Brazilian Journal of Cardiovascular Surgery 30.1

Page 1

30.1 JANUARY/FEBRUARY 2015

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY | REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

VOL. 30 Nยบ 1 JANUARY/FEBRUARY 2015

Save the date and confirm your attendance at the SBCCV 2015

Medical Education

01

March 26 - 28, 2015

2

in light of new technologies

S BCC V

CONGRESS OF THE BRAZILIAN SOCIETY OF

CARDIOVASCULAR

SURGERY

5th Symposium of Nursing in Cardiovascular Surgery 5th Symposium of Physiotherapy in Cardiovascular Surgery 4th Academic Conference on Cardiovascular Surgery

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www.sbccv.org.br

You have four good reasons to participate in this event: 2 HANDS ON

1 PROGRAM Through presentations, round tables, and advanced courses, we will discuss, debate, and share experiences on professional development in light of new technologies.

A teaching and learning approach that fosters the interaction between an expert and surgeons who wish to master new technologies that are proven effective, but have low adoption as well as new procedures with restricted use, but which are in expansion in clinical practice.

PROMOTED BY:

Sociedade Brasileira de Cirurgia Cardiovascular

anúncio sbccv 2015.indd 1

3 SPEAKERS

4 FREE THEME

As usual, the program brings renowned academic experts, highlighting both national and international speakers.

ORGANIZED BY:

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

An opportunity to present and share your innovative scientific production and clinical trial through discussions of themes of importance to cardiovascular surgeons. Share your experience and contribute to the advancement of our medical specialty.

OFFICIAL AGENCY

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

04/02/15 16:29

速

BJCVS

EDITOR-IN-CHIEF Prof. Dr. Domingo M. Braile - PhD

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY

São José do Rio Preto - SP - Brasil domingo@braile.com.br

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

FORMER EDITORS • Prof. Dr. Adib D. Jatene • Prof. Dr. Fábio B. Jatene

EXECUTIVE EDITOR Ricardo Brandau Postgraduate in Science Journalism - S. José do Rio Preto (BRA) brandau@sbccv.org.br

EDITORIAL ASSISTANTS Rosangela Monteiro PhD - São Paulo (BRA) rosangela.monteiro@incor.usp.br

PhD - São Paulo (BRA) [1986-1996] PhD - São Paulo (BRA) [1996-2002]

Camila Safadi S. José do Rio Preto (BRA) camila@sbccv.org.br

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 O. Vrandecic Peredo • 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)

STATISTICS EDITOR • Orlando Petrucci Jr.

Campinas (BRA)

EDITORIAL BOARD • 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 *LOOHV ' 'UH\IXV • Ivo A. Nesralla • Jarbas J. Dinkhuysen • José Antônio F. Ramires • José Ernesto Succi • José Pedro da Silva • Joseph A. Dearani

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) +DUH¿HOG 8.

Porto Alegre (BRA) São Paulo (BRA) São Paulo (BRA) São Paulo (BRA) São Paulo (BRA) Rochester (USA)

ENGLISH VERSION • Fernando Pires Buosi • Marcelo Almeida

• Maria Carolina Zuppardo

GRAPHIC DESIGN AND LAYOUT • Heber Janes Ferreira

• 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 Alves 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)

OFFICIAL ORGAN OF THE BRAZILIAN SOCIETY OF CARDIOVASCULAR SURGERY SINCE 1986

ADDRESS/ENDEREÇO

Sociedade Brasileira de Cirurgia Cardiovascular Rua Afonso Celso, 1178 • Vila Mariana • Phone: 55 11 3849-0341. Fax: 55 11 5096-0079. Zip code: 04119-061 • São Paulo, SP, Brazil E-mail BJCVS/RBCCV: revista@sbccv.org.br • E-mail SBCCV: sbccv@sbccv.org.br • Site SBCCV: www.sbccv.org.br • Sites BJCVS/RBCCV: www.scielo.br/rbccv/www.rbccv.org.br/www.bjcvs.org (also for article submission)

Bimonthly publication/Publicação bimestral Print edition - Print run: 250 copies (*)

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR (Sociedade Brasileira de Cirurgia Cardiovascular) SĂŁo Paulo, SP - Brasil. v. 119861986, 1: 1,2 1987, 2: 1,2,3 1988, 3: 1,2,3 1989, 4: 1,2,3 1990, 5: 1,2,3 1991, 6: 1,2,3 1992, 7: 1,2,3,4 1993, 8: 1,2,3,4 1994, 9: 1,2,3,4 1995, 10: 1,2,3,4 1996, 11: 1,2,3,4

1997, 12: 1,2,3,4 1998, 13: 1,2,3,4 1999, 14: 1,2,3,4 2000, 15: 1,2,3,4 2001, 16: 1,2,3,4 2002, 17: 1,2,3,4 2003, 18: 1,2,3,4 2004, 19: 1,2,3,4 2005, 20: 1,2,3,4 2006, 21: 1 [supl] 2006, 21: 1,2,3,4

