE, Overlapping) reinforce that this logic is true. However, these once again derive from the usual understanding of such geometrical alteration behavior (the sphericity theory). Transoperative mortality, myocardial infarction risk and cardiomyopathy progression after these procedures were problems pointed out[14-17], a fact that perhaps has discouraged further studies. In the development of surgical strategies, besides the doubts about the LV dilation behavior throughout its longitudinal axis (basal, equatorial and apical regions) there are also those related to the proportion of the septal wall dilation versus non-septal or free wall. The understanding of the segmental geometrical alterations in DCM can help determine the prognostic and allow the application of early therapeutic measures, even in more accurate interventions that may cause directly a more anatomic remodeling of the left ventricular chamber[2,12,18]. In general, when establishing the surgical strategies to remodel the distorted LV in idiopathic DCM we should take into account the arrangement of the myocardial fibers[18,19] as well as the restoring or maintenance of proportion rates among regions (base, equator and apex)[7] and LV segments (septum and non-septal or free wall). We do not know how important the morphological relationship between the septum and non-septal or free wall is to LV performance. As this relationship is kept in DCM, we assume that the surgical strategies for LV geometry restoring in this disease might contemplate not only the normal anatomic relationship reestablishment among the perimeters of basal, equatorial and apical regions[7], but also the maintenance of the relationship between the septum and non-septal or free wall, that is, in the case of ventriculectomies, it could be supposed to be more cautious to exclude the proportional segments from the septum and free wall instead of just, as performed so far, taking out segments from the free wall or even septum or free wall disproportional segments. Therefore, it is clear that the understanding of the segmental geometrical alterations in DCM can help determine the prognosis and allow the application of early therapeutic measures, also in more accurate interventions that directly cause a more anatomic remodeling of the left ventricular chamber[2,12,18].

CONCLUSION In idiopathic dilated cardiomyopathy, the left ventricular chamber perimeter transversal dilation occurs proportionally between the segments corresponding to the septum and the free wall, in the basal, equatorial and apical regions of this chamber. Authors’ roles & responsibilities PSJ

EFC ATC RM FBJ

Analysis and/or interpretation of data, final approval of manuscript, conception and design of the study, conduct of operations and/or experiments, drafting of the manuscript and critical review of the content Analysis and/or interpretation of data, Final approval of manuscript, conception and design of the study, drafting of the manuscript and critical review of the content Statistical analysis, final approval of manuscript, analysis and/or interpretation of data, conduct of operations and / or experiments Analysis and/or interpretation of data, final approval of manuscript, Conception and design of the study, drafting of the manuscript and critical review of the content Analysis and/or interpretation of data, final approval of manuscript, Conception and design of the study, drafting of the manuscript and critical review of the content

REFERENCES 1. Hare JM. The dilated, restrictive and infiltrative cardiomyopathies. In: Braunwald E. Braunwald’s heart disease – A textbook of cardiovascular medicine. Philadelphia: Saunders Elsevier. 2012. p.1561-81. 2. Gómez-Doblas JJ, de Tereza E, Lamas GA. Geometria ventricular e insuficiência cardíaca. Rev Esp Cardiol. 1999;52(1):47-52. 3. Tumkosit M, Martin CG, Bayram E, Morgan TM, Lane KS, Rerkpattanapipat P, et al. Left ventricular spherical remodeling and apical myocardial relaxation: cardiovascular MR imaging measurement of myocardial segments. Radiology. 2007;244(2):411-8. 4. van Dalen BM, Kauer F, Vletter WB, Soliman OI, van der Zwaan HB, Ten Cate FJ, et al. Influence of cardiac shape on left ventricular twist. J Appl Physiol (1985). 2010;108(1):146-51. 5. Nikitin NP, Loh PH, de Silva R, Witte KK, Lukaschuk EI, Parker A, et al. Left ventricular morphology, global and longitudinal function in normal older individuals: a cardiac magnetic resonance study. Int J Cardiol. 2006;108(1):76-83. 6. Hueb AC, Jatene FB, Moreira LF, Pomerantzeff PM, Kallás E, de Oliveira SA. Ventricular remodeling and mitral valve modifications in dilated cardiomyopathy: new insights from anatomic study. J Thorac Cardiovasc Surg. 2002;124(6):1216-24.

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7. Juliani, PS. Avaliação morfogeométrica do ventrículo esquerdo e do anel valvar mitral na cardiomiopatia dilatada isquêmica ou idiopática: estudo comparativo computadorizado [Tese de doutorado]. São Paulo: Universidade de São Paulo; 2009.

left ventricle. Eur J Cardiothorac Surg. 2006;29 Suppl 1:S251-8. 14. Bocchi EA, Esteves-Filho A, Bellotti G, Bacal F, Moreira LF, Stolf N, et al. Left ventricular regional wall motion, ejection fraction, and geometry after partial left ventriculectomy. Influence of associated mitral valve repair. Eur J Cardiothorac Surg. 2000;18(4):458-65.

8. Dalva, M. Estudo do remodelamento ventricular e dos anéis valvares na cardiomiopatia dilatada: avaliação anátomohistopatológica [Tese de doutorado]. São Paulo: Universidade de São Paulo; 2012.

15. Starling RC, McCarthy PM, Buda T, Wong J, Goormastic M, Smedira NG, et al. Results of partial left ventriculectomy for dilated cardiomyopathy: hemodynamic, clinical and echocardiographic observations. J Am Coll Cardiol. 2000;36(7):2098-103.

9. Report of the WHO/ISFC task force on the definition and classification of cardiomyopathies. Br Heart J. 1980;44(6):672-3. 10. Nigri M, Rochitte C E, Tarasoutchi F, Grinberg M. A ressonância magnética como método propedêutico em valvopatia. Arq Bras Cardiol. 2006;87(4):534-7.

16. Moreira LFP, Bacal F, Benício A, Bocchi EA, Higuchi ML, Stolf NAG, et al. Fatores prognósticos e evolução da função ventricular em 5 anos de seguimento da ventriculectomia parcial esquerda no tratamento da cardiomiopatia dilatada. Rev Bras Cir Cardiovasc. 2001;16(4):275-88.

11. Parga JR, Avila LF, Bacal F, Moreira LF, Stolf NG, Ramires JA, et al. Partial left ventriculectomy in severe idiopathic dilated cardiomyopathy: assessment of short-term results and their impact on late survival by magnetic resonance imaging. J Magn Reson Imaging. 2001;13(5):781-6.

17. Ueno T, Sakata R, Iguro Y, Yamamoto H, Ueno M, Matsumoto K. Mid-term changes of left ventricular geometry and function after Dor, SAVE, and Overlapping procedures. Eur J Cardiothorac Surg. 2007;32(1):52-7.

12. Batista RJV, Santos JLV, Franzoni M, Araujo ACF, Takeshita N, Furukawa M, et al. Ventriculectomia parcial: um novo conceito no tratamento cirúrgico de cardiopatias em fase final. Rev Bras Cir Cardiovasc. 1996;11(1):1-6.

18. Buckberg GD, RESTORE Group. Form versus disease: optimizing geometry during ventricular restoration. Eur J Cardiothorac Surg. 2006;29 Suppl 1:S238-44.

13. Bockeria LA, Gorodkov AJ, Dorofeev AV, Alshibaya MD, RESTORE Group. Left ventricular geometry reconstruction in ischemic cardiomyopathy patients with predominantly hypokinetic

19. Torrent-Guasp F, Kocica MJ, Corno AF, Komeda M, Carreras-Costa F, Flotats A, et al. Towards new understanding of the heart structure and function. Eur J Cardiothorac Surg. 2005;27(2):191-201.

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Atik FA, et al. ORIGINAL - Addition of long-distance ARTICLE heart procurement promotes changes in heart transplant waiting list status

Addition of long-distance heart procurement promotes changes in heart transplant waiting list status Incorporação da captação à distância promove mudanças na situação dos receptores em fila para transplante cardíaco

Fernando Antibas Atik1, MD, MsC; Carolina Fatima Couto1; Freddy Ponce Tirado1; Camila Scatolin Moraes1; Renato Bueno Chaves1,MD; Nubia W. Vieira1; João Gabbardo Reis1, MD, MsC

DOI 10.5935/1678-9741.20140046

RBCCV 44205-1560

Abstract Objective: Evaluate the addition of long-distance heart procurement on a heart transplant program and the status of heart transplant recipients waiting list. Methods: Between September 2006 and October 2012, 72 patients were listed as heart transplant recipients. Heart transplant was performed in 41 (57%), death on the waiting list occurred in 26 (36%) and heart recovery occurred in 5 (7%). Initially, all transplants were performed with local donors. Long-distance, interstate heart procurement initiated in February 2011. Thirty (73%) transplants were performed with local donors and 11 (27%) with long-distance donors (mean distance=792 km±397). Results: Patients submitted to interstate heart procurement had greater ischemic times (212 min ± 32 versus 90 min±18; P<0.0001). Primary graft dysfunction (distance 9.1% versus local 26.7%; P=0.23) and 1 month and 12 months actuarial survival (distance 90.1% and 90.1% versus local 90% and 86.2%; P=0.65 log rank) were similar among groups. There were marked incremental transplant center volume (64.4% versus 40.7%, P=0.05) with a tendency on less waiting list times (median 1.5 month versus 2.4 months, P=0.18). There was a tendency on reduced waiting list mortality (28.9% versus 48.2%, P=0.09). Conclusion: Incorporation of long-distance heart procurement, despite being associated with longer ischemic times, does

not increase morbidity and mortality rates after heart transplant. It enhances viable donor pool, and it may reduce waiting list recipient mortality as well as waiting time.

Instituto de Cardiologia do Distrito Federal (IC-DF), Brasília, DF, Brazil.

Correspondence address: Fernando Antibas Atik Instituto de Cardiologia do Distrito Federal Estrada Parque Contorno do Bosque s/n - Cruzeiro Novo – Brasília, DF, Brazil - Zip code: 70.658-700 E-mail: atikf@mac.com Article received on October 2nd, 2013 Article accepted on January 7th, 2014

Descriptors: Heart Transplantation. Donor Selection. Cardiomyopathies. Resumo Objetivo: Mostrar a incorporação da captação a distância em um programa de transplante cardíaco e a situação dos receptores em fila após a organização deste sistema. Métodos: Entre setembro de 2006 e outubro de 2012, 72 pacientes foram incluídos na fila de transplante cardíaco. Transplante cardíaco foi realizado em 41 (57%), óbito em fila em 26 (36%) e melhora clínica em 5 (7%). Inicialmente, todos os transplantes foram realizados com captação local. Em fevereiro de 2011, teve início a captação a distância interestadual. Foram realizados 30 (73%) transplantes com captações locais e 11 (27%) em outros estados (distância média=792 km±397). Resultados: Pacientes submetidos à captação à distância tiveram maior tempo de isquemia fria (212 min±32 versus 90 min±18; P<0,0001). A taxa de disfunção primária de enxerto (distância 9,1% versus local 26,7%; P=0,23) e de sobrevida

Work carried out at Instituto de Cardiologia do Distrito Federal (IC-DF), Brasília, DF, Brazil. No financial support.

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meses, P=0,18). Houve ainda tendência a redução na mortalidade em fila de espera (28,9% versus 48,2%, P=0,09). Conclusão: A incorporação da captação a distância, apesar de associada a tempos prolongados de isquemia, não aumenta a morbimortalidade após o transplante cardíaco e aumenta o pool de doadores viáveis, podendo diminuir a mortalidade em fila e o tempo de espera por um órgão.

Abbreviations, acronyms & symbols Cm Centimeters

atuarial em 1 mês e 12 meses (distância 90,1% e 90,1% versus local 90% e 86,2%; P=0,65 log rank) foram similares entre os grupos. Houve expressivo aumento na capacidade do centro em transplantar (64,4% versus 40,7%, P=0,05) com tendência a redução de tempo em fila de espera (mediana 1,5 mês versus 2,4

Descritores: Transplante de Coração. Seleção do Doador. Cardiomiopatias.

INTRODUCTION

myocardial recovery occurred in 5 (7%). Initially, all transplants were performed with local donors. In February 2011, the program of interstate long-distance heart procurement was initiated. Thirty (73%) transplants were performed with local donors and 11 (27%) with long-distance ones. All donors were evaluated with confirmed cerebral death (two neurologic exams with documented absence of cerebral blood flow or cerebral activity) and informed familial consent. Decision of acceptance of a donor involved a clinical assessment, electrocardiogram, chest x-ray, echocardiogram and determination of serum markers of myocardial necrosis. Those donor with age superior to 40 years old were submitted to coronary angiogram. The following criteria were not considered an absolute contraindication to donor refusal: previous history of cardiac arrest, active infection, dyalisis dependent renal failure, severe electrolytic and acid base disturbances, as well as elevated vasopressor infusion. All local donors were assessed and procured in the same hospital where the transplant was performed. Transplants with long-distance donors required complex logistics, organized hospital work and coordinated air and land transportation. Long-distance donors were located in Goiânia/GO (3 times), São Paulo/SP (3 times), Rio de Janeiro/RJ (twice), Ribeirão Preto/SP (once), Sorocaba/ SP (once) and Campo Grande/MS (once). The mean distance was 792 km±397. Interstate transportation was achieved with military airplanes nine times and commercial airplanes twice. Transportation within cities was by helicopters, ambulances or private cars. Coordinated action between procurement and implant teams was crucial in minimizing cold ischemic times. The cardioplegic solution used in the donor heart was St Thomas, hearts were transported in sterile plastic bags filled with chilled saline solution packed in thermic coolers with packed ice in it. Bicaval technique was the transplant technique performed in all patients. Pre, intra and postoperative profiles were prospectively collected and stored in electronic database. Patient clinical outcomes were followed up longitudinally. The study was approved by the Institutional Review Board according to Helsinki’s law.

Heart transplantation is the treatment of choice in endstage heart failure patients with refractory optimized medical treatment, with no possibility of cardiomyopathy cause reversal. Transplant prolongs survival and substantially enhances quality of life. However, there are multiple limiting factors which make it inaccessible for most heart failure patients. In 2012, heart transplantation was responsible for only 19.8% of the population requirements in Brazil[1], and this negative scenario has been constant for the last decade despite the efforts of all Brazilian certified transplant teams. Certainly, the paucity of viable donors for heart transplant is the main limiting factor worldwide[2], and it is not different in Brazil. As a consequence, there are direct impact on recipient waiting list status, characterized by prolonged waiting times and greater mortality prior to transplant, due to the fact that an important proportion of patients are in priority state, in cardiogenic shock with inotrope dependency and/or mechanical assist device use. Besides that, there are regional differences, as well as local particularities. At Instituto de Cardiologia do Distrito Federal[3], in a previous analysis of recipient waiting list from 2006 and 2011, the mortality prior to transplant was remarkably elevated (39%) due to lack of viable donors (74% of donor refusal) which was related to logistics issues on long-distance procurement in 46.7% and cardiac dysfunction in 22.1%. These numbers stimulated the development of a program of interstate long-distance heart procurement in order to increment our transplant capacity, reducing our waiting list times and mortality prior to transplant. The aim of this study was to show the addition of a long-distance heart procurement system on the heart transplant waiting list status. METHODS Between September 2006 and October 2012, 72 patients (52 adults and 20 children) in stage D heart failure were listed as heart transplant recipients. Heart transplant was performed in 41 (57%), death on the waiting list occurred in 26 (36%) and

Statistical analysis Categorical variables were expressed by frequencies and

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percentages and continuous variables by means and standard deviation or with 95% confidence intervals. Comparison between categorical variables were analyzed by chi square test, and between continuous variables by Student's t test and Wilcoxon, when applicable. Longitudinal temporal events were analyzed by the Kaplan Meier method and log rank test was used to determine possible differences among groups.

There were no significant differences between them. The basic profile of this population is of relatively young patients, in the forth decade, predominantly males and in funcional class III. For the most part, they had type A and O blood groups, with Chagas and dilated cardiomyopathy, with no sensitization and favorable hemodynamic profiles to transplant. Intraoperative and postoperative periods Heart transplants with long-distance donors had greater ischemic times (212 min±32 versus 90 min±18; P<0.0001), as opposed to lesser aortic crossclamp times during implant (45 min±8.6 versus 69 min±17; P=0.0003).

RESULTS Transplant recipient profiles Table 1 shows demographic, clinical, echocardiographic and hemodynamic characteristics of the two study groups.

Table 1. Preoperative characteristics of heart transplant recipients in both study groups. Variables Mean age (years) Male sex Black race Blood type A B AB O Functional class (NYHA) III IV Priority state Etiology Chagas Idiopathic Ischemic Congenital Valvar Restrictive Amiloidosis Previous cardiac surgery Previous cardioverter defibrillator Previous cerebrovascular accident Systemic arterial hypertension Serum creatinine Preformed antibodies > 10% Echocardiographic parameters LVDD (mm) LVSD (mm) Left atrium volume RV systolic pressure Ejection fraction Hemodynamic parameters Cardiac index Transpulmonary gradient Pulmonary vascular resistance

Local (N=30) 38±3.5 17 (59%) 14 (48%)

Long-distance (N=11) 32±5.6 7 (64%) 6 (55%)

8 (28%) 3 (10%) 2 (7%) 16 (55%)

6 (55%) 2 (18%) 0 3 (27%)

19 (66%) 11 (34%) 6 (21%)

6 (55%) 5 (45%) 4 (36%)

14 (45%) 6 (21%) 2 (7%) 1 (3%) 2 (7%) 1 (3%) 1 (3%) 3 (10%) 8 (28%) 0 2 (7%) 1.3±0.15 0

6 (55%) 2 (18%) 0 1 (9%) 0 2 (18%) 0 0 5 (45%) 1 (9%) 0 1.1±0.22 0

66.9±13.8 60.3±15.5 72.3±25.9 48.3±3 24.6±12.4

61.9±15.5 50.9±16.2 84.2±38.9 60.4±13.7 33.2±17.1

0.34 0.12 0.35 0.06 0.1

1.28±0.35 4.4±4.3 3.3±1.8

1.23±0.22 3.8±3.7 3±1.3

0.79 0.76 0.69

0.4 0.77 0.74 0.2

0.27 0.92 0.35

0.43 0.28 0.22 0.54 0.45 1

NYHA=New York Heart Association; LVDD= left ventricle diastolic diameter; LVSD=left ventricle systolic diameter; RV=right ventricle

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Primary graft dysfunction, characterized by cardiac dysfunction on echocardiography in addition to clinical and hemodynamic signs of low cardiac output syndrome despite optimal medical treatment occurred in 9.1% of the long-distance donors and in 26.7% of the local donors (P=0.23). Intensive care unit stay was similar (P=0.68) in heart transplant recipients with long-distance donors (9.5 days average, 95%CI 5 - 15.5) and with local donors (8 days average, 95%CI 6.75 - 11.5). The same pattern occurred with total postoperative length of stay (long-distance donors: 36 days average, 95%CI 30 - 46; local donors: 39 days average, 95%CI 29 - 56; P=0.71). Cold ischemic timing did not determine greater hospital mortality. Ischemic times were similar between patients that died as well as in survivors (137 min±79 min versus 122 min±58 min, P=0.5). Actuarial survival, as shown in Figure 1, was similar among groups at 1 month and 12 months, respectively [long-distance donors 90.1% (95%CI 81.4% - 98.8%) and 90.1% (95%CI 81.4% - 90.1%) versus local donors 90% (95%CI 84.5% - 95.5%) and 86.2% (95%CI 79.8% - 92.6%); P=0.65 (log-rank test)].

DISCUSSION This paper described the importance of a long-distance heart procurement program and changes on heart transplant recipient status that happened later on. We described that long-distance procurement can be done with good results if it is organized, with adequate logistics and optimal team coordination aiming a short cold ischemic time. Even working with prolonged ischemic times related to long-distance transportation, we verified that careful myocardial protection, effective heart decompression on procurement and organ preservation at low temperatures during transport are essential to transplant success. That was proved by lower primary graft dysfunction rates, similar intensive care unit and postoperative length of stays, independent of the ischemic time. An excellent actuarial survival post-transplant at 12 months stresses those concepts above. Results from international registries bring some evidence that risk of mortality post heart transplant is maximized when it is performed above 4 hours of ischemic time, with long-term negative impact on survivors[2,4]. Those findings have relation to greater determination of low molecular weight serum myosin in the first week after transplant in prolonged ischemic time patients. Another important issue is the reperfusion injury on myocyte after ischemia. Mechanisms are well known, and it includes oxidative stress activation, of leukocytes, intracellular calcium influx, microcirculation disturbances and sympathetic activation[5]. However, we did not observe a direct relationship between cold ischemic time and mortality using conventional myocardial protection techniques as used in cardiac surgery. On the other hand, some groups[6-9] have neglected this 4-hour “time limit”, in order to enhance transplant viability, especially in priority state patients and in children in which the lack of donors is even more pronounced. Lesser aortic crossclamp time in our study means that we cannot waste any time during surgery in order to minimize ischemic time. For instance, we routinely perform pulmonary artery and superior vena cava anastomoses on the beating heart, particularly when using the long-distance donors. There are a great range of myocardial protection solutions on the market and modes of infusion in heart transplant[10-12]. However, there is controversy on the superiority of one solution over the others. In our study, we used the same cardioplegic solution in local and long-distance procurements with no differences in clinical outcomes besides small denominator. The technology of ex vivo perfusion is a promising field, and it is being developed. It may effectively preserve donor heart during prolonged transportation because avoids ischemia, anaerobic metabolism and reperfusion injury[13,14]. The most important message of this paper is that you may increment the heart transplant center volume by incorporating a long-distance procurement program and as a consequence enhancing the heart donor pool. Implications on the waiting

Fig. 1 - Actuarial survival after heart transplantation in both study groups, showing the number of patients at risk and the log rank test result.

Situation on the waiting list There was a marked increase in the number of heart transplants with the addition of a long-distance procurement program. The number of transplants went from 15 (in 52 months) to 26 (in 22 months). The higher number of transplants determined changes in heart transplant waiting list status. Effective heart transplant rate on the waiting list increased from 40.7% to 64.4% (P=0.05). Moreover, there was a tendency of survival benefit on the waiting list, mortality decreased from 48.2% to 28.9% (P=0.09). There was also a tendency of decrease in waiting list time for a transplant (with an average of 1.5 month versus 2.4 months, P=0.18).

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list are direct and very positive, leading to lesser waiting list time for transplant and lesser mortality before the transplant. Those concepts are fundamental nowadays. The number of recipients is constant and growing because of advanced heart failure is the final path of all cardiomyopathies. Transplant obviously does not fulfill all the demand of recipients. The international registry [2] and the Brazilian registry [1] clearly show a plato in the number of transplants in the last decade, and the main reason for that is the lack of donors. Issues related to that are low notification of potential donors, lack of familial consent, lack of interest of intensive care teams in donor maintenance, and prioritizing kidney and liver procurement. A skewed distribution of transplant centers in the Brazilian territory favors an underutilization of donors in remote areas of the country, which is unacceptable. Better distribution of centers across the country would expand heart transplantation in Brazil, as well as an optimal donor utilization[15]. Finally, organizing logistics related to long-distance procurement in Brazil must be a priority. This is a field that our country lags behind the successful experiences in North America and Europe that have had routine organized systems that allows optimal donor utilization and consequently multiply transplant centers capacity.

Authors’ roles & responsibilities FAA CFC FPT CSM RBC CRC NWV JGR

Data collection, statistical analysis, manuscript writing Data collection Literature review and manuscript review Data collection Manuscript review Literature review and text Manuscript review Manuscript review

REFERENCES 1. Registro Brasileiro de Transplantes. Associação Brasileira de Transplantes de Órgãos. Relatório Anual 2012. 2. Stehlik J, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dipchand AI, et al; International Society of Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: 29th official adult heart transplant report--2012. J Heart Lung Transplant. 2012;31(10):1052-64. 3. Atik FA, Couto CF, Moraes CS, Nascimento CV, Cunha CR, Santos E, et al. Problemas encontrados na lista de espera em relação à oferta de órgãos no transplante cardíaco. Anais do Congresso Brasileiro de Insuficiência Cardíaca 2011.

Limitations of the study Firstly, this is a coorte study with prospectively collected data and its inherit limitations. The two study groups were not contemporary, and it may influence results due to the fact that gain of experience might occurred with time, especially when long-distance procurement has commenced. We did not obtain detailed donor characteristics, which it might determined a non-significant increase in primary graft dysfunction on the local donor group. As a matter of fact, the latter could have received most of the marginal donors.

4. Pfugfelder PW, Singh NR, McKenzie FN, Menkis AH, Novick RJ, Kostuk WJ. Extending cardiac allograft ischemic time and donor age: effect on survival and long-term cardiac function. J Heart Lung Transplant. 1991;10(3):394-400. 5. Charniot JC, Bonnefont-Rousselot D, Albertini JP, Dever S, Vignat N, Nataf P, et al. Oxidative stress implication after prolonged storage donor heart with blood versus crystalloid cardioplegia and reperfusion versus static storage. J Surg Res. 2010;160(2):308-14.

CONCLUSION Long-distance donor procurement, despite being associated with prolonged ischemic times, does not increment morbidity and mortality after the transplant. It enhances viable donor pool, and it may reduce recipient’s mortality and waiting list times. It is particularly useful for priority patients.

6. Scheule AM, Zimmerman GJ, Johnston JK, Razzouk AJ, Gundry SR, Bailey LL. Duration of graft cold ischemia does not affect outcomes in pediatric heart transplant recipients. Circulation. 2002;106(12 Suppl 1):I163-7.

ACKNOWLEDGEMENTS

7. Kawauchi M, Gundry SR, de Begona JA, Fullerton DA, Razzouk AJ, Boucek M, et al. Prolonged preservation of human pediatric hearts for transplantation: correlation of ischemic time and subsequent function. J Heart Lung Transplant. 1993;12(1 Pt 1):55-8.

The authors would like to acknowledge the unconditional support of Brazilian Air Force, Firefighters of Distrito Federal, Military Police of Distrito Federal, Secretary of Health of Distrito Federal, and Transplantation National System from Ministry of Health. They were fundamental to the viability of a long-distance heart procurement program in Distrito Federal.

8. Briganti EM, Bergin PJ, Rosenfeldt FL, Esmore DS, Rabinov M. Successful long-term outcome with prolonged ischemic time cardiac allografts. J Heart Lung Transplant. 1995;14(5):840-5.

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9. Fragomeni LS, Bonser RS, Stempfle U, Ring SW, Kaye MP, Jamieson SW. Relação entre tempo de isquemia e performance pós-operatória no transplante cardíaco. Rev Bras Cir Cardiovasc. 1989;4(2):139-42.

12. George TJ, Arnaoutakis GJ, Baumgartner WA, Shah AS, Conte JV. Organ storage with University of Wisconsin solution is associated with improved outcomes after orthotopic heart transplantation. J Heart Lung Transplant. 2011;30(9):1033-43.

10. Lavagnoli CF, Severino ES, Vilarinho KA, Silveira Filho Lda M, Oliveira PP, Petrucci O, et al. Associated factors with survivals in patients undergoing orthotopic heart transplant using retrograde blood microcardioplegia. Rev Bras Cir Cardiovasc. 2012;27(3):347-54.

13. Smulowitz PB, Serna DL, Beckham GE, Milliken JC. Ex vivo cardiac allograft preservation by continuous perfusion techniques. ASAIO J. 2000;46(4):389-96. 14. Jacobs S, Rega F, Meyns B. Current preservation technology and future prospects of thoracic organs. Part 2: heart. Curr Opin Organ Transplant. 2010:15(2):156-9.

11. Cannata A, Botta L, Colombo T, Russo CF, Taglieri C, Bruschi G, et al. Does the cardioplegic solution have an effect on early outcomes following heart transplantation? Eur J Cardiothorac Surg. 2012;41(4):e48-52.

15. Lima R, Escobar M, Alecrim R, Alves I, Lins T, Arraes N, et al. Programa Nordeste para transplante cardíaco “NE-Tx”: experiência atual. Rev Bras Cir Cardiovasc; 1992;7(3):165-73.

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Cunha SS, et ORIGINAL al. - Psychological assessment of patients undergoing cardiac ARTICLE transplant in a teaching hospital (2004 to 2012)

Psychological assessment of patients undergoing cardiac transplant in a teaching hospital (2004 to 2012) Avaliação psicológica de pacientes submetidos a transplante cardíaco em hospital de ensino (2004 a 2012)

Sara dos Santos Cunha1, MsC; Maria Cristina de Oliveira Santos Miyazaki1, MsC, PhD; Daniel Fernando Villafanha2, MD, MsC, PhD; Randolfo dos Santos Junior1, MsC; Neide Aparecida Micelli Domingos1, MsC, PhD

DOI 10.5935/1678-9741.20140085

RBCCV 44205-1561

Abstract Objective: To analyze the psychological evaluations of patients with heart failure waiting for heart transplantation. Methods: The data were obtained from patient records containing pre-surgery psychological evaluations performed by psychologists from the multidisciplinary cardiology team. The evaluation protocol included the Quality of Life Questionnaire (SF-36), Beck Depression Inventory, and an interview script. Results: The results of psychological evaluations performed between 2004 and 2012 for 60 candidates for heart transplantation were analyzed: 43 men and 17 women aged between 16 and 66 years (Mean=45.18; SD=11.91), predominantly from the São José do Rio Preto area (São Paulo state, Brazil) (83%), with incomplete elementary education (68%), and who were in stable relationships (73%). Although women presented higher mean scores for depression (21.41) than men (14.61), there was no significant difference between genders. Women’s quality of life was impaired in all domains compared to men (below 50%) and was significantly poorer in the physical functioning (P=0.01),

vitality (P=0.00), emotional role functioning (P=0.04), and mental health (P=0.02) domains. Conclusion: Patients with psychosocial vulnerability (e.g., depression) identified before transplantation should receive psychological treatment.

Laboratory of Psychology and Health at Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil. 2 Department of Cardiology and Cardiovascular Surgery at Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil.

Correspondence address: Maria Cristina Miyazaki Laboratory of Psychology and Health - FAMERP Av. Brigadeiro Faria Lima, 5416 - São José do Rio Preto, SP, Brazil. Zip code: 15090-000 E-mail: cmiyazaki@famerp.br

Descriptors: Heart Transplantation. Psychology, Clinical. Behavioral Medicine. Patient Care Team. Resumo Objetivo: Analisar protocolos de avaliação psicológica de pacientes portadores de insuficiência cardíaca, candidatos a transplante cardíaco. Métodos: Os dados da avaliação foram obtidos junto ao arquivo de avaliações psicológicas realizadas pré-cirurgia pelos psicólogos que integram a equipe multidisciplinar de Cardiologia. O protocolo de avaliação inclui o Questionário de Qualidade de Vida – SF-36 o Inventário Beck de Depressão e um roteiro de entrevista.

This study was carried out at Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil e Hospital de Base – Fundação Faculdade Regional de Medicina (FUNFARME), São José do Rio Preto, SP, Brazil.

Article received on September 6th, 2013 Article accepted on June 14th, 2014

CNPq Research Productivity Scholarship: Maria C. O. Santos Miyazaki

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Cunha SS, et al. - Psychological assessment of patients undergoing cardiac transplant in a teaching hospital (2004 to 2012)

mais altos para depressão (21,41) em relação aos homens (14,61), não houve diferença significante entre os gêneros. A qualidade de vida das mulheres mostrou-se prejudicada em todos os domínios (abaixo de 50%) e esse prejuízo foi significantemente inferior aos homens na capacidade funcional (P=0,01), vitalidade (P=0,00), aspectos emocionais (P=0,04) e saúde mental (P=0,02). Conclusão: Pacientes com vulnerabilidades psicossociais identificadas no pré-transplante (ex. depressão) devem receber atendimento psicológico.

Abbreviations, acronyms & symbols CBT

Cognitive Behavioral Therapy

Resultados: Foram analisados os resultados das avaliações psicológicas de 60 pacientes candidatos a transplante cardíaco no período entre 2004 e 2012: 43 homens e 17 mulheres, com idade entre 16 e 66 anos (M=45,18 dp=11,91), 83% provenientes da região, com ensino fundamental incompleto (68%) e união estável (73%). Embora as mulheres tenham apresentado escores

Descritores: Transplante de Coração. Psicologia Clínica. Medicina do Comportamento. Equipe de Assistência ao Paciente.

INTRODUCTION

de Medicina de São José do Rio Preto - FAMERP), São Paulo state, Brazil, between 2004 and 2012.

Heart transplantation aims to improve the life expectancy and quality of life of patients with end-stage heart failure. Although the medical criteria of indication/contraindication for transplantation are well defined, the psychosocial criteria, which also affect the results of the procedure, are more difficult to determine[1-7]. Patients on the heart transplantation waiting list often experience a period of “physical and psychological instability”[1]. Clinical worsening, difficulties in daily activities, impairments in cognitive and social functioning as well as in emotional well-being, and elevated symptoms of depression and anxiety are frequently observed[8,9]. For many patients, the heart transplantation evaluation means the end of a long time living with deteriorating health and the beginning of a new treatment modality. While there is hope for the future, it is necessary to face surgery; despite the risks, the procedure means a chance to survive[1]. The pre-transplantation psychological evaluation aims to investigate the presence and history of mental disorders (e.g., substance abuse, mood disorders), coping style, presence of a social support network, and comprehension of the disease and the procedure. The questions to be answered by the psychological evaluation are described in the literature, and the instruments used may vary among different transplantation centers[2,3,5]. The purpose of this evaluation is not to exclude candidates but rather to identify candidates who need guidance and/or psychotherapeutic intervention to improve their quality of life before and after the transplantation[10]. In general, psychological evaluation reveals the psychosocial status of patients through data that can support interventions performed not only by psychologists but also by other professionals. Thus, the objective of this study is to analyze data from the psychological evaluation protocols of patients with heart failure waiting for heart transplantation at Hospital de Base (Base Hospital), São José do Rio Preto Medical School (Faculdade

METHODS The project was submitted and approved by the FAMERP Research Ethics Committees (protocol no. 03213212.0.0000.5415) on June 12, 2012. The data were obtained from patient records containing the pre-surgery psychological evaluations performed by psychologists from the multidisciplinary cardiology team between 2004 and 2012. The sample size corresponds to the number of patients evaluated during this period and is justified by the relatively low frequency of heart transplantations performed at the Institution. The psychological evaluation protocol includes the Quality of Life Questionnaire (SF-36)[11], the Beck Depression Inventory[12], and an interview script. The SF-36 is a generic self-reporting instrument consisting of 36 items that assess eight domains of quality of life: physical functioning, physical role functioning, bodily pain, general health, vitality, social role functioning, emotional role functioning, and mental health. Higher scores (total score or score of each domain evaluated) indicate a better quality of life[11]. The Beck Depression Inventory is also a self-reporting instrument widely used to assess the presence and severity of symptoms of depression in adults. It consists of 21 items, and the total score measures the severity of the symptoms of depression presented (0-11: minimum; 12-19: mild, 20-35: moderate, 36-63: severe)[12]. The data were analyzed using descriptive statistics and the Mann-Whitney test with P<0.05. RESULTS The data from 60 patients who underwent psychological evaluation between 2004 and 2012 (Table 1) were assessed. The comparisons of the mean Beck Depression Inventory scores between men and women and between single patients

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and patients in a relationship are presented in Table 2. Mean quality of life scores and their comparison between genders are presented in Table 3.

The majority of the patients evaluated were male (71.66%) and aged between 36 and 66 years. According to DATASUS (Department of Informatics of the Unified Health System-SUS), the majority of heart failure hospitalizations occurs in elderly patients, with ages of 60 years or high-

er, followed by patients in the age range of 20-59 years[13]. However, the indication for heart transplantation in other age ranges is associated with factors such as etiology and progression of the disease[14], as observed in this study as well as in a study conducted by Helito et al.[13]. The majority of the patients evaluated were from cities in the São José do Rio Preto area. The Base Hospital provides tertiary care for this area, which comprises 101 municipalities and a population of two million inhabitants. Because the Base Hospital is a reference institution for organs and tissue transplantations, a high concentration of patients from the area is expected.

Table 1. Patients who underwent pre- cardiac transplantation psychological evaluation at the Base Hospital between 2004 and 2012.

Table 3. Comparison of Quality of Life (SF-36) scores between male and female heart transplantation candidates.

Variable Gender

Variable Physical functioning

DISCUSSION

Age Minimum age: 16 Maximum age: 66 Mean: 45.18 SD: 11.91 Origin Educational level

Occupation

Marital status

Male Female Total Age range 16 – 25 years 26 – 35 years 36 – 45 years 46 – 55 years 56 – 66 years São José Rio Preto Surrounding area Illiterate Elementary school Middle school High school/college Homemaker Retired Autonomous Wage earner Stable relationship Single Divorced Widow(er)

N 43 17 60

% 71.66 28.33 100

5 6 18 17 14 10 50 2 41 10 7 8 13 4 35 44 10 4 2

8.33 10 30 28.33 23.33 16.66 83.33 3.33 68.33 16.66 11.66 13.33 21.66 6.66 58.33 73.33 16.66 6.66 3.33

Physical role functioning

Bodily pain

General health

Vitality

Social role functioning

Table 2. Comparison of mean Beck Depression Inventory (BDI) scores between men and women and between single patients and patients in a relationship. Variable Men Women In a relationship Single

Emotional role functioning

BDI – Beck Depression Inventory M SD P 14.61 9.43 0.06 21.41 12.82 17.04 10.62 0.069 10.90 10.77

Mental Health

P<0.05, Mann-Whitney Test

Women M=20.08 SD=12.09 Minimum=0 Maximum=45 M=12.05 SD=19.04 Minimum=0 Maximum=75 M=48.29 SD=26.16 Minimum=10 Maximum=98 M=44.05 SD=19.98 Minimum=9 Maximum=77 M=34.18 SD=18.06 Minimum=1.2 Maximum=70 M=49.80 SD=32.30 Minimum=0 Maximum=100 M=35.68 SD=36.58 Minimum=0 Maximum=100 M=46.56 SD=21.05 Minimum=7 Maximum=76

*P<0.05, Mann-Whitney Test

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Men M=32.73 SD=20.19 Minimum=0 Maximum=80 M=21.97 SD=24.36 Minimum=0 Maximum=80 M=63.01 SD=27.29 Minimum=5 Maximum=100 M=54.81 SD=22.37 Minimum=0 Maximum=90 M=53.47 SD=26.35 Minimum=1.2 Maximum=100 M=55.08 SD=31.13 Minimum=0 Maximum=100 M=57.53 SD=37.98 Minimum=0 Maximum=100 M=62.13 SD=27.60 Minimum=0 Maximum=100

P 0.01*

0.07

0.08

0.00*

0.54

0.04*

0.02*

Cunha SS, et al. - Psychological assessment of patients undergoing cardiac transplant in a teaching hospital (2004 to 2012)

Rev Bras Cir Cardiovasc 2014;29(3):350-4

Elementary school was the most frequent educational level among the patients evaluated (71.6%), and the predominant occupations were associated with manual labor (e.g., mason, farm worker) and thus consistent with the educational level of the sample. This finding is similar to results from other studies[13] performed at the Institution and most likely reflects the profile of patients assisted through the Unified Health System (Sistema Único de Saúde – SUS)[4,8,13]. The low educational level is a factor that can affect treatment adherence because it can impair the comprehension of important aspects of the disease and its management[13,15]. However, another study conducted at the same Institution revealed that the heart transplantation survival rate was not different between patients with low and middle socio-cultural status[16]. According to the authors, this result is associated with the social support network available to the patients, which consists of caregivers, non-governmental organizations, and the Unified Health System itself [16]. Regarding relationship status, 73.3% of patients reported being in a stable relationship. These data are important for treatment because family support is crucial for the care associated with the transplantation. The family members will share the suffering and joy associated with treatment and will also support the patient throughout the entire process. Therefore, the family members should also receive care from the healthcare system, as the caregiver role is associated with stress overload[13,17,18]. The mean depression score was higher in women (21.41) than in men (14.61), although there was no significant difference. This finding is consistent with the literature, which indicates that after puberty, the prevalence of depression in women is twice the prevalence in men[19-21]. Several explanations have been suggested for this fact. Nolen-Hoeksema[20] cites two main aspects identified in studies on this topic: 1) women usually have less power than men and therefore experience certain traumas (e.g., sexual abuse) and other chronic stressors (e.g., poverty, bullying, and restriction of opportunity) more frequently; 2) even when men and women are exposed to the same stressors, women are more vulnerable to depression due to biological differences. Approximately 20% of patients with cardiovascular diseases exhibit depression, which in turn is an important predictor of morbidity, mortality, and poor quality of life[22,23]. Thus, psychological treatment (with or without antidepressant medication, depending on the severity) has been recommended for patients with cardiovascular disease and depression. Among the high quality clinical trials that evaluate psychotherapeutic treatments of depression, Cognitive Behavioral Therapy (CBT) presented positive results[22]. The time when these patients start psychotherapy after the cardiac event can also influence the treatment outcome. However, studies aiming to clarify the proper time to start the psychotherapy, the variables of the psychotherapeutic process itself, and the patient characteristics (e.g., gender) are still needed[22]. It seems that one of the most important problems of the association between cardiovascular disease and depression is that the latter is underdiagnosed[24].

The pre-surgical psychological evaluation is an important tool for the diagnosis of depression among heart transplant patients. The pre-transplant quality of life can be hampered by the worsening of the symptoms and therefore by the difficulties in performing activities of daily living and the associated emotional damage[13,25]. In this study, women presented worse quality of life than men in all domains assessed by the SF-36. This difference was significant in the physical functioning, vitality, emotional role, and mental health domains. Differences in quality of life between men and women, with greater impairment observed in women, have been consistently reported in both the Brazilian and international literature on patients with cardiovascular diseases[26,27]. It is recognized that there are important differences “between women and men with regard to the function and progression of diseases of the cardiovascular system”[27]. Thus, it is necessary to identify these differences to provide adequate treatment according to gender differences. One of these differences, also identified in this study, is that women are more vulnerable to depression. In addition to the need for research on this subject with Brazilian patients, it is very important to have interdisciplinary teams that evaluate the specific needs of each patient within a biopsychosocial health model to provide adequate treatment. The absence of a global and interdisciplinary analysis of patients leads to a poorer quality of services and consequently increases the costs of the disease not only for the patient, family, and society but also for the entire healthcare system. ACKNOWLEDGMENT The authors would like to express appreciation and thanks to Dr. Reinaldo Bestetti for his important comments in the letter published in this issue.

Authors’ roles & responsibilities SSC MCOSM DFV RSJ NAMD

Data collection and tabulation; data interpretation; partial drafting of the final text Study design; data analysis and interpretation; manuscript writing and final review of the paper Study design; data interpretation; final review of the paper Study design;data analysis and interpretation; final review of the paper Study design; data interpretation; first draft and final review of the paper

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2. Levenson JL, Olbrisch ME. Psychosocial evaluation of organ transplant candidates. A comparative survey of process, criteria, and outcomes in heart, liver, and kidney transplantation. Psychosomatics. 1993;34(4):314-23.

Mangini S, et al. II Diretriz Brasileira de Transplante. Arq Bras Cardiol. 2009;94(1 supl.1):e16-e73. 15. Felicio HCC. Manual de orientações para pacientes e familiares: transplante de fígado [Dissertação de Mestrado]. São José do Rio Preto: FAMERP; 2007.

3. Levenson JL, Olbrisch ME. Psychosocial screening and selection of candidates for organ transplantation. In: Trzepacz PT, DiMartini AF, eds. The transplant patient: biological, psychiatric, and ethical issues in organ transplantation. Cambridge: Cambridge University; 2000. p.21-40.

16. Parra AV, Rodrigues V, Cancella S, Cordeiro JA, Bestetti RB. Impact of socioeconomic status on outcome of a Brazilian heart transplant recipient’s cohort. Int J Cardiol. 2008;125(1):142-3.

4. Santos GG, Gonçalves LC, Buzzo N, Mendes TA, Dias TP, Silva RC, et al. Quality of life, depression, and psychosocial characteristics of patients awaiting liver transplants. Transplant Proc. 2012;44(8):2413-5.

17. Brito LMPM, Pessoa VLMP, Santos ZMSA. A família vivenciando o transplante cardíaco. Rev Bras Enferm. 2007;60(2):167-71. 18. Miyazaki ET, Santos R Jr, Miyazaki MC, Domingos NM, Felicio HC, Rocha MF, et al. Patients on the waiting list for liver transplantation: caregiver burden and stress. Liver Transpl. 2010;16(10):1164-8.

5. Miyazaki MCOS, Santos Jr R, Domingos NAM, Valerio NI. Atuação do psicólogo em uma unidade de transplante de fígado: características do trabalho e relato de caso. In: Baptista MN, Dias RR, eds. Psicologia hospitalar. Teoria, aplicações e casos clínicos. Rio de Janeiro: Guanabara-Koogan; 2010. p.45-57.

19. APA (American Psychiatric Association). Manual diagnóstico e estatístico de transtornos mentais. 4a ed. rev. DSM-IV-TR. Porto Alegre: Artmed; 2002.

6. Fiorelli AI, Coelho GHB, Junior JLO, Oliveira AS. Insuficiência cardíaca e transplante cardíaco. Rev Med. 2008;87(2):105-20.

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7. Fiorelli AI, Oliveira Jr JL, Stolf NAG. Transplante cardíaco. Rev Med (São Paulo). 2009;88(3):123-37.

21. Levinson DF. The genetics of depression: a review. Biol Psychiatry. 2006;60(2):84-92.

8. Karapolat H, Eyigor S, Zoghi M, Nalbantgil S, Yagdi T, Durmaz B, et al. Health related quality of life in patients awaiting heart transplantation. Tohoku J Exp Med. 2008;214(1):17-25.

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10. Skotzko CE, Stowe JA, Wright C, Kendall K, Dew MA. Approaching a consensus: psychosocial support services for solid organ transplantation programs. Prog Transplant. 2001;11(3):163-8.

24. Soares HLR, Costa RA, Mesquita ET. Depressão e as doenças cardiovasculares. Rev Dep Psicol UFF. 2006;18(2):197-204.

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27. Norris CM, Ghali WA, Galbraith PD, Graham MM, Jensen LA, Knudtson ML; APPROACH Investigators. Women with coronary artery disease report worse health-related quality of life outcomes compared to men. Health Qual Life Outcomes. 2004;2:21.

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Santos KMS,ORIGINAL et al. - Evaluation of peripheral muscle strength of patients ARTICLE undergoing elective cardiac surgery: a longitudinal study

Evaluation of peripheral muscle strength of patients undergoing elective cardiac surgery: a longitudinal study Avaliação da força muscular periférica de pacientes submetidos à cirurgia cardíaca eletiva: estudo longitudinal

Kelli Maria Souza Santos1; Manoel Luiz de Cerqueira Neto, PhD1; Vitor Oliveira Carvalho1, PhD; Valter Joviniano de Santana Filho1, MD; Walderi Monteiro da Silva Junior1, MD; Amaro Afrânio Araújo Filho2, Ms; Telma Cristina Fontes Cerqueira2, MsC; Lucas de Assis Pereira Cacau1, MsC

DOI 10.5935/1678-9741.20140043

RBCCV 44205-1562

Abstract Introduction: Peripheral muscle strength has been little explored in the literature in the context of cardiac rehabilitation. Objective: To evaluate the peripheral muscle strength of patients undergoing elective cardiac surgery. Methods: This was a longitudinal observational study. The peripheral muscle strength was measured using isometric dynamometry lower limb (knee extensors and flexors) at three different times: preoperatively (M1), the day of discharge (M2) and hospital discharge (M3). Participants received physiotherapy pre and postoperatively during the days of hospitalization during the morning and afternoon. Results: Twenty-two patients were evaluated. The values of peripheral muscle strength of knee extensors preoperative found were about 50% lower than those predicted for the healthy population. When comparing muscle strength prior (M1), with the remaining evaluation, found himself in a fall of 29% for the movement of knee extension and 25% for knee flexion in M2 and a decrease of 10% movement for knee extension and 13% for knee flexion in M3 when comparing with M1.

Conclusion: The values of peripheral muscle strength prior of the study patients were lower than predicted for the healthy population of the same age. After the surgical event this reduction is even more remarkable, being reestablished until the time of discharge, to values close to baseline. Descriptors: Muscle Strength. Muscle Strength Dynamometer. Heart Diseases.

Universidade Federal de Sergipe (UFS), Aracaju, SE, Brazil Universidade Tiradentes, (Unit), Aracaju, SE, Brazil.

Correspondence Address: Lucas de Assis Pereira Cacau Rua Cláudio Batista, s/n - Santo Antônio – Aracaju, SE Brazil - Zip code: 49060-100 E-mail: lucas.cacau@yahoo.com.br

1 2

This study was carried out at Fundação Beneficência Hospital Cirurgia and Universidade Federal de Sergipe (UFS), Aracaju, SE, Brazil.

Resumo Introdução: A força muscular periférica tem sido pouco explorada na literatura atual no contexto da reabilitação cardiovascular. Objetivo: Avaliar a força muscular periférica de pacientes submetidos à cirurgia cardíaca eletiva. Métodos: Trata-se de um estudo observacional e longitudinal. A força muscular periférica foi mensurada por meio de dinamometria isométrica de MMII (extensores e flexores de joelho) em três momentos distintos: pré-operatório (M1), dia da alta da unidade de terapia intensiva (M2) e dia da alta hospitalar (M3). Os participantes receberam atendimento fisioterapêutico pré e

Article received on September 4th, 2013 Article accepted on January 14th, 2014

No financial support.

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(M1), com os demais momentos de avaliação, encontrou-se em M2 queda de 29% para o movimento de extensão do joelho e 25% para o movimento de flexão de joelho e queda de 10% para o movimento de extensão do joelho e 13% para o movimento de flexão de joelho em M3 ao comparar com M1. Conclusão: Os valores de força muscular periférica prévia dos pacientes do estudo foram menores do que o predito para a população saudável com a mesma faixa etária. Após o evento cirúrgico, essa redução é ainda mais notável, sendo reestabelecida até o momento da alta hospitalar a valores próximos ao basal.

Abbreviations, acronyms & symbols CABG FBHC PMS

Coronary Artery Bypass Grafting Fundação de Beneficência Hospital de Cirurgia Peripheral muscle force

pós-operatório durante os dias do internamento, nos períodos matutino e vespertino. Resultados: Foram avaliados 22 pacientes. Os valores de força muscular periférica de extensores de joelho pré-operatórios encontrados foram cerca de 50% menores do que os preditos para a população saudável. Ao comparar a força muscular prévia

Descritores: Força Muscular. Dinamômetro de Força Muscular. Cardiopatias.

INTRODUCTION

deep vein thrombosis, deambulation, walking up and down stairs, active-assisted and active kinesiotherapy of upper and lower limbs, and muscle stretching. The rehabilitation protocol followed the guidelines of the Brazilian Consensus on Cardiovascular Rehabilitation[6].

Cardiovascular diseases are responsible for high rates of morbidity and mortality in Brazil and in the world[1]. For treatment of many of these cardiac conditions, surgery is the main resource[2]. Although very safe, heart surgery is a procedure considered large and is accompanied by the need for general anesthesia, cardiopulmonary bypass, mechanical ventilation and relative restriction to bed rest[3]. The heart disease patients showed loss of functional capacity resulting from decreased oxidative capacity of skeletal muscle and reduced muscle perfusion, such loss being aggravated in case of hospitalization for bed rest, impacting loss of peripheral muscle function[4]. Peripheral muscle strength (PMS) can be considered as a predictor of overall muscular strength, and is associated with functional and nutritional presentation[4]. The PMS is of great interest to cardiac rehabilitation, but it has been little explored in the current literature[5]. The aim of this study was to assess peripheral muscle strength in patients undergoing elective heart surgery.

Study Population Patients were recruited from a tertiary hospital of Cardiology between September and November 2012. Patients undergoing elective cardiac surgery (both genders and aged between 18 and 80 years) were eligible for this study. Inclusion criteria were: absence of neurocognitive decline or dementia that could influence the process of communication, absence of musculoskeletal disorder and previous pulmonary diseases (chronic obstructive pulmonary disease), presence of hemodynamic instability (Mean Arterial Pressure >60 mmHg), dyspnea with oxygen saturation less than 90%. The patient, who refused to sign the Written Informed Consent and those who had the time of stay in the ICU more than 7 days were excluded from the study. This research protocol was approved by the Research Ethics Committee of our institution (CAAE nº 01521012.2.0000.0058). All patients signed a written informed consent prior to participation in this research.