2007, 22: 1 [supl] 2007, 22: 1,2,3,4 2008, 23: 1 [supl] 2008, 23: 1,2,3,4 2009, 24: 1 [supl] 2009, 24: 1,2,3,4 2009, 24: 2 [supl] 2010, 25: 1,2,3,4 2010, 25: 1 [supl] 2011, 26: 1,2,3,4 2011, 26: 1 [supl]

2012, 27: 1,2,3,4 2012, 27: 1 [supl] 2013, 28: 1,2,3,4 2013, 28: 1 [supl] 2014, 29: 1,2,3,4 2014, 29: 1 [supl] 2015, 30: 1

ISSN 1678-9741 - On-line version. ISSN 0102-7638 - Print version RBCCV 44205

CDD 617.4105 NLM18 WG 168

(*) ASSOCIAĂ‡ĂƒO PAULISTA DE BIBLIOTECĂ RIOS. Grupo de BibliotecĂĄrios BiomĂŠdicos. Normas para catalogação de publicaçþes seriadas nas bibliotecas especializadas. SĂŁo Paulo, Ed. PolĂ­gono, 1972

INDEXED IN ‡ 7KRPVRQ 6FLHQWL¿F ,6,

http://science.thomsonreuters.com • PubMed/Medline www.ncbi.nlm.nih.gov/sites/entrez ‡ 6FL(/2 6FLHQWL¿F /LEUDU\ 2QOLQH 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 &LHQWL¿FDV GH $PHULFD /DWLQD HO &DULEH Espaùa y Portugal www.latindex.uam.mx

• ADSAUDE - Sistema Especializado de Informação em Administração de SaĂşde 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

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

“Enhancing the professional on behalf of the patient” BOARD OF DIRECTORS 2014 - 2015 President: Vice-President: Secretary General: Treasurer: 6FLHQWL¿F 'LUHFWRU

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

Advisory Board:

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

Journal Editor: Site Editor: Newsletter Editors:

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 Ribeiro Moraes Neto (PE)

3UHVLGHQWV RI 5HJLRQDO $¿OOLDWHV 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

Departaments DCCVPED: DECAM: DECA: DECEM: 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) Leila Nogueira Barros (SP) Paulo Marcelo Barbosa Mesquita (SP)

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

ISSN 1678-9741 - On-line ISSN 0102-7638 - Print RBCCV 44205

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY

Impact Factor: 0.632

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR Braz J Cardiovasc Surg/Rev Bras Cir Cardiovasc, (São José do Rio Preto, SP - Brazil) jan/feb - 2015;30(1):1-138

CONTENTS EDITORIALS (QJOLVK WKH QHZ RI¿FLDO ODQJXDJH RI %-&96 ,QJOrV QRYR LGLRPD R¿FLDO GD %-&96 Domingo M. Braile.................................................................................................................................................................................. I

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Reviewers BJCVS 30.1 ......................................................................................................................................................................129 (UUDWXP ..............................................................................................................................................................................................130 ,QIRUPDWLRQ IRU DXWKRUV ....................................................................................................................................................................131 0HHWLQJ &DOHQGDU ..............................................................................................................................................................................136 3ULQWHG LQ %UD]LO

Editorial

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Domingo M. Braile1

DOI: 10.5935/1678-9741.20150014

A

year to complete its 30th birthday, the Brazilian Journal of Cardiovascular Surgery (BJCVS) brings great news to its readers. As I advanced in the last edition, from now on the journal will be published only in English. This covers not only articles, but all content, from editorial to the ads. We are taking a historic step towards increasing our internationalization and therefore we turn to raise our Impact Factor (IF), a key parameter in order to continue to receive high-level studies in Brazil and abroad. 7KLV LV DQ LUUHYHUVLEOH SURFHVV ZKLFK WKH %UD]LOLDQ VFLHQWLÂżF publications can not escape. The databases are increasingly adopting strict criteria for a journal is accepted - and maintained - in its collection. The same goes for development agencies, such as CAPES, requiring postgraduate programs to publish studies in journals with higher Qualis, and the CNPq, restricting its Editorial Assistance to publications indexed in PubMed, Scopus, ISI or Scielo and be at least B2 in the Qualis. SciELO released guidelines for its articles have greater international impact. As reported in FAPESP Journal (http://revistapesquisa.fapesp.br/2015/01/19/para-ampliar-o-impacto/), one of the goals to be met by the end of 2016, is the increased amount of articles in English. Within two years, the percentage should reach 75%. Currently, it is about 60%[1]. That is, the BJCVS anticipated this requirement! We are convinced that this decision will bring positive results very soon. I emphasize once again that English is the lingua franca of the world, as were Latin and French, and the scientists who want their studies have repercussions need to publish them in English. Otherwise, a study that could bring advances in the knowledge of a particular disease or spread a new surgical technique remains anonymous. This is the known “Publish or