METHODS Study design This is a pilot, observational, longitudinal study performed at the Fundação de Beneficência Hospital de Cirurgia (FBHC) in the city of Aracaju - SE. The patients’ assessments were performed at three time points: preoperatively (a day before surgery) (M1), on the 1st day after ICU discharge (M2) and the day of discharge (M3), in the form of lower limb isometrics. All study participants received physiotherapy (physical and respiratory therapy), in the pre- and postoperative periods, twice a day for every day of hospitalization in the morning and afternoon. The treatment protocol included: breathing exercises (ventilatory), lung re-expansion maneuvers, bronchial hygiene, postural drainage, exercises to prevent

Data collected from medical records Clinical history, diagnosis, vital signs, type of surgery, total days ofhospital and ICU stay, time of cardiopulmonary bypass and mechanical ventilation time were collected, as well as the patient’s characteristics involved in the study (Table 1). Assessment of peripheral muscle strength The PMS was assessed at three different time points: preoperatively (day before surgery) (M1), on the 1st day after ICU discharge (M2) and the day of discharge (M3), in the form of isometrics for extension and flexion of the right and left knees. The instrument used in this assessment was the portable digital dynamometer, IMPAC®, IP-90DI model with

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scale in kgf, associated with an anatomical adapter for better coupling of the lower end segment[7]. In the assessment of knee isometric strength was observed muscle performance in flexion and extension, bilaterally. The procedure followed in the following standardization: the patient remained seated, hips at 90° of flexion and abduction at shoulder width. Patients performed the movements required under verbal command of the evaluator, exerting a continuous isometric force for 5 seconds. Three independent measurements and with one-minute interval between them for each movement and collection of averaging of such measurements were performed. The digital dynamometer remained leaning against a flat surface in order to maintain the stability of the instrument under the pressure exerted by the subject at the time of isometrics. Patients were instructed not to perform the Valsalva maneuver. The analgesic therapy in the study patients was standardized.

Fig. 1 - Flow of patients in the study.

Table 1. Characteristics of the study patients. Variables

Statistical analysis Data arepresented as mean and standard deviation. The data presented normal behavior (Shapiro Wilk test) and for the analysis of PMS at different times, we used one-way ANOVA test and Bonferroni post-test with 95% confidence interval. We consider the level of less than 5% (P<0.05) significance. For statistical analysis we used SPSS (Chicago IL, USA) version 13.0.

Total of patients Age (years) Type of surgery CABG Valve replacement Valvuloplasty CABG + valve replacement or repair IAC repair Aneurysmectomy Myxoma resection CPB time (minutes) MV time (hours) Length of hospital stay (days) Total ICU

RESULTS In this study, 31 patients were listed for surgery of which 22 met the inclusion criteria. Nine patients were excluded and 22 were assessed until the end of the study (Figure 1, Table 1). Concerning body composition of the sample, BMI (Body Mass Index) had values classified as normal weight (37.5% men, 64.29% women), overweight (50% men, 14.29% women) and obesity grade 1 (12.5% men, 21.42% women). All subjects were considered physically inactive with respect to the level of physical activity after submission to the specific questionnaire. The preoperative values of peripheral muscle strength for knee extension found in study patients (3.5±8.94) were nearly 50% lower than predicted for the healthy population with the same mean age (18.2±2.3)[8]. There was a 29% reduction in the PMS for the movement of knee flexion in the interval between assessments of M1 (7.06±2.8), CI=(3.30, 14.50) and M2 (5.29±1.9) CI (2.55, 10.67) (P=0.056). Comparing M1 and M3 (6.35±2.4), CI=(3.05, 12.82) there is still a deficit of PMS of 10% for movement of knee flexion (P=0.99). For movement of knee extension, there was also a 25% reduction of M1 (8.94±3.5), CI=(5.10, 20.45) for M2 (6.34 ± 2.24), CI=(2.34, 11.92) (P=0.016) and further reduction of 13% when comparing M1 with M3 (7.74±3), CI=(3.91, 17.19) (P=0.057) (Figure 2).

Number of patients (%), number of surgeries (%), Time (min, hours, days) 22 50.4±5 n(%) 8 (36.4%) 7 (31.8%) 2 (9.9%) 2 (9.9%) 1 (4.54%) 1 (4.54%) 1 (4.54%) 94.1±14.8 12.1±1.2 10.1±0.8 2.9±0.3

CABG=coronary artery bypass grafting, IAC=interatrial septal defect, CPB= cardiopulmonary bypass, MV=mechanical ventilation, ICU=intensive care unit

Fig. 2 - Peripheral muscle strength. Peripheral muscle strength in patients undergoing cardiac surgery. M1 (preoperative assessment), M2 (assessment on the day of discharge from ICU), M3 (assessment on the day of hospital discharge). The data were assessed using the one-way ANOVA test and Bonferroni post-test.

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Limitations of the study The fact that this was a pilot study limits the interpretation of some data. Even in the absence of a gold standard for assessment of peripheral muscle strength, dynamometry is an effective, practical and reproducible method has demonstrated in the literature[15].

DISCUSSION The main finding of our study was the reduction in muscle strength of the lower limbs of patients undergoing elective cardiac surgery procedure. Some studies have reported that postoperative complications of cardiac surgery may contribute to the increased staying time of intensive care unit[3], especially respiratory and metabolic complications[9]. Nevertheless, decrease in postoperative functionality of these patients has been reported[10]. Among the postoperative respiratory complications, one aggravating factor is the loss of respiratory muscle strength[11], but so far, it is unknown whether such loss is also reproduced in peripheral muscle strength. Peripheral muscle force (PMS) can be regarded as a predictor of overall muscular strength, and is associated with functional and nutritional presentation of the patient[12,13]. Nevertheless, the PMS has been little explored in the literature, especially in the context of complications from surgery, the reason why the study was proposed. Diffuse neuromuscular abnormalities have been reported in 50% of patients admitted to the ICU after staying on mechanical ventilation, with the primary clinical sign the physical deconditioning and muscle weakness[14]. Immobility in bed following surgical procedures, the use of cardiopulmonary bypass (CPB) and mechanical ventilation, the pain caused by sternotomy and saphenectomy, the presence of drains and venous access, peripheral edema, among other factors, are conditions that limit mobility in bed and consequently the functionality[6]. It is known that the functionality of cardiac patients can be severely limited by the reduction of muscle mass and strength, decreased oxidative capacity and a significant deficit in blood flow affecting the energy intake to the muscle[6]. In the present study, after ten days, on average, CABG patients were discharged from hospital (M3) and currently has detected an increase in the PMS values compared to the values listed in M2, demonstrating loss of only 10% when compared with M1. Even with the limitation of the study, taking into consideration the design and duration of patient follow-up, it is not possible to identify the causes of incomplete restoration of PMS in patients postoperatively, but it is noteworthy that the patients had a good recovery of strength muscle, which was demonstrated by the absence of significant differences when comparing the previous values with the day of discharge. However, it is clear that the moment of greatest restriction on the bed (due to the drains, access and pain) is closely linked to the largest deficit in muscle strength (M2), emphasizing the need for early inclusion of this patient in cardiac rehabilitation protocols with supervised physical exercise.

CONCLUSION Patients undergoing cardiac surgical procedures may present reduction in peripheral muscle strength in the immediate postoperative period, with a tendency to gain strength in subsequent days until the day of discharge. Potential conflict of interest There was no potential relevant conflict of interest.

Authors’ roles & responsibilities KMSS Data collection MLCN Editing VOC Guidance, supervision VJSF scientific writing and supervision WMSJ training and supervision of staff AAAF Data Collection TCFC Evaluation of patients LAPC Coordination and guidance

REFERENCES 1. Azambuja MIR, Foppa M, Maranhão MFC, Achutti AC. Impacto econômico dos casos de doença cardiovascular grave no Brasil: uma estimativa baseada em dados secundários. Arq Bras Cardiol. 2008;91(3):163-71. 2. Braile DM, Godoy MF. History of heart surgery in the world. 1996. Rev Bras Cir Cardiovasc. 2012;27(1):125-36. 3. Laizo A, Delgado FEF, Rocha GM. Complications that increase the time of hospitalization at ICU of patients submitted to cardiac surgery. Rev Bras Cir Cardiovasc. 2010;25(2):166-71. 4. Savage PA, Shaw AO, Miller MS, VanBuren P, LeWinter MM, Ades PA, et al. Effect of resistance training on physical disability in chronic heart failure. Med Sci Sports Exerc. 2011; 43(8): 1379-86. 5. Cacau LAP, Oliveira GU, Maynard LG, Araujo-Filho AA, Silva Júnior WM, Cerqueira Neto ML, et al. The use of the virtual reality as intervention tool in the postoperative of cardiac surgery. Rev Bras Cir Cardiovasc. 2013;28(2):281-9. 6. Sociedade Brasileira de Cardiologia. Diretriz de Reabilitação Cardíaca. Arq Bras Cardiol. 2005;84(5):431-40.

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7. Nadler SF, DePrince ML, Hauessien N, Malanga GA, Stitik TP, Price E. Portable dynamometer anchoring station for measuring strength of the hip extensors and abductors. Arch Phys Med Rehabil. 2000;81(8):1072-6.

12. Dallan LAO, Jatene FB. Myocardial revascularization in the XXI century. Rev Bras Cir Cardiovasc. 2013;28(1):137-44. 13. Baptista VC, Palhares LC, Oliveira PPM, Silveira Filho LM, Vilarinho KAS, Severino ESBO, Lavagnoli CFR, Petrucci O. Six-minute walk test as a tool for assessing the quality of life in patients undergoig coronary artery bypass grafting surgery. Rev Bras Cir Cardiovasc. 2012;27(2):231-9.

8. Baun K, Hildebrandt U, Edel K, Bertram R, Hahmann H, Bremer FJ et al. Comparison of skeletal muscle strength between cardiac patients and age-matched healthy controls. Int J Med Sci. 2009;6(4):184-91. 9. Desai SV, Law TJ, Needham DM. Long-term complications of critical care. Crit Care Med. 2011;39(2):371-9.

14. De Jonghe B, Bastuji-Garin S, Durand MC, Malissin I, Rodrigues P, Cerf C, Outin H, Sharshar T. Groupe de réflexion et d’etude des neuromyopathies en réanimation. Respiratory weakness is associated with limb weakness and delayed weaning in critical illness. Crit Care Med. 2007;35(9):2007-15.

10. Morais DB, Lopes ACR, Sá VM, Silva Júnior WM, Cerqueira Neto ML. Evaluation of functional performance in patients undergoig cardiac surgery. Rev Bras Cardiol. 2010;23(5):263-9.

15. Poulsen E, Christensen HW, Penny JP, Overgaard S, Vach W, Hartvigsen J. Reproducibility of range of motion and muscle strength measurements in patients with hip osteoarthritis – an inter-rater study. BMC Musculoskelet Disord. 2012;13:242.

11. Matheus GB, Dragosavac D, Trevisan P, Costa CE, Lopes MM, Ribeiro GCA. Postoperative muscle training improves tidal volume and vital capacity in the postoperative period of CABG surgery. Rev Bras Cir Cardiovasc. 2012;27(3):362-9.

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Aydin E & Ozkokeli M - Does Homeostasis Model Assessment of Insulin ORIGINAL ARTICLE Resistance have a predictive value for post-coronary artery bypass grafting surgery outcomes?

Does Homeostasis Model Assessment of Insulin Resistance have a predictive value for post-coronary artery bypass grafting surgery outcomes? O Modelo de Avaliação da Homeostase da Resistência à Insulina tem valor preditivo para os resultados após a cirurgia de revascularização miocárdica?

Ebuzer Aydin1, MD; Mehmet Ozkokeli1, MD

DOI: 10.5935/1678-9741.20140105

RBCCV 44205-1563

Abstract Objective: This study aims to investigate whether pre-operative Homeostasis Model Assessment Insulin Resistance (HOMA-IR) value is a predictor in non-diabetic coronary artery bypass grafting patients in combination with hemoglobin A1c, fasting blood glucose and insulin levels. Methods: Eighty one patients who were admitted to Cardiovascular Surgery Clinic at our hospital between August 2012 and January 2013 with a coronary artery bypass grafting indication were included. Patients were non-diabetic with <6.3% hemoglobin A1c and were divided into two groups including treatment and control groups according to normal insulin resistance (HOMA-IR<2.5, Group A; n=41) and high insulin resistance (HOMA-IR>2.5, Group B; n=40), respectively. Pre-operative fasting blood glucose and insulin were measured and serum chemistry tests were performed. The Homeostasis Model Assessment Insulin Resistance values were calculated. Statistical analysis was performed.

Results: There was a statistically significant difference in fasting blood glucose and HOMA-IR values between the groups. Cross-clamping time, and cardiopulmonary bypass time were longer in Group B, compared to Group A (P=0.043 and P=0.031, respectively). Logistic regression analysis revealed that hemoglobin A1c was not a reliable determinant factor alone for pre-operative glucometabolic evaluation of non-diabetic patients. The risk factors of fasting blood glucose and cardiopulmonary bypass time were more associated with high Homeostasis Model Assessment Insulin Resistance levels. Conclusion: Our study results suggest that preoperative screening of non-diabetic patients with Homeostasis Model Assessment Insulin Resistance may improve both follow-up visit schedule and short-term outcomes, and may be useful in risk stratification of the high-risk population for impending health problems.

Kartal Kosuyolu Training and Research Hospital Istanbul, Turkey.

Correspondence address: Ebuzer Aydin Denizer Caddesi no: 2 Cevizli Kavsagi Kartal ,Istanbul, Turkey E-mail: ebuzermd@gmail.com

Descriptors: Atherosclerosis. Blood Glucose. Cardiopulmonary Bypass. Insulin Resistance. Perioperative Care. Prediabetic State.

This study was carried out at Kartal Kosuyolu Training and Research Hospital, Istambul, Turkey.

Article received on December 3th, 2013 Article accepted on March 14th, 2014

No financial support.

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revascularização do miocárdio para pacientes não diabéticos em combinação com a hemoglobina A1c, glicemia em jejum e insulina. Métodos: Oitenta e um pacientes que foram internados no serviço de Cirurgia Cardiovascular em nosso hospital entre agosto de 2012 e janeiro de 2013, com indicação para cirurgia de revascularização do miocárdio indicação foram incluídos. Os pacientes não diabéticos com <6,3% de hemoglobina A1c foram divididos em dois grupos, incluindo os grupos de tratamento e controle de acordo com a resistência à insulina normal (HOMA-IR <2,5, Grupo A, n=41) e alta resistência à insulina (HOMA-IR> 2,5, Grupo B, n=40), respectivamente. Glicemia de jejum pré-operatório e insulina foram medidas e testes de química do soro foram realizados. Os valores de HOMA-IR foram calculados. A análise estatística foi realizada. Resultados: Houve diferença estatisticamente significativa em jejum de valores de glicose no sangue e HOMA-IR entre os grupos. Tempo de pinçamento e tempo de circulação extracorpórea foi maior no grupo B, em relação ao Grupo A (P=0,043 e P=0,031, respectivamente). A análise de regressão logística revelou que hemoglobina A1c não foi um fator determinante para a avaliação confiável sozinho glicometabólico pré-operatória de pacientes não diabéticos. Os fatores de risco de glicemia de jejum e tempo de circulação extracorpórea foram associados com altos níveis do HOMA-IR. Conclusão: Nossos resultados sugerem que a triagem pré-operatória de pacientes não diabéticos utilizando o HOMA-IR pode melhorar tanto o cronograma de acompanhamento quanto resultados de curto prazo, e pode ser útil na estratificação da população de alto risco para iminentes problemas de saúde.

Abbreviations, acronyms & symbols ADA BMI BP CABG CAD CMRI COPD CPB DM EASD ESC FBG FBI HbA1c HOMA-IR ICU IGT IR IRB LVEDV LVM/ht2.7 MACE MI OGTT PAD SPSS TEKHARF

American Diabetes Association Body mass index Blood pressure Coronary artery bypass grafting Coronary artery disease Cardiovascular magnetic resonance imaging Chronic obstructive pulmonary disease Cardiopulmonary bypass Diabetes mellitus European Association for the Study of Diabetes European Society of Cardiology Fasting blood glucose Fasting blood insulin Hemoglobin A1c fraction Homeostasis Model Assessment Insulin Resistance Intensive care unit Impaired glucose tolerance Insulin resistance Institutional Review Board Left ventricular end-diastolic volume Left ventricular mass indexed to height Major adverse cardiac events Myocardial infarction Oral glucose tolerance Peripheral arterial disease Statistical Package for Social Sciences Study Turkish Adult Risk Factor Study

Resumo Objetivo: Este estudo tem como objetivo investigar se a resistência de valor do Modelo de Avaliação da Homeostase da Resistência à Insulina (Homeostasis Model Assessment Insulin Resistance - HOMA-IR) no pré-operatório é um preditor de

Descritores: Atesclerose. Glicemia. Ponte Cardiopulmonar. Resistência à Insulina. Assistência Perioperatória. Estado Pré-Diabético.

INTRODUCTION

(4.1 million) among the population aged ≥35 years in 2007/2008 in Turkey[10]. A large-scale study performed in Turkey revealed that impaired glucose tolerance (IGT) was increased from 6.7% to 13.9% (approximately 14 million patients) in the adult population over 20 years of age in a 12-year period[11,12]. To overcome this impending health problem, guidelines and expert consensus documents for practicing physicians have been developed by the World Health Organization, American Diabetes Association (ADA), European Society of Cardiology (ESC) and European Association for the Study of Diabetes (EASD)[13,14]. However, there are several studies questioning the discriminative power of predictors when they are used alone[15]. In a recent study, hemoglobin A1c (HbA1c) has been shown to be intervened by hemoglobinopathies and any condition which reduces erythrocyte survival or decreases mean erythrocyte age. Although oral glucose tolerance test is accepted as the gold standard for DM today, it is costly, time-consuming, labor-intensive, and impractical for DM screening[15,16].

The cardiovascular risk is increased in individuals, who are non-diabetic, but have elevated insulin and glucose concentrations[1,2]. Elevated insulin and glucose concentrations which are likely to be pro-atherogenic are directly associated with insulin resistance[3,4]. Molecular studies have shown that insulin resistance plays a major role in all stages of atherosclerosis[5]. It promotes atherosclerosis and coronary artery diseases, while metabolic factors such as dyslipidemia, hypertension, and obesity may also contribute to the development of cardiac problems[3,6]. Recently, some authors have suggested that diabetes mellitus (DM) is the measured tip of a much larger ‘dysglycemic iceberg’[7]. There is growing evidence that dysglycemia, irrespective of DM history, is associated with adverse outcomes including prolonged hospitalization and higher mortality in coronary artery bypass grafting (CABG) patients[8,9]. The prevalence of prediabetes was estimated as 13.9%

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Homeostasis Model Assessment Insulin Resistance (HOMA-IR) is a validated and frequently used marker of insulin resistance. It incorporates both glucose and insulin concentrations to represent insulin resistance, which promotes atherosclerosis through endothelial dysfunction due to altered insulin signaling in endothelial cells[17]. As a result, it may be more strongly associated with cardiovascular disease than glucose or insulin concentrations, alone[3,6]. In this study, we aimed to investigate whether pre-operative HOMA-IR value is a predictor in non-diabetic CABG patients when used in combination with HbA1c, fasting blood glucose (FBG) and fasting blood insulin (FBI) levels.

lin resistance (HOMA-IR>2.5, Group B; n=40), respectively. Routine pre-operative laboratory tests including FBI and HOMA, and serum chemistry tests were performed. After an overnight fasting, venous blood samples were collected for the measurement of HbA1c level, plasma concentration of glucose, and insulin. Plasma glucose level was measured by glucose-oxidase method. Hemoglobin A1c was measured by high-performance liquid chromatography, whereas plasma insulin was measured using radioimmunoassay. The patients underwent CABG by our surgical team and using a single technique. Patients were closely monitored intra- and post-operatively for mortality and morbidity.

METHODS

Statistical Analysis Statistical analysis was performed using SPSS for Windows v12.0 software (SPSS Inc., Chicago, IL, USA). At baseline, sample size was estimated by statistical analysis to achieve significant results. Power level was 90% to detect a difference between the group proportions (-0.3000). The proportion in Group A (treatment group) was assumed to be 0.1000 under the null hypothesis and 0.4000 under the alternative hypothesis. The proportion in Group B (control group) was 0.1000. Two-sided Z test was used with pooled variance. The significance level of the test was targeted at 0.0500. The significance level actually achieved by this design was 0.0510. Numerical parameters were expressed in mean, median, standard deviation, and maximum and minimum values. Categorical variables were expressed in numbers and percentages. The Mann-Whitney U test was performed to compare the binary groups in terms of abnormally distributed numerical variables. Cross-table statistics (Chi-square, Fisher, McNemar test) were used to compare categorical variables. Logistic regression analysis was also performed to define risk factors of the disease and to estimate disease probability, when individual characteristics of each patient were known or specific measurements were performed. Analysis of covariance (ANCOVA) was performed to compare the means of numerical variables between the groups. A P value of <0.05 was considered significant.

Study Population This randomized, prospective clinical study included 81 of 557 patients who were admitted to Cardiovascular Surgery Outpatient Clinic at Kartal Kosuyolu Training and Research Hospital between August 2012 and January 2013 with a CABG indication. Patients who neither were previously diagnosed with type 2 diabetes nor on any type of diabetic treatment were screened for HbA1c values. According to 2010 ADA guidelines for HbA1c identification, patients with an HbA1c value of <6.3% were included [14]. Diabetic patients were excluded due to the high mortality and morbidity rates in this population. Patients were divided into two groups: Group A consisted of 41 patients with normal insulin resistance (HOMA <2.5), while Group B consisted of 40 patients with high insulin resistance (HOMA-IR>2.5). The study was performed in accordance with the principles of Declaration of Helsinki. The study protocol was approved by Institutional Review Board (IRB) of Kartal Kosuyolu Training and Research Hospital (IRB No: 538.38792903/ 6010). Written informed consents, which were obtained from the patients, were confirmed by the IRB. Data Collection Blood glucose was measured after 12-hour fasting by using hexokinase method with Olympus AU-640e Chemistry Analyzer (Olympus America Inc., Melville, NY, USA), while FBI was measured by using chemiluminescence method with Siemens Advia Centaur XP Immunoassay System (Siemens Healthcare Diagnostics Inc., NY, USA). The HOMA values were calculated by using either the formula which was described by Matthews et al.[18] (HOMA-IR = insulin (μU/mL) × fasting glucose (mmol/L)/22.5) or using the HOMA calculator website of Oxford University, Endocrinology and Metabolism Centre, Diabetes Trials Unit of Diabetes[19]. The cut-off value of HOMA-IR was considered 2.5[20]. The patients were divided into two groups including treatment and control groups, according to normal insulin resistance (HOMA-IR<2.5, Group A; n=41) and high insu-

RESULTS Of the patients, 70 were males and 11 were females. The mean age was 63.3±9.4 years (range, 34 to 81 years). Group A consisted of 41 patients with normal insulin resistance (HOMA <2.5), while Group B consisted of 40 patients with high insulin resistance (HOMA-IR>2.5). Demographic and clinical characteristics of the patients are summarized in Table 1. There was no statistically significant difference in demographic characteristics between the groups, except hypertension (Table 1). There was either no statistically sig-

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nificant difference in the preoperative characteristics of the patients between the groups. Both groups had similar rates for smoking, preoperative stroke, and chronic pulmonary obstructive disease. The number of patients with hypertension was statistically significantly higher in Group B (P<0.049). Glucometabolic evaluation demonstrated that fasting blood insulin and HOMA-IR values were statistically significant different between the treatment and control group (both P<0.001). However, no significant change in FBG and HbA1c values was observed between the groups. Cross-clamping time, Cardiopulmonary bypass (CPB) time, and length of hospitalization were longer in Group B compared to Group A, however, only cross-clamping and CPB time reached statistically significance (P=0.043 and P=0.031, respectively) (Table 1).

There was also a significant difference in the mean cross-clamping time, which was refined from covariant impact between the HOMA groups (P=0.009). It was observed that FBG and the number of revascularized vessels during CABG affected cross-clamping time (P=0.002, and P<0.001, respectively). In the logistic regression analysis, HbA1c risk factor was less frequently seen in Group B, compared to Group A. The risk factors of FBG and CPB time were highly associated with high HOMA levels (Table 2). There was no statistically significant difference in the postoperative data including inotrope use, postoperative MI, rate of rhythm changes from baseline, the presence of infection, duration of ICU care and length of hospitalization between the groups. Two patients including one in Group A and one in Group B died after surgery due to the low cardiac output.

Table 1. Demographic and clinical data of the study groups. Group A: Group B: P value HOMA <2.5 HOMA>2.5 n=41 (%) n=40 (%) Mean age (yrs, SD) 64.3±9.8 62.3±8.9 0.349 Males 37 33 Smoker 16 (39.0%) 17 (42.5%) 0.750 Renal failure 6 (14.6%) 9 (22.5%) 0.362 Hypertension 21 (51.2%) 29 (72.5%) 0.049 PAD 6 (14.6%) 5 (12.5%) 0.779 COPD 22 (53.7%) 20 (50.0%) 0.742 CVA 4 (9.8%) 1 (2.5%) 0.359 Number of Revascularized Vessels 2.4±1.0 2.7±1.1 0.127 Pre-op MI 22 (53.7%) 21 (52.5%) 0.917 FBG (mg/dL) 99.7±18.6 107.5±25.3 0.094 FBI (µU/mL) 5.3±3.0 23.0±18.5 <0.001 HbA1c (%) 5.9±0.3 5.8±0.4 0.097 HOMA-IR 1.3±0.7 6.0±5.1 <0.001 Cross-clamping time (min) 45.5±18.2 61.9±36.7 0.043 Pump time (min) 75.6±25.3 97.9±46.0 0.031 Hospitalization duration (days) 6.5±1.5 7.2±1.7 0.061 PAD=peripheral arterial disease; COPD=chronic pulmonary obstructive disease; CVA=cerebrovascular event; MI=myocardial infarction; FBG=fasting blood glucose; FBI=fasting blood insulin Parameters

Table 2. Logistic regression model with dependent variable as HOMA (normal/high).

FBG HbA1c PAD (Yes/No) HT (Yes/No) Pump time Post-op EF Hospitalization duration (day) Smoking (Yes/No)

β*

Odds

0.036 -1.553 -1.245 0.785 0.023 0.022 0.159 1.059

0.016 0.782 0.935 0.598 0.011 0.024 0.207 0.693

0.021 0.047 0.183 0.189 0.026 0.363 0.443 0.127

1.036 0.212 0.288 2.193 1.024 1.022 1.172 2.883

%95 Confidence interval Min. Max. 1.005 1.069 0.046 0.979 0.046 1.798 0.679 7.075 1.003 1.045 0.975 1.072 0.781 1.757 0.741 11.210

β=regression coefficient; SE=standard error; FBG=fasting blood glucose; PAD=peripheral artery disease; HT=hypertension; EF=ejection fraction

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DISCUSSION

surgery between the two groups. Although the mean age was not statistically significant between the groups, it was observed that patients who required undergoing CABG with high HOMA levels were 3.3 years younger than those with normal HOMA levels. We considered that it was clinically significant in the clinical practice. Moreover, the surgical team reported worse quality in the vascular structures in Group B, and the incidence of hypertension was statistically significantly higher in this group. In the light of literature, we concluded that insulin resistance levels might be closely related to coronary vascular pathologies leading to CAD development in our study population. Also, we considered that clinical outcomes of the vascular damage presented itself as hypertension disease, poor vascular quality during operation, and longer cross-clamping and CPB pump time in the operation as well as high HOMA levels, and that, thereby, HOMA might be a reliable variable indicating the underlying problem in patients who were progressing to a more complicated stage of pathogenesis. Tekumit et al.[26] conducted a prospective study including a total of 166 patients undergoing CABG. Among them, 60% patients without diabetes history were diagnosed with dysglycemia using the OGTT The authors concluded that fasting blood glucose alone was not sufficient to diagnose nearly half of the patients with dysglycemia. They recommended, thus, addition of HbA1c to the preoperative examination schedule. In another study from Korea investigating the relationship between insulin resistance and post-interventional complications in patients undergoing percutaneous coronary intervention, major adverse cardiac events (MACE) were observed within 30 days after the procedure[27]. It was reported that high HOMA-IR value was related to high incidence of complications and short-term MACE even in non-diabetic patients. Furthermore, in another cross-sectional study including 61 patients with DM undergoing coronary angiogram for the evaluation of CAD, Srinivasan et al.[28] found a statistically significant correlation between HOMA-IR value and severity of CAD, as assessed by Gensini score. The authors concluded that HOMA-IR measurement might be helpful in predicting the severity of CAD. In this present study, HbA1c values were increased more in Group A, whereas FBI (P<0.001), and glucose (P=0.094) levels were higher in Group B, as evidenced by the logistic regression analysis. Review of the literature revealed that insulin resistance was not only a component of glucose metabolism for DM, however, it could also be another missing element in atherosclerosis. We suggested that HOMA-IR might be a reasonable and reliable test for metabolic examination among prediabetic individuals who were referred to a tertiary healthcare center for further diagnosis and treatment of CAD. In our study, it was striking that HbA1c levels were within normal limits in patients with longer cross-clamping time, despite in-

In this study, we investigated whether HOMA-IR value was a predictor in non-diabetic coronary CABG patients when used in combination with HbA1c, FBG and FBI levels. Our results showed that HOMA-IR might provide an insight to the glucometabolic states of non-diabetic individuals before CABG surgery, when used in combination with HbA1c, FBG and FBI levels. With respect to diabetes and aging population of the world, it is certain that more powerful set of tools should be developed for prediabetic individuals to establish effective prevention, management, and treatment options in the following years. Velagalati et al.[21] performed a study in 1603 Framingham Heart Study Offspring participants to elucidate the potential relationship of increasing insulin resistance as well as high levels of insulin and glucose with cardiac structure by using cardiovascular magnetic resonance imaging (CMRI) modality. The authors observed that higher levels of HOMA-IR were related to increasing left ventricular mass indexed to height (LVM)/ht2.7 and left ventricular end-diastolic volume (LVEDV) in both male and females. Sung et al.[22] performed one of the largest-sized clinical trials in 49,076 normoglycemic healthy Korean subjects to define the possible correlation between insulin resistance and high blood pressure. Based on anthropometric measurements, metabolic variables including FBI and HOMA, and serum chemistry tests, a significant and independent correlation among the level of IR, BMI, waist circumference and systolic BP, diastolic BP, and the prevalence of high BP was reported in normoglycemic subjects. Although the correlation between insulin resistance and hypertension has been a subject of long lasting debate in many studies in the literature, the results of large-sample sized study performed on rather young, non-obese, normoglycemic individuals were quite supportive in favor of the existence of a correlation, as the study revealed increased atherogenic risk factors related to insulin resistance in the study population. Furthermore, prolonged fasting, which is a physiological condition characterized by muscular insulin resistance in the presence of increased free fatty acid levels, increased fat oxidation and low glucose and insulin levels, is likely to be associated with insulin resistance[23]. The prolonged preoperative fasting also increases the metabolic stress of the surgery and thereby increases insulin resistance and hyperglycemia[24]. Although the exact underlying mechanism remains to be elucidated, defects in transmembrane proteins appear to play an important role[25]. In addition, cross-clamping time, and CPB time were statistically significantly longer in patients with high HOMA-IR values in our study, despite similar data including preoperative demographic characteristics, number of previous bypass surgery, and number of additional cardiac procedures during

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creased HOMA levels. In the light of literature data regarding the possible factors affecting the results of HbA1c levels[20], we concluded that HOMA-IR might be used during prediabetic patient screening in combination with HbA1c thanks to its promising predictive potential, cost-effectiveness, and easy-to-use handling.

5. Kanan L, Chernoff A. Insulin Resistance and Atherosclerosis: Is it Time to Measure HOMA-IR to Predict Coronary Artery Disease? N Am J Med Sci. 2013;5(10):615-6. 6. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011;14(5):575-85. 7. Gerstein HC. Glycosylated hemoglobin: finally ready for prime time as a cardiovascular risk factor. Ann Intern Med. 2004;141(6):475-6.

Limitations The major limitation of this study was the small sample size. A larger sample size from multiple tertiary healthcare centers would provide higher statistical power for the outcomes.

8. Halkos ME, Lattouf OM, Puskas JD, Kilgo P, Cooper WA, Morris CD, et al. Elevated preoperative hemoglobin A1c level is associated with reduced long-term survival after coronary artery bypass surgery. Ann Thorac Surg. 2008;86(5):1431-7.

CONCLUSION

9. Alserius T, Anderson RE, Hammar N, Nordqvist T, Ivert T. Elevated glycosylated haemoglobin (HbA1c) is a risk marker in coronary artery bypass surgery. Scand Cardiovasc J. 2008;42(6):392-8.

In conclusion, our study results suggest that HOMA-IR is a predictor in non-diabetic CABG patients. We believe that pre-operative screening of non-diabetic patients with HOMA-IR in combination with HbA1c may improve both follow-up visit schedule and short-term outcomes, and may be useful in risk stratification of the high-risk population regarding impending health problems which may likely to be originated from two main chronic diseases: coronary artery disease and diabetes mellitus. However, we believe further studies are required to confirm these findings.

10. Ceyhan K, Altunkas F. [Prediabetes, becoming the equivalent of coronary artery disease]. Turk Kardiyol Dern Ars. 2012;40(5):458-65. 11. Satman I, Yilmaz T, Sengül A, Salman S, Salman F, Uygur S, et al. Population-based study of diabetes and risk characteristics in Turkey: results of the turkish diabetes epidemiology study (TURDEP). Diabetes Care. 2002;25(9):1551-6.

Disclosure No conflict of interest.

12. Satman I, Omer B, Tutuncu Y, Kalaca S, Gedik S, Dinccag N, et al.; TURDEP-II Study Group. Twelve-year trends in the prevalence and risk factors of diabetes and prediabetes in Turkish adults. Eur J Epidemiol. 2013;28(2):169-80.

Authors’ roles & responsibilities

13. World Health Organization. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. 2006; (NLM classification: WK 810) [Accessed Sep 3, 2013]. Available at: http://whqlibdoc.who.int/ publications/2006/9241594934_eng.pdf

EA Main author MO Coauthor

14. Rydén L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, et al; Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC); European Association for the Study of Diabetes (EASD). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J. 2007;28(1):88-136.

REFERENCES 1. Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215-22. 2. Sarwar N, Sattar N, Gudnason V, Danesh J. Circulating concentrations of insulin markers and coronary heart disease: a quantitative review of 19 Western prospective studies. Eur Heart J. 2007;28(20):2491-7.

15. Bennett CM, Guo M, Dharmage SC. HbA(1c) as a screening tool for detection of Type 2 diabetes: a systematic review. Diabet Med. 2007;24(4):333-43.

3. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058-70.

16. Wang W, Lee ET, Fabsitz R, Welty TK, Howard BV. Using HbA(1c) to improve efficacy of the American Diabetes Association fasting plasma glucose criterion in screening for new type 2 diabetes in American Indians: the strong heart study. Diabetes Care. 2002;25(8):1365-70.

4. Yu Q, Gao F, Ma XL. Insulin says NO to cardiovascular disease. Cardiovasc Res. 2011;89(3):516-24.

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17. Aziz A, Wheatcroft S. Insulin resistance in Type 2 diabetes and obesity: implications for endothelial function. Expert Rev Cardiovasc Ther. 2011;9(4):403-7.

23. Hoeks J, van Herpen NA, Mensink M, Moonen-Kornips E, van Beurden D, Hesselink MK, et al. Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance. Diabetes. 2010;59(9):2117-25.

18. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-9.

24. Feguri GR, Lima PR, Lopes AM, Roledo A, Marchese M, Trevisan M, et al. Clinical and metabolic results of fasting abbreviation with carbohydrates in coronary artery bypass graft surgery. Rev Bras Cir Cardiovasc. 2012;27(1):7-17.

19. HOMA calculator web site for Diabetes Trials Unit of Diabetes, Endocrinology and Metabolism. Centre at Oxford University [Acessed Mar 7, 2013]. Available at: http:// www.dtu.ox.ac.uk/ homacalculator/

25. Zecchin HG, Carvalheira JBC, Saad MJA. Molecular mechanisms for insulin resistance in the metabolic syndrome. Rev Soc Cardiol Estado de S達o Paulo. 2004;(4):574-89.

20. Sharma S, Fleming SE. Use of Hba(1C) testing to diagnose prediabetes in high risk African American children: a comparison with fasting glucose and HOMA-IR. Diabetes Metab Syndr. 2012;6(3):157-62.

26. Tekumit H, Cenal AR, Polat A, Uzun K, Tataroglu C, Akinci E. Diagnostic value of hemoglobin A1c and fasting plasma glucose levels in coronary artery bypass grafting patients with undiagnosed diabetes mellitus. Ann Thorac Surg. 2010;89(5):1482-7.

21. Velagaleti RS, Gona P, Chuang ML, Salton CJ, Fox CS, Blease SJ, et al. Relations of insulin resistance and glycemic abnormalities to cardiovascular magnetic resonance measures of cardiac structure and function: the Framingham Heart Study. Circ Cardiovasc Imaging. 2010;3(3):257-63.

27. Yun KH, Jeong MH, Kim KH, Hong YJ, Park HW, Kim JH, et al. The effect of insulin resistance on prognosis of non-diabetic patients who underwent percutaneous coronary intervention. J Korean Med Sci. 2006;21(2):212-6.

22. Sung KC, Kim BJ, Kim BS, Kang JH, Lee MH, Park JR, et al. In normoglycemic Koreans, insulin resistance and adipocity are independently correlated with high blood pressure. Circ J. 2004;68(10):898-902.

28. Srinivasan MP, Kamath PK, Manjrekar PA, Unnikrishnan B, Ullal A, Kotekar MF, et al. Correlation of severity of coronary artery disease with insulin resistance. N Am J Med Sci. 2013;5(10):611-4.

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Aydin E, et al.ORIGINAL - ComparisonARTICLE of superior septal approach with left atriotomy in mitral valve surgery

Comparison of superior septal approach with left atriotomy in mitral valve surgery Comparação da abordagem septal superior com atriotomia esquerda em cirurgia valvar mitral

Ebuzer Aydin1, MD; Akin Arslan1, MD; Mehmet Ozkokeli1, MD

DOI: 10.5935/1678-9741.20140045

RBCCV 44205-1564

Abstract Objective: In this study, we aimed to compare clinical outcomes of superior transseptal approach with the conventional left atriotomy in patients undergoing mitral valve surgery. Methods: Between January 2010 and November 2012, a total of 91 consecutive adult patients (39 males, 52 females; mean age: 54.0±15.4 years; range, 16 to 82 years) who underwent mitral valve surgery in the Division of Cardiovascular Surgery at Koşuyolu Training Hospital were included. The patients were randomized to either superior transseptal approach (n=47) or conventional left atriotomy (n=44). Demographic characteristics of the patients, comorbidities, additional interventions, intraoperational data, pre- and postoperative electrophysiological study findings, and postoperative complications were recorded. Results: Of all patients, 86.7% (n=79) were in New York Heart Association Class III, while 12 were in New York Heart Association Class IV. All patients underwent annuloplasty (42.9%) or valve replacement surgery (57.1%). There was no significant difference in pre- and postoperative electrocardiogram findings between the groups. Change from baseline in the cardiac rhythm was statistically significant in superior transseptal approach group alone (P<0.001). There was no statistically significant difference in mortality rate between the groups. Permanent pacemaker implantation was performed in 10.6% of the patients in superior transseptal approach group and 4.5% in the conven-

tional left atriotomy group. No statistically significant difference in bleeding, total length of hospital and intensive care unit stay, the presence of low cardiac output syndrome was observed between the groups. Conclusion: Our study results suggest that superior transseptal approach does not lead to serious or fatal adverse effects on sinus node function or atrial vulnerability, compared to conventional approach.

Kartal Kosuyolu Training and Research Hospital/ Department of Cardiovascular Surgery, Istanbul, Turkey.

Correspondence address: Ebuzer Aydin Denizer Caddesi no: 2 Cevizli Kavsagi Kartal, Istanbul, Turkey. E-mail: ebuzermd@gmail.com

Descriptors: Atrial fibrillation. Heart Valve Diseases. Postoperative Complications. Heart Atria. Atrial Septum. Electrocardiography. Resumo Objetivo: O objetivo deste estudo é comparar os resultados clínicos da abordagem septal superior com a atriotomia esquerda convencional em pacientes submetidos à cirurgia valvar mitral. Métodos: Entre janeiro de 2010 e novembro de 2012, foi incluído um total de 91 pacientes adultos consecutivos (intervalo de 16 a 82 anos, média 54,0±15,4 anos; 39 homens, 52 mulheres) submetidos à cirurgia valvar mitral no Serviço de Cirurgia Cardiovascular no Hospital Training Koşuyolu. Os pacientes foram randomizados para abordagem septal superior (n=47) ou atriotomia esquerda convencional (n=44). Foram registra-

This study was carried out at Kartal Kosuyolu Training and Research Hospital, Istambul, Turkey.

Article received on September 18th, 2013 Article accepted on November 17th, 2013

No financial support. No conflict of interest

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Resultados: Do total de pacientes, 86,7% (n=79) estavam na Classe III e 12 na Classe IV da New York Heart Association. Todos os pacientes foram submetidos à anuloplastia (42,9%) ou cirurgia de troca valvar (57,1%). Não houve diferença significativa nos resultados do eletrocardiograma pré e pós-operatórios entre os grupos. Mudança da linha de base no ritmo cardíaco foi estatisticamente significativa apenas no grupo abordagem septal superior (P<0,001). Não houve diferença estatisticamente significativa na taxa de mortalidade entre os grupos. Marca-passo definitivo foi implantado em 10,6% dos pacientes no grupo abordagem septal superior e em 4,5% dos pacientes no grupo atriotomia esquerda convencional. Não houve diferença estatisticamente significativa no sangramento, tempo total de internação e de permanência na UTI, tendo sido observada síndrome de baixo débito cardíaco entre os grupos. Conclusão: Nossos resultados sugerem que a abordagem septal superior não leva a efeitos adversos graves ou fatais em função do nó sinusal ou vulnerabilidade atrial, em comparação com a abordagem convencional.

Abbreviations, acronyms & symbols ACC American College of Cardiology AHA American Heart Association CABG Coronary Artery Bypass Grafting CPR Cardiopulmonary Resusitation DVA Valve De Vega Annuloplasty ECG Electrocardiogram ECHO Echocardiography EF Ejection Fraction ESC European Society of Cardiology ICU Intensive Care Unit LA Left Atrium NYHA New York Heart Association PAP Pulmonary Artery Pressure RF Radiofrequency STA Superior Transseptal Approach

das características demográficas dos pacientes, comorbidades, intervenções adicionais, dados intraoperatórios, achados do estudo eletrofisiológico pré e pós-operatório e complicações pós-operatórias.

Descritores: Fibrilação Atrial. Doenças das Valvas Cardíacas. Complicações Pós-Operatórias. Átrios do Coração. Septo Interatrial. Eletrocardiografia.

INTRODUCTION

STA with the conventional left atriotomy (LA) in patients undergoing mitral valve surgery.

Good exposure is mandatory for mitral valve surgery, when the original valve is calcified or a previously implanted mitral prosthesis is removed. Mitral visualization may be insufficient due to the small size of the left atrium and markedly hypertrophic right ventricle. Previous cardiac operations may complicate mitral valve exposure, as adhesions and loss of mobility in the surrounding tissues may be present. In such cases, the conventional left atria1 incision may not offer satisfactory visualization in the surgical site of the valve. Therefore, several alternative approaches have been proposed for satisfactory visualization of the mitral valve intraoperatively[1-5]. Berreklouw et al.[2] and Guiraudon et al.[3] proposed a combined superior-transseptal approach to create a larger operation area which was closer to the mitral valve. Currently, this approach has been adopted by several health care centers[1]. On the other hand, there are possible drawbacks including increased ischemia time, cardiopulmonary bypass (CPB), cross-clamp time, and increased bleeding related to the procedure based on the current clinical experiences[4,5]. Cardiac arrhythmia is one of the main concerns with this procedure. Early atrial tachycardia has been frequently reported[6], while many studies have demonstrated that superior transseptal approach (STA) is commonly associated with sinus node dysfunction[4,7-10]. In this study, we aimed to compare clinical outcomes of

METHOD Patient selection Between January 2010 and November 2012, a total of 91 consecutive adult patients who underwent mitral valve surgery in the Division of Cardiovascular Surgery at Koşuyolu Training and Research Hospital were included. The patients were randomized at a 1:1 ratio to either STA (Group 1, n=47) and conventional LA (Group 2, n=44). Pacemaker implantation criteria were predefined according to the American College of Cardiology / American Heart Association/the European Society of Cardiology (ACC/AHA/ESC) guidelines[11]. The study protocol was approved by the local Ethics Committee of our institution. Surgery Superior transseptal approach A superior venous cannula was inserted directly from the superior vena cava, while an inferior venous cannula was inserted from inferior vena cava. Caval cannulas were inserted more laterally to the right atrium to avoid the appendage of right atrium. The right atriotomy was performed in parallel to the atrioventricular groove and the incision was carried superiorly to the appendage to meet the superior pole of the interatrial septum, leaving a strip of atrial tissue on the ven-

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tricular side to facilitate closure. The retrograde coronary sinus cannulation was performed under vision for the cardioplegia infusion. The aorta was cross-clamped and the heart was arrested with cold blood cardioplegia. The fossa ovalis was incised vertically and the septal incision was carried superiorly to meet the right atriotomy and extended for 2 to 3 cm to the roof of the left atrium. The ventricular side of the septal incision was deflected by two pledgeted sutures which were placed at each pole. After mitral procedure was completed, the left atrial roof was closed primarily with a 3-0 prolene suture to the septum and then the septal incision was closed using another 3-0 prolene suture, starting from the inferior pole of this incision. The air was evacuated from the left side and the aorta was unclamped. The right-sided procedure was carried out when required unclamping the aorta in most cases. The right atriotomy, then, was closed with a 4-0 prolene suture, starting from the two poles to the midpoint of the right atrial wall.

statistics were to analyze the demographic characteristics of the patients. Numerical variables were expressed in mean, median, standard deviation, minimum and maximum values, whereas categorical variables were expressed in numbers and percentages. A P value of <0.05 was considered significant. Either parametric or non-parametric statistical methods were used according to normal distribution of comparative variables. The Student’s t-test was used for numerical variables. This test was also used to compare normally distributed variables between the groups, while the Mann Whitney U test was used to compare abnormally distributed variables. The Wilcoxon test was used to compare pre- and postoperative values. Cross-tabulation was created for categorical variables (Chi -square, Fisher’s exact and McNemar test). RESULTS Of the patients, 39 were males and 52 were females. The mean age was 54.0±15.4 (range, 16 to 82) years. The mean duration of complaints was 1.5±1.1 (range, 0.5 to 10) years. A total of 86.7% (n=79) were in NYHA Class III, while 12 were in NYHA Class IV. A total of 34.1% had diabetes mellitus (DM), 68.1% had chronic obstructive pulmonary disease (COPD), and 11.0% had coronary artery disease (CAD). Demographic and clinical characteristics of the patients undergoing STA or conventional LA are summarized in Table 1. All patients had annuloplasty (42.9%) or valve replacement (57.1%). A total of 48.9% and 36.4% of the patients had annuloplasty in Group 1 and Group 2, respectively, whereas 51.1% and 63.6% of the patients had valve replacement in Group 1 and Group 2, respectively (P>0.05). Nineteen patients in Group 1 and 29 patients in Group 2 required additional interventions including CABG, DVA for tricuspid regurgitation, aortic repair, and RF ablation. Intraoperative data of both groups are summarized in Table 2. The mean diameter of the left atrium (LA) was 4.6±0.6 cm and 4.3±1.0 cm before and after STA, respectively, indicating a statistically significant difference (P<0.001). There was no statistically significant difference in pre- and postoperative diameters of LA between the groups.

Left atrial approach A superior venous cannula was inserted from the right atrial appendage, while an inferior venous cannula was inserted from the inferior vena cava. The procedure was performed between the confluence of the right pulmonary veins and the interatrial groove. Data collection and postoperative patient management Demographic characteristics of the patients, comorbidities, additional interventions such as coronary artery bypass grafting (CABG), De Vega’s annuloplasty (DVA) for tricuspid regurgitation and ring annuloplasty, aortic repair, radiofrequency (RF) ablation, intraoperational data including cross-clamp time, mild hypothermia for myocardial protection, pre- and postoperative electrocardiographic (ECG) findings, postoperative complications including pacemaker implantation and increased bleeding and ischemia time were recorded. Demographic and clinical characteristics of the patients were collected for both groups at the baseline. During surgery, cross-clamp and CPB time, antegrade arrest/prevention, inotropic support and duration of inotropic use were recorded. The amount of bleeding, need for cardiopulmonary resuscitation (CPR), duration of intubation, the presence of a pacemaker, length of hospital and intensive care unit (ICU) stay, postoperative ECHO on the postoperative 6th day and death events were also recorded following surgery. Patients with post- extubation dyspnea received bronchodilators and mechanical or non-invasive mechanical ventilatory support such as continuous positive airway pressure (CPAP) due to low saturation level and/ or decreased partial oxygen pressure.

Postoperative electrophysiological study findings The mean pulmonary artery pressure (PAP) was 46.0±11.6 mmHg preoperatively and 37.0±9.4 mmHg postoperatively. The PAP values for each study group is shown in Table 3. A statistically significant difference in pre- and postoperative values was observed between Group 1 and Group 2 (P<0.001 and P=0.025, respectively). In preoperative and postoperative ECG studies, 78% and 74.2% patients were in sinus rhythm, while 22% and 22.5% had atrial fibrillation, respectively. There was no significant difference in pre- and postoperative ECG findings between the study groups. In Group 1, 32 of 36 patients who were

Statistical analysis A statistical analysis was performed using SPSS v12.0 software (SPSS Inc., Chicago, Illinois, USA). Descriptive

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in sinus rhythm preoperatively remained in sinus rhythm, 1 patient had atrial fibrillation, 2 patients were in nodal rhythm, and 1 had blocked rhythm after surgery. Out of 10 patients with preoperative atrial fibrillation, 3 were switched to sinus rhythm and 7 persisted in atrial fibrillation after surgery. In Group 2,25 of 33 patients who were in sinus rhythm before surgery remained in sinus rhythm, whereas 8 patients had atrial fibrillation postoperatively. Out of 10 patients with preoperative atrial fibrillation, 4 persisted in atrial fibrillation, whereas 6 were in sinus rhythm postoperatively (Figure 1). Change from baseline in the cardiac rhythm was statistically significant in STA group alone (P<0.001). Although clinical stages of the patients in Group 1 were more severe than those in Group 2 (patients in NYHA Class IV 25.5% vs. 0%, respectively), mortality rate was similar between the groups (8.7% vs. 4.5% respectively). A permanent pacemaker was implanted in 5 patients (10.6%) in Group 1, whereas in 2 patients (4.5%) in Group 2 (Table 4).

In the postoperative period, the mean ejection fraction (EF) values were 51.5 ± 14.4% in Group 1 and 40.1 ±12.9% in Group 2. There was a statistically significant difference in postoperative EF values between the groups (P<0.001). Pre- and postoperative mean ejection fractions were 57.2±9.9% and 51.5±14.4% in Group 1, respectively and 57.4±10.0% and 40.1±12.9% in Group 2, respectively. A statistically significant difference in the postoperative ejection fraction values was observed between the groups (P=0.001 and P<0.001 for Groups 1 and 2, respectively). Data are presented in percentages in Figure 2. While there was no statistically significant difference in preoperative EF values between Group 1 and Group 2 (P=0.930), a statistically significant difference in post-operative values was observed between the groups (P<0.001) (Table 3). There was no change from baseline in the number of patients with EF 30-50% (n=13 patients). However, 6 of 29 patients in Group 2 had EF>50% after the operation, while 23 remained at the level of EF 30-50%.

Table 1. Demographic and clinical characteristics of the patients. Variables Median age (yrs, SD) Male Duration of complaints (yrs, SD) New York Heart Association Classification Class III (n, %) Class IV (n, %) Presence of DM (n, %) COPD (n, %) Presence of CAD (n,%) Presence of comorbidities (n, %) Additional intervention (n, %) Number of re-do operation (n, %) Presence of mitral insufficiency (n,%) Presence of mitral stenosis (n,%)

Group 1: Superior Transseptal (n= 47) 53.1±15.4 21 1.5±1.4

Group 2: Left Atriotomy (n= 44) 55.0±15.5 18 1.5±0.5

P value

35 (74.5) 12 (25.5%) 11 (23.4%) 23 (48.9%) 10 (21.3%) 18 (38.3%) 19 (40.4%) 5 (10.6%) 37 (78.7%) 13 (27.7%)

44 (100%) 0 20 (45.5%) 39 (88.6%) 0 3 (6.8%) 29 (65.9%) 4 (4.4%) 31 (70.5%) 11 (25.0%)

<0.001

0.462 0.266

0.027 <0.001 0.001 <0.001 0.015 1.000 0.364 0.774

SD=standard deviation; COPD=chronic pulmonary obstructive disease; DM=diabetes mellitus Table 2. A comparison of intraoperative variables between the groups. Variables Cross-clamp time (min) (mean±SD) CPB time (min) (mean±SD) Antegrade arrest/prevention (n, %) Antegrade + retrograde arrest / prevention (n, %) Inotropic support (n, %) Duration of inotropic use (day) (mean±SD) Presence of respiratory problem (n, %)

Group 1: Superior Transseptal (n= 47) 96.0±26.9 128.3±36.2 9 (19.6%) 37 (80.4%) 36 (76.6%) 1.7±3.2 6 (13.3%)

SD=standard deviation; CPB=cardiopulmonary bypass

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Group 2: Left Atriotomy (n= 44) 83.4±43.1 118.3±56.8 35 (79.5%) 9 (20.5%) 32 (72.7%) 0.7±0.5 0

P value 0.003 0.020 <0.001 0.671 0.046 0.026

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Aydin E, et al. - Comparison of superior septal approach with left atriotomy in mitral valve surgery

Fig. 1 - A comparison of pre- and postoperative ECG findings between the groups.

Fig. 2 - A comparison of pre- and postoperative EF values between the groups.

Table 3. A comparison of pre- and postoperative data. Variables Preoperative EF (mean±SD) Postoperative EF (mean±SD) Preoperative PAP (mean±SD) Postoperative PAP (mean±SD)

Group 1: Superior Transseptal (n= 47) 57.2±9.9 51.5±14.4 45.4±11.3 36.7±9.3

P value

Group 2: Left Atriotomy (n= 44) 57.4±10.0 40.1±12.9 46.7±12.1 38.3±10.3

0.001 <0.001

P value <0.001 0.025

ECMO=extracorporeal membrane oxygenation; EF=ejection fraction; PAP=pulmonary artery pressure; SD=standard deviation

Table 4. A comparison of postoperative variables between the groups. Variables Bleeding (n, %) Postoperative pleural effusion (n, %) Need for revision (n, %) CPR (n, %) Intubation days (mean±SD) Pacemaker implantation (n, %) Length of ICU stay (day) (mean±SD) Length of hospitalization (day) (mean±SD) Exitus (n, %)

Group 1: Superior Transseptal (n= 47) 2 (4.3%) 4 (15.4%) 4 (8.5%) 4 (8.7%) 1.1±0.5 5 (10.6%) 3.7±3.1 15.4±6.4 4 (8.7%)

Group 2: Left Atriotomy (n= 44) 0 0 1 (2.3%) 2 (4.5%) 1.0±0.2 2 (4.5%) 2.6±0.7 14.3±2.9 2 (4.5%)

P value 0.495 0.021 0.362 0.677 0.356 0.436 0.378 0.809 0.677

CPR=Cardiopulmonary ressusitation; ICU=intensive care unit; SD=standard deviation

Among all patients, pacemaker implantation was performed only in 7 (7.7%) patients, including 5 (10.6%) in Group 1 and 2 (4.5%) in Group 2. The difference between the groups was not statistically significant (P=0.436). There was no statistical significance in bleeding, total length of hospital and ICU stay, the presence of low cardiac output syndrome between the groups. A total of 6 patients died; 4 of them were in the Group 1. There was no statisti-

cally significant difference in the mortality rate between the groups (Table 4). DISCUSSION Currently, a changing pattern of mitral valve surgery has been gradually evolving. While the incidence of rheumatic mitral disease has been reducing, there is an increasing

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demand for the correction of mitral insufficiency associated with or without coronary artery disease. These patients have usually small left atria and they are usually scheduled for the operation depending on the coronary artery anatomy, before the left atria have time to enlarge. Moreover, valve replacement surgery is mainly replaced by mitral reconstruction which is performed at earlier stages of the disease thanks to the sophisticated techniques available. Therefore, limited operation area which leads to poor visibility and prevents achieving a better exposure of the mitral valve and subvalvular apparatus during surgery has been one of the main considerations of cardiovascular surgeons. The STA has been defined as one of new surgical approaches to overcome these problems without compromising treatment success. As cardiovasculars surgeons have increased their experiences in new approaches, they prefer superior transseptal incision for patients who are not in sinus rhythm or those with sinus rhythm for whom the surgeon thinks that technical advantages of the incision outweighs the risk of sinus rhythm loss. Similarly, our study results indicate that STA provides an excellent exposure without significant complications in mitral apparatus compared to the conventional LA. The sinus node (SN) function and atrial vulnerability after surgery still remain as important considerations with the STA, since the technique involves transecting the SN artery as well as the anterior internodal conduction pathway. While there are a number of published studies in favor of STA in the literature[1-3,5,12,13], many studies reporting potential concerns regarding the SN dysfunction and atrial vulnerability during postoperative period are available[7,10,14,15]. In a study including 52 patients who underwent mitral valve surgery through STA, the authors reported that the number of the patients with sinus rhythm and atrial fibrillation were equal preoperatively. Eleven patients had transient atrial fibrillation or junctional rhythms for approximately 2 weeks postoperatively. After the mean follow-up period of 15Âą8 months (range, 2-25 months), 25 of 26 patients persisted in sinus rhythm, while 4 patients with preoperative atrial fibrillation showed sinus rhythm at the postoperative 6th month. It was reported that none of the patients required permanent pacemaker implantation due to symptomatic or latent bradycardia as assessed by Holter ECG at the median follow-up time period of 15 months[16]. In our study, we observed favorable changes in ECG results in Group 1, indicating a very low incidence of STA-induced permanent or serious damage, despite the conduction problems and atrial vulnerability in the postoperative period. Depending on our results, we concluded that undesired postoperative events might be decreased by a better operative area exposure, which could also decrease postoperative complications, and increase the success rate of STA. In addition, increasing professional experiences of surgeons and a better

understanding of the conduction system at the sinoatrial node would improve pre- and postoperative evaluation process to decide the most appropriate approach considering the clinical presentation of the patient. In the literature, Lukac et al.[17] reported that STA remained an independent risk factor in their study with a large sample size, in which they compared STA with the left atrial method. However, our results indicated similar mortality rates as well as permanent pacemaker implantation between the groups. Thus, it did not increase fatal or permanent clinical outcomes. Despite possible drawbacks including increased ischemia time, length of hospital stay, CPB, cross-clamp time, and increased bleeding related to the procedure, as previously mentioned, some authors reported no significant difference between the study groups[18,19]. In line with the literature, we observed no significant differences in the amount of bleeding, re-operation, and the length of hospital and ICU stay between the groups in our study. However, intraoperative data revealed that cross-clamp time, CPB time, duration of inotropic use, and respiratory problems were significantly increased in the STA group, compared to the conventional LA group without leading to any severe or unmanageable complications. In our study, the cross-clamp time and CPB time were longer in STA group, as larger incisions were performed and the closure of the incision was performed in two layers as superior and septal. In addition, STA has been a newly used operation method in our clinic, which might also be another reason for prolonged time. When the additional procedures were reviewed, we concluded that tricuspid ring annuloplasty was most commonly performed in the STA group, whereas DVA was the leading method in the conventional LA group. As DVA is more rapidly performed, we believe it might contribute to significant differences between the procedures. The STA group mainly consisted of patients in NYHA Class IV including one of them based on the preoperative extracorporeal membrane oxygenation (ECMO). We believe that preoperative demography and ECMO might significantly prolong the duration of inotropic use in STA group, compared to the conventional LA group. Poor baseline characteristics of the patients in STA group might also lead to increased incidence of postoperative respiratory problems. A higher amount of bleeding in STA group which was not statistically significant between the groups resulted in a higher incidence of pleural effusion. We think that pleural effusion might be another cause of respiratory problems in STA group. Limitations Our study has also some limitations. Firstly, a multi-center study designed for a larger sample size may provide more conclusive results for subgroup analyses in comparison of the two surgical approaches. Secondly, more detailed preoperative electophysiological studies such as sinus node recovery

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time (SNRT), sinoatrial conduction time, intraatrial mapping, and calculation of corrected QT dispersion for each patient may offer a better approximation of the SN function postoperatively for each patient and more detailed information regarding the individually-tailored treatment. This would help us for a better elimination of confounding factors while comparing different approaches, as well as improved postoperative evaluations of clinical outcomes.

transseptal versus conventional left atriotomy: early postoperative study. Ann Thorac Surg. 1995;60(2):426-30. 8. Takeshita M, Furuse A, Kotsuka Y, Kubota H. Sinus node function after mitral valve surgery via the transseptal superior approach. Eur J Cardiothorac Surg. 1997;12(3):341-4. 9. Tambeur L, Meyns B, Flameng W, Daenen W. Rhythm disturbances after mitral valve surgery: comparison between left atrial and extended trans-septal approach. Cardiovasc Surg. 1996;4(6):820-4.

CONCLUSION

10. Utley JR, Leyland SA, Nguyenduy T. Comparison of outcomes with three atrial incisions for mitral valve operations. Right lateral, superior septal, and transseptal. J Thorac Cardiovasc Surg. 1995;109(3):582-7.

Our study results suggest that STA does not increase the incidence of arrhythmia and/or fatal outcomes after mitral valve surgery even in patients with a worse clinical condition.

11. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. Circulation. 2001;104(17):2118-50.

Authors’ roles & responsibilities EA AA MO

Planner, writer, drafting the study, collection, analysis and interprettion of data Collection, analysis and interpretation of data Study Design

REFERENCES

12. Kon ND, Tucker WY, Mills SA, Lavender SW, Cordell AR. Mitral valve operation via an extended transseptal approach. Ann Thorac Surg. 1993;55(6):1413-6.

1. Alfieri O, Sandrelli R, Pardini A, Fucci C, Zogno M, Ferrari M, et al. Optimal exposure of the mitral valve through an extended vertical transseptal approach. Eur J Cardiothorac Surg. 1991;5(6):294-8.

13. Masuda M, Tominaga R, Kawachi Y, Fukumura F, Morita S, Imoto Y; et al. Postoperative cardiac rhythms with superior-septal approach and lateral approach to the mitral valve. Ann Thorac Surg. 1996;62(4):1118-22.

2. Berreklouw E, Ercan H, Schönberger JP. Combined superiortransseptal approach to the left atrium. Ann Thorac Surg. 1991;51(2):293-5.

14. Smith CR. Septal-superior exposure of the mitral valve. The transplant approach. J Thorac Cardiovasc Surg. 1992;103(4):623-8. 15. Arsiwala S, Parikh P, Dixit S, Agney M, Kole S, Saksena D. Combined superior-transseptal approach to the mitral valve. Ann Thorac Surg. 1992;53(1):180-1.

3. Guiraudon GM, Ofiesh JG, Kaushik R. Extended vertical septal approach to the mitral valve. Ann Thorac Surg. 1992;52(5):1058-60.

16. Misawa Y, Fuse K, Kawahito K, Saito T, Konishi H. Conduction disturbances after superior septal approach for mitral valve repair. Ann Thorac Surg. 1999;68(4):1262-4.

4. Masiello P, Triumbari F, Leone R, Itri F, Del Negro G, Di Benedetto G. Extended vertical transseptal approach versus conventional left atriotomy for mitral valve surgery. J Heart Valve Dis. 1999;8(4):440-4.

17. Lukac P, Hjortdal VE, Pedersen AK, Mortensen PT, Jensen HK, Hansen PS. Superior transseptal approach to mitral valve is associated with a higher need for pacemaker implantation than the left atrial approach. Ann Thorac Surg. 2007;83(1):77-82.

5. Gaudino M, Alessandrini F, Glieca F, Martinelli L, Santarelli P, Bruno P, et al. Conventional left atrial versus superior septal approach for mitral valve replacement. Ann Thorac Surg.1997;63(4):1123-7.

18. Nguyen HU. Improved combined superior-transseptal approach to the mitral valve. Asian Cardiovasc Thorac Ann. 2009;17(2):171-4.

6. Lukac P, Hjortdal VE, Pedersen AK, Mortensen PT, Jensen HK, Hansen PS. Atrial incision affects the incidence of atrial tachycardia after mitral valve surgery. Ann Thorac Surg. 2006;81(2):509-13.

19. García-Villarreal OA, Gonzáles-Oviedo R, Rodríquez-Gonzáles H, Martínez-Chapa HD. Superior septal approach for mitral valve surgery: a word of caution. Eur J Cardiothorac Surg. 2003;24(6):862-7.

7. Kumar N, Saad E, Prabhakar G, De Vol E, Duran CM. Extended

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Steinbach M,ORIGINAL et al. - Benefit from using recycling red blood cells in ARTICLE cardiovascular surgery

Benefit from using recycling red blood cells in cardiovascular surgery Benefício do uso de recuperadores de hemácias em cirurgias cardiovasculares

Mariah Steinbach1, MD; Mauricio H. Z. Centenaro1, MD; Rui M. S. Almeida1,2, MD, PhD DOI: 10.5935/1678-9741.20140034

RBCCV 44205-1565

Abstract Objective: To show if blood salvage is indicated in all patients submitted to cardiovascular surgery with cardiopulmonary bypass. Methods: We studied 77 consecutive patients submitted to cardiac surgery with use of blood salvage and cardiopulmonary bypass from November 2010 to June 2012. The sample was divided in three groups, depending on the time of cardiopulmonary bypass. In group A, the time of cardiopulmonary bypass was smaller than 45, in group B from 45 to 90 and in group C greater than 90 minutes. We analyzed the volume of red cells recovered and infused, the pre, intra and post-operative hemoglobin, the number of packed red cells units which were transfused and hematocrit and hemoglobin blood infused. Results: The average group age was 60.44±12.09 years old, of whom 71.43% were males. The group A was formed by 5.19% of the patients, B by 81.82% and C by 12.99%. The volume of erythrocytes recovered and infused was respectively 1,360.50±511.37 ml and 339.75±87.71 ml in group A, 1,436.63±516.06 ml and 518.83±183.0 ml in B and 2,137.00±925.04 ml and 526.20±227.15 ml in C. About packed red cells transfusions, in group A 1,00±2,00 packed red cells were transfused, in B 1.27±1.85 packed red cells and in C 2.56±2.01 packed red cells. The infused blood had a hematocrit of 50.97±12.06% and hemoglobin of 19.57±8.35 g/dl. Conclusion: That blood salvage can be used in patients submitted to cardiovascular surgery with cardiopulmonary bypass. However, it is only cost-effective in surgeries in which the time of cardiopulmonary bypass is greater than 45 minutes.

Resumo Objetivo: Avaliar se o uso de recuperadores de hemácias está indicado nos pacientes submetidos à cirurgia cardiovascular com o uso de circulação extracorpórea. Métodos: Foram estudados 77 pacientes submetidos a cirurgias cardíacas com uso de recuperadores de hemácias e circulação extracorpórea de novembro de 2010 a junho de 2012. A amostra foi subdividida em três grupos, conforme o tempo de circulação extracorpórea. No grupo A , o tempo de circulação extracorpórea foi menor que 45, no grupo B, de 45 a 90 e, no grupo C, maior que 90 minutos. Analisou-se o volume recuperado e infundido de hemácias, a hemoglobina de pré, trans e pós-operatório, número de unidades de concentrado de hemácias transfundidas, volume globular e hemoglobina do sangue infundido. Resultados: A idade média, dos pacientes, foi de 60,44±12,09 anos, sendo 71,43% do sexo masculino. O grupo A é formado por 5,19%, o B por 81,82% e o C por 12,99% dos pacientes. O volume recuperado e infundido foi, respectivamente, de 1.360,50±511,37 ml e 339,75±87,71 ml no grupo A, 1.436,63±516,06 ml e 518,83±183,0 ml no B e 2.137,00±925,04 ml e 526,20±227,15 ml no C. Em relação às transfusões de concentrado de hemácias, no grupo A foram transfundidas 1,00±2,00 concentrado de hemácias, no B 1,27±1,85 concentrado de hemácias e no C 2,56±2,01 concentrado de hemácias. O sangue infundido tinha um volume globular de 50,97±12,06% e hemoglobina de 19,57±8,35 g/dl. Conclusão: O recuperadores de hemácias podem ser usados em pacientes submetidos à cirurgia cardiovascular com circulação extracorpórea, mas somente em cirurgias com tempo de circulação extracorpórea acima de 45 minutos o reaproveitamento de sangue é custo/efetivo.

Descriptors: Operative Blood Salvage. Cardiovascular Surgical Procedures. Cardiopulmonary Bypass.

Descritores: Recuperação de Sangue Operatório. Procedimentos Cirúrgicos Cardiovasculares. Ponte Cardiopulmonar.

Faculdade Assis Gurgacz (FAG), Cascavel, PR, Brazil. Institute of Cardiovascular Surgery of Oeste do Paraná (ICCOP), Cascavel, PR, Brazil.

1st in Free Themes, 2nd Academic Conference on Cardiovascular Surgery - 40th Brazilian Congress of Cardiovascular Surgery - Florianópolis, SC, in 2013.

1 2

Correspondence address: Mariah Steinbach Avenida Barão do Rio Branco, 264 – Centro – Cascavel, PR, Brasil - Zip code: 85812-230 E-mail: mariah_steinbach@hotmail.com

This study was carried out at Faculdade Assis Gurgacz (FAG), Cascavel, PR, Brazil. Financial support: Fellow of the Institutional Program for Scientific Initiation (PIBIC).

Article received on May 23rd, 2013 Article accepted on August 19th, 2013

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C, according to the duration of CPB. In group A, CPB time was less than 45 in group B between 45 and 90 and in group C greater than 90 minutes. All patients made use of partial hemodilution and hemofiltration on CPB and underwent anesthetic induction with use of midazolam and remifentanil and for maintenance sevoflurane was used. After median sternotomy and confection of bags for cannulation, patients received heparin at 300 U/kg in order to obtain an activated clotting time greater than 400 seconds; controls were performed every 60 minutes. It was also used an adult membrane oxygenator (Braile Biomédica, São José do Rio Preto, SP, Brazil), with a total fill volume of 500 ml. We used antegrade blood cardioplegia for infusion. The RBCs salvage used throughout the surgery was autoLog Autotransfusion System (Medtronic, Minesota, USA), and at the end the blood of the CPB system was processed by HR. The criterion for transfusion of red blood cells (RBC) was concentrated hemoglobin (Hb) below 8 g/dl or 9 g/dl when there was hemodynamic instability. The number of units of plasma, platelets and cryoprecipitate used were not assessed because it is not the aim of the study. A blood count was obtained before surgery, on arrival of the patient to the intensive care unit (ICU), and 24 hours after the day of discharge. The packed cell volume (PCV) and Hb were tabulated, as well as the volume of blood aspirated by HR, the volume of blood infused, the number of RBC transfused, the type of surgical procedure and CPB time. The study was approved by the Research Ethics Committee of the Faculdade Assis Gurgacz, under the protocol number 154/2012. Statistically continuous variables are represented by the mean and the standard deviation, which was used in the Fischer test to assess the variables in this study, with a confidence interval of 95%. We use the statistical variables of age, gender, type of surgery, CPB, hemoglobin and unit of RBC transfused, to know whether the use of BS is indicated in all patients undergoing cardiovascular surgery with CPB.

Abbreviations, acronyms and symbols CPB RBC ASD CABG Hb SRBC PCV

cardiopulmonary bypass Red blood cells Atrial septal defect Coronary artery bypass surgery Hemoglobin Salvaged RBC Packed cell volume

INTRODUCTION The operative blood salvage (BS) or red blood cell (RBC) salvage have been used for almost 30 years and have innovated in the field of autotransfusion. BS salvage are used for the intraoperative recovery and re-administration of erythrocytes in most cases, but it can also be used postoperatively[1]. These salvage systems have mainly benefited autologous blood surgical procedures where major blood loss occurs. The benefit is demonstrated by studies that ensure the safety and the quality of the salvaged blood, and it significantly reduces the need for homologous transfusions during surgery and especially in cardiovascular surgery[1,2]. It is known that blood transfusions increase morbidity and mortality in patients undergoing cardiovascular surgery[3,4]. Risks associated with blood transfusions, such as transmission of viruses, also volunteered to search for improvement of these methods to further reduce patient exposure to homologous blood. Another aspect to the use of BS is related to religious beliefs and the right of choice, which have led some patients to refuse the transfusion of blood or its products in any circumstance. But in multicultural health care system of today, patients seeking alternatives to blood transfusion are not only motivated by religious reasons[1]. Several studies have shown that when BS are used a reduction occurs in blood transfusions in patients undergoing cardiovascular surgery[5,6]. However, other authors reported that the use of BS has no clinical benefit in a particular group of patients because it is not cost-effective[7] and does not reduce the need for homologous blood transfusion[8]. In order to clarify the benefit of BS, this study aims to assess if the use of this technique is indicated in patients undergoing cardiovascular surgery with cardiopulmonary bypass (CPB).

RESULTS The age of patients ranged from 26-84 years with a mean of 60.44±12.09 years. Group A consisted of 5.19% (n=4) of patients, 81.82% by B (n=63) and 12.99% by C (n=10). The majority of subjects were male, but presented different predominance in relation to groups, being 25.00% in group A, group B 76.19% and 70.00% in group C. The mean CPB time was 35.00±7.66 minutes in group A, 65.38±10.31 in B and 112.00±22.79 in C. In group A one patient underwent surgery coronary artery bypass graft (CABG), one aortic valve replacement, one mitral valvuloplasty and one correction of an atrial septal defect (ASD); in B 76.19% (n=48) underwent CABG, 20.63% (n=13) valve replacement, 1.59% (n=1) removal of left atrial myxoma

METHODS This is a descriptive, prospective study performed at the Institute of Cardiovascular Surgery of do Oeste do Paraná, in a group of 77 consecutive patients undergoing cardiovascular surgery with CPB and HR, from November 2010 to April 2012. In this study all patients who underwent reoperations were excluded. The sample was divided into group A, B and

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and 1.59% (n=1) aneurysm; in C 80.00% (n=8) underwent CABG and 20.00% (n=2) aneurysm (Table 1). The salvaged volume and infused was respectively 1360.50±511.37 ml and 339.75±87.71 ml in group A, 1,436.63±516.06 ml and 51.83±183.00 ml in B and 2,137.00±925.04ml and 526.20±227.15ml in C (Table 2). The salvaged volume was statistically significant when related to the CPB time in group B (P=0.008) and group C (P<0.001). The volume infused was not significant (Table 2). Regarding RBC transfusions, four units of were used in group A, in group B 80 and 23 in group C. The average usage of RBC units was 1.00±2.00, 1.27±1.85 and 2.56±2.01, in groups A, B and C, respectively (Table 2). Only one patient in group A needed blood transfusion. In B, 31 of 63 subjects

needed 2.58 units of RBC. In group C, as a postoperative death occurred for neurological reasons, this patient did not enter the counting of patients who needed or not RBC, thus 77.77% of patients (n=7) required 3.28 RBC units. The RBC units transfused was related to duration of CPB in each group, but not statistically significant (Table 2). In groups A, B and C, the mean preoperative Hb were 113.45±1.39, 13.58±3.31, 13.0±1.52 g/dl, transoperative Hb of 11.10±1.88, 10.87±1.73, 10.45±1.57 g/dl, postoperative 9.78±1.79, 9.84±1.30, 10.54±1.39 g/dl and Hb at discharge of 10.80±1.18, 9.35±1.10, 9.13±0.93 g/dl. (Table 2). The pre, trans- and postoperative Hb levels were high and were related to the duration of CPB in each group, with significant high Hb in group B (P=0.049) and group C (P=0.028) (Table 2).

Table 1. Type of surgeries.

CABE Aortic valve replacement Mitral repair Removal of left atrial myxoma Aneurysm repair Interatrial communication repair (IAC)

Type of surgeries GROUP A F-TEST P VALUE GROUP B F-TEST 25% (n=1) 1.212 0.274 76.19% (n=48 0.650 25% (n=1) 29.899 <0.001 20.63% (n=13) 0.036 25% (n=1) 29.899 <0.001 0% 6.228 0% 0.176 0.274 1.59% (n=1) 0.036 0% 25% (n=1)

0.468 29.899

0.496 <0.001

1.59% (n=1) 0%

6.774 6.228

P VALUE 0.422 0.112 0.014 0.848 0.011 0.014

GROUP C F-TEST P VALUE 80% (n=8) 0.182 0.670 0% 0 0% 0 0 0% 3.137 0 0.080 20% (n=2) 0%

3.137 0

0.080 0

Table 2. Mean and standard deviation of the salvaged volume, infused volume, Hb infused blood, VG infused blood, preoperative Hb, transoperative Hb, postoperative Hb, high Hb, RBC unit. Mean standard deviations GROUP A F-TEST P VALUE GROUP B F-TEST P VALUE GROUP C F-TEST P VALUE Salvaged volume 1360.50 ± 0.288 0.593 1436.63 ± 7.36 0.008 2137.00 ± 12.96 <0.001 511.37 ml 516.06 ml 925.04 ml Infused Volume 339.75 ± 3.571 0.062 518.83 ± 0.665 0.417 526.20 ± 0.082 0.774 87.71 ml 183.02 ml 227.15 ml Hb of infused blood 18.13 ± 0.149 0.700 17.54 ± 2.824 0.097 20.00 ± 4.583 0.035 3.11 ml 2.91 ml 8.90 ml VG of infused blood 53.56 ± 0.966 0.328 52.76 ± 1.576 0.213 51.00 ± 4.064 0.047 9.46 ml 8.62 ml 12.58 ml Preoperative Hb 13.45 ± 0.001 0.972 13.58 ± 0.182 0.670 13.08 ± 0.217 0.642 1.39 g/dl 3.31 g/dl 1.52 g/dl Transoperative Hb 11.10 ± 0.109 0.741 10.87 ± 0.209 0.648 10.45 ± 0.555 0.458 1.88 g/dl 1.73 g/dl 1.57 g/dl Postoperative Hb 9.78 ± 0.001 0.972 9.84 ± 0.300 0.585 10.54 ± 0.367 0.546 1.79 g/dl 1.30 g/dl 1.39 g/dl High Hb 10.80 ± 0.010 0.919 9.35 ± 3.971 0.049 9.13 ± 4.98 0.028 1.18 g/dl 1.10 g/dl 0.93 g/dl RBC units 1.00 ± 0.176 0.675 1.27 ± 1.394 0.241 2.56 ± 2.718 0.103 2.00 1.85 2.01

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The infused blood had a VG of 50.97±12.06% and 19.57±8.35 Hb g/dl, mean with their standard deviations, and the minimum values of PCV and Hb respectively 22.8% and 7.40 g/dl and maximum of 66.00% and 22,00g/dl. Hb and PCV of the infused blood were 18.13±3.11 ml and 53.56±9.46 ml in group A, 17.54±2.91 ml and 52.76±8.62 ml in B and 20.00±8.90 and 51.00±12.58 ml in group C, with Hb statistical significance (P=0.035) and VG (P=0.047) in group C (Table 2).

and, as previously reported[1,2], this blood recovered has quality, the PCV 50.97±12.06% and Hb 19.57±8.35 g/dl. Several studies have examined the benefits of BS in cardiac surgery using cardiopulmonary bypass[5,19]. It has been reported that the use of BS in on-pump surgery reduces the need for transfusions compared to patients who undergo cardiac surgery without the use of BS[6,20]. This study showed that the duration of CPB is related to the greater use of RBC, with an average of 2.56 units of RBC in group C, 1.27 in B and 1.00 in A, however, it was not a significant factor, and the majority (n=7) from group C required RBC (2.56), 49.21% in group B and a minority (n=1) in group A. The major aim in the use of BS is to present the ability to decrease the use of units of RBC in patients and thus reduce inflammatory reactions and mortality, with no complications or contraindication for the use of the method. This care must be taken simultaneously with a perfect hemostasis both in the initial dieresis as before synthesis in cardiovascular surgery[20].

DISCUSSION The use of SB was started in 1970 in the USA, in response to the increasing number of cardiovascular surgery and at the end of the last century, the use was expanded to Europe[9]. Since then this technique is being discussed[10]. Early in the 80s, some authors have already positioned themselves against the indiscriminate use of SB, because it did not decrease both costs and the use of homologous blood[11]. However, the inherent complications of blood transfusion such as increased risk of infectious events, episodes of atrial fibrillation, acute renal failure, stroke and increased hospital stay[12], or their byproducts, associated with benefits in reducing this use makes that before administering a transfusion, all alternative resources available are tempted. The benefits are: avoid the drastic reduction of the blood supply available, the best result of the treatments, disputes, religious fundamentals, motivation for a more restrictive transfusion practices, satisfaction of the medical-surgical team and still meeting the preferences of patients[1,13]. In addition, there is a reduction in the overall cost of the treatments, as more controls are needed to prevent the transmission of diseases by blood increasing costs of homologous transfusions. This improves the cost-effectiveness of the SB[14]. The aim of BS is to recover the blood that was shed in the surgical field in order to reduce the need for allogeneic transfusion. According to some writers, the BS can be indicated in many types of elective surgery, such as cardiovascular surgery, hip, spine and liver transplants[15,16], and emergency when the blood loss must be at least 800 -1000 mL[2]. Other authors claim that the blood loss can be between 600-800 mL[17]. All our patients were advised to use BS as the minimum of recovered blood was 749 mL, agreeing with the guidelines used by the National Health Service, which states that the use of BS in cardiovascular surgery with CPB should be performed at the surgeon’s discretion and can be cost effective[18]. As, on average, one-third of the recovered blood is infused[17], all patients in this study benefited from the use of BS, but only in groups B and C the BS was cost effective because the volume of blood infused was sufficient to costs which would overcome by the use of RBC. Moreover, the longer the CPB, the greater the volume of blood recovered

CONCLUSION BS can be used in patients undergoing cardiovascular surgery with CPB in view there is no contraindication or morbidity resulting from its use, but only in surgery with CPB time greater than 45 minutes the reuse of blood is cost-effective.

Author’s roles & responsibilities MS RMSA MHZC

Review of medical records, filling out spreadsheets, research references, drafting the text and tables Formatting the study, preparation of spreadsheets, literature review, research references, final revision of the text Statistical analysis, text review, aid in the preparation of tables

REFERENCES

1. Souza MHL, Elias DO. Circulação extracorpórea sem sangue de doadores. In: Souza MHL, Elias DO, eds. Fundamentos da circulação extracorpórea. 2ª ed. Rio de Janeiro: Centro Editorial Alfa Rio; 2006. p.523-39. 2. Liumbruno GM, Bennardello F, Lattanzio A, Piccoli P, Rossetti G; Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) Working Party. Recommendations for the transfusion management of patients in the peri-operative period. II. The intraoperative period. Blood Transfus. 2011;9(2):189-217.

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3. Koch CG, Li L, Duncan AI, Mihaljevic T, Cosgrove DM, Loop FD, et al. Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med. 2006;34(6):1608-16.

12. Dorneles CC, Bodanese LC, Guaragna JC, Macagnan FE, Coelho JC, Borges AP, et al. The impact of blood transfusion on morbidity and mortality after cardiac surgery. Rev Bras Cir Cardiovasc. 2011;26(2):222-9.

4. Reeves BC, Murphy GJ. Increased mortality, morbidity, and cost associated with red blood cell transfusion after cardiac surgery. Curr Opin Cardiol. 2008;23(6):607-12.

13. Souza DD, Braile DM. Avaliação de nova técnica de hemoconcentração e da necessidade de transfusão de hemoderivados em pacientes submetidos à cirurgia cardíaca com circulação extracorpórea. Rev Bras Cir Cardiovasc. 2004;19(3):287-94.

5. Dalrymple-Hay MJ, Dawkins S, Pack L, Deakin CD, Sheppard S, Ohri SK, et al. Autotransfusion decreases blood usage following cardiac surgery: a prospective randomized trial. Cardiovasc Surg. 2001;9(2):184-7.

14. Desmond M. Peroperative cell salvage. Transfus Clin Biol. 2007;14(6):530-2. 15. Murphy MF, Howell C; National Blood Transfusion Committee in England. Survey of the implementation of the recommendations in the Health Service Circular 2002/009 ‘Better Blood Transfusion’. Transfus Med. 2005;15(6):453-60.

6. McGill N, O’Shaughnessy D, Pickering R, Herbertson M, Gill R. Mechanical methods of reducing blood transfusion in cardiac surgery: randomised controlled trial. BMJ. 2002;324(7349):1299. 7. Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Ferraris SP, Saha SP, Hessel EA 2nd, Haan CK, Royston BD, et al; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007;83(5 Suppl):S27-86.

16. Carless PA, Henry DA, Moxey AJ, O’Connell DL, Brown T, Fergusson DA. Cell salvage for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2006;(4):CD001888.

8. Klein AA, Nashef SA, Sharples L, Bottrill F, Dyer M, Armstrong J, et al. A randomized controlled trial of cell salvage in routine cardiac surgery. Anesth Analg. 2008;107(5):1487-95.

18. Kelleher AA, Pepper J, Boecoe M, Shuldham C. Policy for the provision of perioperative red cell salvage. Joint Transfusion Committee Royal Brompton & Harefield Hospitals [Acessed March 22nd 2013]. Disponível em: http://www. transfusionguidelines.org.uk/docs/pdfs/rtc-scent_policy_rcs.pdf

17. Attaran S, McIlroy D, Fabri BM, Pullan MD. The use of cell salvage in routine cardiac surgery is ineffective and not costeffective and should be reserved for selected cases. Interact Cardiovasc Thorac Surg. 2011;12(5):824-6.

9. Murphy MF, Edbury C, Wickenden C. Survey of the implementation of the recommendations in the Health Services Circular 1998/224 ‘Better Blood Transfusion’. Transfus Med. 2003;13(3):121-5. 10. Reyes G, Prieto M, Alvarez P, Orts M, Bustamante J, Santos G, et al. Cell saving systems do not reduce the need of transfusion in low-risk patients undergoing cardiac surgery. Interact Cardiovasc Thorac Surg. 2011;12(2):189-93.

19. Niranjan G, Asimakopoulos G, Karagounis A, Cockerill G, Thompson M, Chandrasekaran V. Effects of cell saver autologous blood transfusion on blood loss and homologous blood transfusion requirements in patients undergoing cardiac surgery on- versus off-cardiopulmonary bypass: a randomised trial. Eur J Cardiothorac Surg. 2006;30(2):271-7.

11. Winton TL, Charrette EJ, Salerno TA. The cell saver during cardiac surgery: does it save? Ann Thorac Surg. 1982;33(4):379-81.

20. Almeida RMS, Leitão L. O uso de recuperador de sangue em cirurgia cardíaca com circulação extracorpórea. Rev Bras Cir Cardiovasc. 2013;28(1):76-82.

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Prieto D, et al. -REVIEW Results ofARTICLE heart transplantation in the urgent recipient - who should be transplanted?

Results of heart transplantation in the urgent recipient - who should be transplanted? Resultados do transplante cardíaco no paciente urgente - quem deve ser transplantado?

David Prieto1; Pedro Correia1; Pedro Antunes1; Manuel Batista1; Manuel J. Antunes1, PhD; DSc

DOI 10.5935/1678-9741.20140072

RBCCV 44205-1566

Abstract Objective: To evaluate immediate and long-term results of cardiac transplantation at two different levels of urgency. Methods: From November 2003 to December 2012, 228 patients underwent cardiac transplantation. Children and patients in cardiogenic shock were excluded from the study. From the final group (n=212), 58 patients (27%) were hospitalized under inotropic support (Group A), while 154 (73%) were awaiting transplantation at home (Group B). Patients in Group A were younger (52.0±11.3 vs. 55.2±10.4 years, P=0.050) and had shorter waiting times (29.4±43.8 vs. 48.8±45.2 days; P=0.006). No difference was found for sex or other comorbidities. Haemoglobin was lower and creatinine higher in Group A. The characteristics of the donors were similar. Follow-up was 4.5±2.7 years. Results: No differences were found in time of ischemia (89.1±37.0 vs. 91.5±34.5 min, P=0.660) or inotropic support (13.8% vs. 11.0%, P=0.579), neither in the incidence of cellular or humoral rejection and of cardiac allograft vasculopathy. De novo diabetes de novo in the first year was slightly higher in Group A (15.5% vs. 11.7%, P=0.456), and these patients were at increased risk of serious infection (22.4% vs. 12.3%, P=0.068). Hospital mortality was similar (3.4% vs. 4.5%, P=0.724), as well as long-term survival (7.8±0.5 vs. 7.4±0.3 years).

Conclusions: The results obtained in patients hospitalized under inotropic support were similar to those of patients awaiting transplantation at home. Allocation of donors to the first group does not seem to compromise the benefit of transplantation. These results may not be extensible to more critical patients.

Cardiothoracic Surgery University Hospital, Coimbra, Portugal.

Correspondence address: Manuel de Jesus Antunes Centro de Cirurgia Cardiotorácica Hospitais da Universidade de Coimbra Praceta Mota Pinto, 3000-375, Coimbra, Portugal E-mail: antunes.cct.chuc@sapo.pt

Descriptors: Heart Transplantation. Thoracic Surgery. Postoperative Complications. Survival (Public Health). Resumo Objetivo: Avaliar os resultados imediatos e de longo prazo do transplante cardíaco em dois níveis diferentes de urgência. Métodos: De novembro de 2003 a dezembro de 2012, 228 pacientes foram submetidos a transplante cardíaco. Crianças e os pacientes em choque cardiogênico foram excluídos do estudo. Do grupo final (n=212), 58 pacientes (27%) estavam hospitalizados e em suporte inotrópico (Grupo A), enquanto 154 (73%) aguardavam transplante em casa (Grupo B). Os pacientes do Grupo A eram mais jovens (52,0±11,3 vs. 55,2±10,4 anos, P=0,050) e tinham menor tempo de espera (29,4±43,8 vs. 48,8±45,2 dias, P=0,006). Não foram encontradas diferenças entre os sexos ou outras comorbidades. Níveis de hemoglobina foram menores e de

This study was carried out at Centre of Cardiothoracic Surgery and Transplantation of Thoracic Organs University Hospital and Faculty of Medicine of University of Coimbra, Portugal.

Article received on May 10th 2014 Article accepted on May 25th 2014

No financial support.

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diabetes de novo no início do primeiro ano foi um pouco maior no Grupo A (15,5% vs. 11,7%, P=0,456), e esses pacientes apresentaram maior risco de infecção grave (22,4% vs. 12,3%, P=0,068). A mortalidade hospitalar foi semelhante (3,4% vs. 4,5%, P=0,724), bem como a sobrevida a longo prazo (7,8±0,5 vs. 7,4±0,3 anos). Conclusões: Os resultados obtidos em pacientes hospitalizados em suporte inotrópico foram semelhantes aos de pacientes que aguardam o transplante em casa. Alocação de doadores para o primeiro grupo não parece comprometer o benefício do transplante. Esses resultados podem não ser estendidos aos pacientes mais críticos.

Abreviations, acronyms & symbols CPB GVD IABP ICU SPT

Cardiopulmonary bypass Graft vascular disease intra-aortic balloon pump Intensive care unit Portuguese Society of Transplantation

creatinina superiores no Grupo A. As características dos doadores foram semelhantes. O acompanhamento foi de 4,5±2,7 anos. Resultados: Não foram observadas diferenças no tempo de isquemia (89,1 ± 37,0 vs. 91,5 ± 34,5 min, P=0,660) ou no suporte inotrópico (13,8% vs. 11,0%, P=0,579), nem na incidência de rejeição celular ou humoral e de vasculopatia do enxerto. Incidência de

Descritores: Transplante de Coração. Cirurgia Torácica. Complicações Pós-Operatórias. Sobrevida.

INTRODUCTION

On a national level, the criteria/priority for heart transplantation of the Portuguese Society of Transplantation (unpublished data; Table 1) include seven degrees in descending order of priority. As a result of this and other types of stratification, the most critical patient passes ahead of others whose clinical condition allows them to wait longer. However, these criteria do not explain or quantify the risk profile. We know that the immediate results of cardiac transplantation are very sensitive not only to the quality of the donor organ but also to the clinical status of the candidate to transplantation[4-6]. Strictly following the scale of priority or urgency for transplantation, we end up transplanting sicker hospitalized patients undergoing intensive treatment for decompensated heart failure, always accompanied by variable multiorgan function deterioration. This will result in a natural increase of morbidity and mortality after transplantation, triggering the question of who should be transplanted (?), which can raise probably insoluble questions of ethics in organ distribution. In this study, we analyzed and compared the early and late results of transplantation following the criteria of priority in use by the Portuguese Society of Transplantation (SPT), in basic clinical aspects similar to the international scale INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) [7,8].

Despite advances in medical and surgical treatment of heart failure, heart transplantation is still the elective treatment for patients refractory to other medical therapies or conventional cardiac procedures. The criteria for selection of candidates for transplantation have been gradually extended and the selection of donors and recipients is essential to the success of a transplantation program[1-3]. However, a significant reduction in supply has forced the spectrum of selection of donors to be broadned. Thus, the profile has changed from a young donor who died of cranio-cerebral trauma to that of an older donor whose death resulted from primary neurological disease. The latter is often accompanied by other types of diseases and cardiovascular risk factors, conditions which determine the choice of the recipient from a scarce and rarely ideal donor. As a result, we have seen an increase in the number of patients in advanced stages of the disease at the time of transplantation, who are admitted for decompensated heart failure requiring intensive pharmacologic support and, at times, cardio-circulatory and mechanical respiratory support in those with worse clinical status, a situation that increases the urgency for transplantation, generally associated with greater risk of failure.

Table 1. Heart transplantation. Priority (descending order) and their criteria (Portuguese Transplantation Society - SPT) I Emergency Primary graft failure in the first 24 hours after cardiac transplantation II Emergency a) Patients in cardiogenic shock requiring ventricular assistance b) Patients in cardiogenic shock requiring artificial heart III Emergency Patients in cardiogenic shock with intra-aortic balloon counterpulsation IV Emergency Patients in cardiogenic shock requiring mechanical ventilator support V Urgent Patients being admitted to both UCI and inotropic support to maintain adequate cardiac output VI Urgent Patients with more than one hospitalization in the ICU in the last 6 months VII Elective Includes the remaining patients

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METHODS

one to 10 years, and no patient was lost to follow-up. The mean follow-up in this study was 4.5±2.7 years (total, 961.8 patient-years).

Origin, definition and collection of data In the period from November 2003 to December 2012, 228 patients were consecutively submitted to heart transplantation at this Centre. Exclusion criteria for this study included patients previously transplanted with other organs (n=2), patients under 18 years of age (n=8), and patients with emergency priority (≤ grade IV, n=8). Thus, the study population included 212 patients, 58 of whom were in the ICU, under inotropic support without respiratory and/or mechanical ventricular assistance (SPT grade V; Group A), and 154 were at home on a waiting list with two or more hospitalization episodes in the ICU in the last 6 months (SPT grade VI; Group B). The data were obtained from a national database, especially designed for the prospective registration (online platform) of data from the recipient, donor, surgery, immunosuppression protocol and follow-up of patients undergoing cardiac transplantation. All surviving patients were followed via regular consultations at the Surgical Centre by a medical/surgical team, from

Recipients and Donors Table 2 shows data from pre-operative variables of the recipients in groups A and B, as well as the results of the comparative analysis. When compared with the population of Group B, patients in Group A were younger (P=0.05), had lower body mass index (BMI; P=0.005), had significantly lower serum haemoglobin (P=0.001), higher total bilirubin (P=0.014) and creatinine (P=0.01), and shorter time on the waiting list (P=0.006). Table 3 details the characteristics of the donors to patients of groups A and B, as well as the results of the comparative analysis, which showed no significant differences in any of the variables. However, male donors were the most common (82% vs. 73%). The cause of death was mostly traumatic (59.6% vs. 57.6%), but there was a growing trend in the number of donors dying from CVA, now approaching two thirds. In group A, there was a significant number of donors with prolonged inotropic or ventilator support (longer than one week, 12%).

Table 2. Recipient data.

Mean age (years) Male sex Body mass index (Kg/m2) Diabetes mellitus Hypertension Reoperation Etiology Ischaemic heart disease Dilated cardiomyopathy Other Peripheral vascular disease Carotid disease Cardiac index (L/min/m2) Transpulmonary gradient (mmHg) Pulmonary vascular resistance (WU) Hemoglobin (g/dL) Platelets LDH (U/L) AST (U/L) ALT (U/L) GGT (U/L) Total bilirubin (mg/dL) GFR (mL/min) Serum creatinine (mg/dL) Mean follow-up (years) Time on waiting list (days)

Group A (N= 58) 52.0±11.3 45 (77.6%) 22.7±2.9 8 (13.8%) 20 (34.5%) 16 (27.6%)

Group B (N=154) 55.2±10.4 120 (77.9%) 24.1±.3 35 (22.7%) 58 (37.9%) 49 (31.8%)

P value

21 (36.2%) 21 (36.2%) 16 (27.6%) 14 (24.1%) 1 (1.7%) 1.9±0.5 9.4±4.5 3.3±2.0 12.2±2.2 216±83 272±184 42±55 51±89 137±112 1.5±1.0 57.2±26.5 1.6±1.2 4.16±2.69 29.4±43.8

63 (40.9%) 55 (35.7%) 36 (23.4%) 54 (35.1%) 8 (5.2%) 1.9±0.5 9.3±4.6 3.4±2.4 13.2±1.9 212±70 250±120 43±47 44±48 118±112 1.1±0.7 60.9±21.2 1.4 ± 0.4 4.68±2.75 48.8 ± 45.2

0.533 0.947 0.786 0.129 0.264 0.997 0.890 0.820 0.001 0.783 0.361 0.903 0.460 0.273 0.014 0.301 0.010 0.219 0.006

0.050 0.958 0.005 0.146 0.645 0.551

LDH=Lactate dehydrogenase; AST=Aspartate aminotransferase; ALT=Alanine aminotransferase; GGT=Gammaglutamyl transferase; GFR=Glomerular filtration rate or creatinine clearance

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Table 3. Donor population data.

Mean age (years) Age ≥ 50 years Male sex Donor female/receptor male Weight ratio donor/recipient >1.2 Weight ratio donor/recipient <0.8 Inotropic support >7 days Ventilation support >7 days Cause of death Ischemic stroke Haemorrhagic stroke Traumatic brain injury Other causes

Group A (N=58) 35.2±11.2 8 (13.6%) 48 (82.8%) 8 (13.8%) 22 (37.9%) 1 (1.7%) 4 (6.9%) 7 (12.1%)

Group B (N=154) 33.9±10.9 18 (11.6%) 114 (74.0%) 28 (18.2%) 42 (27.3%) 5 (3.2%) 6 (3.9%) 18 (11.7%)

P value

2 (3.4%) 23 (39.6%) 31 (53.4%) 2 (3.4%)

2 (1.3%) 50 (32.5%) 92 (59.7%) 10 (6.5%)

0.305 0.326 0.408 0.392

Group A (N=58) 89.1±37.0 98.5±39.5 17.1±15.0 8 (13.8%) 0 (0%) 4 (6.9%) 1 (1.7%) 1 (1.7%) 0 (0%) 0 (0%)

Group B (N=154) 91.5±34.5 99.7±32.0 19.3±22.5 17 (11.0%) 10 (6.5%) 6 (3.9%) 12 (7.8%) 9 (5.8%) 1 (0.6%) 2 (1.3%)

P value

0.429 0.677 0.182 0.448 0.132 0.477 0.358 0.939

Table 4. Operative data.

Total ischemic time (min) Mean CPB time (min) Mechanical ventilation time (hours) Inotropic support >48 hours Mechanical assistance Reoperation for bleeding Associated procedure Mitral valvuloplasty Tricuspid annuloplasty Coronary revascularization

0.660 0.813 0.487 0.579 0.047 0.358 0.101 0.207 0.538 0.383

CPB=Cardiopulmonary bypass

Statistical analysis Continuous variables are presented as mean ± standard deviation and evaluated using independent (comparison between groups) and paired (over time) Student's t-test. Categorical variables are reported as frequency and percentage, and compared using the chi-square test. Survival and event-free survival were calculated using the Kaplan -Meier method. Statistical significance was defined as P-value <0.05. Data were analyzed using the IBM SPSS Statistics for Windows program (Version 20.0. Armonk, NY: IBM Corp; released 2011).

lar assist device, and 5 required total circulatory support with ECMO. No statistically significant differences were observed in relation to other variables, namely times of ischemia and CPB, mechanical ventilation and inotropic support >48 hours. Cellular and humoral rejection and graft vascular disease Table 5 shows the data on acute cellular rejection, humoral rejection and graft vascular disease (GVD) in groups A and B. Ninety patients (42.5%) had no episodes of acute cellular rejection (grade 0R of the ISHLT). The remaining patients (n=122, 57.5%) had at least one episode of rejection; however, in 83 of them it was only mild (1R), requiring no treatment. The results of the comparative analysis of the two groups showed no statistically significant difference in any of the cellular rejection grades. Thirty nine patients (18.4%) had at least one episode of cellular rejection grade ≥ 2R, the majority (33, 84.6%) occurring during the first year. No statistically significant difference (P=0.309) was observed in the comparative analysis of survival free from cellular rejection grade ≥2R between groups A and B (Figure 1A).

RESULTS Surgery Table 4 shows the data for variables related to surgery in groups A and B, as well as the results of the comparative analysis. Patients in Group B had a significantly higher incidence of mechanical circulatory support (P=0.044). Of the ten patients who needed this kind of assistance, 2 required only intra-aortic balloon pump (IABP), 3 required the use of a left ventricu-

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Table 5. Evaluation of acute cellular rejection, humoral rejection and graft vascular disease.

Acute cellular rejection Grade 0R Grade 1R Grade 2R Grade 3R Grade ≥2R Grade ≥2R (first 12 months) Humoral rejection Graft vascular disease

Group A (N=58)

Group B (N=154)

P value

23 (39.7%) 22 (37.9%) 11 (19.0%) 2 (3.4%) 13 (22.4%) 10 (17.2%) 1 (1.7%) 6 (10.3%)

67 (43.5%) 61 (39.6%) 20 (13.0%) 6 (3.9%) 26 (16.9%) 23 (14.9%) 5 (3.2%) 14 (9.1%)

0.613 0.887 0.276 0.879 0.351 0.680 0.551 0.781

Fig. 1A - Survival free from cellular rejection grade ≥2R in groups A and B. 1B - Survival free from graft vascular disease in groups A and B.

Humoral rejection was diagnosed in six patients (2.8%), with no significant difference between the study groups (P=0.551). Graft vascular disease (diagnosed by coronary angiography, as some degree of “new” irregularity or stenosis in any of the major coronary vessels or its main branches, even if less than 50%) was diagnosed in 20 patients (9.4%). The comparative analysis of this event showed no significant difference in the incidence between the study groups (P=0.781). Survival free from GVD in groups A and B was not statistically different (P=0.547, Figure 1B).

cance (P=0.068). Likewise, the incidence of pneumonia in the first 6 months was higher in Group A (17.2% vs. 9.7%), although the difference was not significant (P=0.131). Behavior of renal function after transplantation At the time of transplantation, patients in Group A showed a tendency to have lower rates of glomerular filtration (57.2±26.5 vs. 60.9±21.2 ml/min, P=0.301). However, early renal replacement therapy (≤ 1 month after transplantation) was necessary in only 4 patients, with no difference between groups. In both groups, a tendency towards recovery of renal function was observed after one month of transplantation, although not statistically significant (P=0.343 and P=0.480 for groups A and B, respectively). However, this was followed by a progressive deterioration of the glomerular filtration rate, whose values dropped significantly in Groups A (P=0.050) and B (P<0.001) for the first sixth months post-transplantation, and continued to decline, though at a slower pace, up to twelve months after transplantation (Figure 2).

De novo diabetes and severe infections The incidence of de novo diabetes in the first year after transplantation was 12.7%, with no difference between the two groups (15.5% vs. 11.7%, P=0.456). The incidence of serious infections requiring hospitalization and intravenous antibiotics during the first year post-transplantation was higher in Group A (22.4% vs. 12.3%), but the difference did not reach statistical signifi-

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Mortality and survival After a mean follow-up of 4.5±2.7 years (1 to 10 years; 961.8 patient-years), the overall mortality did not show significant differences between the two groups of patients (19% vs. 23.4%, P=0.491) and the same goes for comparison of in-hospital mortality and death at 6 months, 1 year, and late (Table 6). The most frequent causes of death in both groups were infectious (5.2% vs. 6.5%, P=0.721) and vascular (5.2% vs. 5.8%, P=0.850), with no statistical significance in the comparison between the two groups. The comparative analysis of the survival curves (Figure 3) also showed no significant difference between the two groups (P=0.659) and mean survival is currently 7.8±0.5 years in Group A and 7.4±0.3 years in Group B.

for heart failure, which requires hospitalization in cardiac intensive care units where they are to undergo treatment with intravenous diuretics, inotropes (dobutamine and noradrenaline), and a large majority is treated with cardiotonics (levosimendan). On the other hand, patients having a lesser degree of urgency benefit from home and family environment as well as greater mobility, factors that contribute to improvement and even optimization of their psychological, nutritional, and muscular status, in addition to a drastic reduction of nosocomial infections. Undoubtedly, these are aspects that help decrease the potential for post-transplantation mortality and morbidity[9].

DISCUSSION It is known that the pre-transplantation clinical situation of patients with the highest degree of urgency is different. Decompensated patients are refractory to ambulatory medical treatment

Fig. 2 - Evolution of the mean glomerular filtration rate during the first year after transplant in groups A and B.

Fig. 3 - Actuarial overall survival in groups A and B.

Table 6. Mortality data and causes of death.