Perish�, whose charges are used to relax the environment in FODVVHV DQG OHFWXUHV RQ VFLHQWL¿F GLVVHPLQDWLRQ I insist that the authors are careful to write in English, seeking help of skilled professionals, so that the text is within the standards of international publications. Before publication, the article will go through a review of our corps of translators and, if English is incompatible with the standard of quality, the text will be corrected, with the costs borne by the authors. I count on the cooperation of all to the texts have an English good quality. Periodicity Another novelty, that has also been previously reported, is the change of periodicity. The BJCVS passes from quarterly to bimonthly. It will be 6 issues per year instead of the 4 we had XQWLO 7KLV GHFLVLRQ ZLOO DOORZ HDVLQJ WKH ÀRZ RI DUWLFOHV E\ reducing the time between the approval and the availability in an issue. It is another way to allow wider dissemination of the studies. We remember that the manuscripts, when approved, are available on Ahead of Print already with the award of the '2, 'LJLWDOB2EMHFWB,GHQWL¿HU DQG LW LV WKHUHIRUH ZLWK WKH legitimate origin and may be cited, with positive effects on IF. BSCVS For the English version and the increase in the number of annual editions were possible, I counted on the major support from the Board of the Brazilian Society of Cardiovascular Surgery (BSCVS), under the command of the President, Dr. Marcelo Cascudo, who understood the importance of these changes and discussed the matter with the members, who DSSURYHG WKH LGHD DW D PHHWLQJ , WKDQN WKH VFLHQWL¿F VSLULW RI all who believe in this endeavor.

I Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

End Note Another good news is that, thanks to the efforts and perseverance of Dr. Marcos AurĂŠlio Barboza, who belongs to our body of reviewers, the bibliographic style of BJCVS was included in the EndNote Web site (www.endnote.com) and EndNote Web (www.myendnoteweb.com.br). With these styles, it is possible the formatting and update of the sequence of the entire list of references automatically in the style of our journal, facilitating the work formatting. The use of the online program is already possible free anywhere in the world (see Letter to the Editor on page 127).

New system of evaluation of manuscripts insertion of associate editors on new tasks With the advent of new logistics of BJCVS, some changes ZLOO EH UHTXLUHG LQ WKH Ă€RZ RI WKH VWXG\ VXEPLWWHG IRU SXEOLFDtion in the Journal. Currently, the Chief Editor of the BJCVS, after evaluation of the Executive Editor, for the rules, shall be responsible for all movement of manuscripts, from the initial reading, followed by an indication of the reviewers, to give his opinion following the guidelines contained in the evaluation form. In return these, the Chief Editor will be responsible to analyze them, guiding collaborators to make a synthesis that, once it’s ready, will be reviewed before being sent to the authors. They respond to the questions, describing the measures adopted in the text correction. When the corrected manuscript returns to the Editor, this evaluates the answers and the comparison of the original version with the corrected. Then, he decides whether the study is able to be published or send the material to one of the reviewers, to get a second opinion. If this indicates new corrections, the whole cycle repeats itself. We have had cases of studies with good potential, returning 15 or more times to be suitable for the essential standards. Often, after all this great effort, the manuscript can still be rejected, a decision to be made by the Editor-in-Chief. The aim now is that part of this logical sequence is shared E\ WKH $VVRFLDWHG (GLWRUV VSHFLÂżF IRU HDFK DUHD RI NQRZOHGJH The Editor-in-Chief will continue to receive the manuscripts and after reading them he will indicate an Associate Editor who will be responsible for selecting the Reviewers and take it upon himself the task of leading the phase of reviews and FRUUHFWLRQV XS WR WKH ÂżQDO UHFRPPHQGDWLRQ WKH VWXG\ LV UHDG\ for reviews by the Editor-in-Chief, to whom it will always be WKH ÂżQDO GHFLVLRQ )URP WKLV SRLQW DOO WKH ZRUN LV IRU WKH VXSSRUW WHDP ÂżQDO check list, with attention to names, contributions and credits RI WKH DXWKRUV DQG FRUUHFWLRQ RI UHIHUHQFHV YHULÂżFDWLRQ RI WKH (QJOLVK ODQJXDJH DQG ÂżQDOO\ WKH GLJLWDO RQ OLQH YHUVLRQ DQG the limited printed version. Thus, the system will be more responsive and democratic, easing the work of each, by the division of labor. It will be a great leap in quality to our Journal, for aggregate responsibilities, and disseminate knowledge of the editorial process by enabling new Editors. This whole process counts as invaluable help of the Journal own structure, composed of the Executive Editor Ricardo Brandau, and a lean team of collaborators consisting of the Editorial Assistants Full Professor Rosangela Monteiro and Prof. Camila Safadi. Translators for English Language: Prof. Fernando Pires Buosi, Prof. Marcelo Almeida and Prof. Maria Carolina Zuppardo. 3XEOLVKLQJ DQG *UDSKLF 'HVLJQ +HEHU -DQHV )HUUHLUD We also count on all the great structure of GNI Sistema e Publicaçþes [http://www.gn1.com.br/], responsible for all

42nd Brazilian Congress of Cardiovascular Surgery From 26 to March 28, the 42nd Congress of the Brazilian Society of Cardiovascular Surgery will take place at the Centro de Convençþes Expo Unimed in Curitiba, PR. Each year, the Congress of the BSCVS has grown in quality, attracting professionals from areas related to cardiac surgery. Thus, in parallel, will be held the 5th Nursing Symposium on Cardiovascular Surgery, the 5th Symposium of Physical Therapy in Cardiovascular Surgery and the 4th Academic Congress in Cardiovascular Surgery, in addition to the Surgery Meeting, highlighting the increasing participation of women in our specialty. This year’s theme will be “Medical Education in the face of new technologies.â€? With technological advances incorporating rapidly to medicine, cardiovascular surgeons must be updated permanently and apply new knowledge and skills for WKH EHQHÂżW RI SDWLHQWV , DOVR KLJKOLJKW WKH Âł+DQGV 2Q´ ZKRVH level leaves nothing due to their similar performed in other conferences and the “Professional Defense Symposiumâ€? in which we discuss the future of our specialty. There will be several international guests, consolidating the growing and fundamental integration of BSCVS with international Societies and valuing the fundamental knowledge exchange. In addition, participants will have moments of harmony with colleagues and family, and also will enjoy leisure time knowing the beautiful capital of ParanĂĄ, whose urban solutions have been incorporated in several other cities throughout Brazil. I congratulate the Board of BSCVS and the Organizing Committee, coordinated by Dr. Rui Almeida, by the effort PDGH VR WKDW WKH VFLHQWLÂżF SURJUDP ZDV LQWHUHVWLQJ IRU DOO participants of the Congress. On March 26, from 12am to 14h in the Auditorium 8, there will be a meeting of the Editorial Board of BJCVS with Associate Editors and Editorial Board members, also open to all members. We will address very strongly the issues on which I wrote above and it will be of great importance to all suggestion in this transitional phase, so that we can improve the journal and leave it in accordance with the requirements of all Databases and aspiration of our readers around the globe.

II Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

electronic logistics, Layout, XML markup, conversion and marking - PMC, Conversion and Marking - PMC, Apps - iPad, iPhone and Android, conversion to ePub format, assignment of DOI CrossRef, scanning, CME (Continuing Medical Education), etc. Also in electronics and Internet area, we have the support of information specialist Adriel Menezes.

to be a useful tool to test and update knowledge, is worth 0.5 linear in the BSCVS’ Proof of Title. My warmest regards,

Domingo M. Braile 1 Editor-in-Chief BJVCS

CME The following items are available for testing of Continuing Medical Education (CME) in this issue: “Performance of InsCor and three international scores in cardiac surgery at Santa Casa de Marília” (page 1), “Determinants of peak VO2 in heart transplant recipients” (page 9), “Risk factors for transient dysfunction of gas exchange after cardiac surgery” (page 24) and “Abnormal heart rate variability and atrial ¿EULOODWLRQ DIWHU DRUWLF VXUJHU\” (page 55). CME, in addition

REFERENCE 1. Marques F. Para ampliar o impacto. Revista Fapesp. 2015 Jan;Pag.32-5.

III Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Editorial

TRALI or ARDS or TDGE versus blood transfusion 75$/, RX 6'5$ RX 7'*( YHUVXV KHPRWUDQVIXVmR

Bruno da Costa Rocha, MD, PhD1

DOI: 10.5935/1678-9741.20150015

More recently in 2012 an International Task Force on ARDS-acute respiratory distress syndrome has changed the terminology of acute respiratory disorders gathering several terms in a single nomenclature, then TDGE-transient dysfunction of gas exchange was abandoned[1]. Thus, ARDS was categorized according to PaO2/FiO2 levels into three degrees RI K\SR[HPLD PLOG WR PP+J PRGHUDWH WR PP+J DQG VHYHUH PP+J Rodrigues et al.[2] focused on postoperative acute respiratory disorder concerning adult patients submitted to cardiac surgery. In this retrospective cohort of 717 patients, they accounted for over 60% of patients with moderate or important degree of hypoxemia as above-mentioned. This considerable number of patients with respiratory impairment had an impact in outcomes as ICU (Intensive Care Unit) length of stay and rose susceptibility to pulmonary infection. 7KUHH ULVN IDFWRUV ZHUH LGHQWLÂżHG RQ PXOWLYDULDWH DQDO\VLV renal replacement therapy [P=0.0005, Odds ratio (OR) 2.34], cardiac arrhythmia (P=0.045, OR 1.79) and blood transfusion (P=0.0001, OR 1.72). Indeed, blood transfusion has been considered a key point of TDGE, but in fact it is unduly burdensome. Certainly TRALI- transfusion-related acute lung injury is a well-known acronym used in ICU settings by health personnel as well as TDGE[3]. There is also a widespread concerning about reducing blood transfusion to prevent TRALI or ARDS or TDGE, hence decreasing morbimortality rates[4]. The etiology may be different for acute respiratory distress, but pathophysiology is alike no matter which name is given.

For practical purposes, several studies compared restrictive WUDQVIXVLRQ VWUDWHJ\ J SHU G/ RI KHPRJORELQ FODVV ,,D level of evidence C) versus a liberal transfusion trigger of 10 g per dL of hemoglobin (class III-C). Some strategies have been used in cardiac surgery as intraoperative auto-transfusion (class IIb-C), OPCABG (Off-Pump Coronary Artery Bypass Graft) (class IIa-A), centrifugation of pump-salvaged blood (class IIb-A), red cell savage (class I-A), minicircuits (class I-A), recombinant human erythropoietin (class IIa-A) as other drugs and manoeuvres to prevent blood loss[5]. READ ARTICLE ON PAGE 24

Evidenced-based medicine pointed out the rationale to reduce the use of blood products[5]. Nonetheless, it should have a proper balance between transfusion therapy and “permissive anemia�, it also requires particularly careful on an individual case basis. In conclusion, ARDS is still a source of relevant morbimortality in cardiac surgery, several risk factors have been intelligibly associated to, having a special focus on blood transfusion further studies may help in achieving a gold standard guideline to this complex issue.