Mortality Overall Hospital Early (≤ 6 months) Death ≤1 year Late Death >1 year Causes of death Cardiac Vascular Neoplastic Neuropsychiatric Infectious

384

Group A (N=58)

Group B (N=154)

P value

11 (19.0%) 2 (3.4%) 5 (8.6%) 6 (10.3%) 5 (8.6%)

36 (23.4%) 7 (4.5%) 14 (9.1%) 17 (11.0%) 19 (12.3%)

0.491 0.724 0.915 0.885 0.446

1 (1.7%) 3 (5.2%) 1(1.7%) 2 (3.4%) 3 (5.2%)

6 (3.9%) 9 (5.8%) 7 (4.5%) 1 (0.6%) 10 (6.5%)

0.430 0.850 0.337 0.124 0.721

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Nevertheless, in this series we found a higher incidence of perioperative graft dysfunction in Group B. The most severe cases, in which it was necessary to use mechanical support (0% vs. 6.5%, P=0.047), were also detected in this group. But there was no significant difference in mortality between the two groups (3.4% and 4.5%, respectively, P=0.724). These results point to a little adjusted (skewed) priority rank. The clinical situation of this less urgent group of patients is not homogeneous. The control of symptoms does not imply an improvement in the long-term prognosis. In fact, Lietz & Miller[9] and Mokadam et al.[10] demonstrated deterioration in the clinical status in 32-48% of UNOS 2 patients (equivalent to our lower priority VI–VII) during the waiting time for transplantation. These patients come to transplantation in uncertain clinical condition (intermittent instability, recurrent and frequent decompensation, or chronic persistent symptoms), whose control is not always associated with a better prognosis. In addition, advances in the medical treatment of heart failure by cardiotonic drugs and artificial devices have distorted the actual phenotypic presentation of heart failure in late stage[11,12]. The more favorable response in Group A suggests that patients recently undergoing intensive anticongestive therapy reach transplantation better compensated from the cardiorespiratory point of view, regardless of the fact that the pre-transplantation analytical study showed a higher multi-organ involvement. In fact, bilirubin and creatinine were higher in this group, both variables which are thought to have a strong influence on early mortality after transplantation[13-16]. In addition, patients coming from intensive care are usually more delicate because they are in unfavorable physical, psychological and nutritional situation, exposed to a hospital environment, and they have been subject to different clinical monitoring devices, some quite invasive. Consequently, there was a greater number of serious infections in the first months post-transplantation in Group A, with values close to statistical significance (22.4% vs. 12.3%, P=0.068). The greatest risk of developing serious infections in this group of patients should alert us to the need for taking more forceful prevention measures, including adaptation of the immunosuppression protocol. Also analyzed in this study was the evolution of renal function, measured by serum creatinine level and creatinine clearance during the first year, when one would expect greater divergence. There was an improvement in the values of serum creatinine immediately after transplantation in both groups, but a gradual deterioration over years and no significant difference between the groups. The incidence of de novo diabetes, often related to renal dysfunction, was comparable between the two groups, which is justified by similar immunosuppression protocols. Global survival at 8 years and survival free from severe rejection (2R or 3R) were similar in the two groups. These

results also reinforce the idea that the high risk of transplantation in these patients can be significantly reduced in units with high volume of transplantations[17-20]. The advantage of having teams with greater experience to perform this procedure in high-risk candidates is well known, as the results have been proven superior in these centers[21-23]. The main message derived from this study is that, despite their higher risk profile and a further deteriorated clinical situation, urgent but not emergency patients showed similar outcomes to those of patients with lower priority. This may, therefore, raise the question of waste of a non-insignificant number of donors used in emergency cases with poor results in detriment of patients in better clinical conditions who die or deteriorate while on the waiting list, again conditioning the outcome of the transplantation[24]. Listing for transplantation of some of these patients should probably be revised or delayed to optimize their clinical state[25]. Today, more efficient devices for temporary or permanent mechanical assistance (ECMO, ventricular assistance, artificial heart), can greatly improve the clinical situation and reverse multiorgan deterioration[26]. In addition it seems important to call for other types of priority scales that include the characteristics of the recipient, other than the urgency of transplantation. Hong et al.[24] distinguished five groups of risk for transplantation, according to the presence of pre-transplant risk factors, where groups of higher risk have a first year survival of only 47-66% and a median survival of less than six years, results that, again, seriously question the use of donors that could have greater benefits in lower risk groups. These authors go as far as to say that donors should be allocated in priority for lower risk recipient groups and, only after that, for high-risk groups. They even warned about the need to consider whether we should not exclude high-risk patients from transplantation because the advantage of transplantation in the short and medium term is reduced in these patients, even when compared to medical treatment[27,28]. CONCLUSION The number of patients awaiting transplantation has been increasing, unlike the supply of donors. This situation becomes more complex when one observes an increase in the number of non-priority patients whose clinical condition worsens in the waiting list, turning them into to higher priorities. This panorama requires strengthening of the borders of donation as well as considering responsible and pragmatic allocation of available organs. In our experience, the results obtained from patients in urgent priority were similar to those of patients awaiting transplantation at home. The allocation of donors in this group does not seem to reduce the success of transplantation, a consideration that can probably not be extended to patients in more critical situations.

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7. Starling RC, Naka Y, Boyle AJ, Gonzalez-Stawinski G, John R, Jorde U, et al. Results of the post-U.S. Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol. 2011;57(19):1890-8

Authorsâ&#x20AC;&#x2122; roles & responsibilities DP PC PA MB MJA

Analysis and/or interpretation of data, statistical analysis, final approval of the manuscript conception and design of study, drafting the manuscript; critical review of the content analysis and/or interpretation of data; statistical analysis; final approval of the manuscript Final approval of the manuscript; drafting of the manuscript; ccritical review of the content analysis and / or interpretation of data; completion of the transactions and/or experiments analysis and/or interpretation of data; final approval of the manuscript; conception and design of the study; completion of the transactions and/or experiments; drafting of the manuscript; critical review of the content

8. Stevenson WL, Pagani FD, Young JB, Jessup M, Miller L, Kormos RL, et al. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant. 2009;28(6):535-41. 9. Lietz K, Miller LW. Improved survival of patients with end-stage heart failure listed for heart transplantation: analysis of organ procurement and transplantation network/U.S. United Network of Organ Sharing data, 1990 to 2005. J Am Coll Cardiol. 2007;50(13):1282-90.

REFERENCES

10. Mokadam NA, Ewald GA, Damiano RJ Jr, Moazami N. Deterioration and mortality among patients with United Network for Organ Sharing status 2 heart disease: caution must be exercised in diverting organs. J Thorac Cardiovas Surg. 2006;131(4):925-6.

1. Stehlik J, Edwards LB, Kucheryavaya AY, Aurora P, Christie JD, Kirk R, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult heart transplant report-2010. J Heart Lung Transplant. 2010;29(10):1089-103.

11. Ramani GV, Mehra MR. Risk assessment in critically ill patients awaiting transplantation: a step forward. Rev Esp Cardiol. 2011;64(3):175-6.

2. Russo MJ, Chen JM, Hong KN, Stewart AS, Ascheim DD, Argenziano M, et al; Columbia University Heart Transplant Outcomes Research Group. Survival after heart transplantation is not diminished among recipients with uncomplicated diabetes mellitus: an analysis of the United Network of Organ Sharing database. Circulation. 2006;114(21):2280-7.

12. Ramani GV, Uber PA, Mehra MR. Chronic heart failure: contemporary diagnosis and management. Mayo Clin Proc. 2010;85(2):180-95. 13. Weiss ES, Allen JG, Arnaoutakis GJ, George TJ, Russell SD, Shah AS, et al. Creation of a quantitative recipient risk index for mortality prediction after cardiac transplantation (IMPACT). Ann Thorac Surg. 2011;92(3):914-21.

3. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, BĂśhm M, Dickstein K, et al; Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14(8):803-69.

14. Kilic A, Allen JG, Arnaoutakis GJ, George TJ, Cameron DE, Vricella LA, et al. Adult-derived Index for Mortality Prediction After Cardiac Transplantation (IMPACT) risk score predicts short-term mortality after pediatric heart transplantation. Ann Thorac Surg. 2012;93(4):1228-34. 15. Vanhuyse F, Maureira P, Mattei MF, Laurent N, Folliguet T, Villemot JP. Use of the model for end-stage liver disease score for guiding clinical decision-making in the selection of patients for emergency cardiac transplantation. Eur J Cardiothorac Surg. 2013;44(1):134-8.

4. Fiorelli Al, Branco JN, Dinkhuysen JJ, Oliveira Junior JL, Pereira TV, Dinardi LF, et al. Risk factor analysis of late survival after heart transplantation according to donor profile: a multiinstitutional retrospective study of 512 transplants. Transplant Proc. 2012;44(8):2469-72. 5. Forni A, Luciani GB, Chiominto B, Pizzuti M, Mazzucco A, Faggian G. Results with expanded donor acceptance criteria in heart transplantation. Tranplant Proc. 2011;43(4):953-9.

16. Kilic A, Allen JG, Weiss ES. Validation of the United States-derived Index for Mortality Prediction after Cardiac Transplantation (IMPACT) using international registry data. J Heart Lung Transplant. 2013;32(5):492-8.

6. Holman WL, Kormos RL, Naftel DC, Miller MA, Pagani FD, Blume E, et al. Predictors of death and transplant in patients with a mechanical circulatory support device: a multi-institutional study. J Heart Lung Transplant. 2009;28(1):44-50.

17. Arnaoutakis GJ, George TJ, Allen JG, Russell SD, Shah AS, Conte JV, et al. Institutional volume and the effect of recipient risk on short-term mortality after orthotopic heart transplant. J Thorac Cardiovasc Surg. 2012;143(1):157-67.

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18. Weiss ES, Allen JG, Meguid RA, Patel ND, Merlo CA, Orens JB, et al. The impact of center volume on survival in lung transplantation: an analysis of more than 10,000 cases. Ann Thorac Surg. 2009;88(4):1062-70.

of center volume and outcome after cardiac transplantation. Cir Cardiovasc Qual Outcomes. 2012;5(6):783-90. 24. Hong KN, Iribarne A, Worku B, Takayama H, Gelijns AC, Naka Y, et al. Who is the high-risk recipient? Predicting mortality after heart transplant using pretransplant donor and recipient risk factors. Ann Thorac Surg. 2011;92(2):520-7.

19. Weiss ES, Meguid RA, Patel ND, Russell SD, Shah AS, Baumgartner WA, et al. Increased mortality at low-volume orthotopic heart transplantation centers: should current standards change?. Ann Thorac Surg. 2008;86(4):1250-9.

25. Young JB. Heart failure’s near dead and dying: reconsidering our heart transplant wait list scheme. J Am Coll Cardiol. 2007;50(13):1291-3.

20. Kilic A, Weiss ES, Arnaotakis GJ, George TJ, Conte JV, Shah AS, et al. Identifying recipients at high risk for graft failure after heart retransplantation. Ann Thorac Surg. 2012;93(3):712-6.

26. Wever-Pinzon O, Drakos SG, Kfoury AG, Nativi JN, Gilbert EM, Everitt M, et al. Morbidity and mortality in heart transplant candidates supported with mechanical circulatory support: is reappraisal of the current United network for organ sharing thoracic organ allocation policy justified? Circulation. 2013;127(4):452-62.

21. Hosenpud JD, Breen TJ, Edwards EB, Daily OP, Hunsicker LG. The effect of transplant center volume on cardiac transplant outcome. A report of the United Network for Organ Sharing Scientific Registry. JAMA. 1994;271(23):1844-9.

27. Barge-Caballero E, Paniagua-Martin MJ, Marzoa-Rivas R, CampoPérez R, Rodríguez-Fernández JÁ, Pérez-Pérez A, et al. Usefulness of the INTERMACS Scale for predicting outcomes after urgent heart transplantation. Rev Esp Cardiol. 2011;64(3):193-200.

22. Arnaoutakis GJ, George TJ, Allen JG, Russell SD, Shah AS, Conte JV, et al. Institutional volume and the effect of recipient risk on short-term mortality after orthotopic heart transplant. J Thorac Cardiovasc Surg. 2012;143(1):157-67.

28. González A, Adsuar A, Hernández A, Borrego JM, Gutiérrez E, Lage E, et al. Is an emergency heart transplantation justified? Transplant Proc. 2006;38(8):2531-3.

23. Pettit SJ, Jhund PS, Hawkins NM, Gardner RS, Haj-Yahia S, McMurray JJ, et al. How small is too small? A systematic review

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Yuan SM - Fetal cardiac interventions: REVIEW ARTICLE an update of therapeutic options

Fetal cardiac interventions: an update of therapeutic options Intervenções cardíacas fetais: atualização de opções terapêuticas

Shi-Min Yuan1, MMed, PhD

DOI 10.5935/1678-9741.20140099

RBCCV 44205-1567

Abstract Objective: This article aims to present updated therapeutic options for fetal congenital heart diseases. Methods: Data source for the present study was based on comprehensive literature retrieval on fetal cardiac interventions in terms of indications, technical approaches and clinical outcomes. Results: About 5% of fetal congenital heart diseases are critical and timely intrauterine intervention may alleviate heart function. Candidates for fetal cardiac interventions are limited. These candidates may include critical aortic valve stenosis with evolving hypoplastic left heart syndrome, pulmonary atresia with an intact ventricular septum and evolving hypoplastic right heart syndrome, and hypoplastic left heart syndrome with an intact or highly restrictive atrial septum as well as fetal heart block. The advocated option are prenatal aortic valvuloplasty, pulmonary valvuloplasty, creation of atrial communication and fetal cardiac pacing. Conclusion: Fetal cardiac interventions are feasible at midgestation with gradually improved technical success and fetal/postnatal survival due mainly to a well-trained multidisciplinary team, sophisticated equipment and better postnatal care.

Resumo Objetivo: Este artigo tem como objetivo apresentar opções terapêuticas atualizadas para cardiopatias congênitas fetais. Métodos: Os dados do presente estudo foram baseados em uma revisão abrangente da literatura a respeito de intervenções cardíacas fetais em termos de indicações, abordagens técnicas e resultados clínicos. Resultados: Cerca de 5% das cardiopatias congênitas fetais são críticas e a intervenção intrauterina oportuna pode aliviar a função cardíaca. Os candidatos para intervenções cardíacas fetais são limitados e podem incluir aqueles que são portadores de estenose valvar aórtica crítica com evolução para síndrome de hipoplasia do coração esquerdo, atresia pulmonar com septo ventricular íntegro e com evolução da síndrome de hipoplasia do coração direito e síndrome de hipoplasia do coração esquerdo com septo atrial intacto ou altamente restritivo, bem como bloqueio cardíaco fetal. As opções preconizadas são a valvoplastia aórtica fetal, valvoplastia pulmonar, criação de comunicação interatrial e implante de marca-passos em fetos. Conclusão: Intervenções cardíacas fetais são viáveis na fase intermediária da gestação com sucesso técnico e sobrevivência fetal/pós-natal, sendo aprimorados gradualmente, devido, sobretudo, a uma equipe multidisciplinar bem treinada, equipamentos sofisticados e melhores cuidados no pós-natal.

Descriptors: Fetal Heart. Heart Defects, Congenital. Prognosis.

Descritores: Coração Fetal. Cardiopatias Congênitas. Prognóstico.

The First Hospital of Putian, Teaching Hospital, Fujian Medical University, Putian, China.

Correspondence address: Shi-Min Yuan Longdejing Street, 389 - Chengxian District, Putian, Fujian Province, People’s Republic of China E-mail: shi_min_yuan@yahoo.com

This study was carried out at First Hospital of Putian, Teaching Hospital, Fujian Medical University, Putian, Fujian Province, People’s Republic of China. No financial support.

Article received on April 30th, 2014 Article accepted on July 24th, 2014

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tion secondary to volume overload with right heart failure and hydrops fetalis[11]. It may develop into HLHS prenatally and is associated with poor postnatal survival if left untreated in the uterus[12]. Retrograde flow in the transverse aortic arch, severe left ventricular dysfunction, monophasic and short mitral valve inflow and left-to-right flow across the foramen ovale can be determinants of AS progression into HLHS, in which very few chances of left heart growth and function can be available for a biventricular outcome[13]. Clinical observations also confirmed pre- and postnatal evolution of HLHS were associated with not only prenatal critical AS, but also endocardial fibroelastosis of the left ventricle[14]. By echocardiography, endocardial fibroelastosis is also implicated in post-interventional outcomes and postnatal heart growth[15]. The entry criteria for prenatal intervention for critical AS have been advocated as severe AS or atresia with severe left ventricular dysfunction and the left ventricular length was not <2 SD below the mean for gestational age at diagnosis. The timing of intervention should be on an urgent basis because of the potential for rapid progression into left ventricular growth failure in fetuses[16]. The first intrauterine balloon aortic valvuloplasty was reported in 1989 for the treatment of critical AS in two fetuses[12]. However, one died intrauterine post-intervention and the other died postnatally. The problem encountered during the maneuver was difficulty of needle withdrawal after the access to the fetal heart, which was afterwards resolved by the utilization of a stillette needle. Tworetzky et al.[16] reported successful aortic valvuloplasty, preventing the evolution of HLHS in fetuses with AS in 2004. Of the 20 pregnancies at 21-29-week gestation, technical success rate was 70% and subsequent postnatal biventricular repair rate was 21%. Further observations by echocardiography revealed left heart growth arrest in unsuccessful or declined cases, but ongoing left heart growth in successful cases. Resumed left heart growth leading to a biventricular circulation at birth was observed in three babies[16]. Arzt et al.[17] reported 24 aortic valvuloplasties in 23 fetuses with critical AS at 26 (range, 21-32)-week gestation, both technical success and postnatal biventricular repair rates were 66.7%. Recently, Goldstein et al.[18] introduced a standard 0.014-inch PrimeWire Prestige coronary guidewire for aortic valvuloplasty. With the aid of a micromanometer pressure sensor 3 cm from the tip, it was directed into the left ventricle and across the severely stenotic aortic valve. Immediate aortic pressure drop was seen after the procedure. This technique allows several potential advantages over conventional procedures in continuous monitoring of pressure waveforms, improvement of intraprocedural fetal hemodynamic monitoring and responsiveness to resuscitation. Intrauterine aortic valvuloplasty for AS is technically feasible. Success depends on a series of predictive factors, including cardiac structural changes (severe endocardial fibroelastosis),

Abreviations, acronyms & symbols AS CHD HLHS PA/IVS

Aortic stenosis Congenital heart disease Hypoplastic left heart syndrome Pulmonary atresia with intact ventricular septum

INTRODUCTION Cardiac malformations can be a result of intrinsic myocardial disease or a secondary adaptive mechanism of fetal heart during in utero development[1]. Pressure and volume stimuli of blood flow through the fetal heart are important determinants of the development of fetal heart and circulation during the second and third trimesters[1]. In order to reduce perinatal morbidity and mortality, an early diagnosis of the fetal congenital heart disease (CHD) in the parturients who are at an increased risk of CHD is imperative, particularly for those with a family history of CHD[2]. About 5% of prenatally diagnosed CHDs including severe aortic stenosis (AS) (1.6%), pulmonary atresia with intact ventricular septum (PA/IVS) (1.9%) and severe pulmonary valve stenosis (1.5%) can be critical and therefore require intrauterine therapeutic interventions[3]. Early diagnosis of treatable CHDs may improve fetal intervention outcomes[4], allowing ventricular growth and angiogenesis for fetus with semilunar valve stenosis for successful adaptation to extrauterine life[5]. Advanced imaging technology and equipment have made an accurate diagnosis of most fetal CHDs possible[6]. Among them, echocardiography is a reliable means for prenatal diagnosis of a wide spectrum of CHDs[3]. At present, diagnosis of CHDs at midgestation (18-24-week gestation) has become feasible in almost all situations[7]. However, minor errors might occur in echocardiographic visualization of a CHD probably due to poor image quality, early (<20 weeks) or late (>34 weeks) gestation, or maternal obesity[7]. Prenatal interventions for structural CHDs are now plausible with high rates of technical success at midpregnancy[8]. Boston experiences have confirmed candidates for fetal cardiac interventions, which are critical AS with evolving hypoplastic left heart syndrome (HLHS), PA/IVS and evolving hypoplastic right heart syndrome, and HLHS with an intact or highly restrictive atrial septum[9]. Moreover, fetuses with hypoplasia of the tricuspid valve annulus seem to be good candidates for pulmonary valve intervention, allowing sufficient right heart growth[6]. Minimal invasiveness (percutaneous access, only one cardiac puncture, and placental avoidance) and free from complications (fetal bradycardia, effusions and thrombus) are regarded as an ideal procedure[10]. Fetal Cardiac Intervention Intrauterine balloon aortic valvuloplasty Severe AS is associated with left ventricular outflow obstruction and may lead to irreversible left ventricular dysfunc-

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devices available (angle of cannula entry, cannula designs and catheter and wire configurations), fetal positioning, ultrasound imaging, maneuver sophistications and post-interventional care, etc. In addition, quick maneuvers may minimize the progressive fetal bradycardia. A successful procedure was anyway achieved in 81% at 21-26-week gestation fetuses[16]. The mortality and morbidity of fetal AS were mainly due to technical errors and due to the degree of the hemodynamic effects of the stenosis and left ventricular adaptation, development and function during fetal life[19]. However, fetal aortic valvuloplasty was not a definitive solution for fetal AS. In order to have a biventricular outcome, postnatal interventions are often required, such as repeated aortic valvuloplasty in most cases, temporary left atrial decompression, and frequent surgical interventions, such as coarctation repair, resection of endocardial fibroelastosis, mitral valvuloplasty, etc.[20].

balloon. After the final balloon deflation, the wire, balloon and cannula are removed. The catheter and needle are then withdrawn[26]. Since 2002, prenatal intervention for fetal PA/IVS has been performed for membranous pulmonary atresia with identifiable pulmonary valve leaflets or membrane, an intact or highly restrictive ventricular septal defect and right heart hypoplasia with a tricuspid valve annulus z score of <2. Compared with control fetuses with PA/IVS who did not undergo prenatal intervention with postnatal univentricular circulation, the tricuspid valve annulus, right ventricle length and pulmonary valve annulus grew significantly more from mid- to late gestation in the six fetuses that underwent successful interventions[25]. G贸mez Montes et al.[28] reported fetal intervention was performed for PA/IVS in four fetuses with technical success in all of them and with some improvement of the right heart growth and hemodynamics early after the procedure, thereby increasing the chances for a biventricular repair. Polat et al.[29] also adopted a 0.014-inch floppy tipped coronary guide wire in the maneuver. The wire-catheter assembly was introduced through the needle until the balloon emerged. After deployed in the left pulmonary artery, the balloon was pulled back across the perforated valve with three consecutive inflations. Post-interventional echocardiography showed slight improvement in right ventricular compliance. They performed a successful valvulotomy of the pulmonary valve in a fetus with PA/IVS at 28-week gestation and fetal hemodynamic improvement was observed following the procedure. Galindo et al.[23] reported successful valvuloplasty of the pulmonary valve performed in a fetus with critical pulmonary valve stenosis and heart failure at 25-week gestation. It is important to learn that midgestation fetal tricuspid valve z score>-3 and good tricuspid valve growth are the important factors leading to postnatal biventricular repair in fetuses with PA/IVS. According to the Boston experience, a Z-score >-3 is associated with biventricular outcome and a <-3 score with univentricular palliation[30].

Intrauterine pulmonary valvuloplasty PA/IVS is characterized by complete obstruction to right ventricular outflow tract with varying degrees of right ventricular and tricuspid valve hypoplasia[21]. Intrauterine pulmonary valvuloplasty in fetuses with PA/IVS allows potential growth and functional improvement of the right heart thereby increasing postnatal survival and biventricular repair[22-25]. Prenatal treatment of the lesion may prevent development of non-immune hydrops and intrauterine death[22], however, only limited cases have been reported[26]. Fetal cardiac intervention for PA/IVS is a challenging procedure because of the anatomical features of the right ventricular outflow tract and the difficult access to the pulmonary valve. With advancing gestation, a steady increase of the right ventricle-to-pulmonary artery gradient could lead to a high rate of pregnancy termination (61%) and some intrauterine death (5%) if left untreated[27]. It has been shown that pulmonary valvuloplasty in fetal life is also technically feasible in midgestation. With optimal fetal positioning with the aid of adequate echo imaging, a limited maternal laparotomy without uterine exteriorization or incision could be attained. Fetal pulmonary balloon valvuloplasty can be performed at 21-32-week gestation under maternal local anesthesia and sedation by inserting a needle through maternal abdominal wall into the uterine cavity under ultrasound guidance. Fetal analgesic is then injected before advancing the needle through the fetal chest wall into the right ventricular infundibulum of the fetus. A guidewire is inserted through the needle and across the pulmonary valve. A balloon catheter is inserted and then inflated to dilate the stenotic valve. Access to the right ventricular outflow tract is acchieved through direct puncture by using a 19-gauge cannula via a subcostal approach on the fetal chest or an intercostal space next to the sternum, the cannula tip is directed into the right ventricular outflow tract and the atretic pulmonary valve is dilated by inflating a coronary angioplasty

Prenatal intervention on the atrial septum Hypoplastic left heart syndrome is potentially detectable in fetuses of 18-22-week gestation with a four-chamber view on echocardiography. With left heart obstruction, the existence of an interatrial communication is important for oxygenated blood to be distributed to the body and to prevent pulmonary congestion[31]. Prenatal intervention on the atrial septum is indicated for an intact or highly restrictive atrial septum, which promotes profound cyanosis and pulmonary edema after birth, leading to little effective pulmonary blood flow and resulting in chronic pulmonary venous hypertension and lymphatic dilation. This can in turn result in increased perioperative morbidity and mortality with stage I Norwood procedure. Postnatal atrial septotomy, albeit rapid

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and effective, may not reverse pulmonary vasculature pathologies and further mortality in the first few weeks or months of life. Therefore, midgestation intervention on atrial septum is imperative for preventing pulmonary vasculature changes, reducing the need for additional or urgent procedures and improving the infantâ&#x20AC;&#x2122;s surgical outcome. The maneuver of prenatal interventions on atrial septum has been described. After acessing the fetal heart, a communication is created by directing the needle across the atrial septum. A wire and small balloon are forwarded into the left atrium and a small atrial communication is enlarged by inflation of the balloon[32]. A larger series of intrauterine atrial septoplasty in fetuses with HLHS was reported by Marshall et al.[33]. Of 21 fetuses at 2434-week gestation who received this procedure, there were 19 technical successes and two fetal deaths. An atrial septal defect of at least 3 mm in diameter was confirmed to allow postnatal benefit. However, postnatal outcomes were disappointing with a mortality of 58%. In order to keep septectomy open, a stent can be deployed across the atrial septum. Chaturvedi et al.[34] performed percutaneous ultrasound-guided stenting of the atrial septum in 10 fetuses. Two fetuses developed stent stenosis and died postnatally from pulmonary hypertension and sepsis, respectively. Kalish et al.[35] reported that nine fetuses at 24-31week gestation with HLHS/IAS received fetal atrial septal stent placement, with technical success in five and failure in four cases. Stent deployment may decompress the left atrium. Additionally, there were no maternal complications.

The initially proposed approach was an epicardial pacing lead on the fetal heart with an extra-uterine pulse generator implanted in the mother. However, a lack of myocardial fixation and dislodgment of the percutaneous lead due to fetal movement were the major limitations of the percutaneous approach. To resolve this problem, an entire single chamber pacing system without exteriorized leads without risk of dislodgement of the pacing system was therefore developed[45]. Such a design is now possible because of significant advances made in fetal surgery and fetal intervention, allowing the pacing system to be deployed through the maternal abdomen under ultrasound guidance. Furthermore, Assad et al.[46] designed a novel prototype T-shaped lead for secure fixation onto the fetal myocardium and prevention from electrode dislodgement, which could be introduced via an 18-gauge needle and therefore an open surgery was not needed. The new lead was tested in fetal goats, suggesting that a gradual increase in the fetal rate, beginning at 80 beats per minute after implantation would be more reliable for an adequate fetal cardiac output[47]. Boudjemline et al.[48] developed an implantable fetal pacing lead, which was made of a flexible quadrifilar coil with outer silicone insulation and a fixed screw on its distal tip. Attempts in 12 pregnant Pre-Alp ewes at 110-112 day gestation were successful for anchoring the lead on the ventricular wall in all 12 and on the atrium in three of them. DISCUSSION

Fetal cardiac pacing Complete heart block can be life-threatening in fetuses. The etiologies were considered to be inflammation and fibrosis at the atrioventricular node associated with the production of antibodies[36]. Heart block can progress during pregnancy and may result in hydrops fetalis and eventual fetal demise[37]. There are few effective treatment options for fetal heart block, as side effects of fluorinated steroids (betamethasone or dexamethasone) have been concerned, whereas fetal heart rate and glomerular filtration rate irrespective of the gestational age were not significantly influenced[38,39]. Moreover, poor response of congenital fetal heart block to intravenous maternal isoproterenol can be an indication for permanent pacemaker implant before birth[40]. In general, a permanent pacemaker is required in about 66% of the cases[40]. The first trial of fetal cardiac pacing with a pacemaker implant for complete heart block was reported in 1986[41,42]. Initial attempts of intrauterine percutaneous pacing through a transthoracic approach or an inferior vena cava route resulted in fetal demise shortly after the procedure. Later, Assad et al.[43,44] designed two modified pacing electrodes: a screw-in lead (1Â˝ turns) and a stitch-on lead, which were tested in experimental models of fetal heart block induced by cryosurgical ablation of the atrioventricular node. They found that the screw-in electrode was better for fetal pacing.

The reverse remodeling phenomenon should be even more pronounced in fetal life. Thus, fetal cardiac interventions were attempted aiming at promoting ventricular growth and function, decreasing intrauterine death and increasing survival[10]. Fetal cardiac interventions have been advocated for fetuses with semilunar valve stenosis[16,24,49] or with HLHS with an intact or highly restrictive atrial septum[33]. In the early years, fetal cardiac interventions showed poor outcomes, probably related to poor ultrasonographic imaging, limitations of equipment availability and poor fetal conditions[50]. Technical success of fetal cardiac interventions has greatly enhanced postnatal biventricular outcome, thereby avoiding the need for three-stage palliation or cardiac transplant[51]. Despite the progress made in this field, these fetal cardiac interventions remain controversial in both indications and results[3,52]. There have been relatively fewer prenatal pulmonary valve interventions comparing with prenatal aortic valve intervention[53]. On the other hand, prenatal interventions for the management of pulmonary atresia and intact ventricular septum were often associated with increased risks of preterm delivery and neonatal mortality[49]. Furthermore, pulmonary valve stenosis may be alleviated with the intrauterine right heart growth and the impact of interventional therapy on the pulmonary cir-

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culation does not seem to be as forceful as that on the systemic circulation secondary to fetal aortic valvuloplasty[3]. Candidates for fetal arrhythmic interventions have been considered supraventricular tachycardia refractory to conventional drug with a potential for progression into hydrops fetalis and fetal demise[54,55]. Immune complete heart block with low ventricular rate may cause significant decrease in fetal cardiac output, cardiac failure and hydrops fetalis[56,57]. The poor prognosis of these fetal arrhythmias has incited the development of alternative therapeutic strategies. Fetal ventricular pacing has been found to improve ventricular output in experimentally induced complete atrioventricular block[58]. However, initial attempts of fetal pacing have failed in human fetuses[4,42,45]. As open fetal surgery for intrauterine pacemaker insertion has been associated with unacceptable maternal morbidity and fetal demise, minimally invasive approaches using either transcutaneous ultrasound-guided[59] or fetoscopic approaches[47] have been favored. Both endovascular route for intracardiac[42] and epicardial lead anchorages[59] were attempted. Adaptations of new leads to the fetal anatomy for a secure anchorage are crucial for obtaining better outcomes of fetal pacing. Fetal cardiac interventions by direct cardiac puncture are associated with significant fetal morbidity. In order to avoid direct cardiac puncture, Nugent et al.[60] have employed successfully in an in vitro fetal heart model of approximating a 32-week gestation with magnetically steerable guide wires from the hepatic vein to the descending aorta and balloon to the aortic valve, in between 5 and 10 minutes. The treatment of critical left ventricular outflow tract obstruction in the neonate and infant remains a significant challenge[61]. Postnatal surgical options include biventricular repair (surgical aortic valvotomy, balloon aortic valvotomy, Ross/Konno procedure and arch repair with or without other lesion repair), single ventricular repair (Norwood type), biventricular repair after initial single ventricular repair and cardiac transplantation[61]. Biventricular repair presents obvious advantages over univentricular type of repair in terms of better survival and lower hospitalization costs[62]. Rhodes scores have been taken as reliable indicators for the determination of a biventricular or univentricular repair[63]. For conditions with no possibility of biventricular repair, the expectant parents may choose, between postnatal palliative management (such as the Norwood procedure for HLHS) or for interruption of pregnancy[6]. Heart transplantation can be a third option for the parents in saving the baby with life-threatening, critical AS, which fails to other surgical interventions[64]. At the beginning, the technical success and biventricular repair rates were low, which were now considered to be mostly attributed to postnatal care other than prenatal intervention, while technical failure was only responsible for small parts[47]. Only small part of the mortality could directly correlate with the prenatal intervention; whereas the greater part died postna-

tally probably due to the limited postnatal surgical and intensive care. The considerably improved survival rates and higher rates of postnatal biventricular repair following fetal dilation of severe semilunar valve obstructions were a result of proficient surgical and intensive care managements[47]. Most recently, with well-established multidisciplinary team and equipments, prenatal intervention success and postnatal biventricular repair rates have been significantly improved[17]. In Brazil, fetal interventions for CHDs have achieved a 91% success rate. There were two failures out of the 22 procedures, one was aortic and the other was pulmonary valvuloplasty[65]. Technical challenges and poor candidate selection are the two major restrictive factors limiting the development of fetal cardiac interventions. Lee & Comstock[66] emphasized the importance of a well-established practice guidelines and a standardized diagnostic training team for prenatal diagnosis of CHDs. A multidisciplinary team with the incorporation of a pediatric cardiac surgeon with maternal-fetal medicine, interventional cardiologist and fetal echocardiography subspecialists is warranted. Future directions of fetal cardiac interventions lie on technical advancements such as computer-assisted navigation[66], open fetal cardiac surgery and fetoscopic cardiac surgery (Ebsteinsâ&#x20AC;&#x2122; anomaly with hydrops fetalis, tetralogy of Fallot and pulmonary valve atresia). Open fetal cardiac intervention currently remains stagnant at the stage of animal experiments. It has revealed that midterm ovine fetuses under 30-minute bypass was associated with decreased cardiac output and increased end-diastolic pressure of the right ventricle[67]. Impairment of placental perfusion and respiratory gas exchange have been observed in lamb placenta when the animals were subjected to normothemic or hypothemic CPB with more severe impairment seen under hypothermia[68]. Further studies showed right ventricular function of midterm ovine fetuses under 90-minute bypass was better preserved by fibrillatory arrest than by cardioplegia[69]. During fetal heart bypass, a volume shift of approximately 100 mL/kg, equivalent to 0.8 mL/kg/min, occurred and this may require volume replacements during bypass and normal physiologic supplements after bypass for maintenance of blood volume[70]. Besides, fetal CPB may lead to a profound, early rise of vasopressin levels, which may in turn impair placental function[71]. These achievements have laid sufficient foundation for future clinical practice of open fetal cardiac interventions in human fetuses. CONCLUSIONS Fetal cardiac interventions (intrauterine balloon aortic valvuloplasty, intrauterine pulmonary valvuloplasy, prenatal intervention on the atrial septum and fetal cardiac pacing) for four types of congenital heart defects are feasible during midgestation aiming at improving fetal cardiac function, minimizing loss of fetus and enhancing postnatal biventricu-

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lar repair. The postnatal deaths are more likely to be a result of candidate selection, effects of improvement of ventricular circulation secondary to fetal cardiac interventions and surgical technical errors and probably a limited intensive care. For improving success rate and post-interventional outcomes, a well-trained team with sophisticated equipment is warranted. With improved patient selection, technical modifications, for example with a robotic interventional approach, promising outcomes may be achieved in future cases. Moreover, with the advances of fetal bypass techniques, it is anticipated that open fetal heart operations would become feasible to facilitate the early treatment of fetal CHDs in the future.

10. Bacha E. The impact of fetal cardiac intervention on neonatal cardiac surgery [Accessed July 1, 2014]. Available from: http:// av.conferencearchives.com/pdfs/100502/09.08.pdf 11. Schmider A, Henrich W, Dähnert I, Dudenhausen JW. Prenatal therapy of non-immunologic hydrops fetalis caused by severe aortic stenosis. Ultrasound Obstet Gynecol. 2000;16(3):275-8. 12. Maxwell D, Allan L, Tynan MJ. Balloon dilatation of the aortic valve in the fetus: a report of two cases. Br Heart J. 1991;65(5):256-8. 13. Mäkikallio K, McElhinney DB, Levine JC, Marx GR, Colan SD, Marshall AC, et al. Fetal aortic valve stenosis and the evolution of hypoplastic left heart syndrome: patient selection for fetal intervention. Circulation. 2006;113(11):1401-5.

Authors’ roles & responsibilities SMY

14. Sharland GK, Chita SK, Fagg NL, Anderson RH, Tynan M, Cook AC, et al. Left ventricular dysfunction in the fetus: relation to aortic valve anomalies and endocardial fibroelastosis. Br Heart J. 1991;66(6):419-24.

Main author

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Duarte JJ, et al. - Indication of endovascular treatment of type B aortic REVIEW ARTICLE dissection - Literature review

Indication of endovascular treatment of type B aortic dissection - Literature review Indicação do tratamento endovascular na dissecção de aorta do tipo B - Revisão da literatura

João Jackson Duarte1, MD, MsC; José Carlos Dorsa Vieira Pontes1, MD, PhD; Ricardo Adala Benfatti1, MD, MsC; Adriana Lugo Ferrachini1, MD; Walter Kegham Karakhanian2, MD, PhD; Álvaro Razuk Filho2, MD, PhD

DOI: 10.5935/1678-9741.20140076

RBCCV 44205-1568

Abstract Aortic dissection is a cardiovascular event of high mortality if not early diagnosed and properly treated. In Stanford type A aortic dissection, there is the involvement of the ascending aorta, whereas in type B the ascending aorta is not affected. The treatment of type A aortic dissection is mainly surgical. The hospital mortality of type B aortic dissection surgical treatment is approximately 20%, while medical therapy is 10%. However, half the patients who are discharged from hospital after medical treatment, progress to aortic complications in the following years, and the mortality in three to five years may reach 25-50%. In addition, the surgical treatment of aortic complications after medical treatment, has also a significant mortality. This way, the endovascular treatment comes up as an interesting alternative of a less invasive treatment for this disease. They presented a mortality rate lower than 10% with more than 80% success rate of occlusion and thrombosis of the false lumen. The INSTEAD TRIAL, which randomized patients with uncomplicated type B aortic dissection for optimal medical therapy and endovascular treatment in addition to optimal medical therapy, showed that after three years of follow up, patients who underwent endovascular treatment had

lower mortality and aorta-related complications. Therefore, there is a current tendency to recommend the endovascular treatment as a standard for the treatment of type B aortic dissection

Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, MS, Brazil. 2 Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSC-SP), São Paulo, SP, Brazil.

Correspondence address: Ricardo Adala Benfatti Hospital Universitário, Cardiac ICU Avenida Senador Filinto Muller, s/n, Piratininga, Zip code: 79090-900 Campo Grande, Mato Grosso do Sul, Brazil E-mail: ricardobenfatti@gmail.com

Descriptors: Endovascular Procedures. Aortic Diseases. Aneurysm, Dissecting. Resumo A dissecção da aorta é um evento cardiovascular de alta mortalidade quando não diagnosticado precocemente e tratado adequadamente. Na dissecção de aorta do tipo A de Stanford há o envolvimento da aorta ascendente enquanto na do tipo B este a aorta ascendente não está acometida. O tratamento da dissecção de aorta do tipo A é predominantemente cirúrgico. A mortalidade hospitalar do tratamento cirúrgico da dissecção da aorta do tipo B é de aproximadamente 20%, enquanto a do tratamento clínico é de 10%. Entretanto, metade dos pacientes que recebem alta hospitalar após o tratamento clínico, evoluem com complicações aórticas nos anos subsequentes, sendo que a mortalidade em três a cinco anos pode atingir 25 a 50%. Além disto, o tratamento

This study was carried out at Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, MS, Brazil.

Article received on February 5th, 2014 Article accepted on May 26th, 2014

No financial support.

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cirúrgico das complicações aórticas, após o tratamento clínico, também apresenta alta mortalidade. Desta forma, o tratamento endovascular surge como interessante alternativa para o tratamento menos invasivo desta doença. Inicialmente indicado apenas para os casos complicados, apresentavam mortalidade hospitalar menor que 10% com mais de 80% de sucesso de oclusão e trombose da falsa luz. O INSTEAD TRIAL, que randomizou pacientes com dissecção de aorta do tipo B não complicada para o tratamento médico otimizado e para o tratamento endovascular

em adição ao tratamento médico otimizado, demonstrou que após três anos de acompanhamento, aqueles pacientes submetidos ao tratamento endovascular apresentaram menor mortalidade e complicações relacionados a aorta. Portanto, atualmente há uma tendência em se indicar o tratamento endovascular como padrão para o tratamento da dissecção de aorta do tipo B. Descritores: Procedimentos Endovasculares. Doenças da Aorta. Aneurisma Dissecante.

for false lumen thrombosis. Nienaber et al.[8], in 1999, comparing patients with chronic or subacute dissection endovascular treated with patients who underwent conventional surgery, reported technical success in 100% of cases, with 83.3% of immediate thrombosis of the false lumen. The EUROSTAR registry[9], described in 2004, introduced the first wider case series of patients treated with thoracic aortic stent graft. This registry included patients with aortic dissection, aortic aneurysm, pseudoaneurysm and traumatic aortic lesions. Despite the heterogeneity of the patients, it demonstrated primary technical success of 89%, with 30-day mortality of 6.5%, the one-year survival was 90% in cases of aortic dissection type B, and paraplegia occurred in 0 8%. In Brazil, Fonseca et al.[10], in 1998, present the endovascular treatment of 4 cases of acute type B dissection with stent graft interposition, obtaining success in all the cases with total occlusion of the slot with thrombosis of the false lumen. The premature occlusion of the false lumen entrance seems to improve the prognosis of patients in long-term. Atsuku et al.[11] followed the late evolution (ten years) of patients with type B aortic dissection medically treated. These authors showed that in the group of patients that had thrombosis of the false lumen during medical treatment, the mortality associated with the dissection was 5.6 times lower than in the group of patients in whom the false lumen remained patent, concluding that the patency the false lumen was an independent risk factor for dissection, death or events related to the dissection. Tsai et al.[12] have shown that after discharge from hospital, patients who presented partial thrombosis of the false lumen had higher mortality than patients with complete patency of the false lumen. This happens with the higher incidence of rupture of the aneurysm sac expansion for not having distal reentry and end up in “dead end”, leading to greater subsequent pressurization of the false lumen. In the initial evaluation of acute type B aortic dissection, prognostic indicators of severity as the patency of the false

INTRODUCTION Aortic dissection is a cardiovascular event of high mortality if not early diagnosed and properly treated. In Stanford type A aortic dissection there is the involvement of the ascending aorta, whereas in type B, the dissection is restricted to the descending aorta. The treatment of Type A aortic dissection is mainly surgical. The hospital mortality of surgical treatment of Type B aortic dissection is about 20%, while medical therapy is 10%, therefore the recommendation for intervention in these cases shall be reserved for complicated cases, that are characterized by persistent pain, presence of ischemic complications, uncontrolled hypertension and aortic dilatation[1]. However, half of patients who are discharged after medical treatment, evolves with aortic complications in the following years, and the mortality in three to five years can reach 20% to 50%[2]. Furthermore, the surgical treatment of aortic complications after medical treatment, has also a significant mortality. Endovascular Treatment The endovascular approach in aortic diseases was introduced by Volodos et al.[3] in 1986 and Parodi et al.[4], in 1991, it is the correction of aortic diseases with self expandable prosthesis implantation inside the aorta, starting from catheters introduced through the femoral artery. The endovascular treatment of descending aortic dissections was first described by Dake et al.[5] in 1994. In 1997, the group of the Paulista School of Medicine led by Dr. Honorio Palma and Dr. Ernie Buffolo described, in a series of seventy patients with aortic dissection type B treated with the elephant trunk technique, two cases where the tube Dacron was replaced by anterograde released stent graft during total circulatory arrest of five minutes[6]. In 1999 Dake et al.[7] in 19 patients with complicated type b aortic dissection who underwent endovascular treatment, reported hospital mortality of 16% for aortic rupture and 79%

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lumen and aortic diameter greater than 40 mm as it should be considered in the choice of the appropriate therapy[13]. Loewe et al.[14] demonstrated a higher incidence of complications in acute type B aortic dissection in which the location of the entrance hole is in the small aortic curvature and recommended that these patients should be considered as high risk and with indication of premature endovascular treatment. Eggebrecht et al.[15], in a meta-analysis of 39 published studies from 1999 to 2005, which involved 609 patients, proved the technical success in 98.2% of patients; hospital mortality of 5.3%, presence of neurological complications of 3.1 %, 1% of paraplegia and 2.1% of ischemic stroke. During follow-up, there was 2.3% of aortic rupture. Xiong et al.[16], also from meta-analysis of 39 studies published from 2001 to 2007 in China, involving 1304 patients, showed a hospital mortality of 2.6Âą0.1%, and a 5-year survival of 95.2%. The low mortality rate for endovascular treatment in a significant number of patients with type B aortic dissection complicated[15,16] allowed to question the indication of medical treatment as an approach to uncomplicated type B aortic dissections. The INSTEAD[17] was the first prospective, randomized, multicenter trial that compared endovascular treatment added to optimal medical treatment exclusively in uncomplicated type B aortic dissections in the subacute and chronic stage. After two years of follow up, there was no difference in mortality from all causes and events related to the aorta between the two groups, although the aortic remodeling, defined as an increase of the true lumen and false lumen thrombosis was higher in patients undergoing endovascular treatment, 91.3% versus 19.4% in the group of medical treatment[18]. At late follow-up of these patients, between 2-5 years, the group of patients randomized to endovascular and optimized medical treatment showed lower mortality due to events related to the aorta, 6.9% versus 19.3% in the group that was selected for exclusive optimized medical treatment[19]. Furthermore, patients of the endovascular treatment also presented reduced disease progression of 27% against 46.1% in the medical treatment[19]. The efficacy of endovascular treatment of type B aortic dissections is conditioned to occlusion of the entrance and complete thrombosis of the false lumen. The literature describes a variation in the rate of complete thrombosis of the false lumen in the descending thoracic aorta, between 22.2% and 100%[7,8,20-24]. This wide variation is related to the stage of the disease presentation in which it was proposed the treatment as well as the studied segment of the descending thoracic aorta. Shimono et al.[22], in a late follow-up of 24.5 months after endovascular repair, reported that the complete thrombosis of the false lumen was more frequent in patients treated in the

acute phase 66.7% than those treated during the chronic phase 38.5%. According to these authors the persistent false lumen perfusion was correlated with late complications such as aortic dilation and rupture with subsequent death. Kusagawa et al.[25] reported that after two years of follow-up after endovascular repair of type B aortic dissection, the false lumen thrombosis occurred in 76% of patients undergoing repair in the acute phase of the disease and in 36% of those who have corrected in the chronic phase. They also reported that after treatment of acute cases, the average diameter of the false lumen in the descending aorta early reduced, between one and six months. In the cases treated in the chronic phase, this reduction occurred later, between six and twelve months, confirming that the false lumen thrombosis is more likely when treatment is instituted in the acute phase. Fioranelli et al.[26] reported that the presence of reentry thoracic aorta was correlated with the patency of the false lumen in the postoperative follow-up and agreed with the findings of Kato et al.[23]; Shimono et al.[22] and Kusagawa et al.[25] who stated that the delamination, sometimes fragile in the acute phase, becomes more fibrotic and stable in the chronic phase thereby decreasing the potential for aortic remodeling in this stage. Lopera et al.[27], also reported that the presence of reentry at the level of the descending thoracic aorta associated with fibrosis in chronic cases, contribute to the reduced chance of sealing the intimal-middle layer and consequent reduction of thrombosis of the thoracic false lumen. Dias et al.[28], despite the small number of patients studied, concluded that the endovascular treatment of type B aortic dissection, in the chronic phase, did not decrease the diameter of the descending aorta and showed persistence of the false lumen in the descending segment of the thoracic aorta in 27.3% and abdominal aorta of 81.8%. Kusagawa et al.[25], in a 6-year experience with endovascular treatment for acute and chronic dissection, reported that the presence of reentry in the thoracic and abdominal aorta were correlated with the maintenance of the false lumen diameter in the thoracic aorta. The presence of abdominal visceral level reentry allowed the reduction or thrombosis of the false lumen of the thoracic aorta, demonstrating that the presence of reentry into the descending thoracic aorta is the limiting factor in this segment of the aortic remodeling. Schoder et al.[29] demonstrated that endovascular treatment determined the false lumen thrombosis at the level of the stent graft in 90% of cases, 60% in the most distal segment of the stent graft and 22% in the segment of the abdominal aorta. It was justified by the presence of distal reentries. Eggebrecht et al.[24], in 38 patients with complicated type B dissection underwent endovascular treatment, 10 patients in the acute phase and 28 in the chronic phase, reported early mortality of 11%, all of them occurring in patients treated in the acute phase.

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Böckler et al.[30], studying 37 patients with complicated dissection, also demonstrated a 19% incidence of early mortality in patients treated during the acute phase of dissection and no deaths in patients treated in the chronic phase. These authors considered that this high mortality rate is due to the selection of patients, the severity of the case that requires immediate intervention. Given that these patients, despite the technical success of the occlusion of the false lumen by the stent graft, evolve with systemic complications from previous clinical condition. Thus, the cause of early death in the present study was mostly due to multiple organ failure and mesenteric ischemia, and other causes not related to the aorta. Therefore, in relation to the developmental stage of the disease in which the endovascular treatment is indicated, it seems that the incidence of false lumen thrombosis is higher in acute cases, despite early mortality also being higher in these patients, although it is determined by the previous clinical severity of these patients. The retrograde dissection has also been described in the literature in up to 8% of cases[31]. According to Rubin et al.[32], this complication can take place early or even at a later period of the treatment. The possible causes for retrograde dissection are inherent to the technical procedure, and as with intimal injury of the aortic wall by the tip of super-hard guide wires, or the ends of the stent delivery systems. It has also been linked to retrograde dissection. The proximal balloon inflating for accommodation can also lead to intimal injury[26]. The choice of prosthesis with much larger diameters than the lap anchor, which presented higher radial force against the aortic wall, is also an important cause of retrograde dissection or even rupture of the aortic wall[33]. According to Pamler et al.[34], Kasirajan et al.[33] and Rubin et al.[32] The presence of free proximal stent, “Free Flo”, in close and direct contact with the weakened aortic wall, may also cause intimal injury. Bortone et al.[35], in 43 studied cases, reported 7.0% of early mortality because of retrograde dissection due to the use of stent graft with proximal free stent. Dialetto et al.[36], in 28 patients treated with complicated Stanford type B dissection, presented 10.7% (03 patients) of early mortality, and the causes of death were retrograde dissection and rupture of the false lumen in two cases. Recently, Fattori et al.[37] published data from 1995 to 2012 from the international registry of aortic dissection. 1129 consecutive patients with type B acute aortic dissection were monitored. Uncomplicated patients were medically treated (75.6%) and those with complicated dissection were indicated for the endovascular procedure (24.4%). The hospital mortality between the two groups was similar, but at a 5 year follow-up, the group that underwent endovascular treatment had a lower mortality of 15.5% compared to 29% of death in patients who were medically treated. As a conclusion, we can say that the best current scientific evidence suggests that in complicated cases, endovascular

therapy is the best treatment option, in the subacute and chronic uncomplicated cases, the endovascular treatment and the clinical treatment have similar short-term results, however in the long-term evaluation, the endovascular treatment has lower mortality rate, lower incidence of complications related to the aorta and lower disease progression. Regarding the treatment of this disease in its acute phase, future comparative and randomized studies are needed to define the best treatment to be indicated. Authors’ roles & responsibilities JJD JCDVP RAB ALF WKK ARF

Final approval of the manuscript, drafting the manuscript; review it critically Drafting of the manuscript; review it critically Final approval of the manuscript, drafting the manuscript; review it critically Drafting of the manuscript; review it critically Drafting of the manuscript; review it critically Final approval of the manuscript

REFERENCES 1. Hagan PG, Nienaber CA, Isselbacher EM, Bruckman D, Karavite DJ, Russman PL, et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA. 2000;283(7):897-903. 2. Fann JI, Smith JA, Miller DC, Mitchell RS, Moore KA, Grunkemeier G, et al. Surgical management of aortic dissection during a 30-year period. Circulation. 1995;92(9 Suppl):II113-21. 3. Volodos’ NL, Shekhanin VE, Karpovich IP, Troian VI, Gur’ev luA. [A self-fixing synthetic blood vessel endoprosthesis]. Vestn Khir Im I I Grek. 1986;137(11):123-5. 4. Parodi JC, Palmaz JC, Barone HD. Transfemoral intraluminal graft implantation for abdominal aortic aneurysms. Ann Vasc Surg. 1991;5(6):491-9. 5. Dake MD, Miller DC, Semba CP, Mitchell RS, Walker PJ, Liddell RP. Transluminal placement of endovascular stent-grafts for the treatment of descending thoracic aortic aneurysms. N Engl J Med. 1994;331(26):1729-34. 6. Palma JH, Almeida DR, Carvalho AC, Andrade JC, Buffolo E. Surgical treatment of acute type B aortic dissection using an endoprosthesis (elephant trunk). Ann Thorac Surg. 1997;63(4):1081-4. 7. Dake MD, Kato N, Mitchell RS, Semba CP, Razavi MK, Shimono T, et al. Endovascular stent-graft placement for the treatment of acute aortic dissection. N Engl J Med. 1999;340(20):1546-52.