REFERENCES 1. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al. Acute UHVSLUDWRU\ GLVWUHVV V\QGURPH WKH %HUOLQ 'HÂżQLWLRQ -$0$ 2012;307(23):2526-33. 2. Rodrigues CDA, Moreira MM, Lima NMF, FigueirĂŞdo LC, FalcĂŁo ALE, Petrucci Jr O, et al. Risk factors for transient dysfunction of gas exchange after cardiac surgery. Rev Bras Cir Cardiovasc. 2015;30(1):24-32.

+RVSLWDO $QD 1HU\ 3HGLDWULF &DUGLRYDVFXODU 6XUJHU\ +RVSLWDO 6DQWD ,]DEHO - Adult and pediatric Cardiovascular Surgery, Salvador, Brazil. E-mail: brunorochaccv@hotmail.com 1

IV Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

7R\ 3 3RSRYVN\ 0$ $EUDKDP ( $PEUXVR '5 +ROQHVV /* .RSNR 30 HW DO 1DWLRQDO +HDUW /XQJ DQG %ORRG ,QVWLWXWH Working Group on TRALI. Transfusion-related acute lung injury: GHÂżQLWLRQ DQG UHYLHZ &ULW &DUH 0HG

5. Society of Thoracic Surgeons Blood Conservation Guideline Task )RUFH )HUUDULV 9$ %URZQ -5 'HVSRWLV *- +DPPRQ -: 5HHFH TB, Saha SP, et al.; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion; International Consortium for Evidence Based Perfusion. 2011 Update to The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011;91(3):944-82.

4. Sharma S, Sharma P, Tyler LN. Transfusion of blood and blood products: indications and complications. Am Fam Physician. 2011;83(6):719-24.

V Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Editorial

Fetal cardiac tumors: prenatal diagnosis and outcomes 7XPRUHV FDUGtDFRV IHWDLV GLDJQyVWLFR SUp QDWDO H UHVXOWDGRV

Milene Carvalho Carrilho1, MD; Gabriele Tonni2, MD, PhD; Edward Araujo JĂşnior1, MD, PhD

DOI: 10.5935/1678-9741.20150003

transplantation is indicated[4,6]. Teratomas generally present as extracardiac masses located close to the aorta and pulmonary artery. They have multicystic formation and may evolve with pericardial effusion[4,6]. Diagnosing cardiac tumors by means of two-dimensional echocardiograms is a fundamental step towards follow-up and prognostic evaluation (Figure 1).

Fetal cardiac tumors are rare conditions and their incidence ranges from 0.08% to 0.2% [1] +RZHYHU WKLV percentage during fetal life may be underestimated, given that regression commonly occurs. It should also be noted that atrial tumors may be small or, when located in the septum or ventricular cavity, often mimic an echogenic focus (golf ball VLJQ WKXV OHDGLQJ WR GLIÂżFXOW\ LQ UHFRJQL]LQJ WKHP WKURXJK ultrasonographic screening[2]. Among the various histological types, the three commonHVW W\SHV LQ IHWXVHV QHZERUQV DQG FKLOGUHQ DUH ÂżUVWO\ UKDEGRP\RPD DQG WKHQ WHUDWRPDV DQG ÂżEURPDV

[1,3,4] . These histological types are benign tumors, since malignant types are extremely rare in fetuses[4]. Rhabdomyomas are the commonest subtypes and present as homogenous hyperechogenic masses that are generally multiple, with variable sizes. They may be intramural or intracavitary, and generally occupy the interventricular septum or right ventricle, close to the moderator band, but they can be located in any cardiac chamber[4]. Rhabdomyomas are hormone-dependent tumor, which explains their well-known capacity for spontaneous regression or reduction, along with their close relationship with tuberous sclerosis[5]. Fibromas rarely present during fetal life, but are generally located in the interventricular septum or the free wall of the left ventricle. They present as large single masses and, differently from rhabdomyomas, do not regress after birth. For this reason, they may cause obstructions[4]. Fibromas require clinical follow-up at birth because they may lead to sudden death. Because they are JLDQW PDVVHV UHVHFWLRQ PD\ EH GLIÂżFXOW DQG WKHUHIRUH KHDUW 1

Division of Obstetrics,Universidade Federal de SĂŁo Paulo (UNIFESP), SĂŁo Paulo, SP, Brazil. 2 'LYLVLRQ RI 2EVWHWULFV DQG *\QHFRORJ\ *XDVWDOOD &LYLO +RVSLWDO 5HJJLR Emilia, Italy. E-mail: araujojred@terra.com.br

Fig. 1 - Two-dimensional echocardiographic at 22 weeks of gestation in the “four-chamber� view showing a rhabdomyoma in the internal wall of fetal left ventricle (white arrow).

VI Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Three-dimensional echocardiography is now acquiring an important role in detection and evaluation of the characteristics of these masses, and it has the capacity to provide greater SUHFLVLRQ DQG HI¿FDF\ LQ GHWHUPLQLQJ WKHLU VL]H DQG KRZ WKH\ compromise adjacent structures[7-9]. Depending on the histological type, location and number of nodules, cardiac tumors have a range of presentations, going from silence to development of severe clinical manifestaWLRQV VXFK DV DUUK\WKPLDV DQG EORRG ÀRZ UHVWULFWLRQV GXH WR obstruction of the ventricular cavities or the atrioventricular and semilunar valves, thereby causing valve regurgitation due to changes to the mobility of these valves, depending on the GHJUHH RI LQVXI¿FLHQF\ SUHVHQFH RI WKHVH WXPRUV PD\ OHDG WR a hemodynamic disorder. Alteration of the ventricular ejection fraction, hydrops or congestive heart failure may occur and, if such situations develop, the prognosis will consequently be worse[4]. Rhabdomyomas can often impair the conduction system of the fetal heart and lead to heart rate disorders such as extrasystoles, supraventricular tachycardia or, less commonly, SURORQJDWLRQ RI WKH 35 VSDFH QRQVSHFL¿F DOWHUDWLRQV RI 67 follow-up, Wolf-Parkinson-White syndrome or aberrant atrioventricular conduction[1,5,7,10]. Wacker-Gussmann et al.[1] evaluated the heart rate of 10 fetuses with rhabdomyoma, by means of electrophysiology, and observed that even the asymptomatic fetuses presented conduction disorders. Management of fetuses with diagnoses of cardiac tumors requires serial echocardiograms, and the approach will vary according to the symptoms. An expectant approach is used in cases of asymptomatic tumors. The echocardiographic evaluation in cases of obstructions should be very detailed, VR DV WR EH DOHUW ZLWK UHJDUG WR WKH SUHVHQFH RI UHYHUVH ÀRZ LQ the ascending aorta and pulmonary trunk, caused by obstruction of the right and left outlets. Another important sign is LQFUHDVHG ÀRZ LQ WKH FLUFXPÀH[ DUWHU\ ZKLFK PD\ QRXULVK the tumor mass[3] ,Q FDVHV RI REVWUXFWLRQ RI WKH EORRG ÀRZ the management should be conservative and preterm delivery should be avoided, except in cases in which the fetus is in the third trimester and presents severe hemodynamic disorders. In these cases, delivery needs to be induced and should be done in a tertiary-level center with a multidisciplinary team, JLYHQ WKDW LPPHGLDWH VXUJLFDO UHVHFWLRQ WR UHOLHYH WKH ÀRZ sometimes becomes necessary[2,4,6]. In cases of malignant arrhythmias such as supraventricular WDFK\FDUGLD DQG DWULDO ÀXWWHU GUXJ WUHDWPHQW ZLWK DQWL DUUK\WKmia agents should be started immediately, remembering that the arrhythmia may often be refractory to treatment. In cases of IHWDO K\GURSV ZLWK VLJQL¿FDQW SHULFDUGLDO HIIXVLRQ LQWUDXWHULQH

pericardiocentesis may be necessary[1,4,8]. In summary, attention is drawn to cardiac tumors because of their diversity of forms of clinical manifestations. Early diagnosis by means of fetal echocardiograms is essential, in order to evaluate the prognosis and schedule the best prenatal and delivery management, with the multidisciplinary team. REFERENCES 1. Wacker-Gussmann A, Strasburger JF, Cuneo BF, Wiggins DL, Gotteiner NL, Wakai RT. Fetal arrhythmias associated with FDUGLDF UKDEGRP\RPDV +HDUW 5K\WKP 2. Croti UA, Mattos SS, Pinto VC Jr, Aiello VD, Moreira VM. Cardiologia e cirurgia cardiovascular pediåtrica. 2nd ed. São Paulo: Roca; 2012. 1LHZLDGRPVND -DURVLN . 6WDĔF]\N - -DQLDN . -DURVLN 3 0ROO JJ, Zamojska J, et al. Prenatal diagnosis and follow-up of 23 cases of cardiac tumors. Prenat Diagn. 2010; 30(9):882-7. ,VDDFV + -U )HWDO DQG QHRQDWDO FDUGLDF WXPRUV 3HGLDWU &DUGLRO 2004; 25(3):252-73. 5. Carvalho SR, Marcolin AC, Cavalli RC, Crott GC, Mendes MC, 'XDUWH * HW DO >)HWDO FDUGLDF UKDEGRP\RPD DQDO\VLV RI ¿YH cases]. Rev Bras Ginecol Obstet. 2010;32(4):156-62. <LQRQ < &KLWD\DW ' %ODVHU 6 6HHG 0 $PVDOHP + <RR 6- HW al. Fetal cardiac tumors: A single-center experience of 40 cases. Prenat Diagn. 2010;30(10):941-9. *XLPDUmHV )LOKR +$ $UDXMR -~QLRU ( 3LUHV &5 &RVWD // Nardozza LM, Mattar R. Prenatal sonographic diagnosis of fetal cardiac rhabdomyoma: a case report. Radiol Bras. 2009; 42(3):203-5. +ROOH\ '* 0DUWLQ *5 %UHQQHU -, )\IH '$ +XKWD -& .OHLQPDQ CS, et al. Diagnosis and management of fetal cardiac tumors: a multicenter experience and review of published reports. J Am Coll Cardiol. 1995;26(2):516-20. 9. Geipel A, Krapp M, Germer U, Becker R, Gembruch U. Perinatal diagnosis of cardiac tumors. Ultrasound Obstet Gynecol. 2001;17(1):17-21. 10. Pipitone S, MongiovÏ M, Grillo R, Gagliano S, Sperandeo V. Cardiac rhabdomyoma in intrauterine life: clinical features and natural history. A case series and review of published reports. Ital +HDUW -