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8. Nienaber CA, Fattori R, Lund G, Dieckmann C, Wolf W, von Kodolitsch Y, et al. Nonsurgical reconstruction oh thoracic aortic dissection by stent-graft placement. N Engl J Med. 1999;340(20):1539-45.

investigation of stent grafts in aortic dissection trial. Circ Cardiovasc Interv. 2013;6(4):407-16. 20. Czermak BV, Waldenberger P, Fraedrich G, Dessl AH, Roberts KE, Bale RJ, et al. Treatment of Stanford type B aortic dissection with stent-grafts: preliminary results. Radiology. 2000;217(2):544-50.

9. Leurs LJ, Bell R, Degrieck Y, Thomas S, Hobo R, Lundbom J; UK Thoracic Endograft Registry collaborators. Endovascular treatment of thoracic aortic diseases: combined experience from the EUROSTAR and United Kingdom Thoracic Endograft registries. J Vasc Surg. 2004;40(4):670-9.

21. Bortone AS, Schena S, D’Agostino D, Dialetto G, Paradiso V, Mannatrizio G, et al. Immediate versus delayed endovascular treatment of post-traumatic aortic pseudoaneurysms and type B dissections: retrospective analysis and premises to the upcoming European trial. Circulation. 2002;106(12 Suppl 1):1234-40.

10. Fonseca JHP, Buffolo E, Carvalho AC, Geisthvel N, Almeida DR, Souza JA, et al. Utilização de endoprótese auto-expansível introduzida através da artéria femoral para tratamento de dissecção da aorta descendente. Arq Bras Cardiol. 1998;70(6):389-92.

22. Shimono T, Kato N, Yasuda F, Suzuki T, Yuasa U, Onoda K, et al. Transluminal stent-graft placements for the treatment of acute onset and chronic aortic dissections. Circulation. 2002;106(12 Suppl.):1241-7.

11. Akutsu K, Nejima J, Kiuchi K, Sasaki K , Ochi M, Tanaka K, et al. Effects of the patent false lumen on the long-term outcome of type B acute aortic dissection. Eur J Cardiothorac Surg. 2004;26(2):359-66.

23. Kato N, Hirano T, Ishida M, Shimono T, Cheng SH, Yada I, et al. Acute and contained rupture of the descending thoracic aorta: treatment with endovascular stent grafts. J Vasc Surg. 2003;37(1):100-5.

12. Tsai TT, Evangelista A, Nienaber CA, Myrmel T, Meinhardt G, Cooper JV, et al; International Registry of Acute Aortic Dissection. Partial thrombosis of the false lumen in patients with acute type B aortic dissection. N Engl J Med. 2007;357(4):349-59.

24. Eggebrecht H, Herold U, Kuhnt O, Schmermund A, Bartel T, Martini S, et al. Endovascular stent-graft treatment of aortic dissection: determinants of post-interventional outcome. Eur Heart J. 2005;26(5):489-97.

13. Onitsuka S, Akashi H, Tayama K, Okazaki T, Ishihara K, Hiromatsu S, et al. Long-term outcome and prognostic predictors of medically treated acute type B aortic dissections. Ann Thorac Surg. 2004;78(4):1268 -73.

25. Kusagawa H, Shimono T, Ishida M, Suzuki T, Yasuda F, Yuasa U, et al. Changes in false lumen after transluminal stent-graft placement in aortic dissections: six years’ experience. Circulation. 2005;111(22):2951-7.

14. Loewe C, Czerny M, Sodeck GH, Ta J, Schoder M, Funovics M, et al. A new mechanism by which an acute type B aortic dissection is primarily complicated, becomes complicated, or remains uncomplicated. Ann Thorac Surg. 2012;93(4):1215-22.

26. Fioranelli A, Razuk Filho A, Castelli Júnior V, Karakhanian W, Godoy JM, Caffaro RA. Mortality within the endovascular treatment in Stanford type B aortic dissections. Rev Bras Cir Cardiovasc. 2011;26(2):250-7.

15. Eggebrecht H, Nienaber CA, Neuhäuser M, Baumgart D, Kische S, Schmermund A, et al. Endovascular stent-graft placement in aortic dissection: a meta-analysis. Eur Heart J. 2006;27(4):489-98.

27. Lopera J, Patiño JH, Urbina C, García G, Alvarez LG, Upegui L, et al. Endovascular treatment of complicated type-B aortic dissection with stent-grafts:: midterm results. J Vasc Interv Radiol. 2003;14(2 Pt 1):195-203.

16. Xiong J, Jiang B, Guo W, Wang SM, Tong XY. Endovascular stent graft placement in patients with type B aortic dissection: a metaanalysis in China. J Thorac Cardiovasc Surg. 2009;138(4):865-72. 17. Nienaber CA, Zanetti S, Barbieri B, Kische S, Schareck W, Rehders TC; INSTEAD study collaborators. INvestigation of STEnt grafts in patients with type B Aortic Dissection: design on the INSTEAD trial--a prospective, multicenter, European randomized trial. Am Heart J. 2005;149(4):592-9.

28. Dias RR, Judas G, Oliveira MA, Malbouisson LM, Fiorelli AI, Stolf NA. Is the endovascular procedure an option for treatment of cronic type B aortic dissections? Rev Bras Cir Cardiovasc. 2007;22(4):441-7. 29. Schoder M, Czerny M, Cejna M, Rand T, Stadler A, Sodeck GH, et al. Endovascular repair of acute type B aortic dissection: long-term follow-up of true and false lumen diameter changes. Ann Thorac Surg. 2007;83(3):1059-66.

18. Nienaber CA, Rousseau H, Eggebrecht H, Kische S, Fattori R, Rehders TC, et al; INSTEAD Trial. Randomized comparison of strategies for type B aortic dissection: the INvestigation of STEnt Grafts in Aortic Dissection (INSTEAD) trial. Circulation. 2009;120(25):2519-28.

30. Böckler D, Schumacher H, Ganten M, Von Tengg-Kobligk H, Schwartzbach M, Fink C, et al. Complications after endovascular repair of acute symptomatic and chronic expanding Stanford type B aortic dissections. J Thorac Cardiovasc Surg. 2006;132(2):361-8.

19. Nienaber CA, Kische S, Rousseau H, Eggebrecht H, Rehders TC, Kundt G, et al; INSTEAD-XL trial. Endovascular repair of type B aortic dissection: long-term results of the randomized

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aortic dissection. J Endovasc Ther. 2002;9(6):822-8. 35. Bortone AS, De Cillis E, D’Agostino D, de Luca Tupputi Schinosa L. Endovascular treatment of thoracic aortic disease: four years of experience. Circulation. 2004;110(11 Suppl 1):II262-7.

32. Rubin S, Bayle A, Poncet A, Baehrel B. Retrograde aortic dissection after a stent graft repair of a type B dissection: how to improve the endovascular technique. Interact Cardiovasc Thorac Surg. 2006;5(6):746-8.

36. Dialetto G, Covino FE, Scognamiglio G, Manduca S, Della Corte A, Giannolo B, et al. Treatment of type B aortic dissection: endoluminal repair or conventional medical therapy? Eur J Cardiothorac Surg. 2005;27(5):826-30.

33. Kasirajan K. Re: “extension of dissection in stent-graft treatment of type B aortic dissection: lessons learned from endovascular experience”. J Endovasc Ther. 2005;12(5):620-1.

37. Fattori R, Montgomery D, Lovato L, Kische S, Di Eusanio M, Ince H, et al. Survival after endovascular therapy in patients with type B aortic dissection: a report from the International Registry of Acute Aortic Dissection (IRAD). JACC Cardiovasc Interv. 2013;6(8):876-82.

34. Pamler RS, Kotsis T, Görich J, Kapfer X, Orend KH, SunderPlassmann L. Complications after endovascular repair of type B

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Ferrari ADL, etREVIEW al. - Cardiomyopathy ARTICLE induced by artificial cardiac pacing: myth or reality sustained by evidence?

Cardiomyopathy induced by artificial cardiac pacing: myth or reality sustained by evidence? Miocardiopatia dilatada induzida por estimulação cardíaca artificial: mito ou realidade sustentada pelas evidências?

Andrés Di Leoni Ferrari1, MD; Anibal Pires Borges1, MD; Luciano Cabral Albuquerque1, PhD; Carolina Pelzer Sussenbach1, MD; Priscila Raupp da Rosa1, MD; Ricardo Medeiros Piantá1, MD; Mario Wiehe1, PhD; Marco Antônio Goldani1, MD

DOI: 10.5935/1678-9741.20140104

RBCCV 44205-1569

Abstract Implantable cardiac pacing systems are a safe and effective treatment for symptomatic irreversible bradycardia. Under the proper indications, cardiac pacing might bring significant clinical benefit. Evidences from literature state that the action of the artificial pacing system, mainly when the ventricular lead is located at the apex of the right ventricle, produces negative effects to cardiac structure (remodeling, dilatation) and function (dissinchrony). Patients with previously compromised left ventricular function would benefit the least with conventional right ventricle apical pacing, and are exposed to the risk of developing higher incidence of morbidity and mortality for heart failure. However, after almost 6 decades of cardiac pacing, just a reduced portion of patients in general would develop these alterations. In this context, there are not completely clear some issues related to cardiac pacing and the development of this cardiomyopathy. Causality relationships among QRS widening with a left bundle branch block morphology, contractility alterations within the left

ventricle, and certain substrates or clinical (previous systolic dysfunction, structural heart disease, time from implant) or electrical conditions (QRS duration, percentage of ventricular stimulation) are still subjecte of debate. This review analyses contemporary data regarding this new entity, and discusses alternatives of how to use cardiac pacing in this context, emphasizing cardiac resynchronization therapy.

São Lucas Hospital of the Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.

Correspondence adress: Andrés Di Leoni Ferrari Av. Ipiranga, 6690 – Centro Clínico PUCRS - Conj. 506 – Jardim Botânico – Porto Alegre, RS, Brazil – Zip code: 90610-000 E-mail: dileoniferrari@cardiol.br

Descriptors: Pacemaker, Artificial. Cardiomyopathy, Dilated. Ventricular Dysfunction. Resumo A estimulação cardíaca artificial (ECA) é o tratamento mais seguro e eficaz para a bradicardia sintomática irreversível. Nas indicações propícias, pode trazer grande benefício clínico. Contudo, as evidências mostram que a ação da ECA geraria, em alguns casos, efeitos deletérios à estrutura e fisiologia

This work was carried out in São Lucas Hospital of the Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.

Article received on April 7th, 2014 Article accepted on August 5th, 2014

No financial support.

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comprometimento prévio da função ventricular esquerda e, sobretudo, quando o eletrodo é colocado em posição apical do ventrículo direito (VD). Intrigante é, contudo, que após quase 6 décadas de ECA do VD, apenas uma reduzida parcela de pacientes apresenta esta condição clinicamente manifesta. Os determinantes do surgimento ou não da cardiopatia por ECA não estão totalmente esclarecidos. Ainda é motivo de debate a existência de uma relação de causalidade entre o padrão de BRE artificial secundário à ativação antifisiológica ventricular, alterações da dinâmica contrátil ventricular, e condições clínicas (disfunção sistólica prévia, cardiopatia estrutural preexistente, tempo desde o implante) ou elétricas (duração do intervalo QRS, dose percentual de estimulação ventricular). Esta revisão aborda dados contemporâneos sobre esta nova entidade e discute alternativas de como utilizar a ECA neste contexto, com ênfase na terapia de ressincronização cardíaca.

Abreviations, acronyms & symbols %CVP AAI ACP AF AV AVB HF HR iAV ICD LBBB PPM RMit SND VVI

Percentual ventricular pacing Atrial detection and stimulation Artificial cardiac pacing Atrial fibrillation Atrioventricular Atrioventricular block Heart failure Heart rate Atrioventricular interval Implantable cardioverter-defibrillators Left Bundle Branch Block Permanent pacemaker Mitral regurgitation Sinus node dysfunctions Ventricular detection and pacing

cardíacas. Este potencial efeito negativo da ECA convencional poderia ser mais acentuado principalmente em pacientes com

Descritores: Marca-Passo Artificial. Cardiomiopatia Dilatada. Disfunção Ventricular.

INTRODUCTION

single ventricular chamber mode (VVI - ventricular detection and pacing) would not bring any benefits because of the worse clinical outcome (loss of AV synchrony during sinus rhythm with risk of appearance of the pacemaker syndrome)[2,6]. When the heart rate (HR) response is inadequate for the patient’s level of activity (chronotropic incompetence), and when it has to be brought towards the metabolic demand of the moment, the enabling of biosensors is indicated. In this case, the letter R is added to the nomenclature, which indicates the mode of operation of the device. For example: DDD-R. In patients with symptomatic atrioventricular block (AVB), the dual chamber mode is once again the one of choice, especially because it maintains the AV sequence, although in specific patient profiles, as well as in chronic atrial fibrillation (AF) with slow ventricular response, VVI pacing offers similar results[7,8]. Less often, in 1st degree AVB with a very prolonged PR interval (PRi) (>300 ms), dual chamber ACP is employed to correct the dyssynchrony due to the AV decoupling[2-5,9-11].

Artificial cardiac pacing (ACP) is a consolidated, safe and effective treatment strategy that has been evolving for 60 years. A large number of devices are implanted annually in Brazil and the world. Although permanent pacemakers (PPM) and implantable cardioverter-defibrillators (ICD), associated or not with cardiac resynchronization therapy (CRT), have improved the prognosis of millions of patients[1], in some cases, cardiomyopathy appears as a result of the artificial antiphysiological ventricular activation induced by the ACP. The goal of this review is to address the evidence on the causes and consequences related to this secondary heart disease in relation to the profile of patients where this condition is more prevalent, in addition to the possible strategies to prevent it from occurring in patients who need ACP. Artificial cardiac pacing in different contexts The classic recommendations for the implantation of electronic ACP devices have been properly listed in the various Guidelines on the subject2-5]. In general, PPMs are associated with an improvement in symptoms and quality of life in sinus node dysfunctions (SND), but without any significant impact on survival[2-5]. The prescribed systems are dual chamber, with its variations (DDD - sequential atrioventricular detection and stimulation; DDI - detection and atrioventricular pacing not synchronized to the P wave), or the single-atrial chamber system (AAI - atrial detection and stimulation). The latter, only in well-selected patients, when the atrioventricular (AV) conduction has been preserved. The

Atrioventricular, intraventricular and interventricular synchrony In the 1990s, Pachón et al.[6] described the ventricular pacemaker syndrome. They observed that right ventricular ACP produced negative effects on the myocardial structure and function, with clinical expression of heart failure (HF). These harmful effects originated primarily in ventricular dyssinchrony (QRS widening), artificial left bundle branch block pattern (LBBB), the appearance or worsening of mitral regurgitation (RMit), and other effects attributed to the action

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of the anti-physiological activation of the RV (Chart 1). They distinguished it from classic pacemaker syndrome, which is typically caused by AV dyssynchrony in patients with PPM[6]. It is known that maximum cardiac efficiency depends on the mechanically synchronous contraction of the ventricular walls, enabled by the coordinated action of different segments through the propagation of the electrical stimulus in all components of the conduction system[12-15]. This is represented graphically in the ECG by duration of the QRS interval (diQRS) of less than 120ms. Conventional ACP of the RV alters the morphology and the diQRS, varying according to the degree of activation of the specific conduction tissue, the presence of previous heart disease and the topography of the electrode in the RV. The appearance of abnormal electrical delay because of the spreading of the stimulus outside the physiological conduction system, compromises the mechanical ventricular efficiency and characterizes the dyssynchrony. It is generally acknowledged[6,16] that the LBBB pattern alters the contractile pattern of the ventricular walls and promotes the paradoxical contraction of the interventricular septum. It also causes dyssynchrony of the papillary muscles, with additional functional impairment of the RMit[17], generating loss of systolic efficiency and higher morbidity and mortality due to HF[6,10,12-15,18-23]. It is estimated that up to 50% of the cases of ACP of the RV evolve in this way, and this would explain the reason why some patients do not present a satisfactory clinical improvement, even though the electrical disturbance is being treated by the ACP[6]. The myocardial contraction by the ACP would be hemodynamically efficient, but mechanically antiphysiological. This forces the patient to live with a certain

degree of ventricular dysfunction and dyssynchronopathy, which is clinically more or less evident depending mostly on the myocardial functional reserve mechanisms and on the pre-existing myocardial condition[18]. For this reason, in some cases of normal hearts, LBBB induced by ACP may apparently not cause a very significant impairment of the left ventricular function, or the dysfunction may remain subclinical and take years to be noticed, making it seem that other factors were involved in this dyssynchronopathy[24-27]. Hori et al. [27] , on the other hand, suggested that electromechanical dyssynchrony in the context of ACP could be more serious if associated with systolic dysfunction and LBBB from other causes, more than when normal LV ejection fraction (LVEF) and LBBB by artificial activation of the RV occurs isolated. However, the diQRS could not exactly reflect the degree of mechanical dyssynchrony generated by the ACP in patients with preserved systolic function. Although the ECG appears similar, LBBB from ACP has some peculiar characteristics[28]. When analyzed by Tissue Doppler Echocardiography, the artificially induced contractile delay pattern can be different when compared to LBBB from other causes, not necessarily expressing a significant underlying heart disease[29]. The BioPace study[30] (follow-up longer than 5 years of more than a thousand patients) is under way, which addresses the potential secondary negative effects of ACP of the RV prospectively, especially whether the electrical dyssynchrony generated by artificial LBBB is comparable to the LBBB of other etiologies, or if the damage depends on the pre-existence of ventricular dysfunction or structural heart disease. Still from a hemodynamic perspective, it is said that the maintenance of intra- and interventricular synchrony would be more important than the AV synchrony for a better myocardial function[6,11]. These events, however, are definitely related. When we program the atrioventricular interval (iAV), and depending on the underlying disease (SND or AVB), we can generate different percentage (â&#x20AC;&#x153;dosesâ&#x20AC;?) of cumulative ventricular pacing (%CVP) and, therefore, potentially several degrees of dyssynchronopathy[20,21], which may already be present with a CVP between 25% and 40%[5,31,32]. Despite the great theoretical importance of the sequential atrioventricular electrical coordination, this does not mean the certainty of mechanical synchrony between these chambers. Studies[33,34] have found that ACP, especially when RV apical, impairs the left atrial drain, which harms ventricular filling despite maintaining the AV sequence. This effect would also be more pronounced in patients with previous systolic dysfunction, and less when the iAV is optimized and the LVEF is preserved. This stresses both, the role of better iAV to mitigate the iatrogenic potential of the artificial activation of the RV, as the importance of the existence of a substrate, for example the systolic dysfunction, for the synergism of these effects.

Chart 1. Acute and chronic effects associated with conventional right ventricle apical pacing. Myocardial metabolism/perfusion

Variations in regional blood flow Variations in regional demand for oxygen

Remodeling

Asymmetric myocardial hypertrophy Histopathological changes (ion channels) Ventricular dilation

Hemodynamics

Reduction of cardiac output Increased filling pressures

Electrical

Slowing of intrinsic electrical activation Artificial left bundle branch block

Mechanical

Changes of regional contraction (strain) Mechanical interventricular dyssynchrony Mechanical interventricular dyssynchrony Functional mitral regugitation

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Evidence, myths and truths: how much is important? The specific profile of patients predisposed or vulnerable to the emergence of harmful electromechanical effects produced by ACP is still up to debate and the subject of research. Due to factors that haven’t yet been fully understood, but that are evident after 6 decades of cardiac pacing, the unfavorable clinical outcome is not a condition that can be associated 100% with ACP[13,15]. A substantial number of studies associated ACP of the RV with an increased risk of HF and other outcomes (especially atrial fibrillation). Almost none of these, however, directly registered a higher mortality, and many were based on the analysis of small populations (Table 1). Several of them are also the result of comparisons between the AAI and DDD modes against the VVI mode, counting, in the latter case, with the potential bias of AV dyssynchrony in the genesis of these alterations. The importance of such clinical characteristics as the substrate for the development of heart disease in the context of ACP, and not necessarily because of ACP, has been emphasized in other publications. Studies show that the greatest risk of an unfavorable outcome could be determined by the pre-existence of other factors, such as: structural heart disease, systolic dysfunction (LVEF<40 %), left ventricular mass index >130g/m2 or coronary artery disease[27,32]. In patients with recommendation for PPM in SND, the risk of developing chronic AF and cerebral vascular accident (CVA) – stroke - was more strongly determined by previously present clinical variables than by artificial pacing of the RV, when AV synchrony was maintained[33-36]. A post-hoc analysis of DANPACE[37] revealed that it can be safe to use the DDD-R mode in patients with SND and without heart disease with preserved systolic function. The DDD-R pacing in this study did not generate differences in terms of HF when compared to the AAI-R mode (with intrinsic ventricular activation). After a mean follow-up of 5.4 years (which some consider insufficient for the profile of the patients under study), the absolute drop in LVEF was less than 5%. The authors stressed, however, that the clinical characteristics (age, hypertension, coronary artery disease, left ventricular diastolic diameter and/or previous systolic dysfunction) are probably the major determinants of the risk of developing symptomatic HF in the presence of ACP, independent of the site of the electrode (apical vs. non apical) and the percentage of CVP[37]. The classic MOST study [38] , which was designed to demonstrate the differences between the ACP with physiological AV sequence (DDD-R) versus VVI-R in 2,010 patients with SND and preserved LVEF, revealed that a percentage of CVP exceeding 40% is an independent predictor of the onset of HF. This point is taken as a reference in several Guidelines[3-5]. Although seemingly contradictory, however, until today no full light has been shed on the reasons that explain this study’s observation that in the bicameral mode,

which is theoretically more physiological for the temporal preservation of AV, the required dose of CVP to trigger deleterious effects attributed to ACP corresponded to half (40% vs. 80%) of the one required in the VVIR system for the same damage[39]. A possible explanation could be the dyssynchrony aggregated to an iAV that was not ideally programmed in the DDD group, confirming that the AV sequence is, in fact, different from the concept of AV synchrony. Also relevant in this context, a sub-analysis of MOST revealed that the evolution to HF actually happens in less than 10% of cases, mostly associated with coronary artery disease or prior structural heart disease[40]. Although the literature[6,9,12,13,19,21,22] and the positioning of the scientific community are strongly indicative of the fact that any patient under the action of ACP is potentially vulnerable to the appearance of this heart disease, many of the same publications also stress that patients without previous heart disease have a good tolerance to artificial pacing of the RV[6,13,15,37]. For Sweeney and Prinzen, the risk of developing HF in 2 years in structurally normal hearts lies between 0.76% and 1.7 %, which is probably similar to what can be expected in the normal population without a PPM[13,31]. However, even depending on the relationship between the elapsed time since the implant and the percentage of CVP dose, it is interesting to see that today there are millions of patients with devices that artificially activate the RV, and we are nevertheless not experiencing an HF epidemic due to this fact. On this point about the relationship between the time since the first implant and the progression to heart disease because of ACP in patients with congenital AVB and without known prior structural heart disease, Yu et al.[41] define heart disease associated with ACP when the LVEF <45% and there is ventricular dyssynchrony caused by artificial activation of the RV, in the absence of another cardiomyopathy that could justify it. In this profile of patients with prolonged follow-up times, an incidence of 9% in the 1st year after implantation of PPM is described[41]. Other authors presented a variable prevalence: 13% After 9.7 years (± 2.9 years) of artificial pacing of the RV[42], up to 15.4% after almost 25 years (24.6±5.6 years) of ACP[43]. When assessing the correlation between ACP, HF and the presence of specific antibodies, Sagar et al.[44] found an association with specific antibodies in a group of patients with a PPM for congenital AVB without structural heart disease. This restates that, in this context, the risk could very well not derive simply from the effect of ACP, but instead be related to other etiological agents. As cited, several publications[15,27,45] confirm the negative effects of ACP of the RV (Table 2) in this clinical- pathological context. There is a record that the highest risk of heart disease by ACP occurs when this generates greater degrees of intraventricular dyssynchrony[43], in addition to the presence of other factors being necessary, for example, ventricular remodeling, arterial hypertension, coronary heart disease etc., reinforcing the thesis of the need for a substrate.

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Table 1. Studies on the stimulation of the right ventricle associated with outcomes. Author

Type of study RCT

Operation Mode DDDxAAI

Follow-up

Patients in study

LVEF

Results

1 Year

SND

>60%

Cohort

DDD

1 Year

153

Sub-groups

Nahlawi (2004) Vernooy (2006)

Cohort

DDD

1 Week

Subgroups according to LVEF Preserved LVEF

Mean 66.5%

Cohort

DDD

Mean 7 years

Ablation of the His bundle

Schmidt (2007)

RCT

DDDxAAI

Subgroups according to LVEF

>35% or <35%

Cohort

6 Months

Ablation of the His bundle

Andersen (1997)

RCT

AAIxVVI

8 Years

SND

225

Nielsen (2003)

RCT

AAIRxDDDR-1 and DDDR-S

3 Years

SND

177

Lamas (2002)

RCT

VVIRxDDDR

33 Months

SND

2010

Wilkoff (2002)

RCT

VVIxDDDR

18 Months

Indication of ICD

506

VVIxDDD hysteresis VDD

1 Year

Indication of ICD AV and ablation od the AV node

988

RCT

Mean 46%

Reduction of LVEF in group DDD Apical RV pacing induces LV dyssynchrony depending on basal LVEF RV pacing results in worsening of LVEF Prolonged RV pacing induces ventricular remodeling and reduction of LVEF RV pacing prolongs QRS independent of LVEF. Dyssynchrony related with LVEF <35% 57% of those with RV pacing presented LV dyssynchrony, reduction of LVEF and worsening of functional class AAI mode with improvement in survival (RRR 34%), lower incidence of AF (RRR 46%) and thromboembolic events (RRR53%) AAI mode with lower incidence of AF (7.4% x 17.5% in DDDR-1 MODE X 23.3% in DDDR-s mode) DDDR Mode with lower incidence of AF (HR 0.79) and reduction of HF symptoms, with no difference in mortality due to CVA VVI mode with more hospitalization for HF, and death (HR 1.61) DDD Mode with less events (RRR 33%) 49% developed dyssynchrony of the LV

Albertsen (2008) Pastore (2008)

Tops (2007)

Olshansky (2007) Tops (2006)

Cohort

1 Year

RCT=randomized clinical trial; SND=sinus node disease; LVEF=left ventricular ejection fraction; RV=right ventricle; LV=left ventricle; RRR=relative risk reduction; AF=atrial fibrillation; HF=heart failure; CVA=cerebral vascular accident-stroke; ICD=implantable cardioverter defibrillator

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The vast majority of patients with implantable cardioverterdefibrillators (ICD) have a pre-existing heart disease. There are records that these conditions have a worse evolution with artificial (apical) activation of the RV, the main site for placing the shock electrode[6,18]. In these cases, the risk approximates 50% for the development of ACP’s associated cardiomyopathy within 2 years[13]. Retrospective studies of the results of DAVID[32] and MADIT-II[46] indicate that ACP of the RV is less tolerated when there is previous systolic dysfunction. Up to the 1st year, HF symptoms arose in the dependence of CVP percentage (>40% in DAVID[32] and >50% in the MADIT II[46]), which was a clear doseresponse relationship[22]. It is important to highlight, however, that in DAVID[32], the patients programmed for a DDD-R with a long IAV, who accumulated 11% of CVP, made up the group with the best tolerance for ACP. This could suggest that, in this population, it is best not to stimulate the RV from the apex. And if there is no other way, then it should be done with the best AV synchrony. This hypothesis also proved to be valid according to the results of the INTRINSIC RV[47], confirming that in some scenarios, a certain CVP percentage of the RV may be necessary, provided that the AV synchrony is preserved. This study revealed after 1 year of follow-up that a high cumulative CVP percentage is associated with a higher rate of hospitalization for HF, ventricular tachycardia and mortality. However, better results were obtained in the group with a CVP between 10-19% (2.8% of occurrences) when compared to the group with <10% (8.1% of occurrences)[47]. The reason for these findings would once again lie in the inherent harm of the decoupling of the AV produced by the algorithm that minimized the activation of the RV. It is important to highlight, however, that there is no concrete data on the role that some assisting drugs, such as those that affect the renin-angiotensin-aldosterone system and that have proven beneficial in the context of the clinical treatment of HF, would play in secondary structural remodeling of the ACP of the RV, both in the scenario of patients without heart disease (preventive effect), as in those with impaired systolic function.

probably in this group that ACP of the RV should be minimized or even eliminated, when possible[52,55]. In search of a better clinical outcome, we grouped the ways of using ACP in two sets: • Using algorithms to minimize RV pacing through the manipulation of the iAV (programming of the device); • Using variants of cardiac stimulation systems: a) atrial single-chamber (AAI); b) alternative sites for the electrode implant; c) multisite pacing: biventricular and bifocal of the RV. Most of the algorithms that minimize the ACP of the RV are basically looking for functionality in the AAI-R mode. Some of them are complemented with backup ventricular pacing (change to the DDD-R mode). However, these algorithms can at the same time produce AV decoupling and dyssynchrony by allowing for long, unrestricted and non-physiological iAVs. A better AV synchrony optimizes the myocardial pump by allowing atrial contraction at the appropriate pre-ejective ventricular moment. It also maximizes the diastolic ventricular filling (pre-loading). The AV synchrony is also beneficial to the mitral valve functioning and maintains the atrial pressures at significantly lower levels[17]. AV dyssynchrony, on the other hand, reduces cardiac output at rest from 20% to up to 50%[6,56]. A meta-analysis of more than 7,000 patients (Figure 1), which compared the ACP based on atria (AAI operation and, therefore, intrinsic QRS) with conventional stimulation of the RV, did not reveal significant differences in mortality or in the combined outcome of stroke and mortality or hospitalization for HF[57]. In another publication it was demonstrated that the iPR and the dose (%) of atrial stimulation were independent predictors of AV dissociation. When AV decoupling occurred, the cumulative CVP increased 10 times in comparison to patients without this electromechanical effect[58].

With technological developments, is there a best strategy for cardiac pacing? As of today, there is no unanimous definition of the best system, mode of operation or anatomic site for ACP[19]. Among the vulnerable individuals, the unfavorable evolution for the appearance of heart disease because of ACP could be linked to the interaction of at least 3 factors: (1) patient-substrate: normal heart versus pre-existing heart disease and systolic dysfunction (LVEF< 45 %)[13,15,18,27,31,48,49]; (2) ACP time and dose (%CVP): worse if >40% of time[32,35,46,50]; and (3) degree of dyssynchrony generated (ventricular lead site[4849,51,52], diQRS generated[53] and artificial LBBB[54]). The interposition of RV pacing in individuals with pre-existing systolic dysfunction (variable proportion of those who receive a conventional PPM, but a significant group within those who implant ICDs)[21] accelerates the onset of heart disease by ACP and it is

Fig. 1 - Meta-analysis of atrial-based pacing vs. ventricular pacing. In a comprehensive manner, without distinguishing between patients with normal systolic function and those with impaired LVEF, the current Guidelines[2-5] recommend (level of evidence C) the use of algorithms that are able to

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maximally exploit the intrinsic AV conduction. However, we are not sure if with this form of stimulation we are not at the same time, in certain contexts and patient profiles (iPR> 300 ms), changing the sequence of mechanical coupling between atria and ventricles[52]. The maximum limit of iAV before AV dyssynchrony appears, however, has not been determined exactly, and neither are there data available to establish how much the minimization of the stimulus of the RV, at the expense of AV dyssynchrony, outweighs the risk of artificial ventricular activation. When alternative ACP strategies are considered, through single-chamber atrial functioning, either by placing a single electrode or by programming the AAI mode, one must face the non-negligible risk of symptomatic associated AVB, which incidence is variable in the literature. The Brazilian Guidelines[2] cite an incidence of 8.4% in this context. If the patient with SND has some other kind intraventricular conduction or atrial fibrillation disorder, the incidence increases to more significant values[59-62]. It is worth pointing out that the first clinical manifestation of AV dysfunction is syncope in up to 50% of cases[21], which, paradoxically, is one of the most important symptoms to be relieved by implantation of a PPM. Endocardial cardiac pacing has traditionally been performed with implantation of the electrode at the apex of the RV because of the electrical stability and, above all, the surgical ease, since it is the most accessible transvenous way[18]. Virtually all studies on artificial ventricular pacing have shown some kind of influence of the activation site on the cardiac hemodynamics. For this reason, alternatives for the stimulation of different topographies instead of the apex of the right ventricle have been assessed, especially the outflow tract of the RV, a septal and para-Hissian location, or even the endocardial pacing of the LV. Studies in patients with SND and preserved AV conduction, with randomization for the apical versus the outflow tract of the RV, and that contemplated these aspects, demonstrated the superiority of the latter location in terms of LVEF and remodeling when the follow-up exceeded 18 months[63,64]. Because of the methodological differences for the confirmation of the position of the electrode, however, and because we know that a great part of the hemodynamic results would depend on the obtained diQRS[65], until the moment these findings have not been incorporated into the Guidelines. Pachón et al. [66-68] used bifocal pacing of the RV (conventional electrodes in septum and apex) in an attempt to promote the resynchronization of the LV. Despite the relatively small number of patients, the authors observed a reduction in diQRS and mitral regurgitation, in addition to significant improvement of systolic and diastolic function, which resulted in functional and quality of life improvements for the individuals. They proposed this alternative for cases with less myocardial impairment, as would be the case in heart conditions exclusively secondary to ACP, and/or when CRT is not possible by placing the LV electrode via coronary

sinus. Despite the apparent good results, the most recent Guidelines[4,5] also don’t consider this proposal. With the evidence and the clinical practice, an understanding is mounting of the role of primary prevention of HF by CRT. To prevent heart disease induced by ACP, there could be benefits to the upgrade to a multisite pacing system when is indicated to implant a device (PPM or ICD) and there is reduced when there is reduced LVEF (<35 or 40%), and the prediction of high cumulative CVP[3-5] (Table 2). While the European Guidelines[3] do not establish a definite value for CVP, the American Guidelines[5] mention that it must exceed 40% for a recommendation IIa. The American Guidelines also state that despite the absence of symptoms at the time of elective replacement of the conventional PPM generator, when there is reduced LVEF, the upgrade to CRT could be associated with a better outcome[65,69,70]. Table 2. ESC Guidelines – Recommendations for cardiac resynchronizatin therapy directly or upgrade from a conventional pacing system in patients with heart failure and formal indication for cardiac pacing therapy. Recommendation

Class

1. Upgrade of conventional PM or ICD CRT is indicated in HF patients with LVEF <35% and a demand for high percentage of ventricular pacing who persist in the NYHA functional class III or IV even with optimized medical treatment

Level of evidence B

IIa

2. CRT in a direct way CRT should be considered in patientis with HF, depressed LVEF and a demand for high percentage of ventricular pacing under risk of worsening od HF symptoms

PM=pacemaker; ICD=mplantable cardioverter defibrillator; CRT=cardiac resynchronization therapy; HF=heart failure; LVEF=left ventricular ejection graction; NYHA=New York Heart Association. Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt OA, et al.[3]

However, from the same perspective that the role of multisite pacing is more a preventive than a therapeutic strategy, the theory arises that in patients with preserved or less compromised systolic function, CRT could revert the dyssynchrony artificially produced by the action of ACP[69,71]. There is also evidence[14,72] that it would be plausible to prescribe CRT for these patients since the first implant. A prospective and randomized study[73] reported the superiority of CRT in comparison to apical RV pacing in patients with preserved LVEF and bradycardia. A post-hoc analysis of the MADIT-CRT[74] found up to 38% of patients with EF>30% (ranging from 30-45.3%), with these patients having significant

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clinical benefits with CRT and, surprisingly, showing an even more pronounced reduction of the risk of events when compared to those with more depressed LVEF (reduction of 44% of primary outcomes, including mortality from any cause). Another study[75] that compared conventional pacing in complete AVB with CRT in 918 patients with a mean LVEF of 40%, showed that the combined outcome of death from any cause, emergency treatment for HF, and increase in end-systolic volume of the LV, was less frequent with biventricular pacing (53.3% vs. 64.3%). The result of this study suggests that CRT supports the ventricular function in patients who require ACP and with moderately reduced LVEF. These data were supported by the PACE study[71], which demonstrated that the potential deleterious effects of RV apical pacing could be avoided with CRT in patients with moderately reduced LVEF. In conclusion, is there a best strategy for cardiac pacing? The analyzed literature reports that the vast majority of patients with a structurally normal heart and preserved systolic function tolerates, in varying degrees, any changes generated by ACP of the RV. This is possible due to the operation of mechanisms of the myocardial functional reserve. When there is a prior impairment of systolic function and, probably, these compensatory mechanisms have been exhausted, the set of alterations, such as the increase of diQRS, ventricular dyssynchrony and the artificially generated LBBB, gives rise to the ventricular pacemaker syndrome[6] and clinically manifest HF. Therefore, when the implantation of a device is indispensable, one must thoroughly assess the patient-substrate set, the systolic function and the AV conduction in order to estimate the cumulative CVP and to establish, based on this, the decision flow (Figure 2)[52]. In patients with AV dyssynchrony and a structurally normal

heart (preserved LVEF), a programming that allows for nonphysiological iAVs or that may cause AV uncoupling, may not be suitable. When the AV conduction is preserved, one should look to minimize RV pacing by the use of specific algorithms, also trying not to generate paradoxical AV dyssynchrony. If ACP of the RV is mandatory, and if there is no concomitant systolic dysfunction or structural heart disease, we can be confident that the probability of the patient progressing to HF by ACP is low[13,15,22,23,27,37,39]. In these patients, one can try to implant the electrode in a septal position or in the RV outflow tract in order to obtain a more favorable activation vector with greater probability of capturing the intrinsic conduction system and producing lower diQRS. In patients with LVEF <50% and anticipation of high CVP percentage (>40%), CRT should be stratetic choice. CONCLUSION ACP is a safe and effective therapy for the treatment of irreversible bradyarrhythmias, but it is not devoid of potential adverse effects. Patients who receive devices for conventional indications, and who have structurally normal hearts and preserved LVEF, often present less secondary heart diseases from ACP, even with high doses of cumulative artificial activation (%CVP) of the RV. In the absence of a substrate and predisposing factors, some doubt remains about which clinical, hemodynamic, structural or even genetic circumstances we should care for to avoid heart disease induced by ACP of the RV. Cardiac resynchronization therapy emerges, in the context of dyssyncropathy, extended diQRS, artificial LBBB pattern and %CVP by ACP, as the most promising option for treatment, while the role of other strategies remains controversial. Authorsâ&#x20AC;&#x2122; roles & responsibilities ADLF APB LCA CPS PRR RMP

Fig. 2 - Proposed flowchart on how to avoid unnecessary right ventricular pacing in patients with indication for conventional pacemakers and without indication for cardiac resynchronization therapy.

MW MAG

409

Analysis and/or interpretation of data, Final approval of the manuscript Conception and design of the study, Implementation of the operations and/or experiments, Drafting of the manuscript or critical review of its contents Analysis and/or interpretation of data, Final approval of the manuscript Conception and design of the study, Implementation of the operations and/or experiments, Drafting of the manuscript or critical review of its contents Final approval of the manuscript, Drafting of the manuscript or critical review of its contents Analysis and/or interpretation of data, Implementation of the operations and/or experiments Analysis and/or interpretation of data, Implementation of the operations and/or experiments Analysis and/or interpretation of data, Drafting of the manuscript or critical review of its contents Final approval of the manuscript, Drafting of the manuscript or critical review of its contents Implementation of the operations and/or experiments, Drafting of the manuscript or critical review of its contents

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41. Yu CM, Chan JY, Zhang Q, Omar R, Yip GW, Hussin A, et al. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med. 2009;361(22):2123- 34. 42. Thambo JB, Bordachar P, Garrigue S, Lafitte S, Sanders P, Reuter S, et al. Detrimental ventricular remodeling in patients with congenital complete heart block and chronic right ventricular apical pacing. Circulation 2004;110(25):3766-72.

31. Sweeney MO, Hellkamp AS. Heart failure during cardiac pacing. Circulation. 2006;113(17):2082-8. 32. Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, et al.; Dual Chamber and VVI Implantable Defibrillator Trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial. JAMA. 2002;288(24):3115-23.

43. Dreger H, Maethner K, Bondke H, Baumann G, Melzer C. Pacing-induced cardiomyopathy in patients with right ventricular stimulation for > 15 years. Europace. 2012;14(2):238-42. 44. Sagar S, Shen WK, Asirvatham SJ, Cha YM, Espinosa RE, Friedman PA, et al. Effect of long-term right ventricular pacing in young adults with structurally normal heart. Circulation. 2010;121(15):1698-705.

33. Sgarbossa EB, Pinski SL, Maloney JD, Simmons TW, Wilkoff BL, Castle LW, et al. Chronic atrial fibrillation and stroke in paced patients with sick sinus syndrome. Relevance of clinical characteristics and pacing modalities. Circulation. 1993;88(3):1045-53.

45. Varma N. Left ventricular conduction delays induced by right ventricular apical pacing: effect of left ventricular dysfunction and bundle branch block. J Cardiovasc Electrophysiol. 2008;19(2):114-22.

34. Sgarbossa EB, Pinski SL, Maloney JD. The role of pacing modality in determining long-term survival in the sick sinus syndrome. Ann Intern Med. 1993;119(5):359-65.

46. Steinberg JS, Fischer A, Wang P, Schuger C, Daubert J, McNitt S, et al.; MADIT II Investigators. The clinical implications of cumulative right ventricular pacing in the multicenter automatic defibrillator trial II. J Cardiovasc Electrophysiol. 2005;16(4):359-65.

35. Sweeney MO, Hellkamp AS, Ellenbogen KA, Greenspon AJ, Freedman RA, Lee KL, et al.; MOde Selection Trial Investigators. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation. 2003;107(23):2932-7.

47. Olshansky B, Day JD, Lerew DR, Brown S, Stolen KQ; INTRINSIC RV Study Investigators. Eliminating right ventricular pacing may not be best for patients requiring implantable cardioverter-defibrillators. Heart Rhythm. 2007;4(7):886-91.

36. Sgarbossa EB, Pinski SL, Trohman RG, Castle LW, Maloney JD. Single-chamber ventricular pacing is not associated with worsening heart failure in sick-sinus syndrome. Am J Cardiol. 1994; 73(9):693-97.

48. Schmidt M, Brömsen J, Herholz C, Adler K, Neff F, Kopf C, et al. Evidence of left ventricular dyssyncrhony resulting from right ventricular pacing in patients with severely depressed left ventricular ejection fraction. Europace. 2007;9(1):34-40.

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49. Thackray SD., Witte KK, Nikitin NP, Clark AL, Kaye GC, Cleland JG. The prevalence of heart failure and asymptomatic left ventricular systolic dysfunction in a typical regional pacemaker population. Eur Heart J. 2003;24(12):1143-52.

60. Brandt J, Anderson H, Fåhraeus T, Schuller H. Natural history of sinus-node disease treated with atrial pacing in 213 patients: implications for selection of stimulation mode. J Am Coll Cardiol. 1992;20(3): 633-9.

50. Sweeney MO, Bank AJ, Nsah E, Koullick M, Zeng QC, Hettrick D, et al.; Search AV Extension and Managed Ventricular Pacing for Promoting Atrioventricular Conduction (SAVE PACe) Trial. Minimizing ventricular pacing to reduce atrial fibrillation in sinusnode disease. N Engl J Med. 2007;357(10):1000-8.

61. Haywood GA, Ward J, Ward DE, Camm AJ. Atrioventricular Wenckebach point and progression to atrioventricular block in sinoatrial disease. Pacing Clin Electrophysiol. 1990;13(12 Pt 2): 2054-8. 62. Andersen HR, Nielsen JC, Thomsen PE, Thuesen L, Vesterlund T, Pedersen AK, et al. Atrioventricular conduction during longterm follow-up of patients with sick sinus syndrome. Circulation. 1998;98(13):1315-21.

51. Barsheshet A, Moss AJ, McNitt S, Jons C, Glikson M, Klein HU, et al.; MADIT-II Executive Committee. Long-term implications of cumulative right ventricular pacing among patients with an implantable cardioverter-defibrillator. Heart Rhythm. 2011;8(2):212-8.

63. Vancura V, Wichterle D, Melenovsky V, Kautzner J. Assessment of optimal right ventricular pacing site using invasive measurement of left ventricular systolic and diastolic function. Europace. 2013;15(10):1482-90.

52. Akeström F, Arias MA, Pachón M, Jiménez-López J, Puchol A, Juliá-Calvo J. The importance of avoiding unnecessary right ventricular pacing in clinical practice. World J Cardiol. 2013;5(11):410-9.

64. Mabo P, Gras D, Degand B. Jean Dupuis J, Pellissier A, Solnon A, et. Septal Right Ventricular lead position in and optimized DDD pacing in sinus node disease: comparison to preserved intrinsic conduction – the OPTIMIST Trial. Poster Session Heart Rhythm. 2014; May 9th [Acessed Jun 6, 2014]. Available from: http://ondemand.hrsonline.org/common/presentation-detail. aspx/15/35/1293/8587

53. Wang NC, Maggioni AP, Konstam MA, Zannad F, Krasa HB, Burnett JC Jr, et al.; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Clinical implications of QRS duration in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction. JAMA. 2008;299(22):2656-66.

65. Spanish Society of Cardiology Working Group for the 2013 ESC Guidelines on Cardiac Pacing and Cardial Resynchronization Therapy, Fernández Lozano I, Mateas FR, Osca J, Sancho Tello MJ, García Bolao I, et al. Comments on the 2013 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy. Rev Esp Cardiol. 2014;67(1):6-14.

54. Olshanksky B. Wide QRS, narrow QRS. What’s the difference? J Am Coll Cardiol. 2005;46(2):317-9. 55. Ahmed M, Gorcsan J 3rd, Marek J, Ryo K, Haugaa K, R Ludwig D, et al. Right ventricular apical pacing-induced left ventricular dyssynchrony is associated with a subsequent decline in ejection fraction. Heart Rhythm. 2014;11(4):602-8.

66. Pachón Mateos JC, Albornoz RN, Pachón Mateos EI, Gimenez VM, Pachón MZ, Santos Filho ER, et al. Right ventricular bifocal stimulation in the treatment of dilated cardiomyopathy with heart failure. Arq Bras Cardiol. 1999;73(6):485-98.

56. Syed FF, Hayes DL, Asirvatham SJ, Friedman PA. Hemodynamics of cardiac pacing: optimization and programming to enhance cardiac function. In: Hayes DL, Asirvatham SJ, Friedman PA, eds. Cardiac pacing, defibrillation and resynchronization: a clinical approach. Hoboken: Wiley-Blackwell; 2008.

67. Pachón JC, Pachón EI, Albornoz RN, Pachón JC, Kormann DS, Gimenes VM, et al. Ventricular endocardial right bifocal stimulation in the treatment of severe dilated cardiomyopathy heart failure with wide QRS. Pacing Clin Electrophysiol 2001;24(9 Pt 1):1369-76.

57. Healey JS, Toff WD, Lamas GA, Andersen HR, Thorpe KE, Ellenbogen KA, et al. Cardiovascular outcomes with atrialbased pacing compared with ventricular pacing: meta-analysis of randomized trials, using individual patient data. Circulation. 2006;114(1):11-7.

68. Pachón Mateos JC, Albornoz Vargas R, Pachón Mateos EI, Gimenez VM, Pachón MZC, Pachón Mateos JC, et al. Estimulação ventricular bifocal no tratamento da insuficiência cardíaca com miocardiopatia dilatada. Rev Bras Cir Cardiovasc. 2000;15(1):44-54.

58. Sweeney MO, Ellenbogen KA, Tang AS, Johnson J, Belk P, Sheldon T. Severe atrioventricular decoupling, uncoupling, and ventriculoatrial coupling during enhanced atrial pacing: incidence, mechanisms, and implications for minimizing right ventricular pacing in ICD patients. J Cardiovasc Electrophysiol. 2008;19(11):1175-80.

69. Acena M, Regoli F, Auricchio A. Cardiac resynchronization therapy. Indications and contraindications. Rev Esp Cardiol. 2012;65(9):843-9.

59. Sutton R, Kenny R. The natural history of sick sinus syndrome. Pacing Clin Electrophysiol. 1986; 9(6 Pt 2):1110-4.

70. Gierula J, Cubbon RM, Jamil HA, Byrom R, Baxter PD, Pavitt S, et al. Cardiac resynchronization therapy in pacemaker-

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dependent patients with left ventricular dysfunction. Europace. 2013;15(11):1609-14.

73. Yu CM, Chan JY, Zhang Q, Omar R, Yip GW, Hussin A, et al. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med 2009;361(22):2123-34.

71. Nazeri A, Massumi A, Rasekh A, Saeed M, Frank C, Razavi M. Cardiac resynchronization therapy in patients with right ventricular pacing-induced cardiomyopathy. Pacing Clin Electrophysiol. 2010;33(1):37-40.

74. Kutyifa V, Hall WJ, Solomon S, Knappe D, Pouleur AC; Scott McNitt, et al. Predictors of dyssynchrony and its role in subsequent outcome in CRT-D patients: results from the long-term follow-up of MADIT-CRT. J Am Coll Cardiol. 2013;61(10_S) doi: 10.1016/S0735-1097(13)61087-6.

72. Chen S, Yin Y, Lan X, Liu Z, Ling Z, Su L, et al.; PREDICTHeart Failure study international group. Paced QRS duration as a predictor for clinical heart failure events during right ventricular apical pacing in patients with idiopathic complete atrioventricular block: results from an observational cohort study (PREDICT-HF). Eur J Heart Fail. 2013;15(3):352-9.

75. Curtis AB, Worley SJ, Adamson PB, Chung ES, Niazi I, Sherfesee L, et al.; Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) Trial Investigators. biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med. 2013;368(17):1585-93.

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Yuan SM - Postperfusion lung syndrome: physiopathology and therapeutic REVIEW ARTICLE options

Postperfusion lung syndrome: physiopathology and therapeutic options Síndrome pós-perfusão pulmonar: fisiopatologia e opções terapêuticas

Shi-Min Yuan1, MMed, PhD

DOI 10.5935/1678-9741.20140071

RBCCV 44205-1970

Abstract Postperfusion lung syndrome is rare but can be lethal. The underlying mechanism remains uncertain but triggering inflammatory cascades have become an accepted etiology. A better understanding of the pathophysiology and the roles of inflammatory mediators in the development of the syndrome is imperative in the determination of therapeutic options and promotion of patients’ prognosis and survival. Postperfusion lung syndrome is similar to adult respiratory distress syndrome in clinical features, diagnostic approaches and management strategies. However, the etiologies and predisposing risk factors may differ between each other. The prognosis of the postperfusion lung syndrome can be poorer in comparison to acute respiratory distress syndrome due to the secondary multiple organ failure and triple acid-base imbalance. Current management strategies are focusing on attenuating inflammatory responses and preventing from pulmonary ischemia-reperfusion injury. Choices of cardiopulmonary bypass circuit and apparatus, innovative cardiopulmonary bypass techniques, modified surgical maneuvers and several pharmaceutical agents can be potential preventive strategies for acute lung injury during cardiopulmonary bypass.

Resumo Síndrome pós-perfusão pulmonar é rara, mas pode ser letal. O mecanismo subjacente permanece incerto, mas desencadear cascatas inflamatórias tornou-se uma etiologia aceita. É imperativo uma melhor compreensão da fisiopatologia e os papéis de mediadores inflamatórios no desenvolvimento da síndrome na determinação de opções terapêuticas e de promoção do prognóstico e sobrevida dos pacientes. Síndrome pós-perfusão pulmonar é semelhante à síndrome da angústia respiratória do adulto em características clínicas, métodos diagnósticos e estratégias de gestão. No entanto, as etiologias e fatores de risco predisponentes podem ser diferentes entre si. O prognóstico da síndrome pós-perfusão pulmonar pode ser mais pobres em comparação com síndrome da angústia respiratória aguda, devido à falência de múltiplos órgãos secundária e desequilíbrio ácido-base triplo. Estratégias de gestão atuais centram-se em atenuar reações inflamatórias e impedir lesão pulmonar de isquemia-reperfusão. Escolhas do circuito de circulação extracorpórea e aparelhos, técnicas inovadoras de circulação extracorpórea, manobras cirúrgicas modificadas e vários agentes farmacêuticos podem ser potenciais estratégias preventivas para lesão pulmonar aguda durante a circulação extracorpórea.

Descriptors: Acid-Base Imbalance. Cardiopulmonary Bypass. Multiple Organ Failure. Respiratory Insufficiency. Ventilators, Mechanical.

Descritores: Desequilíbrio Ácido-Base. Ponte Cardiopulmonar. Insuficiência de Múltiplos Órgãos. Insuficiência Respiratória. Ventiladores Mecânicos.

The First Hospital of Putian, Teaching Hospital, Fujian Medical University, Putian, China.

Correspondence address: Shi-Min Yuan Longdejing Street, 389 - Chengxian District, Putian, Fujian Province, People’s Republic of China E-mail: shi_min_yuan@yahoo.com

This study was carried out at First Hospital of Putian, Teaching Hospital, Fujian Medical University, Putian, Fujian Province, People’s Republic of China.

Article received on March 30th, 2014 Article accepted on August 19th, 2014

No financial support.

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FiO2 ≤300 mmHg) moderate (100 mmHg <PaO2/FiO2 ≤200 mmHg) and severe (PaO2/FiO2 ≤100 mmHg); and 4 ancillary variables for severe ARDS: radiographic severity, respiratory system compliance (≤40 mL/cmH2O), positive end-expiratory pressure (≥10 cmH2O) and corrected expired volume per minute (≥10 L/min)[7]. The pulmonary inflammatory responses subsequent to CPB mostly result in subclinical symptoms, but may lead to major organ dysfunction and multiple organ failure including ARDS in only 2% of the patients[4]. In spite of rarity, ALI/ARDS remains the important cause leading to patients’ death[8]. CPB may be of considerable pulmonary pathophysiological consequences in terms of the alveolar-arterial oxygenation gradient [P(A-a)O2], intrapulmonary shunt, degree of pulmonary edema, pulmonary compliance and pulmonary vascular resistance, and may eventually lead to pulmonary dysfunction[7]. The respiratory dysfunction can be a result of pulmonary ischemia-reperfusion injury, interstitial edema and impaired microcirculation induced by CPB with activated cytokines, enhanced reactive oxygen species and reduced endogenous nitric oxide production[9,10]. At present, the underlying mechanisms of postoperative ALI/ARDS still remain uncertain and the pathophysiological aspects have not been comprehensively stated. A better understanding of the pathophysiology and roles of inflammatory mediators in the development of the syndrome is imperative in the determination of therapeutic options and promotion of patients’ prognosis and survival[11]. This article aims to highlight postperfusion lung syndrome in terms of the pertinent pathophysiological changes, mechanisms and risk factors as well as the potentially effective management and preventive strategies.

Abreviations, acronyms & symbols ALI Acute lung injury ARDS Acute respiratory distress syndrome CPB Cardiopulmonary bypass ECMO Extracorporeal membrane oxygenation EVLWI Extravascular lung water index HMGB1 High-mobility group box 1 IL Interleukin P(A/a)O2 Arterial/alveolar oxygen tension ratio P(A-a)O2 Alveolar-arterial oxygen pressure difference PaO2/FiO2 Arterial oxygen tension/fractional inspired oxygen PEEP Positive end-expiratory pressure RI Respiratory index TNF Tumor necrosis factor

INTRODUCTION Acute respiratory distress syndrome (ARDS), also known as respiratory distress syndrome, adult respiratory distress syndrome, or shock lung, is a fatal pulmonary parenchymal disorder as sequelae of respiratory infection, trauma, or stress triggered by pulmonary cytokine release, impaired endothelial barriers and surfactant deficiency resulting in fluid accumulation in the distal airspaces, fibrotic changes and eventually impaired gas exchange. The ARDS that develops early after cardiopulmonary bypass (CPB) is known as postperfusion or post-pump syndrome, which remains a significant clinical problem on those patients receiving heart operations under CPB[1]. In the early years, postperfusion lung syndrome was taken as a prerequisite condition of cardiac surgical patients that may develop into ARDS if it is not properly treated[2]. However, this argument is not supported by modern theories. Postperfusion lung syndrome is rare but refractory. It was reported that the incidence of postperfusion lung syndrome was 1-2%[3], but the mortality could be as high as 91.6%, with 70% patients developing multiple organ failure[4]. An early diagnosis and timely treatment are crucial for the patients’ outcomes. A consensus committee has provided objective criteria for the diagnosis of ARDS, and has defined acute lung injury (ALI) as a less severe form of ARDS[5]. In 1994, the American-European Consensus Conference on ARDS set the criteria for the diagnosis of ALI and ARDS[6]. Both ALI and ARDS were characterized by an acute onset, bilateral pulmonary infiltrations on chest X-ray and pulmonary wedge pressure <18 mmHg. The only differential criterion for both disorders was arterial oxygen tension (PaO2)/fractional inspired oxygen (FiO2) <300 mmHg in ALI, but PaO2/FiO2 <200 mmHg in ARDS. In 2012, the Berlin Definition was developed, focusing on feasibility, reliability, validity and objective evaluation of the performances. ARDS was classified into 3 levels based on degree of hypoxemia: mild (200 mmHg < PaO2/

MAJOR DIFFERENTIATIONS BETWEEN ACUTE RESPIRATORY DISTRESS SYNDROME AND POSTPERFUSION LUNG SYNDROME Both ARDS and postperfusion lung syndrome have similar mechanisms of triggering inflammatory processes. They also share similar clinical features, diagnostic approaches and management strategies. However, their etiologies and predisposing risk factors differ between each other. As the pulmonary pathologies are more severe in the patients with postperfusion lung syndrome, the prognosis of these patients are always poorer than those with ARDS. The multiple organ failure rate was likely to be higher in the patients with postperfusion lung syndrome than with ARDS. Ge et al.[12] reported 15 patients with ARDS, the extrapulmonary organ failure involving 0, 1, 2 and 3 organs were found in 20% (3/15), 20% (3/15), 26.7% (4/15) and 33.3% (5/15) patients, respectively with the heart being the most involved organ followed by kidney, digestive tract, central nervous system, hematological system and liver. The mortalities were respectively 0% (0/3), 33.3% (1/3), 50% (2/4) and 100% (5/5) with an

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overall mortality of 53.3% (8/15). The major similarities and differences between the two syndromes are listed in Table 1.

enced by mechanical ventilation and FiO2 and also influenced by geographic diversity and patientâ&#x20AC;&#x2122;s age. As PaO2 decreases in all types of respiratory failure, it cannot reflect the actual respiratory function and may therefore be less reliable, but leading to a delayed diagnosis if taken for an early diagnosis of ARDS[17]. P(A-a)O2 is an indicator of gas exchange (oxygen intake) impairment. Increase of P(A-a)O2 mean deficiency of gas exchange and is likely to be more sensitive than the

Pathophysiology Respiratory indicators PaO2/FiO2, PaO2 and arterial/alveolar oxygen tension ratio [P(A/a)O2] are all simple and noninvasive indicators of pulmonary gas exchange impairment. PaO2 is easily influ-

Table 1. Major differentiations between acute respiratory distress syndrome and postperfusion lung syndrome. Variable

Acute respiratory distress syndrome

Postperfusion lung syndrome

Alias

Respiratory distress syndrome, adult respiratory distress syndrome, or shock lung

Pump lung, or systemic inflammatory response syndrome to CPB

Incidence

1.5-8.3 cases per 100,000 population per year[3]

0.4-2.0% of the patients[4]

Etiology

Trauma, operation, stress, shock, infection, inflammation, fat embolism, massive blood transfusion and drug interaction

Cardiac operation under CPB

Mechanism

Complement activation and organ neutrophil sequestration

Complement activation, organ neutrophil sequestration and circulating endotoxin activation during CPB

Pathology

Alveolar-capillary membrane damage due to direct toxicity, prolonged hypoperfusion, or direct cellular damage[13]

Same

Predisposing risk factor

>65 years old, smoking cigarettes, chronic lung disease and a history of alcoholism[14]

Cardiac and pulmonary ischemia/ reperfusion, hypothermic cardioplegic arrest and heparinprotamine interactions

Clinical manifestation

Tachypnea, tachycardia and respiratory alkalosis (12-24 hours after onset); respiratory failure (48 hours)

Breathing problems, weakness, anorexia, fever and hypoventilation

Diagnosis

Chest radiographs: diffuse interstitial infiltrates to diffuse, fluffy, alveolar opacities (acute phase) and reticular opacities (fibroproliferative stage); chest computed tomography: bilateral alveolar opacities (acute phase) and bilateral reticular opacities, reduced lung volumes and occasionally large bullae (fibroproliferative stage)[3]

Same

Differential diagnosis

Cardiogenic pulmonary edema

Postoperative atelectasis

Management

Etiological therapy, ventilatory support, pharmacologic treatment, extracorporeal membrane oxygenation support, long-term supportive care and tracheostomy

Same

Subsequent multiple organ failure (%)

53.4-80[12,15]

63.2-91.6[8]

Mortality (%)

67[16]

50-91.6[8]

CPB=cardiopulmonary bypass

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decrease of PaO2. As P(A-a)O2 is affected by FiO2, its use in patients with oxygen therapy is limited. It is also affected by patient’s age, position, cardiac output, oxygen dissociation curve and closing capacity. PaO2/FiO2, also termed as oxygenation index, shows a good correlation with intrapulmonary shunting, and can better reflect anoxia even in the condition of oxygen therapy. PaO2/FiO2 is affected by methods of oxygen supply and oxygen concentration, and hence it is an indicator of impairments of the pulmonary vascular beds and alveoli, irrelevant to extrapulmonary organ failure[18]. Respiratory index (RI) is the ratio of P(A-a)O2 to PaO2, less affected by ventilation method or FiO2. Therefore, it may reflect the actual pulmonary function and is helpful in the early diagnosis of ARDS. The normal range of RI is 0.1-0.3. RI ≥2.5 represents a high risk for the development of ARDS, and RI ≥3.0 is a diagnostic indicator of ARDS[19]. RI <2.5 as shown in daily repeated blood-gas analysis can be an indicator for safe extubation[20]. ARDS patients with sustained RI elevation may eventually develop multiple organ failure[21]. Lung compliance Type II cells are thicker, square-shaped cells and their main function is to produce surfactant. Surfactant plays an essential role in preventing the alveoli from collapsing. Increase in capillary endothelial and/or alveolar epithelial permeability and pulmonary surfactant deficiency from type II cell impairment may inevitably result in pulmonary compliance reduction. The inflammatory process and alveolar flooding lead to severe ventilation-perfusion mismatch and intrapulmonary shunt, which are manifested clinically as severe hypoxia with a decrease in the PaO2/FiO2 ratio. Generally, with a marked reduction in lung compliance, the work of breathing and the physiologic dead space increase. Mechanical ventilation may reverse hypoxemia of ALI and prevent from developing into ARDS. However, airway injury and hypokinemia may occur under the treatment of a high positive end-expiratory pressure (PEEP) and positive pressure support. This may in turn worsen the systemic inflammatory reactions and lead to extrapulmonary organ dysfunction or failure[22]. With increasing PEEP, PaO2/ FiO2 increases and static lung compliance stabilizes. However, a 20-cmH2O PEEP can be a turning point of PaO2/FiO2 and static lung compliance fall[23]. Clinical studies revealed close positive correlations between PEEP, cardiac output or peak pressure of airway and PaO2/FiO2, and weak correlations between PaO2/FiO2 and oxygen supply or static lung compliance (Figure 1)[23]. Pulmonary dynamic compliance and oxygenation index correlated significantly in ARDS patients irrespective of patients’ outcome (Figure 2)[24]. In ALI models, RI correlated positively, but PaO2/FiO2 correlated negatively to plasma soluble intercellular adhesion molecule-1, showing a significant correlation in the experimental other than in the control group (Figure 3)[25].

Fig. 1 - Linear correlations between respiratory mechanics and PaO2/FiO2[23]. PaO 2/FiO 2=arterial oxygen tension/fractional inspired oxygen; PEEP=positive end-expiratory pressure

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but negatively correlated pulmonary compliance[27]. Stratified analysis illustrated a strong negative correlation between EVLWI and PaO2/FiO2 when EVLWI â&#x2030;Ľ12 mL/kg and also a strong negative correlation between pulmonary vascular permeability index and PaO2/FiO2 when pulmonary vascular permeability index â&#x2030;Ľ5[28]. Kushimoto et al. [29] found, in a multicenter retrospective study, that the severity of ARDS closely correlated with increase of EVLWI and pulmonary vascular permeability index. A report also stressed on that EVLWI may be associated with severity of ARDS, ventilation duration, Intensive Care Unit stay and mortality[30]. EVLWI is therefore a useful tool for the evaluation of pulmonary function, superior to PaO2/FiO2 and chest roentgenogram. Intrapulmonary shunting The major etiology of hypoxia in ARDS patients is functional intrapulmonary shunting. A pulmonary shunt is a condition of ventilation-perfusion mismatch with normal blood perfusion but insufficient ventilation of the lungs. Intrapulmonary shunting has a close relation negative to PaO2/FiO2, but positive to P(A-a)O2[31], and is also affected by pulmonary artery wedge pressure and cardiac index[32]. Normally, pulmonary shunt is 2-5%[33]. The intrapulmonary shunt is optimal in assessing the severity of hypoxemia. An intrapulmonary shunt <15% as well as P(A-a)O2 difference <75 mmHg is helpful for the exclusion of ARDS[34]. A shunt of 10-19% usually does not need ventilation support; whereas a shunt of 20-29% can be a fatal sign in patients with impaired cardiac function, and a shunt >30% requires circulatory support[35]. In normal subjects and experimental animals with ARDS, PEEP did not alter the distribution of blood flow; the apparent perfusion ratio remained constant when PEEP was increased from 5 to 10 cmH2O[36]. However, when a positive end-expiratory plateau was added to intermittent positive pressure ventilation, intrapulmonary shunting may decrease and the disrupted surfactant production may take into action[37].

Fig. 2 - Linear correlations between pulmonary dynamic compliance and oxygenation index in patients with acute respiratory distress syndrome[24]. Upper panel=cured patients; Lower panel=dead patients. PaO2/FiO2=arterial oxygen tension/fractional inspired oxygen

Acid-base imbalances In the early stage of ARDS, respiratory alkalosis is the most common type of acid-base imbalance followed by metabolic acidosis and combined respiratory alkalosis and metabolic alkalosis. In its late stage, patients may develop respiratory acidosis, respiratory acidosis associated with metabolic acidosis and even triple acid-base imbalance. The triple acid-base imbalance can be a respiratory alkalosis or a respiratory acidosis type. The respiratory alkalosis type is respiratory alkalosis associated with metabolic acidosis and metabolic alkalosis, which is often developed from uncorrected primary respiratory alkalosis, while using diuretics and glucocorticoids (for metabolic alkalosis), or in the presence of severe hypoxia, renal dysfunction, or shock (for metabolic acidosis) and electrolyte imbalance (hypokalemia, normal or high blood chloride, and normal or reduced blood

Extravascular lung water Extravascular lung water is the fluid distributed beyond the pulmonary vessels. It is composed of intracellular, intra-alveolar and alveolar interstitial fluid. Little intracellular fluid change stands out the effects of intra-alveolar and alveolar interstitial fluid in the formation of pulmonary edema. Increase of extravascular lung water is a prominent feature of ARDS and the actual reason for refractory hypoxemia. Clinically, extravascular lung water index (EVLWI) is an indicator for the description of extravascular lung water. The normal range of EVLWI is 3.0-7.0 mL/kg. An EVLWI >7.0 mL/kg suggests the presence of pulmonary edema[26]. Extravascular lung water positively correlated with lung injury severity and oxygenation

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Fig. 3 - Linear correlations between soluble intercellular adhesion molecule-1 and respiratory index or PaO2/FiO2[25]. Left panel=control group; Right panel=experimental group with intercellular adhesion molecule-1 antibody 2 mg/kg was given to the rabbit; PaO2/FiO2=arterial oxygen tension/ fractional inspired oxygen; ICAM=intercellular adhesion molecule

Fig. 4 - Linear correlations between tumor necrosis factor-Îą or interleukin-6 and respiratory index or P(A-a)O2[68]. Left panel=control group; Right panel=penehyclidine hydrochloride; P(A-a)O2: alveolar-arterial oxygen pressure difference.

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sodium). Patients with this type triple acid-base imbalance are often with a poor outcome[38]. The respiratory acidosis type triple acid-base imbalance is respiratory acidosis associated with metabolic acidosis and metabolic alkalosis, which is less common but may occur in the condition of reduced ventilation and carbon dioxide retention, often associated with normal or high blood potassium and normal or reduced blood chloride and sodium [38].

among indirect risk factors[13]. Christenson et al.[2] reported insufficient perfusion of visceral organs caused by low output syndrome and prolonged hypotension might be responsible for the development of postperfusion lung syndrome. Rady et al.[45] observed that early postoperative pulmonary dysfunction was associated with preoperative (age ≥75 years, body mass index ≥ 30 kg/m2, mean pulmonary arterial pressure ≥ 20 mmHg, stroke volume index ≥30 mL/m2, serum albumin and history of cerebral vascular disease), operative (emergency surgery and CPB duration ≥140 min) and postoperative variables (hematocrit ≥30%, mean arterial pressure ≥90 mmHg and cardiac index ≥3.0 L/min/m2). Besides, preoperative cardiac function impairment, bloodstream infection, prolonged crossclamp and operation durations, hypotension episodes and hypogammaglobulinemia can be risk factors of postperfusion lung syndrome[46].

MECHANISMS The exact mechanism of postperfusion lung syndrome remains uncertain, but it may probably be due to the inflammatory cascade induced by contact between blood and CPB circuit and the subsequent activations of leukocytes, platelets, coagulation and fibrinolysis system and kallikrein-bradykinin and complement system. After crossclamp removal, joint actions of protease release by leukocytes in the pulmonary vascular beds, production of oxygen free radicals and intestinal endotoxin translocation lead to increased pulmonary microvascular permeability, microthrombus formation in the pulmonary vessels and the quality and quantity changes of pulmonary surfactant predispose to the development of postperfusion lung syndrome[39]. The significant complement activation and organ neutrophil sequestration contribute to vascular injury, and hence patients undergoing cardiac operation under CPB showed increased circulating endotoxin and tumor necrosis factor (TNF) levels[40,41]. Alveolar macrophages are prone to be activated, releasing many inflammatory mediators including TNF-α, interleukin (IL)-6 and IL-8 and superoxide dismutase, etc., and damaging vascular endothelium and alveolar epithelium, thus making the lungs being the first target organ of insult. TNF-α and IL-6 may cause direct lung injury effects by inducing early inflammatory reactions, releasing toxic products and increasing pulmonary permeability[42]. In the lung, TNF-α is generated by activated pulmonary macrophages and accumulates in the bronchoalveolar lavage fluid of ALI patients[43]. The pathogenesis of TNF-α with receptors in neutrophil activation and infiltration of lung injury remain unclear. However, it has been noted that neutrophil accumulation and lung leak were abrogated in mice lacking the p55 TNF-α receptor[44]. TNF-α also stimulates the adhesions of the endothelial cells and neutrophils, and impacts a toxic effect by release of proteases, oxygen free radicals and superoxide dismutase. Productions of ILs including ILs-1, -2, -6 and -8 would be increased by stimulations of mon-macrocytes strengthening the lung injury. Accordingly, an early appearance of TNF-α may herald the development of ARDS and the synthesis and secretion of ILs.

PREVENTION Apostolakis et al.[47] summarized preventive strategies for operative lung injury, which included choices of CPB circuit (use of miniaturized circuits of CPB and circuit with biocompatible surfaces ultrafiltration) and apparatus (leukocyte depletion filters and ultrafiltration), innovative CPB techniques (partial restoration of pulmonary artery perfusion during CPB), modified surgical maneuvers (reducing the use of cardiotomy suction device and reducing the contact-time between free blood and pericardium) and medicinal agents (corticosteroids and aprotinin) as preventive strategies for ALI during CPB, which were proved to be of satisfactory outcomes on improving the lung function. Moreover, hyperonocotic CPB-prime with hydroxyethyl starch 10% (200:0.5) may improve cardiac function and reduce pulmonary water content in the early postoperative period[48]. Studies have shown that Travenol bubble oxygenator was associated with significant increases of EVLWI and pulmonary vascular resistance and greater blood component trauma than the membrane[49], and bubble oxygenators caused more leukocyte sequestrations[50]. Care has to be taken with choice of oxygenator in risky patients. MANAGEMENT Ventilatory treatment Mechanical ventilation remains the primary support technique for ARDS. New ventilation strategies, such as high-frequency oscillatory ventilation appear to be promising[51]. However, in patients with ALI/ARDS, mechanical ventilation with a lower tidal volume (6 mL/kg) than is traditionally used[52]. Low tidal volume ventilation reduces volutrauma, and is the standard care for ARDS patients with mechanical ventilation. A strategy of low tidal volume ventilation of 6-8 mL/kg reduces absolute mortality by about 7-9% in compar-

RISK FACTORS Both direct and indirect lung injuries can be predisposing risk factors leading to ARDS. Surgical trauma and CPB are

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ison to using ≥10 mL/kg tidal volumes. Mechanically ventilated patients with ARDS appear to tolerate very low blood pH and very high carbon dioxide partial pressure without any adverse sequelae. Based on this theory, permissive hypercapnia can be attempted in ARDS patients in order to achieve normal blood gas values. Adequate PEEP levels avoid alveolar collapse and maintain sufficient pulmonary volume at the end of expiration. Excessive PEEP increases the risk of pneumothorax and airway impairment, causing adverse hemodynamic effects by increasing intra-thoracic pressure and reducing venous return. Meanwhile, inadequately low PEEP level provokes cyclic alveolar collapse and re-opening, resulting in atelectrauma[51]. Most ventilation modes used in ARDS are those cycled by time and controlled by volume or pressure. In ARDS patients randomized to high frequency oscillatory ventilation, mortality was significantly reduced and so was the treatment failure rate comparing to conventional ventilation[53]. Recruitment is a strategy aimed at re-expanding collapsed lung tissue, and then maintaining high PEEP to prevent subsequent “de-recruitment”. Various ventilation modes such as inverse ratio pressure-controlled ventilation, airway-pressure release ventilation and even high-frequency oscillatory ventilation have been used to promote recruitment [54]. Prone positioning improves gas exchange and has long been used as an adjunct or salvage therapy for severe or refractory ARDS. A strategy employing higher PEEP along with low tidal volume ventilation should be considered for ARDS patients receiving mechanical ventilation. ARDS patients receiving higher PEEP had a strong trend toward improved survival. However, higher PEEP had a strong trend toward harm as higher PEEP can conceivably cause ventilator-induced lung injury by increasing plateau pressures, or cause pneumothorax or decreased cardiac output[55].

inhaled nitric oxide in ARDS. They found by incorporating the results of 14 randomized clinical trials that inhaled nitric oxide resulted in a transient improvement in oxygenation without reducing mortality but was probably harmful[61]. Therefore physicians have to take care when using this agent for ARDS. Prostaglandins are endogenous derivatives of arachidonic acid with properties of vasodilation, platelet aggregation inhibition and anti-inflammation. Inhaled prostacyclins cause selective pulmonary vasodilation, thereby enhancing lung function by improving ventilation-perfusion mismatch and oxygenation and by reducing pulmonary vascular resistance[62]. Inhaled prostaglandin E2 had a comparable effect to nitric oxide on pulmonary vasculature and oxygenation with minimal systemic effects[62]. Continuous infusion of prostaglandin E1 may induce oxygen delivery and obtain better tissue oxygenation, while increasing cardiac output[63]. Prostacyclin is also a promising vasodilator in decreasing pulmonary artery pressure and improving PaO2/FiO2[64], but it may cause compromised hemodynamics[65]. Glucocorticoids Glucocorticoids can reduce inflammation and fibrosis through inhibition of several cytokines including ILs-1, -3, -5, -6 and -8, TNF-α and granulocyte macrophage-colony stimulating factor[66]. Lisofylline, like pentoxifylline, has been shown to diminish proinflammatory cytokine expressions of TNF-α, IL-1 and IL-6 and to inhibit neutrophil accumulation and edema formation. Unlike pentoxifylline, lysofylline partly exerts its anti-inflammatory properties by inhibiting the release of oxidized free fatty acids from cell membranes under oxidative stress[62]. Anti-inflammatory agents High-mobility group box 1 (HMGB1) is a critical mediator in the pathogenesis of many inflammatory diseases. Penehyclidine hydrochloride inhibits the translocation of release of HMGB1 from the nucleus to the cytoplasm and the expression of HMGB1 messenger ribonucleic acid in a dose-dependent manner[66]. Administration of penehyclidine hydrochloride reduces lung water gain, bronchoalveolar lavage protein content, infiltration of neutrophils, malondialdehyde content and lactate dehydrogenase activity and enhances superoxide dismutase activity[67]. Penehyclidine hydrochloride also significantly reduces P(A-a)O2 and RI as well as TNF-α and IL-6 of lung injury, and both RI and P(A-a)O2 shows a close correlation with TNF-α and IL-6 (Figure 4)[68]. Ulinastatin decreases free radical productions, lowers ratio of physiological dead space to tidal volume and improves respiratory function after CPB[69]. Induction of anesthesia with ulinastatin 10,000 units/kg inhibits the excessive release of serum HMGB1, TNF-α and IL-8 concentrations[70]. Ulinastatin was shown in a systematic review to have a significant effect on improv-

Pharmaceutical treatment Surfactant Surfactant therapy has shown beneficial effects on oxygenation and survival of children with ALI/ARDS, however, no effect or even adverse effects of exogenous surfactant has been shown on survival in adult patients[56-58]. Instillation of a natural lung surfactant (calfactant) contains high levels of surfactant-specific protein B. Calfactant (2 doses of 80 mL/ m2 calfactant, 12 hours apart) acutely improved oxygenation and significantly decreased mortality in infants, children and adolescents with ALI[59]. Vasodilators Nitric oxide is a powerful endogenous vasodilator. A placebo-controlled study demonstrated that the ARDS patients receiving 5 ppm inhaled nitric oxide showed significantly improved oxygenation parameters with better survival comparing with placebo[60]. Some authors suspected the role of

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ing oxygenation and shortening the length of Intensive Care Unit stay[71]. The large dose of propofol (15 mg/kg/hour) attenuated lung leukocyte sequestration, pulmonary edema and pulmonary hyperpermeability and resulted in better oxygenation, lung mechanics and histological changes; while the small dose (4 mg/kg/hour) did not, in endotoxin-induced ALI rabbit model[72]. Treatment with propofol by intravenous infusion (6 mg/kg/min for 5 min) abrogated or reversed the oleic acid-induced ALI changes in rats[73]. However, the use of propafol may induce ALI in particular in the presence of an increased alveolar-capillary permeability, which allowed the propofol emulsion to leak into the alveoli[74]. Studies have suggested activation of adenosine receptors may enhance alveolar fluid clearance and regulate the fluid transport in the lung. The adenosine 2A receptor agonist GW328267C improves lung function of ALI rats[75]. A randomized clinical trial of simvastatin in ALI patients revealed the simvastatin-treated group had improvements in nonpulmonary organ dysfunction on day 14 of treatment. Simvastatin was well tolerated, with no increase in adverse events. Simvastatin improved oxygenation and respiratory mechanics, and decreased bronchoalveolar lavage IL-8 by 2.5-fold[76]. Experimental studies on rats revealed that endothelin-1 inhibited alveolar fluid clearance by inhibition of amiloride-sensitive epithelial Na+ channels. Endothelin-1 may increase capillary pressure and contribute to pulmonary edema formation[77]. The endothelin-1 receptor subtype blockers significantly prevented the pulmonary vasoconstriction induced by endothelin-1[78]. Atrial natriuretic peptide had a protective effect in the lipopolysaccharide-induced ALI model[79]. H2 treatment markedly attenuated lipopolysaccharide-induced lung neutrophil recruitment and inflammation and intraperitoneal injection of 10 mL/ kg hydrogen-rich saline also significantly attenuated the lipopolysaccharide-induced ALI[80].

1,058 patients with 386 of them treated with ECMO revealed ECMO increased the mortality of ARDS patients. Therefore, it seems that ECMO is not beneficial in adult patients with ARDS as in neonates[85]. CONCLUSIONS Postperfusion lung syndrome is rare but can be refractory. Both ARDS and postperfusion lung syndrome have similar mechanisms of triggering inflammatory processes. They also share similar clinical features, diagnostic approaches and management strategies. However, their etiologies and predisposing risk factors differ between each other. Inflammatory cascade induced by CPB has been an acceptable mechanical hypothesis. The prognosis of the postperfusion lung syndrome can be poorer than that of the ARDS. The potential sequelea of postperfusion lung syndrome such as multiple organ failure and triple acid-base imbalance can be the principle causes of poor outcome rather than the lung disorder itself. Choices of CPB circuit and apparatus, innovative CPB techniques, modified surgical maneuvers and some medicinal agents can be potential preventive strategies for ALI during CPB. Mechanical ventilation (with low tidal volume and proper PEEP), pharmaceutical agents and ECMO can be therapeutic options of postperfusion lung syndrome. With the mature therapeutic options, the survival rate of the patients with postperfusion lung syndrome and ARDS would be further improved.

Author roles & responsibilities SMY

Extracorporeal membrane oxygenation (ECMO) ECMO is a therapeutic option for patients with severe ARDS. The indications for ECMO use in ARDS patients are failed conventional therapy for 24-96 hours and the conformity of two of the three required slow-entry criteria for ECMO including PaO2/FiO2 <150 mmHg at PEEP >5 cmH2O, semistatic compliance <30 mL/cmH2O and right-left shunt >30%. Only in the patients with life-threatening hypoxemia (PaO2<50 mmHg at FiO2 1.0 and PEEP>5 cmH2O for>2 hours (fast-entry criteria) is immediate ECMO commenced[81]. Mols et al.[82] reported one-quarter of their 245 ARDS patients received ECMO treatment. The survival rate was 55% in ECMO patients and 61% in non-ECMO patients. However, the role of ECMO in the treatment of ARDS is controversial[83]. In neonates treated with ECMO, a survival rate of 80% was achieved. In adult patients with ARDS, two randomized controlled trials revealed the survival rates were 10% and 33%, respectively, in the ECMO groups[84]. Meta-analysis of 9 studies on a total of

Main author

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Araujo Júnior SPECIAL E, et al. - Sonocubic fine: new three-dimensional ultrasound ARTICLE software to the screening of congenital heart diseases

Sonocubic fine: new three-dimensional ultrasound software to the screening of congenital heart diseases Sonocubic fine: novo software de ultrassonografia tridimensional para o rastreamento das doenças cardíacas congênitas

Edward Araujo Júnior1, MD, MsC, PhD; Luciane Alves da Rocha1, MD; Luciano Marcondes Machado Nardozza1, MD, MsC, PhD DOI: 10.5935/1678-9741.20140040

RBCCV 44205-1571

Abstract Congenital heart disease is the most common fetal congenital malformations; however, the prenatal rate detection still is low. The two-dimensional echocardiography is the “gold standard” exam to screening and diagnosis of congenital heart disease during the prenatal; however, this exam is operator-depending and it is realized only in high risk pregnancies. Spatio-temporal image correlation is a three-dimensional ultrasound software that analyses the fetal heart and your connections in the multiplanar and rendering modes; however, spatio-temporal image correlation too is operator-depending and time-consuming. We presenting a new three-dimensional software named Sonocubic fine to the screening of congenital heart disease. This software applies intelligent navigation technology to spatio-temporal image correlation volume datasets to automatically generate nine fetal echocardiography standard views. Thus, this new software tends to be less operator-depending and time-consuming.

Resumo Doenças cardíacas congênitas são as malformações congênitas mais frequentes, entretanto, a detecção pré-natal ainda permanece baixa. A ecocardiografia bidimensional é o “padrão-ouro” para o rastreamento e diagnóstico das doenças cardíacas congênitas durante o pré-natal, entretanto, é operador dependente e realizada somente em gestantes de alto risco. Spatio-temporal image correlation é um software de ultrassonografia tridimensional que analisa o coração fetal e suas conexões vasculares nos modos multiplanar e superfície, contudo, também é operador dependente e consome muito tempo. Apresentamos um novo software: Sonocubic fine para o rastreamento das doenças cardíacas congênitas. Este software aplica a inteligência da tecnologia de navegação em volumes de spatio-temporal image correlation para automaticamente gerar nove planos ecocardiográficos padrões. Além disso, esta técnica tende a ser menos operador dependente e consumir menor tempo.

Descriptors: Fetal Heart. Ultrasonography, Doppler. Pregnancy.

Descritores: Coração Fetal. Ultrassonografia Doppler. Gravidez.

INTRODUCTION

two-dimensional echocardiography; however, despite the efforts realized in the last 20 years, the detection rate of CHD ranges from 31 to 96%[3]. Despite of two-dimensional echocardiography to be the gold standard exam to the screening of CHD during the prenatal period, this exam is operator dependent, is not available in all prenatal care centers and it is performed only in high risk pregnancies[4]. Due to this, some associations as Inter-

Congenital heart diseases (CHD) are the most common fetal congenital malformations, corresponding an incidence six times higher than chromosome anomalies and four times higher than neural tube defects[1]. The prevalence of CHD in newborns ranges from 0.6 to 5%[2]. The gold standard exam to the screening of CHD during the prenatal period is the

Watch the videos acessing the link below: http://www.rbccv.org.br/video/2276/Sonocubic_fine__new_three_dimensional_ultrasound_software_to_the_screening_of_ congenital_heart_diseases 1

Correspondence address: Edward Araujo Júnior Universidade Federal de São Paulo (UNIFESP) Rua Napoleão de Barros, 875 - Vila Clementino, São Paulo, SP, Brazil Zip code 04024-002 E-mail: araujojred@terra.com.br Article received on August 26th, 2013 Article accepted on March 11th, 2014

Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.

This study was carried out at Department of Obstetrics, Paulista School of Medicine, Federal University of São Paulo (EPM-UNIFESP), São Paulo, SP, Brazil. No financial support.

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Benefits of intelligent navigation Once a correct volume is acquired (STIC), intelligent navigation has a role in obtaining the target diagnostic planes automatically, minimizing the intra-operator variability and the exam duration. The obtained planes are obtained following an expert criterion with a high rate of accuracy. The final images will be consistent in terms of orientation, sizes and positions simplifying the clinical evaluation of cases. Intelligent navigation identifies, isolates and independently process a sequence of selected particular morphology features of the anatomy in order to decide the more adequate plane to be extracted for that particular case. As an example, the greater accuracy on the final image of a given cardiac volume is provided by the combination of anatomical probabilistic assumptions with corrective decision trees that increases the tolerance of the model to unprecedented range of fetal ages, position and anatomical variations. Intelligent navigation can label structures within the images for better interpretation.

Abreviations, acronyms & symbols AIUM CHD ISUOG STIC

American Institute of Ultrasound in Medicine Congenital heart disease International Society of Ultrasound in Obstetrics & Gynecology Spatio-temporal image correlation

national Society of Ultrasound in Obstetrics & Gynecology (ISUOG) and American Institute of Ultrasound in Medicine (AIUM) have proposed the screening of CHD in the second trimester scan including the outflow right and left ventricles tract to the four chamber view[5,6]. Spatio-temporal image correlation (STIC) is a software application that enables acquisition of fetal heart volume and vascular connection data. The images generated by this software can be evaluated both in multiplanar and rendering modes. They can also be evaluated both static and movement (4D) through a cineloop sequence that simulates an entire cardiac cycle[7-9]. Some studies have used the STIC in the screening of CHD; however, the results still are controversies[10-13]. In part, these controversy results are due of ability of examiners, being necessary specific training for long time to obtain the standard fetal heart views using STIC. Recently, new software named Sonocubic fine (Medge Platforms Inc., New York, NY, USA) applies intelligent navigation technology to STIC volume datasets to automatically generate fetal echocardiography standard views. Thus, this new software tends to be less operator-depending and time-consuming. The aim this study is to present the new software Sonocubic fine and its possible applications in screening of CHD.

Definition of Sonocubic fine Sonocubic fine program has an intelligent navigation. The algorithm processes the volume data using some user marked reference points. These points, or landmarks, are marked on the original 2D sweep. The landmarks are specific anatomical spots sufficient for the algorithm to perform the volume navigation and deliver the diagnostic planes. Acquisition and storage of STIC volume datasets The volume to be available by Sonocubic fine should be acquired by STIC from Voluson 730 Expert or E8 (General Eletric, Medical System, Zipf, Austria) ultrasound machine using a convex volumetric transductor (RAB 4-8L). The best volume is obtained in four chamber view with the fetus spine in 6 o’ clock position. The opening angle varies in according the gestational age, rather 20º to 25º in the second and 35º to 40º in the third trimesters. The acquisition time varied between 7.5 and 15 seconds, depending of fetus movements[14]. The volumes should be acquired only in gray scale. To storage of STIC volume datasets, we do not need to use the standardization proposed by Paladini[15] for fetuses with pelvic presentation, because the system automatically recognizes this situation and it requests to examiner to modify the fetus presentation.

METHODS Technical description of the Sonocubic fine software: intelligent navigation; benefits of intelligent navigation; definition of Sonocubic fine; acquisition and storage of STIC volume datasets; anatomic box; intelligent alerts and virtual intelligent sonographer assistance (VIS-Assistance) Intelligent navigation Intelligent Navigation is referred to a completely unsupervised procedure able to find, extract and navigate target planes from a volume dataset using a predictive adapted algorithm. Any volume modality like ultrasound, computed tomographic, magnetic resonance imaging, could be used. The term “intelligent” describes the “operator independent” ability to solve a particular case by automated analysis of a number of variables leading to consequent adjustment of the predetermined imaging criteria.

Anatomic box Before to active the anatomic box, the examiner should to click in the center of thoracic aorta in the four chamber view to observe the position of descendent aorta in the sagittal view. If the descendent aorta has linear direction, the STIC volume is appropriate to be analyzed by Sonocubic fine. Anatomic box is a technology allows the examiner to mark anatomical structures within the STIC volume (displayed as a cinellop – Video

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1), which then allows geometrical modeling of the fetal heart and the automatic display of standard fetal echocardiography views. The seven landmarks structures to obtain the nine fetal echocardiography views are: 1) in the center of abdominal aorta in the upper abdomen; 2) center of thoracic aorta in the four chamber view; 3) heart crux in the four chamber view; 4) line

crossing the middle of interventricular septum and reaching the internal wall of the right atrium in the four chamber view; 5) at level of pulmonary valve in three vessels and trachea view; 6) in the center of superior vena cava in the three vessels and trachea view; 7) in the transverse aortic arch in the three vessels and trachea view (Figure 1).

Fig. 1 - The seven landmarks necessary to obtain the nine fetal echocardiography standard views: center of abdominal aorta in the upper abdomen; center of thoracic aorta in the four chamber view; heart crux in the four chamber view; line crossing the middle of interventricular septum and reaching the internal wall of the right atrium in the four chamber view; at level of pulmonary valve in three vessels and trachea view; center of superior vena cava in the three vessels and trachea view; transverse aortic arch in the three vessels and trachea view (white arrows).

Fig. 2 - The nine fetal echocardiography standard views in sequence on the screen: three vessels and trachea; four chamber view; five chamber view; left ventricle outflow tract; right ventricle outflow tract; abdomen view; ductal arch; aortic arch and venae cavae (white arrows).

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After the examiner to complete all landmarks, the program displays automatically the nine fetal echocardiography views: three vessels and trachea; four chamber view; five chamber view; left ventricle outflow tract; right ventricle outflow tract; abdomen view; ductal arch; aortic arch and venae cavae (Figure 2 and Video 2). The program permits too to add labels in each fetal echocardiography standard views, facilitating the correct understanding of fetal heart structure and the standard views (Figure 3). The examiner can make the adjustments of brightness, midtones and contrast; moreover, the fetal echocardiography views can be displayed in gray, sepia and ice colors. In some cases, the program not shows the exact plane to examiner to mark the correct structures. In these cases, the examiner can make some adjustments using 2D plane position.

Intelligent Alerts Intelligent alerts notify the examiner about the potential about potential issues with the STIC volume dataset (e.g. location of fetal spine in 8 oâ&#x20AC;&#x2122; clock) (Figure 4). Marking alerts are captions notifying the examiner that the fetal anatomical structures for making may in different locations that is expected. Virtual Intelligent Sonographer Assistance (VIS-Assistance) VIS-Assistant is an operator-independent tool that allows sonographic navigation and exploration of surrounding structures in each of fetal echocardiography standard views (Video 3). This algorithm is the particular importance in suspected cases of CHD, because it permits to find the best plane in each fetal echocardiography views.

Fig. 3 - The labels indicating the fetal heart structures and the fetal echocardiography standard views.

Fig. 4 - Intelligent alert algorithm showing that the structure marked is incorrect (white arrow).

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Supplementary materials Video 1. STIC volume dataset in cinellop sequence making an axial scan over the fetal chest and upper abdomen. Video 2. The nine fetal echocardiography standard views on the screen in the cinellop sequence. Video 3. Virtual Intelligent Sonographer Assistance (VIS-Assistance) navigation and exploration of surrounding structures in the ductal arch view.

DISCUSSION Limitations Despite of potential benefits in the screening of CHD, some limitations are observed. The STIC volume should be scanned with the fetus spine between 7 and 8 o’clock position, because the Sonocubic fine software does not present the option of rotation of volume in the three orthogonal planes. This limitation can be time-consuming to scan the best volume in the four chamber view. The new software too does not have capacity to make measurements, which can be important in suspicion of some types of CHD. Other limitation of new software is not capacity to analyze STIC volumes with color Doppler; despite of the color Doppler is not part of guidelines of screening of CHD[5,6].

Authors’ roles & responsibilities EAJ LAR LMMN

Advantages over STIC Sonocubic fine is a software that display in the screen the nine fetal echocardiography standard views. Differently of STIC, which the standard planes are obtained by several reconstructions techniques[16,18], damaging the quality of the planes; Sonocubic fine provides direct views without artifacts transmission. Moreover, the Sonocubic fine is not operator-depending differently of STIC, not being necessary specific knowledge in fetal cardiology. Sonocubic fine is too less time-consuming, because it display automatically all fetal echocardiography standard views on the screen.

Proposal, preparation and article writing Learning and collection of cases Critical review

REFERENCES

1. Carvalho JS, Mavrides E, Shinebourne EA, Campbell S, Thilaganathan B. Improving the effectiveness of routine prenatal screening for major congenital heart defects. Heart. 2002;88(4):387-91. 2. Grandjean H, Larroque D, Levi S. The performance of routine ultrasonographic screening of pregnancies in the Eurofetus Study. Am J Obstet Gynecol. 1999;181(2):446-54.

First experience with Sonocubic fine in the assessment of fetal heart Recently, Yeo & Romero described the first experience of Sonocubic fine in the assessment of fetal heart. These authors tested the Sonocubic fine in 50 STIC volumes of normal cases and 4 STIC volumes of CHD (coarctation of aorta, tetralogy of Fallot, transposition of great vessels and pulmonary atresia with intact ventricular septum). They assessed the rate of visualization of fetal echocardiography views using diagnostic planes and/or VIS-Assistance. Sonocubic fine was able to generate nine fetal heart standard views using diagnostic planes in 78-100%, VIS-Assistance in 98-100% and a combination of diagnostic planes and/or VIS-Assistance in 98-100% of cases. In all cases of CHD, the new software demonstrated evidences of fetal heart abnormalities[19].

3. Stümpflen I, Stümpflen A, Wimmer M, Bernaschek G. Effect of detailed echocardiography as part of routine prenatal ultrasonographic screening on detection of congenital heart disease. Lancet. 1996;348(9031):854-7. 4. Allan L. Prenatal diagnosis of structural cardiac defects. Am J Med Genet C Semin Med Genet. 2007;145C(1):73-6. 5. International Society of Ultrasound in Obstetrics & Gynecology. Cardiac screening examination of the fetus: guidelines for performing the ‘basic’ and ‘extended basic’ cardiac scan. Ultrasound Obstet Gynecol. 2006;27(1):107-13. 6. Fetal Echocardiography Task Force; American Institute of Ultrasound in Medicine Clinical Standards Committee; American College of Obstetricians and Gynecologists; Society for MaternalFetal Medicine. AIUM practice guideline for the performance of fetal echocardiography. J Ultrasound Med. 2011;30(1):127-36.

CONCLUSION

7. Gonçalves LF, Lee W, Chaiworapongsa T, Espinoza J, Schoen ML, Falkensammer P, et al. Four-dimensional ultrasonography of the fetal heart with spatiotemporal image correlation. Am J Obstet Gynecol 2003;189(6):1792-802.

In summary, we presented a new software to the screening of CHD. Sonocubic fine permits the achievement of nine fetal echocardiography view using seven landmarks from STIC volume datasets. This software is less time and operator-depending than STIC; however, future studies comparing both techniques are necessary to prove the real applicability of Sonocubic fine in the screening of CHD.

8. DeVore GR, Falkensammer P, Sklansky MS, Platt LD. Spatiotemporal image correlation (STIC): new technology for evaluation of the fetal heart. Ultrasound Obstet Gynecol. 2003;22(4):380-7.

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9. Araujo Júnior E, Rolo LC, Simioni C, Nardozza LM, Rocha LA, Martins WP, et al. Comparison between multiplanar and rendering modes in the assessment of fetal atrioventricular valve areas by 3D/4D ultrasonography. Rev Bras Cir Cardiovasc. 2012;27(3):472-6.

14. Gonçalves LF, Lee W, Espinoza J, Romero R. Examination of the fetal heart by four-dimensional (4D) ultrasound with spatiotemporal image correlation (STIC). Ultrasound Obstet Gynecol. 2006;27(3):336-48.

10. Viñals F, Poblete P, Giuliano A. Spatio-temporal image correlation (STIC): a new tool for the prenatal screening of congenital heart defects. Ultrasound Obstet Gynecol. 2003;22(4):388-94.

15. Paladini D. Standardization of on-screen fetal heart orientation prior to storage of spatio-temporal image correlation (STIC) volume datasets. Ultrasound Obstet Gynecol. 2007;29(6):605-11.

11. Wanitpongpan P, Kanagawa T, Kinugasa Y, Kimura T. Spatio-temporal image correlation (STIC) used by general obstetricians is marginally clinically effective compared to 2D fetal echocardiography scanning by experts. Prenat Diagn. 2008;28(10):923-8.

16. DeVore GR, Polanco B, Sklansky MS, Platt LD. The ‘spin’ technique: a new method for examination of the fetal outflow tracts using three-dimensional ultrasound. Ultrasound Obstet Gynecol. 2004;24(1):72-82.

12. Cohen L, Mangers K, Platt L, Julien S, Gotteiner N, Dungan J, et al. Quality of 2- and 3-dimensional fast acquisition fetal cardiac imaging at 18 to 22 weeks: ramifications for screening. J Ultrasound Med. 2009;28(5):595-601.

17. Espinoza J, Kusanovic JP, Gonçalves LF, Nien JK, Hassan S, Lee W, et al. A novel algorithm for comprehensive fetal echocardiography using 4-dimensional ultrasonography and tomographic imaging. J Ultrasound Med. 2006;25(8):947-56.

13. Araujo Júnior E, Rolo LC, Nardozza LM, Moron AF. Fetal cardiac evaluation by 3D/4D ultrasonography (STIC): what is its real applicability in the diagnosis of congenital heart disease? Rev Bras Cardiovasc. 2013;28(1):III-V.

18. Yeo L, Romero R. Fetal Intelligent Navigation Echocardiography (FINE): a novel method for rapid, simple, and automatic examination of the fetal heart. Ultrasound Obstet Gynecol. 2013;42(3):268-84.

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Oliveira MAB,SPECIAL et al. - Modes of induced cardiac arrest: hyperkalemia and ARTICLE hypocalcemia - Literature review

Modes of induced cardiac arrest: hyperkalemia and hypocalcemia - Literature review Modalidades de parada cardíaca induzida: hipercalemia e hipocalcemia - revisão de literatura

Marcos Aurélio Barboza de Oliveira1, MD, MsC; Antônio Carlos Brandi2, MD; Carlos Alberto dos Santos2, MD; Paulo Henrique Husseini Botelho2, MD; José Luis Lasso Cortez3, MD; Domingo Marcolino Braile4, MsC, PhD

DOI: 10.5935/1678-9741.20140074

RBCCV 44205-1572

Abstract The entry of sodium and calcium play a key effect on myocyte subjected to cardiac arrest by hyperkalemia. They cause cell swelling, acidosis, consumption of adenosine triphosphate and trigger programmed cell death. Cardiac arrest caused by hypocalcemia maintains intracellular adenosine triphosphate levels, improves diastolic performance and reduces oxygen consumption, which can be translated into better protection to myocyte injury induced by cardiac arrest.

Resumo A entrada de sódio e cálcio desempenham efeito chave no miócito submetido à parada cardíaca por hiperpotassemia. Eles provocam edema celular, acidose, consumo de trifosfato de adenosina e desencadeiam processo de morte celular programada. A parada cardíaca provocada por hipocalcemia mantém os níveis intracelulares de trifosfato de adenosina, melhora o rendimento diastólico e reduz o consumo de oxigênio, o que pode ser traduzido em melhor proteção do miócito às lesões provocadas pela parada cardíaca induzida.

Descriptors: Heart Arrest, Induced. Myocardial Ischemia. Hyperkalemia. Hypocalcemia.

Descritores: Parada Cardíaca Induzida. Isquemia Miocárdica. Hiperpotassemia. Hipocalcemia.

INTRODUCTION

to approach intracardiac diseases[3] by using substances that trigger controlled cardiac arrest, commonly known as cardioplegic agents [4]. Although several myocardial protection methods produce satisfactory results, none can be considered ideal. The perfect cardioplegic agent must meet the following requirements [5]: 1. Cardiac arrest: fast and efficient induction, with relaxed myocardium and minimum ATP consumption;

The first cardiac surgeries were performed on a beating heart, being limited to the correction of minor illnesses, such as suturing of cardiac wounds, pericardial drainage, and closing of the arterial channel. At that time, complications were related to myocardial depression [1,2]. In 1953, John Gibbon performed the first open heart surgery, making it possible

São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, SP, Brazil; Centro Universitário de Votuporanga (UNIFEV), Santa Casa Votuporanga, Votuporanga, SP, Brazil. 2 São José do Rio Preto Base Hospital. São José do Rio Preto, SP, Brazil. 3 Santa Casa Votuporanga, Votuporanga, SP, Brazil. 4 São José do Rio Preto Medical School (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

Work carried out at São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, SP, Brazil.

Article received on December 15th, 2013 Article accepted on May 26th, 2014

No financial support.

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In addition, the L-type calcium channel (dihydropyridine), which is activated when Em is between -20mV and -30mV, allows calcium to enter the cytosol[13], a phenomenon known as calcium window[5]. The Na+/Ca2+ exchanger is then activated on reverse mode, removing intracellular sodium and allowing Ca2+ influx. H+ ions (resulting from ischemia) leave the cell via Na+/H+ antiporter, contributing to even higher sodium influx (Figure 1)[5,10]. The Na+/K+ pump is inhibited by the increased concentration of extracellular potassium, acidosis, and hypothermia, allowing intracellular Na levels to continue elevated and, consequently, the Na+/Ca2+ exchanger to continue working on reverse mode. The elevated intracellular calcium causes myocyte contraction, without action potential being triggered and with energy consumption. Elevated sodium levels lead to cellular edema and cytolysis during reperfusion[5]. Thus, hyperkalemic cardioplegia can neither inhibit calcium influx in myocardial cells nor avoid its negative effects (Figure 1)[12,13].

Abbreviations, acronyms & symbols ATP Adenosine triphosphate CPB Cardiopulmonary bypass HTK Histidine-tryptophan-ketoglutarate Em Resting potential CPK Creatine phosphokinase

2. Myocardial protection: protective effects to delay irreversible cell injury caused by global ischemia as well as to limit the extent of the reperfusion injury; 3. Reversibility: immediate reversal of cardiac arrest with heart rate and force of contraction, allowing for early weaning from cardiopulmonary bypass (CPB); 4. Low toxicity: short half-life without toxic effects to other systems after termination of CPB; 5. Allowing good visualization of the operative field. In this context, the aim of this study is to discuss a few biochemical and physiological considerations related to hyperkalemic and hypocalcemic cardioplegia. Hyperkalemic Cardioplegia In 1955, Melrose et al.[6] introduced myocardial perfusion using hypothermic crystalloid solution containing 2.5% potassium citrate, but soon gave up employing this technique due to myocardial necrosis and death of several patients. Gay & Ebert[7] reintroduced this technique with lower concentrations of potassium and they were able to provide metabolic and functional benefits to the myocardium without any apparent structural change. Based on these results, the use of potassium-rich, hypothermic crystalloid solution for myocardial protection became widespread. In 1975, Hearse et al.[8] introduced the St. Thomas solution, containing 10-30 mM potassium chloride. With these solutions, stone heart was no longer a problem and solutions containing adequate concentrations of potassium to induce cardiac arrest became the gold standard in myocardial protection [9,10]. However, Cohen et al.[11] later found a correlation between the use of these solutions and postoperative myocardial dysfunction due to failure to fully protect the myocardium from ischemia and reperfusion injury, which led to the search for safer alternatives for patients.

Fig. 1 - Schematic of the metabolic pathways of hyperkalemic cardioplegia harmful to myocytes

Calcium physiology in cardiac fibers Calcium functions as an effector in cardiac fibers, connecting the ventricular contraction phase to the excitation phase through action potential. Such mechanism is known as excitation-contraction coupling[14] and it is also present in skeletal striated muscle cells; however, there are a few differences in cardiac fibers with important implications to their contraction[15]. Similar to skeletal muscle, when action potential travels through the myocardial membrane, it also propagates to the interior of cardiac muscle fibers along the t-tubule membranes. Action potential in t-tubules, in turn, cause the instant release of calcium ions from the sarcoplasmic reticulum

Metabolic pathways of hyperkalemic cardioplegia Elevated extracellular potassium concentration (1040mM) alters resting potential (Em) for myocyte, from -85mV to between -65mV and -40mV, leading to fast sodium channels inactivation. The new Em blocks conduction of myocardial action potential, thereby inducing depolarized arrest. However, slow sodium channels are not fully inactivated (sodium window), causing a slow increase in its intracellular concentration (Figure 1)[5,10,12].