VII Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Editorial

Effectiveness of a cardiac rehabilitation program during hospital stay (IHWLYLGDGH GH XP SURJUDPD UHDELOLWDomR FDUGtDFD GXUDQWH D IDVH KRVSLWDODU

Neuseli Marino Lamari, PhD1

DOI: 10.5935/1678-9741.20150017

The article “Analysis of steps adapted protocol for cardiac rehabilitation during hospitalizationâ€?[1] aims to demonstrate the effectiveness of a cardiac rehabilitation program carried out by the physiotherapist during hospitalization in respect to post-operative complications, mortality and length of hospital stay. It stresses that there is a lack of cardiac rehabilitation protocols and is supported by the current literature on the effectiveness of physiotherapy techniques after heart surgery, as well as new strategies centered on multidisciplinary care. All this demonstrates that the article is in tune with proposals RI WKLV VSHFLDOL]HG VFLHQWLÂżF XQLYHUVH It is noteworthy that the treatment of complex cardiovasFXODU GLVHDVHV KDV FKDQJHG VLJQLÂżFDQWO\ ZLWK WKH GHYHORSPHQW of new care strategies, with an ever increasing amount of data EDVHG RQ VFLHQWLÂżF HYLGHQFH DQG FULWHULD RQ DSSURSULDWH XVH DW presentation and recommendations to the patient and family[2]. This article adopted a protocol that ensured that the heart surgery team could standardize the care of professionals and document activities in a comprehensive and systematic way, ZLWK LPPHGLDWH EHQHÂżWV IURP WKH DSSOLFDELOLW\ RI HDUO\ PRELOLzation, followed by sitting and assisted or unassisted standing. The progression of the amount of effort exerted followed the Steps program depending on the situation of each patient. This program corresponds to a group of exercises at an intensity and repetition, wherein the energy spent is related to the FRQVXPSWLRQ RI R[\JHQ UHTXLUHG E\ WKH ERG\ +RZHYHU WKLV protocol is not used in the daily clinical practice, and therefore the morbidity and mortality rates are higher with increased FRVWV WR WKH 1DWLRQDO +HDOWK 6HUYLFH DV ZDV UHFHQWO\ UHSRUWHG by the British Cardiovascular Society[3]. 1

Faculdade de Medicina de SĂŁo JosĂŠ do Rio Preto, SĂŁo JosĂŠ do Rio Preto, SP, Brazil. E-mail: neuseli@neuselilamari.com

I should also stress the importance of this article to heart surgery which is a complex procedure that has important organic implications and causes changes to the physiological mechanism of the patient, resulting in a higher incidence of FRPSOLFDWLRQV WKDW WHQG WR VLJQLÂżFDQWO\ DIIHFW UHFRYHU\ +HQFH rehabilitation, by improving physical functioning, reducing immediate disability, and preventing or minimizing future dysfunction or disability, proposes a multiprofessional approach to recover the biopsychosocial well-being of the patient by a technically autonomous team. With this in mind, early mobilization interventions are necessary to prevent physical and psychological problems, and to avoid the risks involved with prolonged hospitalization and immobility. READ ARTICLE ON PAGE 40

It seems appropriate to mention that the treatment program for myocardial infarction until 1960 recommended six weeks of bed rest which frequently resulting in postural hypotension and venous thrombosis. In fact, muscle hypertrophy can be LGHQWLÂżHG DIWHU RQO\ KRXUV RI SK\VLFDO LQDFWLYLW\ +\SHUWURphy is a condition in which the muscle responds to immobili]DWLRQ E\ UHGXFWLRQV LQ WKH VL]H RI PXVFOH ÂżEHUV WRWDO ZHLJKW in the size and number of mitochondria, in the muscle tension produced, in the adenosine triphosphate (ATP) and glycogen levels during rest, and in the synthesis of protein, all of which contribute to the increase in muscle weakness. Protected early mobilization with support of body weight avoids the deleterious effects of immobilization and prevents secondary problems caused by immobilization. These effects include weakening of the spine and limb muscles, osteoporosis, cardiovascular deconditioning, and degenerative joint disease, regardless of age or gender.

VIII Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

+HDOWK 6\VWHP QRW VWDQGDUGL]H WKLV W\SH RI SURWRFRO LQ UHKDbilitation?