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into the sarcoplasm. Then, in a few thousandths of a second, calcium ions diffuse into myofibrils and catalyze chemical reactions that promote sliding of actin and myosin filaments, which in turn produces muscle contraction. So far, the excitation-contraction coupling mechanism is the same as that of skeletal muscle; however, from this point on, a fundamental difference starts to emerge. Besides the calcium ions released into the sarcoplasm from the sarcoplasmic reticulum, great quantities of calcium are also diffused into the sarcoplasm during t-tubule action potential[15]. In fact, without the extra calcium in the t-tubules, cardiac muscle contraction strength would be considerably reduced since cardiac muscle cisternae are less developed than in skeletal muscle and thus are unable to store enough calcium to produce effective muscle contraction. On the other hand, cardiac muscle t-tubules have a diameter five times greater than that of skeletal t-tubules. Within cardiac t-tubules, there are large quantities of negatively charged mucopolysaccharides that bind and store calcium ions, making them always available to be diffused into cardiac muscle fiber when action potential occurs in the t-tubule. The extra supply of calcium from t-tubules is at least one of the factors that contribute to longer action potential in cardiac muscle and its contraction for 0.3 seconds as opposed to 0.1 second in skeletal muscle[15]. At the end of the action potential plateau, influx of calcium ions into muscle fibers is suddenly interrupted, and the calcium ions in the sarcoplasm are rapidly pumped back into the sarcoplasmic reticulum and t-tubules, thereby ending contraction until the next action potential[15]. Of particular interest is the fact that the strength of cardiac muscle contraction depends on the concentration of calcium ions in the extracellular fluids, which is usually not true of striated muscle. This is likely because the amount of calcium ions in t-tubules is directly proportional to its concentration in extracellular fluids. Therefore, the availability of calcium ions to cause cardiac contraction is directly dependent on the extracellular fluid calcium ion concentration[15].

Baker et al.[17], when comparing the effects of several concentrations of calcium in St. Thomas solution in immature rabbit hearts, found that the lower the concentration of calcium, the lower the concentration of creatine phosphokinase (CPK). However, they also found that recovery of aortic flow did not follow the same distribution. It showed parabolic behavior with its zenith at 0.3 mmol/L, when the heart obtained the highest aortic flow values. Comparing hypocalcemic and normocalcemic solutions in blood cardioplegia in immature pig hearts, with or without ischemia, under CPB, Bolling et al. [18] observed that the nonischemic group benefited from both types of cardioplegia. On the other hand, in the ischemic group, myocardial function and ATP levels worsened and coronary vascular resistance increased in those undergoing normocalcemic cardioplegia whereas for those undergoing hypocalcemia, values were the same as the ones for the nonischemic group, indicating that hypocalcemia protected the heart from ischemia. In assessing oxygen consumption in rat hearts subjected to hypocalcemic or hyperkalemic cardioplegia, Burkhoff et al.[19] ascertained that the hypocalcemic group consumed less oxygen compared to the group that used a potassium-rich solution. Kronon et al.[20] concluded that a cardioplegic solution containing physiological calcium concentration is deleterious to immature pig hearts, except when magnesium was added to the solution (10 mEq/L), which protected the myocardium from the deleterious effects of calcium. In another study, the same authors found that when magnesium (either 5-6 mEq/L or 10-12 mEq/L) was added to the hypocalcemic solution there was significant improvement in myocardial contraction and reduction in diastolic rigidity[21]. In a study of rabbit hearts subjected to cardioplegia solutions either with low calcium concentration (0.5 mmol/L) or without calcium, Mori et al.[22] reported that hearts subjected to the low calcium cardioplegic solution showed better recovery from left ventricular developed pressure (dP/dt) and coronary flow, lower CPK values, and less cellular edema. Robinson et al.[23], using lower concentrations of calcium in St. Thomas solution (0.6 mmol/L), found there was 64% improvement in recovery of aortic flow, 84% reduction in CPK as well as reduction in postischemic reperfusion arrhythmia and faster return to normal sinus rhythm when compared to the traditional solution. Zweng et al.[24] reported improved recovery of aortic flow, developed pressure, and dP/dt in immature rabbit hearts with calcium concentrations between 0.6 and 1.2 mmol/L, subjected to an hour of normothermic ischemia. Several authors have shown that cardioplegia without calcium is associated with worse recovery of cardiac function[22,24-26] and of coronary [22] and aortic[24] flow as well as increase in creatine phosphokinase[22,25] and cellular edema[22]. These changes are due to a phenomenon known as the â&#x20AC;&#x153;calci-

Hypocalcemic cardioplegia In the absence of extracellular calcium ions, there is no calcium influx, neither via cell membrane nor via sarcoplasmic reticulum, preventing myofilament contraction. Even if there is action potential, there is no myocardial contraction[5]. By investigating the effects of hypocalcemic cardioplegic solution in immature sheep hearts subjected to ischemia and hypothermia, Aoki et al.[16] noted that in the presence of physiological calcium concentration there was worsening of left ventricular and diastolic functions as well as increase in oxygen consumption and in coronary vascular resistance when compared to hypocalcemia, indicating that low levels of calcium protected the heart from the deleterious effects of hypothermia and ischemia.

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um paradox”, which does not happen when small quantities of calcium are added to the solution[14,27]. Bretschneider solution is an example of a hypocalcemic solution. In addition to traces of calcium, it also incorporates the benefits of histidine, tryptophan, ketoglutarate, and mannitol. Histidine (amino acid) acts as a temperature-dependent buffer system. When placed under 22oC, histidine keeps pH at 7.02-7.20 whereas when the temperature is 4oC, pH value is about 7.40. This means that the optimal temperature of the solution is 4oC, since it maintains physiological pH. This amino acid also inhibits matrix metalloproteinases, which are responsible for the development of tissue damage from cold storage. Furthermore, histidine regulates cell membrane permeability, enhancing the osmotic effect of mannitol[28]. Tryptophan contributes to maintaining the integrity of cell membranes[28]. Hachida et al.[29] reported that the absence of tryptophan in the solution caused significant decrease in maximum developed pressure and coronary blood flow. In addition, Hachida et al.[29] also assessed the absence of ketoglutarate in the solution, which led to significant decrease in maximum developed pressure and significant increase in creatine phosphokinase MB fraction.

REFERENCES 1. Rosky LP, Rodman T. Medical aspects of open-heart surgery. N Engl J Med. 1966;274(16):886-93. 2. Prates PR. Pequena história da cirurgia cardíaca: e tudo aconteceu diante de nossos olhos... Rev Bras Cir Cardiovasc. 1999;14(3):177-84. 3. Miller BJ, Gibbon JH, Jr., Greco VF, Smith BA, Cohn CH, Allbritten FF Jr. The production and repair of interatrial septal defects under direct vision with the assistance of an extracorporeal pump-oxygenator circuit. J Thorac Surg. 1953;26(6):598-616. 4. Godoy MF, Braile DM. Cardioplegia: exegesis. Arq Bras Cardiol. 1994;62(4):277-8. 5. Fallouh HB, Kentish JC, Chambers DJ. Targeting for cardioplegia: arresting agents and their safety. Curr Opin Pharmacol. 2009;9(2):220-6. 6. Melrose D, Dreyer B, Bentall H, Baker JB. Elective cardiac arrest. Lancet. 1955;266(6879):21-2. 7. Gay WA Jr, Ebert PA. Functional, metabolic, and morphologic effects of potassium-induced cardioplegia. Surgery. 1973;74(2):284-90.

CONCLUSION

8. Hearse DJ, Stewart DA, Braimbridge MV. Hypothermic arrest and potassium arrest: metabolic and myocardial protection during elective cardiac arrest. Circ Res. 1975;36(4):481-9.

Hypocalcemic cardioplegia provides safe protection of myocytes, both in immature and older hearts, since it prevents depletion of ATP and acidosis and it is associated with good recovery of ventricular function. Hypocalcemic cardioplegic solutions, such as histidine-tryptophan-ketoglutarate, have been commonly used in cardiac surgery worldwide, but it is still not the ideal solution. New studies are needed to find cardioplegia that is fast-acting and atoxic, metabolizes rapidly, promotes good visualization of the operative field, and adequately protects the myocyte.

9. Shiroishi MS. Myocardial protection: the rebirth of potassiumbased cardioplegia. Tex Heart Inst J. 1999;26(1):71-86. 10. Chambers DJ, Hearse DJ. Developments in cardioprotection: “polarized” arrest as an alternative to “depolarized” arrest. Ann Thorac Surg. 1999;68(5):1960-6. 11. Cohen NM, Damiano RJ Jr, Wechsler AS. Is there an alternative to potassium arrest? Ann Thorac Surg. 1995;60(3):858-63. 12. Silveira Filho LM, Petrucci O Jr, Carmo MR, Oliveira PP, Vilarinho KA, Vieira RW, et al. Padronização de modelo de coração isolado “working heart” com circulação parabiótica. Rev Bras Cir Cardiovasc. 2008;23(1):14-22. 13. Chen RH. The scientific basis for hypocalcemic cardioplegia and reperfusion in cardiac surgery. Ann Thorac Surg. 1996;62(3):910-4.

Authors’ roles & responsibilities MABO

ACB CAS PHHB JLLC DMB

14. Oliveira MAB, Godoy MF, Braile DM, Lima-Oliveira APM. Solução cardioplégica polarizante: estado da arte. Rev Bras Cir Cardiovasc. 2005;20(1):69-74.

Analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; conception and design of the study; carrying out of operations and/or experiments; drafting of the manuscript or critical review Drafting of the manuscript or critical review Drafting of the manuscript or critical review Drafting of the manuscript or critical review Drafting of the manuscript or critical review Final approval of the manuscript; conception and design of the study

15. Guyton AC. Músculo cardíaco; o coração como bomba. In: Guyton AC, ed. Fisiologia humana e mecanismos das doenças. 6 ed. Rio de Janeiro: Guanabara Koogan; 2008. p.130. 16. Aoki M, Nomura F, Kawata H, Mayer JE Jr. Effect of calcium and preischemic hypothermia on recovery of myocardial

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function after cardioplegic ischemia in neonatal lambs. J Thorac Cardiovasc Surg. 1993;105(2):207-12.

23. Robinson LA. Calcium in neonatal cardioplegia. Ann Thorac Surg. 1991;51(6):1043-4.

17. Baker EJ 5th, Olinger GN, Baker JE. Calcium content of St. Thomas’ II cardioplegic solution damages ischemic immature myocardium. Ann Thorac Surg. 1991;52(4):993-9.

24. Zweng TN, Iannettoni MD, Bove EL, Pridjian AK, Fox MH, Bolling SF, et al. The concentration of calcium in neonatal cardioplegia. Ann Thorac Surg. 1990;50(2):262-7.

18. Bolling K, Kronon M, Allen BS, Ramon S, Wang T, Hartz RS, et al. Myocardial protection in normal and hypoxically stressed neonatal hearts: the superiority of hypocalcemic versus normocalcemic blood cardioplegia. J Thorac Cardiovasc Surg. 1996;112(5):1193-200.

25. Hendriks FF, Jonas J, van der Laarse A, Huysmans HA, van RijkZwikker GL, Schipperheyn JJ. Cold ischemic arrest: comparison of calcium-free and calcium-containing solutions. Ann Thorac Surg. 1985;39(4):312-7. 26. Pearl JM, Laks H, Drinkwater DC, Meneshian A, Sun B, Gates RN, et al. Normocalcemic blood or crystalloid cardioplegia provides better neonatal myocardial protection than does low-calcium cardioplegia. J Thorac Cardiovasc Surg. 1993;105(2):201-6.

19. Burkhoff D, Kalil-Filho R, Gerstenblith G. Oxygen consumption is less in rat hearts arrested by low calcium than by high potassium at fixed flow. Am J Physiol. 1990;259(4 Pt 2):H1142-7. 20. Kronon M, Bolling KS, Allen BS, Rahman S, Wang T, Halldorsson A, et al. The relationship between calcium and magnesium in pediatric myocardial protection. J Thorac Cardiovasc Surg. 1997;114(6):1010-9.

27. 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.

21. Kronon MT, Allen BS, Hernan J, Halldorsson AO, Rahman S, Buckberg GD, et al. Superiority of magnesium cardioplegia in neonatal myocardial protection. Ann Thorac Surg. 1999;68(6):2285-91.

28. Antunović M, Aleksić D. Preparation and testing of solutions for organ perfusion and preservation in transplantation. Vojnosanit Pregl. 2008;65:596-600.

22. Mori F, Suzuki K, Noda H, Kato T, Tsuboi H, Miyamoto M, et al. Evaluation of a new calcium containing cardioplegic solution in the isolated rabbit heart in comparison to a calcium-free, low sodium solution. Jpn J Surg. 1991;21(2):192-200.

29. Hachida M, Ookado A, Nonoyama M, Koyanagi H. Effect of HTK solution for myocardial preservation. J Cardiovasc Surg (Torino). 1996;37(3):269-74.

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Sant'Anna RT, SPECIAL et al. - Direct intramyocardial transthoracic transplantation of ARTICLE bone marrow mononuclear cells for non-ischemic dilated cardiomyopathy: INTRACELL, a prospective randomized controlled trial

Direct intramyocardial transthoracic transplantation of bone marrow mononuclear cells for non-ischemic dilated cardiomyopathy: INTRACELL, a prospective randomized controlled trial Ensaio clínico prospectivo randomizado sobre terapia com células mononucleares da medula óssea para cardiomiopatia dilatada idiopática: INTRACELL

Roberto T. Sant’Anna1, MD; James Fracasso1, MD, MSc; Felipe H. Valle1, MD; Iran Castro1, MD, PhD; Nance B. Nardi1, PhD; João Ricardo M. Sant’Anna1, MD, PhD; Ivo Abrahão Nesralla1, MD; Renato A. K. Kalil1, MD, PhD

DOI 10.5935/1678-9741.20140091

RBCCV 44205-1573

Abstract Objective: We tested the hypothesis that direct intramyocardial injection of bone marrow mononuclear cells in patients with non-ischemic dilated cardiomyopathy can improve left ventricular function and physical capacity. Methods: Thirty non-ischemic dilated cardiomyopathy patients with left ventricular ejection fraction <35% were randomized at a 1:2 ratio into two groups, control and treated. The bone marrow mononuclear cells group received 1.06±108 bone marrow mononuclear cells through mini-thoracotomy. There was no intervention in the control group. Assessment was carried out through clinical evaluations as well as a 6-min walk test, nuclear magnectic resonance imaging and echocardiogram.

Results: The bone marrow mononuclear cells group showed a trend toward left ventricular ejection fraction improvement, with magnectic resonance imaging - at 3 months, showing an increase from 27.80±6.86% to 30.13±9.06% (P=0.08) and returning to baseline at 9 months (28.78%, P=0.77). Magnectic resonance imaging showed no changes in left ventricular ejection fraction during follow-up of the control group (28.00±4.32%, 27.42±7.41%, and 29.57±4.50%). Echocardiogram showed left ventricular ejection fraction improved in the bone marrow mononuclear cells group at 3 months, 25.09±3.98 to 30.94±9.16 (P=0.01), and one year, 30.07±7.25% (P=0.001). The control group showed no change (26.1±4.4 vs 26.5±4.7 and 30.2±7.39%, P=0.25 and 0.10, respectively). Bone marrow mononuclear cells group

Cardiology Institute/University Foundation of Cardiology (IC/FUC), Cardiovascular Surgery Service, Porto Alegre, RS, Brazil.

Correspondence address: Renato Abdala Karam Kalil Instituto de Cardiologia /Fundação Universitária de Cardiologia (IC/FUC). Avenida Princesa Isabel, 395 – Santana – Porto Alegre, RS Brazil – Zip Code: 90620-000 E-mail: kalil.pesquisa@gmail.com

This study was carried out at the Cardiology Institute/University Foundation of Cardiology (IC/FUC), Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil. Financial support from Brazilian government agencies CNPq, CAPES, Ministry of Health and FAPERGS.

Article received on February 20th, 2014 Article accepted on July 7th, 2014

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portadores de cardiomiopatia dilatada não-isquêmica pode melhorar a função ventricular e a capacidade física. Métodos: Trinta pacientes com cardiomiopatia dilatada não isquêmica e fração de ejeção 35% foram randomizados na razão 1:2 em grupos controle e tratado. Grupo células mononucleares de medula óssea recebeu 1,06 ± 108 células mononucleares de medula óssea por mini-toracotomia. Grupo controle não recebeu intervenção. Avaliação foi feita clinicamente e por teste de caminhada 6 minutos (T6m), ressonância magnética e ecocardiogramas. Resultados: Grupo células mononucleares de medula óssea mostrou tendência de melhora da Fração de ejeção - ressonância magnética aos 3 meses, 27,80±6,86% para 30,13±9,06% (P=0,08), retornando ao basal aos 9 meses (28,78%, P=0,77). Grupo controle não apresentou variação (28,00±4,32%; 27,42±7,41% e 29,57±4,50%). Ecocardiogramas - fração de ejeção melhorou no grupo células mononucleares de medula óssea aos 3 meses: 25,09±3,98 para 30,94±9,16 (P=0,01) e aos 12 meses (30,07±7,25%, P=0,001), enquanto o controle não variou: 26,1±4,4 vs. 26,5±4,7 e 30,2±7,39%, P=0,25 e 0,10, respectivamente). Células mononucleares de medula óssea melhorou classe funcional New York Heart Association: 3,40±0.50 para 2,41±0,79 (P=0,002); controles não mudaram (3,37±0,51 para 2,71±0,95; P=0,17). T6m melhorou no grupo células mononucleares de medula óssea (348,00±93,51 m inicial para 370,41±91,56 m aos 12 m, P=0,66) e declinou sem significância no controle (361,25±90,78 m para 330,00±123,42 m aos 12 meses, P=0,66). Não houve diferenças significativas entre os grupos. Conclusão: A tendência intragrupo de melhora funcional e subjetiva não se confirmou quando comparado com controle. Portanto, a injeção direta intramiocárdica de células mononucleares de medula óssea não se associou a mudança significativa na função ventricular. As diferenças observadas no grupo tratado poderiam ser devidas a efeito placebo ou a baixo poder estatístico.

Abbreviations, acronyms & symbols BMMC Bone marrow mononuclear cells DCM Dilated cardiomyopathy LVEF Left ventricular ejection fraction MLHF Minnesota Living with Heart Failure MRI Magnetic resonance cardiac imaging NIDCM Non-ischemic dilated cardiomyopathy NYHA New York Heart Association PO Post-operatively

showed improvement in New York Heart Association functional class, from 3.40±0.50 to 2.41±0.79 (P=0.002); patients in the control group showed no change (3.37±0.51 to 2.71±0.95; P=0.17). Six-minute walk test improved in the bone marrow mononuclear cells group (348.00±93.51m at baseline to 370.41±91.56m at 12 months, P=0.66) and there was a non-significant decline in the control group (361.25±90.78m to 330.00±123.42m after 12 months, P=0.66). Group comparisons were non-significant. Conclusion: The trend of intragroup functional and subjective improvement was not confirmed when compared to the control group. Direct intramyocardial application of bone marrow mononuclear cells in non-ischemic dilated cardiomyopathy was not associated with significant changes in left ventricular function. Differences observed within the bone marrow mononuclear cells group could be due to placebo effect or low statistical power. Descriptors: Cardiomyopathy, Dilated. Heart Failure. Cells. Myocardial Contraction. Transplantation. Resumo Objetivo: Testamos a hipótese de que a injeção intramiocárdica direta de células mononucleares de medula óssea em pacientes

Descritores: Cardiomiopatia dilatada. Insuficiência Cardíaca. Células. Contração Miocárdica. Transplante.

INTRODUCTION

tracoronary route, showed small, but significant increase in left ventricular ejection fraction (LVEF) after treatment[5,6]. Recently, intracoronary injection of CD34+ was associated with medium-term improvement of ventricular function, exercise tolerance, and long-term survival in randomized trial of patients with DCM[7]. Intracoronary injection is associated with a small percentage of transplanted cells effectively retained in the myocardium, which could limit results when that route is used for cell therapy[10]. In a pilot study, we found that direct application of BMMC through a small thoracotomy was safe and associated with a significant, although transitory, increase in LVEF in patients with non-ischemic dilated cardiomyopathy (NIDCM) [11] . In the present study, we tested the hypothesis that direct intramyocardial injection of BMMC in patients with NIDCM could improve LVEF assessed by cardiac magnetic resonance imaging (MRI) and echocardiogram, physical capacity evaluated by the six-minute walk test (6WT), and heart failure class functional (NYHA), when compared to conventional treatment.

Dilated cardiomyopathy is a leading cause of heart failure and the primary indication for heart transplantation[1,2]. The prevalence of this disease tends to increase according to population ageing and survival improvement achieved through advances in pharmacological treatment and implantable devices[3]. However, current therapeutic approaches are palliative in the sense that they are unable to directly address the underlying problem of the loss of cardiac tissue[4]. Cell therapy with bone marrow mononuclear cells (BMMC) has been associated with beneficial effects in patients with acute myocardial infarction and ischemic heart failure. Data for non-ischemic dilated cardiomyopathy (NIDCM), however, is more limited[5-7]. Experimental studies suggest that stem cells improve heart function through both paracrine regulation of cytokines production and cell transdifferentiation, albeit in a small proportion of the transplanted cells[8,9]. Two small trials, using BMMC through in-

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METHODS

opathy for at least 12 months before enrollment; (3) Coronary angiography with normal coronary arteries, which defined cardiomyopathy as non-ischemic for the purposes of this trial; (4) negative serology for Chagas Disease; and (5) Absence of other significant systemic disease limiting midterm prognosis. We excluded patients with: (1) Documented episodes of ventricular tachycardia; (2) Moderate to severe mitral regurgitation or any other significant valve disease; (3) History of myocardial infarction; and (4) Previous cardiac surgery.

Study design We conducted an open, parallel-group, explanatory randomized study in a single center to evaluate the safety and efficacy of BMMC in patients NIDCM. Thirty patients that fulfilled the criteria for inclusion were randomly assigned to each of the groups by means of a computer software for simple randomization: BMMC or control, in a 2:1 proportion. After randomization, functional status of both groups was assessed at baseline using (6WT), New York Heart Association (NYHA) and Minnesota Living with Heart Failure (MLHF) questionnaires, which had been previously validated for the Brazilian population[12]. We used cardiac magnetic resonance imaging (MRI) to measure left ventricular diameters and ejection fraction. Functional status was reassessed every three months and MRI repeated three and nine months after inclusion. All patients were treated by the same physician at a dedicated outpatient clinic, according to ACC/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults[1]. Functional status was evaluated by a separate team. In this article, we present the results of the first year of follow-up. We were unable to perform a blind study because of the invasive nature of the procedure proposed. The study was submitted to the National Comission in Research (CONEP) and approved. All patients signed an informed consent. Patients in the BMMC group, in addition to conventional treatment, were submitted to BMMC transplantation as described below up to one month after randomization. In this group, we also conducted flow citometry and imunohistochemistry to characterize bone marrow cells. Our primary objective was to evaluate changes in left ventricular ejection fraction assessed with MRI. Secondary objectives consisted of evaluation of: 1) Safety; 2) New York Heart Association (NYHA) functional class and quality of life measured with Minnesota Living with Heart Failure Questionnaire; 3) Effects in mortality; 4) Left ventricular diameters using MRI.

Bone marrow mononuclear cells isolation and transplantation Approximately four hours before the operation and with the patient under sedation, a volume of about 80 mL of bone marrow was aspirated from the anterior iliac crest and placed in an anticoagulated medium. Mononuclear cell fraction was separated by density centrifugation over Ficoll-Hypaque-1077 (Sigma Diagnostics, St Louis, MO) and washed in a heparinized saline solution containing 5% autologous serum. Cells were counted and suspended in 5 mL saline solution for intramyocardial injection. A small fraction was utilized for sterility and viability tests and for immunophenotyping. Viability greater than 90% was considered acceptable. For detection of surface antigens the cells were trypsinized, centrifuged, and incubated for 30 minutes at 4°C with phycoerythrin (PE)- or fluorescein isothiocyanate (FITC)-conjugated antibodies against human CD3, CD4, CD14, CD34, CD38 and CD45 (Pharmingen BD, San Diego, CA). Excess antibody was removed by washing. The cells were analyzed using a FACScalibur cytometer equipped with 488 nm argon laser (Becton Dickinson, San Diego, CA) with the CellQuest software. At least 10,000 events were collected. WinMDI 2.8 software was used for building histograms. Surgical approach was through a left mini-thoracotomy, consisting of an approximately 5 cm incision in the anterolateral portion of the fifth left intercostal space to expose the pericardium. A T-shaped pericardial incision was made to access the free wall of the left ventricle. Coronary arteries were identified and the cell suspension was directly injected, using a 21F Butterfly needle that was introduced about 5mm intramyocardially and connected to an extension managed by the surgical assistant. Twenty 0.25 mL injections were given in the myocardium and in the anterior, lateral, posterior, and apical faces of the left ventricular free wall. After reviewing the hemostasis, pericardium was approximated, the thoracic cavity was drained and the chest wall closed.

Inclusion and exclusion criteria The study was approved by the Ethics Review Board of Instituto de Cardiologia do Rio Grande do Sul/ Fundação Universitária de Cardiologia (IC/FUC), as well as by the National Ethics Committee in Research of Brazil, under protocol number 10376 and registered in ClinicalTrials.gov under number: NCT00743639. Both the study and the registry were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient. We screened for patients with heart failure, LVEF less then 35% and functional class III or IV, despite full medical treatment. Specific inclusion criteria were: (1) Age between 20 and 65 years; (2) Diagnosis of non-ischemic cardiomy-

Echocardiogram Two-dimensional echocardiograms were obtained for measuring end-systolic volume (ESV), end-diastolic volume (EDV), and LVEF, according to standard protocols. All exams were performed by the same person, who was unaware of the

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treatment group and was not part of the study team. It should be noted, however, that treated patients had a visible scar in the left chest, which made it impossible to guarantee blindness to the echo examinator.

Cells from the first five samples were analyzed in greater detail. Immunophenotyping of the mononuclear cell fraction showed the following composition: CD34+ cells (1.5±0.7%), CD45+ (74.6±8.5%), CD14+ (8.4±4.7%), CD3+CD4+ (22.8±4.6%), CD3+CD8+ (8.2±6.1%), and CD34+CD38cells (0.7±0.5%).

Magnetic Resonance Imaging All MRI image analyses were performed by the same investigator, which was blind to the assignment of the patient. We used a 1.5-T scanner (GE Excite HDx) with ECG gating and a 4-element phased-array surface coil. Scan planes were planned according to standard procedures. Endocardial and epicardial borders were traced in all end-diastolic and end-systolic short-axis slices to determine LV end-diastolic and end-systolic volumes (LVEDV and LVESV). Global LVEF was calculated [(LVEDV-LVESV)/LVEDV]/100 LVEDV. Systolic ventricular wall thickening was calculated for different heart segments and it was used for an already published sub-study[11].

Procedural safety and clinical outcomes Surgical procedure was effectively performed in 19 patients, since one patient asked to be withdrawn soon after randomization. Table 2 summarizes surgical results. Four subjects died in the first month after the procedure. Two died of refractory cardiogenic shock in the first 72 hours post-operatively (PO). One of them presented with cardiac tamponade 7 hours after surgery and was submitted to reoperation. The patient's hemodynamic condition continued to deteriorate and he died due to cardiogenic shock 3 days PO. Another patient died on the 15th day PO due to incessant ventricular tachycardia. Finally, one patient died on the 28th day PO: he had been discharged from hospital, but was readmitted one week later due to heart failure, which was refractory to treatment. All of the patients above had LVEF below 21% before operation.

Statistical analysis Continuous variables are presented as mean±SD, if not stated otherwise. Categorical variables were compared with the x2 test or Fisher’s exact test. Statistical comparisons between initial and follow-up data were performed in a nonparametric paired fashion using the Wilcoxon signed rank test. Nonparametric Mann–Whitney U and Kruskal–Wallis tests were used to compare continuous and categorical variable, as well as the results between different groups. All tests were performed as 2-sided tests at a significance level of 0.05. In the first three months of follow-up, 25% of the patients from the BMMC group had either died or been withdrawn from the study, resulting in a decrease in the number of treated cases available for late follow-up. Since those patients had a lower mean ejection fraction than the whole group (18.26 % vs. 21.75%), we excluded them from comparative analysis, in order to avoid overestimation of treatment effect. In other words, outcome analysis was performed in as-treated basis, not as intention-to-treat.

Table 1. Baseline patients characteristics.

Male Age NYHA class Minnesota QOL score (Minnesota) Six minute walk test (min) LVEF by ECHO (%) Final diastolic diameter, ECHO (mm) LVEF by MRI (%) Nº of injected cells

RESULTS

BMMC group (n=20) 13 (65%) 48.3 (8.71) 3.5 (0.52) 66.2 (22.46)

Control group (n=10) 5 (50%) 51.6 (7.79) 3.35 (0.48) 50.6 (14.84)

358.5 (88.69) 21.75 (41.19) 73.4 (8.18)

353 (86.67) 24.76 (4.64) 70.3 (7.4)

27.80±6.86 1.06 x 108

28.00±4.32 none

Data expressed as mean (% or SD); LVEF by ECHO=left ventricular ejection fraction by echocardiogram; MRI=nuclear magnetic resonance imaging; QOL=quality of life by Minnesota Living with Heart Failure Questionnaire. There were no statistically significant differences between baseline groups characteristics

Baseline Baseline characteristics are detailed in Table 1. There were no significant differences in baseline data between BMMC and control groups. All patients had severe heart failure and were highly symptomatic by the time of inclusion, despite maximum medical therapy.

Table 2. Surgical results.

Cell analysis A mean of 1.06±0.43 x 108 mononuclear cells per patient were available for injection using this method. Cell viability was greater than 99%, and fungal and bacterial cultures were negative.

Surgery Thoracotomy procedure (min) Post-operative, % Length of ICU Stay (days) Length of hospital stay (days)

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Mean ±DP 84.7±29

Max value 120

1.86±1.3 4.50±2.0

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Three patients from the BMMC group died between 30 days and 12 months after surgery. In two patients, death was sudden, at 10 and 11 months PO. Another patient died 6 months PO due to heart failure. In the control group, one patient died three months after randomization due to heart failure and another patient was lost for follow-up two months after randomization. There was no statistically significant difference in safety outcomes between BMMC and control groups: Fischer´s test showed no difference in mortality between groups in the first 30 days (P=0.371) or up to 12 months (P=1.000).

cedure, from 25.09±3.98 to 30.94±9.16 (P=0.01). This benefit was maintained after one year of follow-up (30.07±7.25, P=0.001). The control group has showed no change in the same period (26.1±4.4 vs. 26.5±4.7 and 30.2±7.39, P=0.25 and 0.10, respectively). Differences between treated and control groups, however, were not statistically significant. Left ventricular fractional shortening evaluation showed similar results. End-systolic and end-diastolic diameters had a small reduction in both groups. (Figure 1, Table 4). Quality of life and 6-minute walk test Quality of life, evaluated by MLHFQ (Minnesota Living with Heart Failure Questionnaire), improved significantly in the BMMC group three months after the procedure (69.00±20.71 vs. 43.13±27.92 points, P=0.005), a benefit maintained during 6 and 12 months of follow-up (48.92±24.26 points, P=0.018; 37.08±21.15 points, P=0.001; respectively). Patients of the control group showed a non-significant improvement, with smaller differences between baseline and 12 months follow-up (minus 31.92 points for BMMC group and minus 7.16 points for Control group). Differences between groups were not statistically significant. Functional class, evaluated using NYHA Classification, showed similar results with a statistically significant improvement in the BMMC group, no change in the control group. However, once again, there were no statistically significant differences between groups. (Figure 2, Table 5).

Effects of BMMC on LV Function MRI evaluations Patients of the BMMC group maintained LVEF at 3 months, from 27.80±6.86% to 30.13±9.06% (P=0.08), and at 9 months (28.78%, P=0.77). The control group also maintained systolic function during follow-up (28±4.32% vs. 27.4±7.4%, at 3 months, P=0.79, and vs. 29.57±4.50 at 9 months, P=0.46, respectively). Differences between groups were non-significant. Both groups maintained end-systolic and end-diastolic volumes during follow-up. (Table 3). Echocardiographic evaluations Patients of the BMMC group had a significant improvement in left ventricular ejection fraction 3 months after the pro-

Table 3. Left ventricular volumes and function as assessed by Magnetic Resonance Imaging (MRI). Parameter Ejection Fraction, % Baseline 3 months Change from baseline P value comparing to baseline 9 months Change from baseline P value comparing to baseline End-diastolic volume, mL Baseline 3 months Change from baseline P value comparing to baseline 9 months Change from baseline P value comparing to baseline End-systolic volume, mL Baseline 3 months Change from baseline P value comparing to baseline 9 months Change from baseline P value comparing to baseline

BMMC group (n = 15)

Control group (n=9)

27.80±6.86 30.13±9.06 2.33 0.08 28.78±9.97 0.98 0.77

28.00±4.32 27.42±7.41 -0.58 0.79 29.57±4.50 +1.57 0.46

NS NS

272.73±63.41 264.86±72.24 -7.87 0.41 258.64±82.97 -14.09 0.54

250.85±67.00 222.42±96.19 -28.43 0.32 258.85±75.55 +8.00 0.71

NS NS

200.40±61.59 195.93±78.49 -4.47 0.66 190.00±82.18 -10.40 0.73

182.00±55.70 161.67±67.83 - 20.43 0.18 184.14±58.55 2.14 0.91

NS NS

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Fig.1 - A) Left ventricular ejection fraction and B) end-systolic diameter by echocardiography at baseline and during follow-up

Six-minute-walk test results were maintained in the BMMC group (from 348.00±93.51min in baseline to 370.41±91.56 min after 12 months, P=0.66) and in control group (from 361.25±90.78 min in baseline to 330.00±123.42 min after 12 months, P=0.66). Again, differences between groups were not statistically significant. (Table 5).

more pronounced in the BMMC group, but there was no statistical difference between groups in the outcomes studied. The seven deaths (35%) observed in patients who received BMMC were due to pump-failure in the early post-operative period (2 cases; 28.5%), congestive heart failure (2 cases, 28.5%) and documented ventricular arrhythmia or sudden death (3 cases, 42.8%). Using the Seattle Heart Failure Model, a tool with excellent accuracy for predicting survival among patients with heart failure[13], we could anticipate one-year mortality between 20% and 25%. Incidence of death attributable to arrhythmia (42,8%) was higher than expected for patients in NYHA functional class III (10.5%) or IV (18.6%) at one year[14]. This higher than expected risk of ventricular tachyarrhythmia after surgery could be related to the intrinsic high risk of any procedure in patients with severe heart failure or to a more specific mechanism secondary to BMMC injection. Stem cell pro-arrhythmic potential is a matter of intense debate[15,16]. Clinically, bone marrow progenitor cells were not associated with increased risk of arrhythmias using different routes of delivery in different clinical scenarios[17-19]. Yet, experimental studies have shown that mesenchymal stem cells (MSCs) implantation altered cardiac conduction[20] and created areas of slow conduction, predisposing it to reentry

DISCUSSION In this study, we tested the hypothesis that transplantation of BMMC through a small thoracotomy could improve left ventricular function in patients with refractory heart failure due to NIDCM. Our main findings were: (1) Mortality associated with the procedure was directly related to preoperative disease severity. In particular, patients with LVEF below 21% had a poor surgical result. Early deaths were related to postoperative pump-failure and congestive heart failure, while deaths at medium term were sudden, probably caused by cardiac arrhythmias. These results differ from our previous pilot study, in which there had been no deaths[11]. (2) Survivors treated with BMMC maintained left ventricular function relative to baseline according to MRI. (3) Overall, patients had symptomatic improvement during follow-up, which was

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Table 4. Left ventricular volumes and function as assessed by echocardiography (ECO). Parameter Ejection Fraction, % Baseline 3 months Change from baseline P value comparing to baseline 6 months Change from baseline P value comparing to baseline 12 months Change from baseline P value comparing to baseline End-diastolic diameter, mm Baseline 3 months Change from baseline P value comparing to baseline 6 months Change from baseline P value comparing to baseline 12 months Change from baseline P value comparing to baseline End-systolic diameter, mm Baseline 3 months Change from baseline P value comparing to baseline 6 months Change from baseline P value comparing to baseline 12 months Change from baseline P value comparing to baseline

BMMC group (n = 15)

Control group (n=9)

25.09±3.98 28.11±7.22 3.02 0.06 30.94±9.16 5.85 0.01 30.07±7.25 4.98 0.01

26.10 ± 4.49 26.525 ± 4.71 0.425 0.628 28.51 ± 6.98 2.41 0.250 30.23±7.39 4.13 0.100

NS NS

69.80±4.41 68.33±6.38 -1.47 0.18 68.28±6.48 -1.52 0.27 68.66±7.35 -1.14 0.49

69.375±7.81 68.62±8.39 0.75 0.170 69.85±9.66 0.479 0.98 68.28±8.47 -1.09 0.612

NS NS

61.46±4.65 60.33±7.64 -1.13 0.47 58.14±8.12 -3.32 0.08 58.83±8.50 -2.63 0.17

60.75±7.86 60.00±8.28 -0.75 0.28 60.42±9.98 -0.33 0.63 58.42±9.10 -2.33 0.42

NS NS

episodes[21,22]. Intramyocardial injections can create clusters of cells leading to heterogeneity in conduction and have been associated with greater risk of ventricular premature complexes than intracoronary injection[23]. How this translates into clinical practice, where patients are treated with anti-arrhythmic drugs, needs to be further clarified. At this point, however, we cannot dismiss the possibility of a pro-arrhythmic effect related the newly implanted cells. BMMC treated patients who survived for more than one month after the procedure showed significant improvements in both symptoms and quality of life. Left ventricular ejection fraction was maintained one year after the procedure (P=0.77). Results with echocardiography are more pronounced as they showed improvement in LVEF of patients treated with BMMC after 6 months (from 25.09±3.98 to 30.94±9.16, P=0.01). Nevertheless, since operators were not blind for patients' group, results from this method should be interpreted with caution.

NS NS

Clinical experience with mononuclear cells in patients with DCM is limited. Fischer-Rasokat et al performed infusion of BMMC in 33 patients with DCM using an over-thewire balloon catheter in the left descending coronary artery[8]. After 3 months, regional wall motion of the target area and global left ventricular ejection fraction had a small (about 10%) but statistically significant improvement. Increase of regional contractile function was directly related to the functionality of infused cells as measured by their colony-forming capacity. Safety data was remarkably good, with no procedure related complications and no deaths, stroke or myocardial infarction up to one year follow-up. Compared to our study, patients were less symptomatic (67% in NYHA class II) and had better ventricular function (mean LEVF=0.2%). Vrtovec et al.[7] conducted a study with 110 patients with NIDCM, which were randomized to receive CD34+ stem cell transplantation and 55 received no cell therapy. Patients underwent myocardial scintigraphy and cells were injected

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Fig. 2 - A) Quality-of-Life score (Minnesota), B) Six-minute walk test and C) NYHA Functional class at baseline and during follow-up

in the artery supplying segments with the greatest perfusion defect. At 5 years, stem cell therapy was associated with increased LVEF (from 24.3±6.5% to 30.0±5.1%; P=0.02), increased 6-minute walk distance (from 344±90 m to 477± 30 m; P<0.001), and decreased N-terminal B-type natriuretic peptide (from 2322±1234 pg/mL to 1011±893 pg/mL; P<0.01). Left ventricular ejection fraction improvement was more significant in patients with higher myocardial homing of injected cells. Total mortality was lower in patients treated with CD 34+ cells (14% vs. 35%; P=0.01) and the procedure was considered safe, with low morbimortality.

Several limitations of our study are recognized. First: the trial was projected with a small sample that was further reduced due to early mortality. This drawback was unexpected, since we had no early major complications or mortality in a previous safety study[11]. High mortality could be attributed to very low LVEF, which expressed extremely deteriorated LV function in those patients who died early. There was no low LVEF limitation for patient inclusion in the trial: all patients with LVEF<35% were candidates. Perhaps we could have avoided including patients with very low LVEF (for example, LVEF<25%) or, alternatively, once they were included, we

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Table 5. Minnesota Living with Heart Failure Questionnaire, New York Heart Association Functional Class and 6-Minutes-Walk Test results. Parameter Minnesota LHFQ Baseline 3 months Change from baseline P value comparing to baseline 6 months Change from baseline P value comparing to baseline 12 months Change from baseline P value comparing to baseline 6-minutes-walk test Baseline 3 months Change from baseline P value comparing to baseline 6 months Change from baseline P value comparing to baseline 12 months Change from baseline P value comparing to baseline NYHA Baseline 3 months Change from baseline P value comparing to baseline 6 months Change from baseline P value comparing to baseline 12 months Change from baseline P value comparing to baseline

BMMC group (n = 15)

Control group (n=9)

69.00±20.71 43.13±27.92 -25.87 0.005 48.92±24.26 -20.08 0.018 37.08±21.15 -31.92 0.001

48.87±16.32 54.37±23.71 +5.50 0.57 40.28±23.59 -8.58 0.31 41.71±27.46 -7.16 0.48

NS NS

348.00±93.51 338.66±116.48 -9.34 0.73 355.35±67.77 7.35 0.81 370.41±91.56 22.41 0.66

361.25±90.78 336.25±114.38 - 25 0.44 365.00±126.45 3.75 0.98 330.00±123.42 -31.25 0.39

NS NS

3.40±0.50 2.60±0.82 -0.8 0.005 2.50±0.75 -0.9 0.005 2.41±0.79 -0.99 0.002

3.37±0.51 3.00±0.75 - 0.37 0.19 2.57±0.78 -0.8 0.04 2.71±0.95 - 0.66 0.17

NS NS

could have employed special measures of support during and after treatment. Besides, since observed increments in contractility reported on several studies with cell therapy are small (in the range of 5 to 10%), the clinical impact of a small increase in heart function in a very ill population may be negligible. Due to these reasons, we can conclude that, in further studies, patients with LVEF<25% should be avoided. Secondly, we opted to analyze data by protocol instead of intention to treat, since patients who died had lower LVEF and maintaining their baseline data would have overestimated treatment effect. Thirdly, this was a non-blinded trial: it is possible that differences observed in quality of life and functional class could be due to placebo effect. Results from the 6-minute walk test would have been useful to assess more objectively functional capacity, but they were highly variable among patients, creat-

NS NS

ing high values of standard deviation that precluded an appropriate analysis. Finally, high dispersion of data, from a wide range of parameters, such as LVEF and LV diameters, resulted in increased standard deviations in most outcome parameters, which in this small sample could have also precluded achievement of statistically significant differences between groups. In conclusion, besides intragroup improvement in echocardiographic data, quality of life and NYHA class, when compared to control direct intramyocardial application of BMMC in NIDCM was not associated with sustained significant changes in left ventricular function. Functional capacity did not differ between groups. In future studies, less invasive forms of cell transplantation should be evaluated considering the high mortality observed, particularly for patients with severely impaired LVEF.

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5. Seth S, Bhargava B, Narang R, Ray R, Mohanty S, Gulati G, et al. The ABCD Autologous Bone Marrow Cells in Dilated Cardiomyopathy) trial a long-term follow-up study. J Am Coll Cardiol. 2010;55(15):1643-4.

Authors’ roles & responsibilities RTSA

JF FHV

IC NBN JRMSA IAN RAKK

Analysis and/or interpretation of data, statistical analysis, final approval of the manuscript, conception and design of the study, realization of operations and/or experiments, drafting of the manuscript and critical review of the content Analysis and/or interpretation of data, realization of operations and/or experiments Analysis and/or interpretation of data, statistical analysis, final approval of the manuscript conception and design of the study, realization of operations and/or experiments, Drafting of the manuscript and critical review of the content Analysis and/or interpretation of data, realization of operations and/or experiments Analysis and/or interpretation of data, statistical analysis, final approval of the manuscript, realization of operations and/or experiments Analysis and/or interpretation of data, realization of operations and/or experiments Analysis and/or interpretation of data, final approval of the manuscript conception and design of the study, realization of operations and/or experiments Analysis and/or interpretation of data, statistical analysis, final approval of the manuscript conception and design of the study, realization of operations and/or experiments, drafting of the manuscript and critical review of the content

6. Fischer-Rasokat U, Assmus B, Seeger FH, Honold J, Leistner D, Fichtlscherer S, et al. A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circ Heart Fail. 2009;2(5):417-23. 7. Vrtovec B, Poglajen G, Lezaic L, Sever M, Domanovic D, Cernelc P, et al. Effects of intracoronary CD34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year followup. Circ Res. 2013;112(1):165-73. 8. Ishida M, Tomita S, Nakatani T, Fukuhara S, Hamamoto M, Nagaya N, et al. Bone marrow mononuclear cell transplantation had beneficial effects on doxorubicin-induced cardiomyopathy. J Heart Lung Transplant. 2004;23(4):436-45. 9. Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, et al. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation. 2005;112(8):1128-35. 10. Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, et al. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation. 2005;111(17):2198-202.

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2. Manolio TA, Baughman KL, Rodeheffer R, Pearson TA, Bristow JD, Michels VV, et al. Prevalence and etiology of idiopathic dilated cardiomyopathy (summary of a National Heart, Lung, and Blood Institute workshop. Am J Cardiol. 1992;69(17):1458-66.

13. Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD, Cropp AB, et al. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation. 2006;113(11):1424-33.

3. Kubo T, Matsumura Y, Kitaoka H, Okawa M, Hirota T, Hamada T, et al. Improvement in prognosis of dilated cardiomyopathy in the elderly over the past 20 years. J Cardiol. 2008;52(2):111-7.

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4. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics–2009 update: a report from the American Heart Association statistics committee and stroke statistics subcommittee. Circulation. 2009;119(3):e21-181.

15. Ly HQ, Nattel S. Stem cells are not proarrhythmic: letting the genie out of the bottle. Circulation. 2009;119(13):1824-31. 16. Macia E, Boyden PA. Stem cell therapy is proarrhythmic. Circulation. 2009;119(13):1814-23.

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17. Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, Hornung CA, et al. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007;167(10):989-97.

21. Beeres SL, Atsma DE, van der Laarse A, Pijnappels DA, van Tuyn J, Fibbe WE, et al. Human adult bone marrow mesenchymal stem cells repair experimental conduction block in rat cardiomyocyte cultures. J Am Coll Cardiol. 2005;46(10):1943-52.

18. van Ramshorst J, Bax JJ, Beeres SL, Dibbets-Schneider P, Roes SD, Stokkel MP, et al. Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial. JAMA 2009;301(19):1997-2004.

22. Pijnappels DA, Schalij MJ, van Tuyn J, Ypey DL, de Vries AA, van der Wall EE, et al. Progressive increase in conduction velocity across human mesenchymal stem cells is mediated by enhanced electrical coupling. Cardiovasc Res. 2006;72(2):282-91.

19. Zhao Q, Sun Y, Xia L, Chen A, Wang Z. Randomized study of mononuclear bone marrow cell transplantation in patients with coronary surgery. Ann Thorac Surg. 2008;86(6):1833-40.

23. Fukushima S, Varela-Carver A, Coppen SR, Yamahara K, Felkin LE, Lee J, et al. Direct intramyocardial but not intracoronary injection of bone marrow cells induces ventricular arrhythmias in a rat chronic ischemic heart failure model. Circulation. 2007;115(17):2254-61.

20. Chang MG, Tung L, Sekar RB, Chang CY, Cysyk J, Dong P, et al. Proarrhythmic potential of mesenchymal stem cell transplantation revealed in an in vitro coculture model. Circulation. 2006;113(15):1832-41.

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Barros TLV, et SPECIAL al. - Congenital cardiac disease in childhood x socioeconomic ARTICLE conditions: a relationship to be considered in public health?

Congenital cardiac disease in childhood x socioeconomic conditions: a relationship to be considered in public health? Cardiopatia congênita na infância x condições socioeconômicas: uma relação a ser considerada na saúde pública?

Thayanny Lopes do Vale Barros1; Marly de Jesus Sá Dias2, PhD; Rachel Vilela de Abreu Haickel Nina2, MD, MsC, PhD

DOI: 10.5935/1678-9741.20140042

RBCCV 44205-1574

Abstract Introduction: Congenital heart defects, cardiac malformations that occur in the embryonic period, constitute a serious health problem. They cover a proportion of 8-10 per 1000 live births and contribute to infant mortality. Objective: To identify the socioeconomic status of children undergoing cardiac surgery at the Hospital Universitário da Universidade Federal do Maranhão, in São Luis, the existence of material elements that contribute to worsening conditions. Methods: We conducted a retrospective study with a quantitative approach, descriptive and reflective, from the interviews conducted by the Social Service Social with families of children with heart disease from January 2011 to July 2012. Results: A total of 95 interviews, the results reveal that (75.79%) of children have elements that suggest poor socioeconomic conditions. It also shows that only 66.33% lived in brick house, while (31.73%) in mud, adobe and straw houses. With regard to income, it showed that only 4.08% received 1-2 minimum wages, while the remaining (95.9%) with benchmarks oscillating half the minimum wage (27.55%), ¼ of the minimum wage and

(24.48%) and income below 70 dollars per person, featuring extreme poverty. On the social security situation prevailing at children with no ties to 61.22%. With respect to benefits, we found that only (12.24%) of children were in the enjoyment of the Continuous Cash Benefit – CCB. Conclusion: Poor socioeconomic conditions listed as major obstacles in meeting the needs, resulting in the maintenance of health conditions and even allowing the aggravation of an existing pathology.

Hospital Universitário da Universidade Federal do Maranhão (HUUFMA), São Luís, MA, Brazil. 2 Universidade Federal do Maranhão (UFMA), São Luís, MA, Brazil.

Correspondence address: Thayanny Lopes do Vale Barros Hospital Universitário da Universidade Federal do Maranhão (HUUFMA) Rua Barão de Itapary, n° 227 - Centro - São Luís, MA, Brazil Zip code: 65020-070

Descriptors: Child. Socioeconomic Factors. Heart Diseases. Resumo Introdução: As cardiopatias congênitas, são malformações cardíacas que ocorrem no período embrionário e configuram um sério problema de saúde. Incidem numa proporção de 8 a 10 em cada 1000 crianças nascidas vivas e contribuem para mortalidade infantil. Objetivo: Identificar na situação socioeconômica das crianças submetidas à cirurgia cardíaca no Hospital Universitário em São

This study was carried out at Hospital Universitário da Universidade Federal do Maranhão (HUUFMA), São Luís, MA, Brazil.

Article received on October16th, 2013 Article accepted on February 25th, 2014

No financial support.

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Resultados: De um total de 95 entrevistas, os resultados revelaram que pelo menos 75,79% das crianças apresentaram elementos que sugerem condições socioeconômicas precárias. Evidenciaram que somente 66,33% viviam em casa de tijolo, enquanto 31,73%, em casas de taipa, adobe e palha. No que concerne à renda, foi constatado que apenas 4,08% das famílias recebiam de 1 a 2 salários mínimos, enquanto os demais 95,9% possuíam aferimentos oscilantes de 1/2 salário mínimo; 27,55% de ¼ do salário mínimo e 24,48% renda inferior a 70 reais por pessoa, caracterizando situação de extrema pobreza. Sobre a situação previdenciária prevaleceram as crianças sem vínculo com (61,22%). No que tange a benefícios, observou-se que somente 12,24% delas estavam em gozo de Benefício de Prestação Continuada - BPC. Conclusão: condições socioeconômicas precárias figuram como importantes obstáculos no atendimento das necessidades infantis, impactando nas condições de saúde e até possibilitando o agravamento de uma afecção existente.

Abbreviations, acronyms & symbols CETICCCs IAC IVC ACP BSCVS SCA/ECA SETRACCC SUS UNICEF

Integral Treatment Centers for Children with Congenital cardiopathies Interatrial communication Interventricular communication Arterial channel persistence Brazilian Society of Cardiovascular Surgery Statute of the Child and Adolescent Special Secretariat for the Treatment of Children with Congenital cardiopathies Unified Health System United Nations Children’s Fund

Luís a existência de elementos materiais que concorrem para o agravamento desta afecção. Métodos: Realizou-se um estudo retrospectivo, com abordagem quantitativa de caráter descritivo-reflexivo, a partir das entrevistas sociais realizadas pelo Serviço Social junto às famílias das crianças cardiopatas no período de janeiro de 2011 a julho de 2012.

Descritores: Cardiopatias Congênitas. Fatores Socioeconômicos. Criança.

INTRODUCTION

indigence[3,4]. Faced with this social conjuncture, that certainly permeates the childhood of Maranhão’s people, that concerns were present, in the sense to understand in what measure a restrictive conjuncture limits the possibilities of healthy growth of the children who live (or survive) in those conditions. In this scenario, characterized by the absence of basic elements, for example the health, habitation, feeding, income, besides overcoming these obstacles, how are these people who were born with cardiac malformation living? Considering that the childhood is the phase of life which the human being is more exposed to iniquities and to poverty, being easy targets to the most diverse forms of domination and exploration[5,6], we intended to perform an analysis of the socioeconomic conditions of a part of these children, the cardiopathic that, besides the limitations imposed by the disease, face limited life conditions by the absence of material and financial resources. The congenital cardiopathies can be defined as cardiac malformations that occur in the embryonic period, associated or not to genetic factors and/or chromosomal alterations. It happens in a proportion of 8 to 10 for each 1000 children born alive, represent a percentage of 25% of all congenital malformation and are the cause of child mortality in the proportion of 15%[6]. They can still be corrected with surgical procedures, allowing a better quality of life[7]. Data from the Brazilian Society of Cardiovascular Surgery (BSCVS) (SBCCV in Portuguese) review that only 30% of the children with congenital cardiopathies have access to surgical treatment, generating a 65% deficit and that, in the north and

Brazil has a population of 200 million people, which at least 29 million are from 0 to 9 years old, and approximately 45 million are from 10 to 19 years old, which is equivalent to almost one third of all population of children and adolescents of Latin America and Caribbean. There are tens of millions of people which have rights and duties and that need conditions to develop themselves using their full potential[1]. Children are especially vulnerable to violations of rights, to poverty and to iniquity in the country, even with the uncountable legal advances acquired like the Statute of the Child and Adolescent (SCA/ECA)[2]. According to the United Nations Children’s Fund (UNICEF)[1], 29% of the population live in poor families, but, among the children, this number comes to 45.6%. Black children, for example, have almost 70% more chance to live in poverty than the white ones; the same can be seen in children who live in rural areas. In the semi-arid region, where 13 million children live, more than 70% of children and adolescents are classified as poor. In Maranhão, this reality about childhood worsens as the State, historically marked by the extreme concentration of income and by the meager results obtained from the public policies, where many families live in miserable conditions. In 2000, 68.42% of the people who live in Maranhão were included in the hunger map of Brazil. In relation to childhood in 2002, 74.2% of children and adolescents from 0 to 17 years old were included in families with per capital income of up to half minimum wage, experiencing a growing situation of

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northeast regions, this deficit can reach to a fraction of 97.5% in the first one and 92% in the second[8]. This occurs because of a set of elements, such as the process of universalization of the Unified Health System (SUS in Portuguese), which presents the necessity of an upgrade in the number of hospital beds, qualified professionals, as well the construction of more service centers that allow accessibility with quality. In Maranhão this reality is far more serious, since there is only one Unit of Public Health that can be taken as reference, the University Hospital (HUUFMA in Portuguese) which, for more than a decade, daily attends several children from the whole State in order to subject them to surgeries for correcting congenital cardiopathies. The hypothesis that appeared with the research is that the socioeconomic conditions, when applied in poverty situations, may contribute to the worsening of a pathology, in the specific case of this work, represented by congenital cardiopathy. Thus, it is considered that the non-treatment of basic needs of these children might, in a certain way, interfere in their process of recovery and health maintenance.

researchers. The research was submitted and properly approved by the Research Ethics Committee of the University Hospital –UFMA (process 177.580). RESULTS In the period of 2011 and the first semester 2012 were registered, in the data bank of Social Service of the University Hospital Presidente Dutra, 95 social interviews performed with the children’s families who were submitted to surgery for correction of congenital cardiopathies from 0 to 12 years old. In relation to the initial diagnoses of children, 26.31% had interventricular communication (IVC); 25.26%, interatrial communication (IAC); 16.84% arterial channel persistence (ACP); 5.26% Fallot’s Tetralogy; 22.10% with associated cardiopathies (those composed by two or more cardiopathies); 2.10% with pulmonary atresia and 1.05% tricuspid atresia. Concerning to the children profile, it was observed the predominance of the female gender with the percentage of 53.68%, while the male gender corresponded to 46.31%. In relation to age, the majority belonged to the group of 0 to 3 years old with the percentage of 38.94%; from 4 to 6 years old in 22.10%;from 7 to 9 years old in 24.21% and from 10 to 12 years old in 15.78%. About the origin, It was observed that 69.47% belonged to continental cities (countryside) and 28.42% belonged to the capital city; 1.05% came from another State. Among children who came from other cities, 13.68% didn’t have any family or governmental support in the treatment space. Regarding religion, the largest group belonged to Catholics with 57.89%, followed by protestants with 22.10%; 9.47% mentioned other religions; in 10 interviews the religion option was not marked. About ethnicity, the brown group was the largest number with 58.94%; the white group represented 16.84%; black 16.84%; yellow and indigenous presented 0%. In 8 interviews the ethnicity option was not marked. Concerning the scholarity variable, most of the children, 57.89%, were not alphabetized. Followed by children with incomplete fundamental education (1st to 4th grade), represented by 21.05% of the total; 10 children were attending middle school (5th to 8th grade), with a percentage of 10.52%; followed by the group of alphabetized with 10.52% of the children. With respect to dwelling, data showed that 94.73% of the children had a house as living option, followed by apartment with 3.15% and room with 2.10%. About the financial condition, 81.05% have their own house; followed by 7.36% with rental housing, 5.26% granted housing, 2.10% buying their own home, and 44.21% other situations non-specified. Concerning to the conditions of housing wall (Figure 1), 66.31% lived in a brick housing, 26.31% mud, 4.1% adobe and 1.05% of table. Concerning the housing roofs, 80% were cover with tile, 11.57% of straw, 3.15% of slab and 5.26% of tile lining; others

METHODS Quantitative research based on a retrospective study of descriptive-reflexive character. The present method was elected to consider that everything can be counted, translating in numbers informations that create useful knowledge to the advance of science[9]. The data were obtained from social interviews performed by the Social Service of HUUFMA with 95 families of cardiopathic children. These interviews are usually applied in the reception process, after the admission in the hospital unit, and remain stored in a computerized data bank counting with socioeconomic data, housing, environmental, health indicators, pension situation, diagnostic and hospitalization period. It needs to be mentioned the implementation of a computerized registry to the Social Service Division that was created from the project “The construction of the Information Policy and computer science in Health of SUS, with the goal to advance in the use of computer science to improve the productivity and quality in health. The results were quantified in statistic based on percentage in the Microsoft Office Excel 2007, analyzed and interpreted by using theoretical references, to characterize the socioeconomic conditions of the research subjects and show, in what measure these conditions compete to its social vulnerabilities. The research presented as inclusion criteria: children from 0 to 12 years old submitted to cardiac surgery in the period of January 2011 to July 2012 and of exclusion: children who had been through surgery to correct their acquired cardiopathies; hospitalized children only for clinic compensation. The secrecy of the informations was properly respected by the means of the non-identification of the involved parts, as well the commitment term undersigned by the responsible

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were counted as 4.21%. Concerning the number of rooms, 62.10% had a home with 4 to 6 rooms, 17.89% had from 1 to 3 rooms, 17.78% from 7 to 9, and 4.21% with more than 9 rooms. Still about home, 58.94% referred that their homes did not have coated floor; the ones who had it represented 41.05%. Concerning per capita income (Figure 2), 44.21% had an income of ½ minimum wage, 27.36% up to ¼ minimum wage, 24.21% with an income lower than 70 reais per person, only 4.21% had income between 1 and 2 minimum wages; it didn’t occur families with more than 3 minimum wages per person. In the health indicators, specially referred to trash collection, it was observed that 63.15% had trash collected by the public service, 28.47% burn their trash, 2.10% bury and 5,26% throw it at open sky. Information related to trash destination can be found in Table 1. About the conditions of water use, 55.78% used public network water, 43.15% used water from well, and 1.05% from river. About the treatment of this water, 75.78% filtered it, 13.68% did not take any previous care, 6.31% took mineral water, and 3.15% boiled it. About the welfare situation (Figure 3), prevailed the children without welfare bonds with the percentage of 60%; followed by children with welfare bonds as dependents of INSS in the proportion of 35.78%; and 4.21% were in condition of dependent with state bond. None of the interviewed had private welfare assistance. Among those who possess welfare bonds, 18.94% were dependent of parents who had formal jobs; 6.31% special insured; 2.10% facultative insured. Concerning benefits, it was observed that only 12.63% of the children had the Continuous Cash Benefit (CCB - BPC in Portuguese).

Fig. 2 - Per capita income of the families of the children with congenital cardiopathies in São Luís (2011 and first semester 2012).

Table 1. Distribution of trash destination of children with congenital cardiopathies in São Luís. Trash destination Septic Tank Cesspit Sewer Open Sky Total

Fig. 1 - Housing wall of children with congenital cardiopathies in São Luís (2011 and 1st semester 2012).

Quantity 42 21 23 09 98

% 44.21% 22.10% 24.21% 9.47% 100.0

Fig. 3 - Welfare situation of children with congenital cardiopathies hospitalized at HUUFMA in São Luís (2011 and first semester 2012).

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DISCUSSION

to highlight that the State assumes a minimum role up to the social cut policies, and even the monetary aspect revealing itself to be one of the constraints of poverty, it is characterized as a multidimensional phenomenon, presenting a theoretical construction full of concepts that, many times, were conflicted or continued. According to Araujo[11], initially, the poverty presents itself as something of moral and natural order; posteriorly, it begins to be seem as structural, showing itself as an reflection of the way of production and consumption adopted. More recently, it became object of State official organisms, being one element that teaches other social programs. Another relevant aspect in the survey of socioeconomic conditions of children with congenital cardiopathy that can contribute to the aggravation of their pathology refers to the sanitation issue, such as: sanitary sewage, sewers’ collect network, as well trash collection as fundamental elements to a decent life and, specially, healthy. The results show that only a reduced number of families of children have a sewer network (24.21%), being the great majority dependent to the fosse system or even open sky at the proportion of 75.78%. This reality is above the average of all country, once that 30.06% of the national population, represented by 16 million people, do not have homes with access to appropriate sanitation[12]. Concerning water distribution, the results show that the largest part of children use water from the public system, but an expressive number 43.15% of them use water from the well. It is important to say that these waters do not always have an appropriate treatment to human consume due to the absence of sewers network or satisfactory garbage collection, which results in the contamination of the groundwater which represents a large risk to children. It is important to say that this chain of services is not simultaneous, because, despite the majority has water from the general network, do not possess the sanitation sewers network and satisfactory garbage collection. This is seen in all national territory. In 2011, according to IBGE[12], 48.5% of children up to 14 years old, 21.9 million approximately lived in houses that at least one sanitation service was not appropriate (water, sewer or trash). It is noted that there wasn’t refueling of water through the general network, or septic tank linked to the collector network, or trash that wasn’t collected. When these inequality forms of sanitation existed simultaneously in houses, around 4.8 million children in the proportion of 10.7% were seriously exposed to disease risks, and this indicator concerned 17.2% of children of Northeast region and, in contrast, 3.7% in the southeast region[12]. Taking this scenario into consideration, the closer follow-up of this public by the basic care teams (health family strategy and community health agents) is extremely important, in order to better assist the children with this kind of pathology and speed up in case of bigger complications, taking to reference hospitals. And also to identify risk factors to these individuals health, among so many already mentioned, proceed and articulate to this network may function through the intersectoriality

It was observed that the incidence of congenital cardiopathy keeps the same proportion between the genders, with a light domain of the female gender. About age, it is predominant the age group of the first childhood that goes from 0 to 6 years old, representing a little more than half of all children. This condition is probably because in this initial childhood phase that is performed the surgical procedure to correct the pathology in a palliative or definitive way. However, it should be consider too the proportion of children in a high age (24.21%) to this correction by surgical procedure is highly probable since this kind of surgery should be performed in the first years of life. The late submission to surgical procedure can be deriving from the difficulty to access the health service, once that in all state there is only one public unity taken as reference to correct congenital cardiopathy. About the origin, the great majority belongs to cities in the countryside, having even the presence of children from another State (1.05%). It is also revealed that the children who did not count on family or governmental support, which means, have no presence of family members in the treatment city and do not count on support from their hometown which should ensure the minimum of attendance to their needs through the program Out of House Treatment (TFD in Portuguese). Still referring to children’s profile, prevailed those considered brown, fact that happens due to ethnic mix so present in the State or to the lack of racial identity. In the religious aspect, the catholic are still more frequent in the religion option. In relation to children scholarity, this study shows that the majority was not alphabetized yet. This data is justified by the fact of children that are not yet in school age. According to UNICEF[1], the premature scholarity intervention in children of 4 to 6 years old can make a difference in the upgrade of chances of achieving a higher level of scholarity, reducing school failure and achieve a higher income in the future. Concerning the dwelling conditions, the findings of this study show that the majority of children live in their own house made of bricks. However, it is relatively remarkable the expressive number of mud houses, without coated floor, with straw roof with the percentage of 26.21%, 58.94% and 11.57% respectively. This shows that the housing conditions of these children are still precarious, with poor infrastructure since 31.57% of these children do not live in a brick house. This indicator is a reflex of the absence or low range of a habitational policy to the low income families. The study also revealed that the great majority of children live with a per capita income up to ½ minimum wage, which, according to IBGE[10], represents a poverty condition. Other fraction lives with an income lower than seventy reais, revealing a situation of extreme poverty. Thus, even with the economic growth of the country and the gradual reduction of social inequities through income transfer policies, the poverty still characterizes as a present problematic and exacerbated by neoliberal adjustment. It is worth

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among educational public policies, social assistance, health and previdence. Associated to other social indicators, the welfare situation is another element that is worth to be considered as a factor of social vulnerability. It was observed in the study that most of the children did not have a welfarebond, which means, that their parents or responsibles do not contribute with the social welfare, and this can happen due to a difficulty of insertion in formal jobs, specially in a conjecture such as the neoliberal in which the unemployment in these conditions becomes a growing problem. Still in the welfare matter, it is important to mention about the concession of the Continued Render Benefit (BPC) to these children. The BPC is a benefit in effect since 1993 which concedes the unconditional income transfer in an amount of a minimum wage to elders and people with deficiency whose per capita income is inferior to ¼ of a minimum wage, independent of previous contributions to the welfare system. For the elders, the concession of the benefit is made under two conditions: being 65 years old and be considered poor[13]. Concerning people with deficiency, beside the condition of poverty, it is necessary a limitation to an independent life and to work that are confirmed through some tests performed by experts of INSS, evaluating both the social status as the deficiency with systematic revaluations each 2 years to verify the persistence of the conditions that originated the benefit. However, a study reviews to exist a controversy of the adopted model to the comprehension of what is a deficiency[14], what can, in some way, interfere in the beneficiary selection. The decree nº 6.214 of 2007[15,16] , establishes the person with deficiency as being ”the one unable to independent life and to work, because of irreversible anomalies or injuries of hereditary nature, congenital or acquired that forbid the performance of activities of the daily life and work”. Thus, the more severe congenital cardiopathies can be scaled in the list of possible deficiencies that can be selected to the BPC. However, the present study showed that only 12.24% of the children were using this benefit. Analyzing the factors of concession of the benefit becomes a hard task, because involves evaluation, besides the social condition, the level of deficiency and how much it can limit the independent life of this child. This means that the analysis of the benefit concession brings into consideration not only the level of the deficiency, but, above all, the complex relation between the limitation of the body and the impositions of society. Thus, in case of congenital cardiopathy, the frontier between the deficiency (notion of permanence) and disease (notion of temporality) is latent and that, depending on subjective factors of each requiring subject and evaluator expert, can affect the benefit’s deferring[16]. In the other hand, it is worth noting that social assistance is a constitutional right that also support children. Although the real conditions of existence of great part of these children from Maranhão’s State be permeated by the most diversified precarious forms of social and economic conditions

and specially the appropriate access to medical treatment, it is important to mention that some efforts have contributed in some measure to call the attention to congenital cardiopathy and its treatment forms. They are: the creation of the congenital cardiopathies consciousness day, celebrated since June 12th 2012, with the goal to inform the general population about diseases caused by cardiac malformation and the medical class mobilization to create the Special Secretariat to the Treatment of Children with Congenital cardiopathies (SETRACCC) with by the Ministry of Health, whose primordial objective will be to enable the integral attendance of the child with congenital cardiopathy, aiming to reduce the high levels of mortality by the lack of access to surgical and percutaneous treatment by the creation of Integral Treatment Centers to Children with Congenital cardiopathies (CETICCCs)[17] in all national territory. LIMITATIONS It was considered as limitation to our study the impossibility to measure data referred to characteristics of the progenitors or responsibles for children with congenital cardiopathies, because these pieces of information were not available in the studied data bank. CONCLUSION Regarding all indicators of social economic conditions of children with congenital cardiopathies registered in this research, it is evident that material elements such as income, basic sanitation, housing conditions and welfare situation make it more difficult to deal with their needs[18]. The lack of their basic needs has direct implications on the health conditions of these individuals, resulting in the obstruction of people to obtain favorable living conditions for their participation in society. It is worth remembering that the health policy preconized in the country has intersectoral and inter institutional character, and they become effective which implies a strengthening of Brazilian social security system. Another problem is what concerns income access, which in scholar children, represents one of the largest faced obstacles, once that the bigger the income of their families, better their housing and sanitation conditions are. These precarious conditions of housing, sanitation and also access to information that can contribute to aggravate the health conditions of the infantile public, because of its natural fragility, putting their development at risk. The challenge that is presented with this study is how to guarantee the satisfaction of these children’s needs. Brazil has legal devices of childhood and youth protection as the Law nº 8069 of 1990[2] by understanding that life quality of this population group is the source of national development. Therefore it has invested in income transfer Programs such as Bolsa Família (Family allowance), BPC and, more recently, the

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program Brasil carinhoso (Fond Brazil) that aims to overcome extreme poverty in the first step of the childhood. Although the importance of these actions, it is important to go beyond them and guarantee the satisfaction of these public needs in all life segments in society through the strengthening of jobs generation policies, housing policies and basic health with housing expansion with sewer sanitation network, public water and garbage collection and, more important, the strengthening of education policy so that even more children have the opportunity to grow in a health environment, overcoming these iniquities that affect so much this population group. Finally public policies of social cut that exercise a fundamental role in this process are expected, reason which arises a need of more debate, evaluation and, specially, monitoring so that the childhood becomes more assisted and indeed have an advance in the effectiveness of social rights in citizen perspective.

6. Del Priore M, org. História das crianças no Brasil. 7ª ed. São Paulo: Contexto; 2010. 7. Ribeiro C, Madeira MF. O significado de ser mãe de uma criança com cardiopatia congênita: um estudo fenomenológico. Rev Esc Enferm USP. 2006;40(1):42-9. 8. Pinto Junior VC, Daher CV, Salum FS, Jatene MB, Croti UA. Situação das cirurgias cardíacas congênitas no Brasil. Rev Bras Cir Cardiovasc. 2004;19(2):III-IV. 9. Moresi E. Metodologia da Pesquisa. Distrito Federal. 2003 [Acesso 18 de maio 2013]. Disponível em: http://www.unisc.br/portal/ upload/com_arquivo/metodologia_da_pesquisa.pdf 10. Instituto Brasileiro de Geografia e Estatística IBGE. Síntese de Indicadores Sociais: uma análise das condições de vida da população brasileira. Rio de Janeiro: IBGE; 2012.

ACKNOWLEDGMENT

11. Araujo CC. Pobreza e programas de transferência de renda: concepções e significados. 1ª ed. São Luís: Edufma; 2009.

To the Social Service Division of the University Hospital –HUUFMA that made possible the accomplishment of the study and to Social Assistance of the Cardiology Service for their effort in performing and registering social interviews in the data bank.

12. Brasil. Pesquisa Nacional por Amostras de Domicílios - PNAD 2009: Síntese de Indicadores. Rio de Janeiro, 2010.

Authors’ roles & responsibilities

13. Brasil. Lei n° 8.742, de 07 de dezembro de 1993. Lei Orgânica da Assistência Social – LOAS. Diário Oficial da República Federativa do Brasil, Brasília, DF, 08 dez. 1993.

TLVB MJSD RVAHN

14. Diniz D, Squinca F, Medeiros M. Perícia Médica e assistência social no Brasil. Cad Saúde Pública. 2007;23(11):2589-96.

Manuscript drafting, analysis and interpretation of data Analysis and critical review Study design and search for references

15. Brasil. Decreto nº 6.214, de 26 de setembro de 2007. Regulamenta o benefício de prestação continuada da assistência social devido à pessoa com deficiência e ao idoso de que trata a Lei no 8.742, de 7 de dezembro de 1993, e a Lei no 10.741, de 1o de outubro de 2003, acresce parágrafo ao art. 162 do Decreto no 3.048, de 6 de maio de 1999, e dá outras providências. Diário Oficial da República Federativa do Brasil, Brasília, DF, 28 set. 2007.

REFERENCES 1. UNICEF. Situação Mundial da Infância. Distrito Federal. Janeiro de 2008 [Acesso 12 de jun 2012]. Disponível em: http://www. unicef.org/lac/cadernobrasil2008.pdf 2. Brasil. Lei n°. 8069 de 13 de julho de 1990. Estatuto da Criança e do Adolescente. Diário Oficial da República Federativa do Brasil, Brasília, DF, 14 jul. 1990.

16. Brasil. Decreto nº 6.564, de 12 de setembro de 2008. Altera o Regulamento do Benefício de Prestação Continuada, aprovado pelo Decreto no 6.214, de 26 de setembro de 2007, e dá outras providências. Diário Oficial da República Federativa do Brasil, Brasília, DF, 13 set. 2008.

3. Crianças e adolescentes no Maranhão: uma prioridade fora do orçamento. PDF. Revista. São Luís, 2006 [Acesso 13 de jun 2012]. Disponível em: http://www.unicef.org/brazil/pt/ observatorio_crianca_ma_parteI.pdf

17. Sociedade Brasileira de Cardiologia. Jornal SBC. Ano XIX, número 120 – Julho 2012 [Acesso 20 de novembro 2013]. Disponível em: http://jornal.cardiol.br/2012/julho/pdf/ jornalsbc-120.pdf

4. Instituto Brasileiro de Geografia e Estatística IBGE. Censo Demográfico 2010: características da população e dos domicílios. Rio de Janeiro; 2011.

18. Pereira PAP. Necessidades humanas: subsídios à crítica dos mínimos sociais. 4ª ed. São Paulo: Cortez; 2007.

5. Freitas MC, org. História social da infância no Brasil. 5ª ed. São Paulo: Cortez; 2003.

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Molinari GJDP,HOW et al. TO - Avoiding DO IT pitfalls of intraoperative peripheral endovascular surgery with the aid of OsiriX: expanding the use of virtual fluoroscopy

Avoiding pitfalls of intraoperative peripheral endovascular surgery with the aid of OsiriX: expanding the use of virtual fluoroscopy Como evitar armadilhas do intraoperatório em cirurgia endovascular periférica com o auxílio do OsiriX: ampliando o uso da fluoroscopia virtual

Giovani José Dal Poggetto Molinari1, MD, Andréia Marques de Oliveira Dalbem1, MD, Ana Terezinha Guillaumon1, MD, MsC, PhD DOI: 10.5935/1678-9741.20140094

RBCCV 44205-1575

Abstract We have shown how the analysis of the angiotomography reconstruction through OsiriX program has assisted in endovascular perioperative programming. We presented its application in situations when an unexpected existence of metallic overlapping artifact (orthopedic osteosynthesis) compromised the adequate visualization of the arterial lesion during the procedure. Through manipulation upon OsiriX software, with assistance of preview under virtual fluoroscopy, it was possible to obtain the angles that would avoid this juxtaposition. These angles were reproduced in the C-arm, allowing visualization of the occluded segment, reducing the need for repeated image acquisitions and contrast overload, allowing the continuation of the procedure.

Resumo Temos demonstrado como a análise da reconstrução da angiotomografia utilizando o programa OsiriX tem auxiliado na programação perioperatória endovascular. Apresentamos aqui sua aplicação em situação em que a existência de artefato metálico (osteossíntese ortopédica) comprometia a adequada visibilização de lesão arterial durante o procedimento. Pela manipulação da angiotomografia no software OsiriX e com o auxílio das imagens sob fluoroscopia virtual foi possível obter-se automaticamente uma angulação que evitasse esta justaposição. Os ângulos foram reproduzidos no arcoscópio, o que permitiu expor o segmento ocluído, reduzindo a sobrecarga de contraste e de repetidas tomadas, permitindo a continuação do procedimento. Descritores: Fluoroscopia. Interface Usuário-Computador. Tomografia Computadorizada Multidetectores. Procedimentos Endovasculares.

Descriptors: Fluoroscopy. User-Computer Interface. Multidetector Computed Tomography. Endovascular Procedures.

INTRODUCTION

The introduction of multi-slice CT scans (from 16 channels), allowed the acquisition of larger anatomic volumes[2], making it an accurate method for the study of peripheral arteries[1]. Although digital subtraction angiography is considered the gold standard for peripheral arterial assessment, this has been replaced by CT due to the increasing number of detectors and collimators increasingly thin[3]. When compared to

Prior to computed tomography (CT) scans with multichannel detector technology (implemented only from 1998 when the first 4-channel equipment became available), the assessment of peripheral arterial disease by CT scan could only be performed only in a small segment of vascular system[1,2]. 1

Universidade Estadual de Campinas, Campinas, SP, Brazil.

Correspondence adress: Giovani José Dal Poggetto Molinari Universidade Estadual de Campinas - Unicamp/Cidade Universitária Zeferino Vaz - Rua Vital Brasil, 251 - Barão Geraldo - Campinas, SP, Brazil Zip Code: 13083-888 Mail box: 6142 E-mail: drgiovani.molinari@uol.com.br

This work was carried out in Hospital de Clínicas da Universidade Estadual de Campinas (Unicamp) Centro de Referência em Alta Complexidade em Cirurgia Endovascular, Campinas, SP, Brazil.

Article received on June 14th, 2014 Article accepted on July 21st, 2014

No financial support.

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Molinari GJDP, et al. - Avoiding pitfalls of intraoperative peripheral endovascular surgery with the aid of OsiriX: expanding the use of virtual fluoroscopy

(with placement of implantable system for osteosynthesis fixation with plate and pins) with no major complications. For 3 months, she developed pain, paresthesia, coldness of the limb and progressive strength loss, with recent recrudescence. Physical examination presented a preserved sensibility, decreased motor function and slowed perfusion. The values of segmentar pressures registered in the left arm through a continuous wave doppler assessment were reduced, with a brachy-brachial index of 0,55 (N.V.: 0,9-1,1), reinforcing the hypothesis of an arterial involvement of this territory. She underwent CT angiography exam of the supra-aortic trunks and left upper limb. It was identified an image of interrupted contrast, suggestive of occlusion of left subclavian artery (near the metallic prosthesis) with refilling in its distal part. The axial sections had impairment of appropriate visualization of the artery due to streak artifacts produced by the osteosynthesis, reason why it was opted for the intraoperative arteriography, for purposes of establishing an exclusive endovascular treatment (recanalization and covered stent implantation). During surgical procedure, there was difficulty in the correct visualization of the lesion (ie., unfilled portion of the artery by intravascular contrast) due to the overlapping of radiopaque metallic rod included in the angiographic image (Figure 1A). After some attempts to capture new images posterior to the angular repositioning of the fluoroscopy unit, it was decided to resort to auxiliary study of CT in OsiriX software. At first, the manipulation of the axial images was performed, marking the proximal and distal portions of the subclavian artery with the point tool (Figure 1B). A three-dimensional volume reconstruction under virtual fluoroscopy was obtained, where it was able to identify an overlap of this demarcation by the orthopedic prosthesis (Figure 1C).

Abbreviations, acronyms & symbols CT

Computed Tomography

the first, CT angiography is less invasive, less expensive and exposes patients to lower doses of radiation[4]. However, the study of CT angiography generates a massive number of digital data and unwieldy, which interpretation and discrimination of changes are best evaluated when post processed in software, such as multi-planar reconstruction, volume rendering and maximum intensity projection[4]. We have shown how the analysis of tomographic reconstruction of fine sections through the OsiriX program has aided in perioperative programming of endovascular abdominal aneurysms, in prediction of the intra-luminal placement of angiographic catheters and in correction of angular positioning of the fluoroscopy unit[5,6]. We also reported how concepts of angulation and Virtual Fluoroscopy used on OsiriX (from multichannel CT angiography) are used to obtain the best intraoperative angle of visual exposure of peripheral artery, in situations where the existence of artifacts (like metallic orthopedic fixation) compromises its proper visualization during endovascular procedures. CASE REPORT Female patient, 24 years old, assisted at the Outpatient Clinic for High Complexity Endovascular Surgery at University of Campinas, with history of motorcycle trauma (fall) for 6 months, causing injury with fracture of clavicle, 3rd and 4th left ribs. She underwent on occasion to an orthopedic surgery

Fig. 1 - A) Intraoperatory image of digital subtraction angiography, which displays an overlapping caused by the orthopedic metallic rod over the arterial thrombosed segment. B) Study of the tomographic axial view, where marks with the OsiriXâ&#x20AC;&#x2122;s point tool were performed, over the estimated trajectory of the left subclavian artery. C) Three-dimensional-by-volume reconstruction under virtual fluoroscopy, after marking with points. It was possible to identify, in fact, the overlapping of the structures and the need of the C-arm angular repositioning intraoperatively.

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Fig. 2 - A) Three-dimensional-by-volume image rotation avoiding the overlap of the osteosynthesis upon the tomographic point marks. The angles used for C-arm repositioning were automatically yielded by the software (right inferior corner). B) Digital subtraction angiography after the angular correction of the radioscopic device, with minimum effect of image superposition, allowing the preview of the thrombosed arterial segment. C) Final outcome after arterial recanalization and the covered-stent implant.

By rotational manipulation of three-dimensional image, it was possible to obtain an angle that would avoid this juxtaposition (Figure 2A). The angles were reproduced in the C-arm, allowing visualization of the exposed occluded segment, allowing the rest of the procedure to follow (Figure 2B). Therefore, we proceeded to the artery recanalization with coated stent (Gore Viabahn 7x50) which was performed without any complications (Figure 2C).

Despite the many advantages, CT angiography also has its limitations. It can be ineffective in the diagnosis if the contrast reaches the studied segment too soon or too late at the period of image acquisition by the device. Another scenario in the diagnosis of arterial lesions after trauma is the presence of artifacts caused by metallic fragments on the periphery of the vessel, such as projectiles from firearms. These streaks make it impossible to analyze the correct image[7]. Anyway, it is important to remember that in any tomographic analysis is necessary to review the images of axial views to confirm the findings presented in reconstructions and define the possible presence of these or other artifacts that simulate disease[9]. In our case the analysis of the image in axial views showed these streaks artifacts, compromising the injury extension evaluation, even after adjusted values of windowing (brightness and contrast). Therefore it was decided to supplement with subtraction arteriography intraoperatively. Thus, it would be possible to estimate, based on the gap of intravascular contrast fill of the left subclavian artery, the extent of the lesion, the size and required length of the stent(covered stent graft). However when facing the radiopaque image produced by the orthopedic fixation of the clavicle, it prevented the perfect view of the angiographic image due to its overlapping and radiopacity. To continue with the procedure without visualization of the arterial segment with intravascular contrast refill would increase risk of false paths, extensive dissections and the failure of the intervention.

RESULTS AND DISCUSSION Until recently, digital subtraction arteriography was the modality of choice for evaluating patients with suspected vascular injury. However, due to the wide access of multichannel exams, it has rapidly replaced the conventional angiography in the diagnosis of vascular trauma[7]. In a meta-analysis by Jens et al.[8] sensitivity and specificity for vascular injury (when compared to subtraction arteriography or surgery) was 99.2% and 96.2% respectively. This justifies why all service centers should have a trauma tomography as an accurate method for diagnosis of vascular injury in extremity trauma,Â by reserving the conventional angiography for interventional or when the first is inconclusive. Vascular abnormalities in the upper limbs are found less frequently than those affecting the lower extremities. Arterial imaging studies of the upper limbs is usually performed in trauma victims with ischemic symptoms of upper extremities, prep planning of complex vascular reconstructions and dialysis access as well as follow up of endovascular or surgical procedures[9].

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We used the angiotomography previously performed in attempt to simulate the optimum viewing angle of the occluded segment to be recanalyzed. The OsiriX point tool marks permanently a voxel from a three-dimensional image which is defined as the representation of a pixel (the smallest point of a digital image) in a volumetric grid originated from a series of pictures - and is reproduced in a three-dimensional-by-volume reconstruction. Doing so, it’s possible to obtain any information of spatial positioning of this mark, such as the path of the occluded subclavian artery in this case. Thus, when marking with points the trajectory of the artery, it was possible to visualize it in any sort of reconstruction, axial, three-dimensional-by-volume or multiplanar. Through rotational manipulation of the three-dimensional-by-volume image, we could illustrate the studied artery avoiding overlapping the osteosynthesis plaque. The angles obtained automatically from the software were reproduced in the fluoroscopy unit, allowing the correct visualization of the angiographic image. Thereafter, it was possible to reduce the need for repeated angiographic takes in attempt to obtain the best exposure of the artery, avoiding iodinated contrast overload. Therefore we proceeded to the recanalization of the thrombosed segment with placement of a covered stent with therapeutic success (which can be observed by control angiography). The patient’s clinical improvement was evident, verified with the complete resolution of the symptoms. The use of OsiriX as a complementary tool allows doctors to assist in the preparation of surgeries (as endovascular) extending it beyond the field of diagnostic radiology. These tasks can be easily incorporated into the armamentarium of the surgeon to avoid pitfalls and unforeseen situations that are identified intraoperatively, increasing the operatory risk and oftentimes leading to intervention failure.

REFERENCES 1. Brockmann C, Jochum S, Sadick M, Huck K, Ziegler P, Fink C, et al. Dual-energy CT angiography in peripheral arterial occlusive disease. Cardiovasc Intervent Radiol. 2009;32(4):630-7. 2. Hiatt MD, Fleischmann D, Hellinger JC, Rubin GD. Angiographic imaging of the lower extremities with multidetector CT. Radiol Clin North Am. 2005;43(6):1119-27. 3. Kock MC, Dijkshoorn ML, Pattynama PM, Myriam Hunink MG. Multi-detector row computed tomography angiography of peripheral arterial disease. Eur Radiol. 2007;17(12):3208-22. 4. Walls MC, Thavendiranathan P, Rajagopalan S. Advances in CT angiography for peripheral arterial disease. Cardiol Clin. 2011;29(3):331-40. 5. Molinari GJDP, Dalbem AMO, Menezes FH, Guillaumon AT. Proposal of renal artery’s ostial projection under virtual geometric correction in infrarenal aneurysms: initial results of a pilot study. Rev Bras Cir Cardiovasc. 2014;29(1):78-82. 6. Molinari GJDP, Dalbem AMO, Guillaumon AT. The use of virtual resources for pre operatory study in correction of infrarenal aneurysms: exploring the OsiriX’s potential. Rev Bras Cir Cardiovasc. Rev Bras Cir Cardiovasc. 2014;29(2):279-84. 7. Jens S, Kerstens MK, Legemate DA, Reekers JA, Bipat S, Koelemay MJ. Diagnostic performance of computed tomography angiography in peripheral arterial injury due to trauma: a systematic review and meta-analysis. Eur J Vasc Endovasc Surg. 2013;46(3):329-37. 8. Kock MC, Dijkshoorn ML, Pattynama PM, Myriam Hunink MG. Multi-detector row computed tomography angiography of peripheral arterial disease. Eur Radiol. 2007;17(12):3208-22.

Authors’ roles & responsibilities GJDPM

AMO ATG

9. Waliszewska M, Jakubiak A, Guzinski M, Sasiadek M. Application of the 64-slice computed tomography as a diagnostic method in acute posttraumatic ischaemia of the upper limbs - 3 case reports. Pol J Radiol. 2010;75(2):94-7.

Analysis and/or interpretation of data; statistical analysis; final manuscript approval; conception and design of the study; conduct of operations and/or experiments; manuscript drafting or critical review of its content Analysis and/or interpretation of data; conduct of procedures and/or experiments Analysis and/or interpretation of data; manuscript drafting and review of its content

10. Walls MC, Thavendiranathan P, Rajagopalan S. Advances in CT angiography for peripheral arterial disease. Cardiol Clin. 2011;29(3):331-40.

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Guida M, et al. - New technique HOW TO DO"Right IT Anterior Small Thoracotomy (RAST operation)" for beating heart grafting of the right internal thoracic artery to the posterior descending artery to the posterior descending artery in a third redo CABG patient. A novel coronary technique.

New technique "Right Anterior Small Thoracotomy (RAST operation)" for beating heart grafting of the right internal thoracic artery to the posterior descending artery to the posterior descending artery in a third redo CABG patient. A novel coronary technique. Nova técnica "Pequena toracotomia anterior direita (operação RAST)“ para enxerto da artéria torácica interna direita para a artéria descendente posterior com o coração batendo em paciente de terceira RM. Uma técnica coronária nova.

Maximo Guida1, MD, PhD; Gustavo Guida1, MD; Giuseppina Pecora1, MD; Estefania De Garate1,MD

DOI 10.5935/1678-9741.20140080

RBCCV 44205-1576

Abstract Third REDO-CABG is a challenge for the surgical team. Usually a patent mammary is the only graft working and the sternotomy becomes a risky procedure. Injury to a patent graft has been associated to a high mortality rate. Many different approaches have been proposed. We describe a novel technique to approach the right coronary artery through a right anterior small thoracotomy using the right mammary prolonged with saphenous vein for grafting the posterior descending artery on the beating heart. The technique is very simple and feasible because anatomically the right coronary artery and the right mammary are very close and the mobilization of the heart is minimal.

Resumo A terceira reoperação de revascularização miocárdica é um desafio para a equipe cirúrgica. Normalmente, uma mamária patente é a única possibilidade de enxerto e a esternotomia torna-se um procedimento arriscado. A lesão de enxerto patente tem sido associada a uma alta taxa de mortalidade. Muitas abordagens diferentes têm sido propostas. Descrevemos uma nova técnica de abordagem da artéria coronária direita através de uma pequena toracotomia anterior direita usando a mamária direita prolongada com enxerto de veia safena para a artéria descendente posterior com o coração batendo. A técnica é muito simples e viável, pois anatomicamente a artéria coronária direita e a mamária direita estão muito próximas e a mobilização do coração é mínima.

Descriptors: Coronary Artery Bypass. Thoracotomy. Myocardial Revascularization.

Descritores: Ponte de Artéria Coronária. Toracotomia. Revascularização Miocárdica.

Fundacardio Foundation, Valencia, Venezuela.

Correspondence address: Maximo Guida Fundacardio Foundation - Valencia – Venezuela Av. Bolivar Norte 137-A Street, Sector Camoruco, Res. Pecchinenda D Planta Baja- Valencia, Venezuela E-mail: maximo_guida@hotmail.com Article received on March 5th, 2014 Article accepted on June 8th, 2014

This study was carried out at Fundacardio Foundation, Valencia, Venezuela. No financial support.

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no graft of enough length available. The use of the right gastroepiploic artery was also considered, but the patient had previous partial gastrectomy. As we had the experience before operating on a patient with dextrocardia through a right thoracotomy[4], we decided to perform a right anterior thoracotomy for grafting the RCA to the PDA branch. A fully written informed consent was obtained and signed from the patient and his wife, as well as their consent for the use of the information and pictures for scientific reason. Before anesthetic induction, the patient was premedicated with 100 mg of Ketoprofen, 2 grams of Dipirone, 8 mg of Dexametasone, and antibiotic profilaxis as per protocol, an intra-aortic balloon pump was inserted via a right femoral artery to assist the left ventricle and improve the severe patient ischemia. The patient received a 1.5 mg/kg Propofol, 0.07 mcg/kg/min Remifentanyl over 10 min, and 1 mg/kg Rocuronium. Then a bronchial blocker was inserted after the induction in order to exclude the right lung, but the patient didnâ&#x20AC;&#x2122;t tolerate the exclusion and we had to do a partial exclusion with the use of lap sponges. The position was on a left lateral supine at approximately 30 degrees with the right arm elevated (Figure 1). A right anterior thoracotomy was performed at the 6th intercostal space. Bupivacaine was then injected on the upper and lower side of the incision as a part of our pain control protocol. With the use of Finocchietto retractor in combination with a Rultract retractor, the right pleural space was approached. A lot of pleural adhesions were removed from the right lung to achieve a proper surgical field. The pericardial fat and thymus rest were removed. The right internal thoracic artery was dissected in a skeletonized fashion with the use of ultracision harmonic scalpel and a special forceps. Systemic heparin (2 mgs/kg) was given to maintain an activated clotting time around 350 seconds. The right internal thoracic artery was transected distally and a terminal-terminal anastomosis was performed with a small piece of

Abbreviations, acronyms & symbols CABG PDA RAST RCA RITA SVG

Coronary artery bypass grafting Posterior descending artery Right anterior small thoracotomy Right coronary artery Right mammary thoracic artery Saphenous Vein

INTRODUCTION The Third Redo-CABG (coronary artery bypass grafting) is always a challenge for the surgical team. Usually, the patient has a patent mammary as the only graft working just in the midline which represents a risky situation for a re-sternotomy[1-2]. Most of the time other conditions as renal failure, low ejection fraction, increased age, unstable angina, cardiac failure and pulmonary hypertension are present, representing also an increased risk for prolonged mechanical ventilation[3]. Worsening this situation is the absence of available conduit for the grafting because most of them have been already used for the previous surgeries. We are proposing a technique to reduce the risk in this special group of patients, avoding the re-sternotomy, thus avoiding the cardiopulmonary bypass, and using the skeletonized right internal thoracic artery for grafting the right coronary or the posterior descending artery (PDA) with minimal manipulation of the heart. TECHNIQUE A 78 year-old diabetic patient was admitted in our service with recurrent angina for a REDO third coronary surgery. He had had triple bypass in 1994 via median sternotomy. After that, he had PTCA stents two times in 1996 and 1998. In 2004, our team performed a double bypass from a left thoracotomy using a saphenous vein graft from the descending thoracic aorta to the diagonal and the marginal branch. The angiogram showed: RCA 100% occluded on the distal third. LAD 100% occluded proximally. Left main with patent stent. CX 80% on the medium third. Collateral circulation from the left to the right coronary artery, the ascending, arch and descending aorta were severely calcified, a patent LITA to LAD was keeping the patient alive. The ejection fraction was of 30% assessed by transesophageal echo. Because of the patient was not suitable for PTCA, and there were no conduits available for grafting, we decided the use of the right internal thoracic artery (RITA), prolonged with a small segment of saphenous vein available on the left groin for grafting the Posterior Descending Artery (PDA). The patient approach was very risky from median Sternotomy because there was a patent LITA to LAD. The left thoracotomy, as we use as a routine, was not possible because there was

Fig. 1 - Patient position - the patient is positioned with the right arm elevated at approximately 30Â° toward left side.

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saphenous vein previously removed from the left groin, using an 8/0 Prolene running suture (Figure 2). Papaverine solution was spread around the RITA to improve its diameter and relieve from a possible spasm. The right side of the heart was dissected from the adhesions of the previous surgeries very carefully avoiding lesion of the right atrium and the right ventricle. The target vessel was founded following the previous occluded saphenous vein graft to the PDA performed in 1994. Using a Maquet Acorbat-i stabilizer速, the artery was dissected, inspected to ensure the feasibility of the anastomosis and opened very carefully. A 1.5 mm flow-through intracoronary shunt was inserted as a part of our routine (Figure 3). The distal anastomosis was then performed in the usual fashion on the beating heart with the continuous running polypropylene 7/0 suture (Figure 4).The Butterfly Medistim Flowmeter was used to check the graft flow, the PI (pulsatility index) was 2,9, the mean flow was 28 ml/min and DF (dyastolic filling) was 62% which was considered satisfactory. Protamine was administered to achieve full heparin reversal and a further dose of Bupivacaine was injected on the upper and lower side of the incision as usual. Transesophageal echo was performed before and after the anastomosis in the same patient conditions: anesthetic drugs, use of inotropics and balloon assistance and an impressive improvement of the postero-lateral wall contraction was showed, increasing the left ventricular ejection fraction from 30 to 45% (Figure 5). A multi-orifice catheter was placed inside the incision for a postoperative pain control and the incision closed conventionally. The patient was awakened at the end of the procedure and extubated on the table. The postoperative course was really uneventful. The intraortic balloon pump removed in the ICU 1 hour after and the patient discharged at home on the third postoperative day.

Fig. 2 - Anastomosis RITA-SVG - A small piece of SVG is anastomosed to the RITA with running suture of 8/0 prolene.

Fig. 3 - PDA stabilization and shunt in - The PDA is stabilized with the use of the Maquet-Acrobat and a 1,5 flow-thru shunt is placed.

COMMENT The coronary surgery has changed a lot in the last two decades. Now the surgeon has the obligation to know how to perform many different procedures for the same purpose, thus resolving the patient ischemia. From the standard on pump, median sternotomy coronary artery bypass grafting, which was the only technique used before, actually, we have the off pump-median sternotomy, lateral thoracotomy, minimally invasive coronary surgery, video-assisted, robotic and hybrid procedures. And for the REDO-CABG we have also the axillo-coronary via left thoracotomy, postero-lateral approach using the descending aorta and the xiphoidal approach using the right gastroepiploic artery[5-9]. This novel technique that we describe may help to resolve many difficult situations like the above patient, who was no candidate for any of the above mentioned techniques. Moreover, especially in REDO-CABG, would be a good choice

Fig.4 - Anastomosis performed - The anastomosis RITA-SVG-PDA is performed with an excellent result.

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Fig. 5 - Transesophageal echo performed before (left) and after (right) the anastomosis in the same patient

conditions: anesthetic drugs, use of inotropics and balloon assistance.

for a hybrid procedure when the LAD or the circumflex could be stented and the RCA or PDA resolved by this RAST operation. Our only concern about this case is the long term patency of the saphenous vein anastomosed to the RITA, of which good short term results are reported[10], but could be a choice when there is a lack of conduit, like in our case. It’s very important for the cardiac surgeon in the current era to keep open eyes at any new procedure, because the coronary Surgery is becoming more and more complex every day.

4. Romano G, Guida G, De Garate E, Guida MC. Minimally-invasive coronary surgery in dextrocardia and situs inversus totalis. Interact CardioVasc Thorac Surg. 2010;11(6):820-1. 5. Ascione R, Narayan P, Rogers CA, Lim KH, Capoun R, Angelini GD. Early and midterm clinical outcome in patients with severe left ventricular dysfunction undergoing coronary artery surgery. Ann Thorac Surg. 2003;76(3):793-9. 6. Calafiore AM, Gianmarco GD, Teodori G, Bosco G, D’Annunzio E, Barsotti A, et al. Left anterior descending coronary artery grafting via left anterior small thoracotomy without cardiopulmonary bypass. Ann Thorac Surg. 1996;61(6):1658-63.

Authors’ roles & responsibilities MG GG GP EG

Main author Conception and design of the study Final approval of manuscript Drafting of the manuscript and critically review

7. Borst HG. Leftsided thoracotomy for coronary artery reoperation. Thoraxchir Vasc Chir. 1978;26(2):95-7. 8. Guida MC, Pecora G, Bacalao A, Muñoz G, Mendoza P, Rodríguez L. Multivessel revascularization on the beating heart by anterolateral left thoracotomy. Ann Thorac Surg. 2006;81(6):2142-6.

REFERENCES 1. Loop FD. Catastrophic hemorrhage during sternal reentry. Ann Thorac Surg. 1984;37(4):271-3. 2. Dobell AR, Jain AK. Catastrophic hemorrhage during redo sternotomy. Ann Thorac Surg. 1984;37(4):273-8.

9. Burlingame MW, Bonchek LI, Vazales BE. Left thoracotomy for reoperative coronary bypass. J Thorac Cardiovasc Surg. 1988;95(3):508-10.

3. Piotto RF, Ferreira FB, Colósimo FC, Da Silva GS, De Souza AC, Braile DM. Independent predictors of prolonged mechanical ventilation after coronary artery bypass surgery. Rev Bras Cir Cardiovasc. 2012;27(4):520-8.

10. Cirillo M, Messina A, Dalla Tomba M, Brunelli F, Mhagna Z, Villa E, et al. A new no-touch aorta technique for arterialsource, off-pump coronary surgery. Ann Thorac Surg. 2009;88(4):e46-7.

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Letters to the Editor/Cartas ao Editor

DOI: 10.5935/1678-9741.20140098

RBCCV 44205-1577

Psychological assessment before heart transplantation: more hope to candidates in Brazil?

logical support to vulnerable patients, mainly to women, we can perform heart transplantation successfully in patients with minor psychological disorders, as we did to patients with low socioeconomic profile[6].

To the Editor,

Reinaldo B. Bestetti - Universidade de Ribeirão Preto, Ribeirão Preto, SP, Brazil

I have read with great interest the paper by Cunha et al.[1] which presents the results of a psychological assessment of candidates to heart transplantation. They evaluated 60 candidates to heart transplantation from 2004 to 2012, 73% with a stable partner. By using the SF-36 Health survey, the Beck Depression Inventory, and a personal interview, they observed that indices of quality of life were lower in women in comparison to men, specifically on functional capacity, vitality, emotional aspects, and general mental health. They concluded that patients with psychosocial vulnerability should receive psychological care. I agree. Psychological evaluation is paramount in candidates to heart transplantation, inasmuch as pretransplant factors may be associated with adverse outcome in post-transplant patients. In fact, lower received social support, higher education, and lower conscientiousness detected on the waiting list are independent predictors of post-transplant adherence with medication, which is associated with acute rejection[2]. Furthermore, the presence of psychiatric problems in the pretransplant period continues following heart transplantation[3], including substance abuse[4]. Moreover, previous suicide attempt, alcohol rehabilitation, and depression are associated with decreased survival[3]. Therefore, unfavorable psychological profile, characterized by previous suicide attempt as well as substance abuse, may preclude candidates to undergo heart transplantation[5]. It is, therefore, reassuring to see that patients reported by Cunha et al.[1] do not fit, in general, in the unfavorable psychological profile, as outlined earlier, to the point to be excluded from the waiting list of heart transplantation. In addition, it is of utmost importance to perceive that the majority of them had a stable partner who will act as caregiver following the procedure. Thus, I believe that, by offering proper psycho-

REFERENCES

1. Cunha SS, Miyazaki MCOS, Villafanha DF, Santos Junior R, Domingos NAM. Psychological assessment of patients undergoing cardiactransplant in a teaching hospital (2004 to 2012). Rev Bras Cir Cardiovasc. 2014;29(3)350-4. 2. Dobbels F, Vanhaecke J, Dupont L, Nevens F, Verleden G, Pirenne J, et al. Pretransplant predictors of posttransplant adherence and clinical outcome: an evidence base for pretransplant psychosocial screening. Transplantation. 2009;87(10):1497-504. 3. Owen JE, Bonds CL, Wellisch DK. Psychiatric evaluations of heart transplant candidates: predicting post-transplant hospitalizations, rejection episodes, and survival. Psychosomatics. 2006;47:(3):213-22. 4. Paris W, Muchmore J, Pribil A, Zuhdi N, Cooper DK. Study of the relative incidences of psychosocial factors before and after heart transplantation and the influence of posttransplantation psychosocial factors on heart transplantation outcome. J Heart Lung Transplant. 1994;13(3):424-30. 5. Bacal LF, Souza-Neto JD, Fiorelli AI, Mejia J, MarcondesBraga FG, Mangini S, et al. II Diretriz Brasileira de Transplante Cardíaco. Arq Bras Cardiol. 2009;94(Suppl 1):16-73. 6. Parra AV, Rodrigues V, Cancella S, Cordeiro JA, Bestetti RB. Impact of socioeconomic status on outcome of a Brazilian heart transplant recipients cohort. Int J Cardiol. 2008;125(1):142-3.

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REVIEWERS

Reviewers BJCVS/RBCCV 29.3 The Brazilian Journal of Cardiovascular Surgery/Revista Brasileira de Cirurgia Cardiovascular (BJCVS/RBCCV), once again, is grateful for the work of reviewers, who with his critical and constructive evaluation collaborate to improve the scientific level of our journal.

Domingo Braile Editor-in-Chief BJCVS/RBCCV

Alexandre Hueb Alexandre Visconti Brick Alfredo Inácio Fiorelli Alfredo José Rodrigues Antonio Carlos Brandi

Jayme Pinto Ortiz José Carlos Pachón Mateos José Glauco Lobo Filho Josiane Marques Felcar Lais Helena C. Marino Lindemberg da Mota Silveira Filho

Carla Tanamati Charles Simão Filho

Marcus Vinicius Pinto e Silva Maria Cristina Miyazaki Miguel Angel Maluf

David Peitl Edmo Atique Gabriel

Orlando Petrucci Otoni Moreira Gomes

Fabio Antonio Gaiotto Fernando Antibas Atik Fernando Antoniali Francisco Ubaldo Vieira Junior

Paulo M. Pêgo-Fernandes Paulo Roberto Barbosa Evora

Gibran Roder Feguri Gilberto Venossi Barbosa Guilherme Agreli Guilherme Benjamin Pitta Guilherme de Menezes Succi Gustavo Calado Aguiar Ribeiro

Reinaldo Bestetti Reinaldo Wilson Vieira Renato Samy Assad Rubens Thevenard Tomas A. Salerno

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