Thus, the human body moves in order to survive in almost all impaired health conditions and so early physical therapy interventions are imperative. Just standing uses approximately 20% more energy compared to resting and with locomotion or strenuous physical activity, the metabolic rate of muscles can increase 50-100 times above that of resting, with a greater cardiopulmonary response as blood supply increases by approximately 20 times. Thus, inactivity directly affects muscle strength, resistance to fatigue and physical vigor, with consequent implications to organs and systems. &RQVLGHULQJ WKH DIRUHPHQWLRQHG EHQHÂżWV RI HDUO\ PRELlization resulting from physiotherapy techniques in cardiac rehabilitation and the evidence of a multidisciplinary approach of its effectiveness, we ask: Why does the Brazilian National

REFERENCES 1. Winkelmann ER, Dallazen F, Bronzatti ABS, Lorenzoni JCW, WindmÜller P. Analysis of steps adapted protocol in cardiac rehabilitation in the hospital phase. Rev Bras Cir Cardiovasc. 2015;30(1)40-8. +ROPHV '5 -U 5LFK -% =RJKEL :$ 0DFN 0- 7KH KHDUW WHDP of cardiovascular care. J Am Coll Cardiol. 2013;61(9):903-7. 3. British Cardiovascular Society. From Coronary Care Unit to Acute Cardiac Care Unit – the evolving role of specialist cardiac care [Accessed Feb 18 2015]. Available from: http://www.bcs.com/ documents/BCS_Report_on_Coronary_Care_Units.pdf

IX Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

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

X Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Tiveron MG, ORIGINAL et al. - Performance of InsCor and three international scores in ARTICLE cardiac surgery at Santa Casa de MarĂ­lia

Braz J Cardiovasc Surg 2015;30(1):1-8

Performance of InsCor and three international scores in cardiac surgery at Santa Casa de MarĂ­lia Desempenho do InsCor e de trĂŞs escores internacionais em cirurgia cardĂ­aca na Santa Casa de MarĂ­lia

Marcos Gradim Tiveron1 0' +HOWRQ $XJXVWR %RPÂżP1; Maycon Soto SimplĂ­cio1, MD; Marcos Henriques Bergonso1; Milena Paiva Brasil de Matos1, MD; Sergio Marques Ferreira1, MD; Eraldo AntĂ´nio Pelloso1, MD; Rubens Tofano de Barros1, MD, MsC

DOI 10.5935/1678-9741.20140116

RBCCV 44205-1607 0.770, P=0.012), Eurosc1 0.706 (95% CI 0.589 to 0.823, 3”0.001), Eurosc2 was 0.704 (95% CI 0.590-0.818, P=0.001) and InsCor 0.739 (95% CI 0.638 to 0.839, 3”0.001). Conclusion: We can say that overall, the InsCor was the best model, mainly in the discrimination of the sample. The InsCor showed good accuracy, in addition to being effective and easy to apply, especially by using a smaller number of variables compared to the other models.

Abstract Objective: To apply and to compare the Society of Thoracic Surgery score (STS), EuroSCORE (Eurosc1), EuroSCORE II (Eurosc2) and InsCor (IS) for predicting mortality in patients undergoing to coronary artery bypass graft and/or valve surgery at the Santa Casa Marilia. Methods: The present study is a cohort. It is a prospective, observational, analytical and unicentric. We analyzed 562 consecutive patients coronary artery bypass graft and/or valve surgery, between April 2011 and June 2013 at the Santa Casa Marilia. Mortality was calculated for each patient through the scores STS, Eurosc1, Eurosc2 and IS. The calibration was calculated using the Hosmer Lemeshow test and discrimination by ROC curve. Results: The hospital mortality was 4,6%. The calibration is generally adequate group P=0.345, P=0.765, P=0.272 and P=0.062 for STS, Eurosc1, Eurosc2, and IS respectively. The discriminatory power of STS score 0.649 (95% CI 0.529 to

Descriptors: Risk Factors. Hospital Mortality. Cardiovascular Surgical Procedures. Validation Studies. Resumo Objetivo: Aplicar e comparar o Society of Thoracic Surgery score (STS), EuroSCORE (Eurosc1), EuroSCORE II (Eurosc2) e InsCor (IS) na predição de mortalidade nos pacientes submetidos à revascularização do miocårdio e/ou cirurgia valvar na Santa Casa de Marília.

1

Irmandade da Santa Casa de MisericĂłrdia de MarĂ­lia, MarĂ­lia, SP, Brazil.

Correspondence address: Marcos Gradim Tiveron Santa Casa de MisericĂłrdia de MarĂ­lia Av. Vicente Ferreira, 828 - Cascata, MarĂ­lia, SP, Brazil - Zip code: 17515-000 E-mail: mgtiveron@yahoo.com.br

This study was carried out at Irmandade da Santa Casa de MisericĂłrdia de MarĂ­lia, MarĂ­lia, SP, Brazil.

Article received on May 27th, 2014 Article accepted on October 12th, 2014

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1 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Tiveron MG, et al. - Performance of InsCor and three international scores in cardiac surgery at Santa Casa de Marília

Braz J Cardiovasc Surg 2015;30(1):1-8

com o uso dos escores STS, Eurosc1, Eurosc2 e IS. A calibração foi calculada utilizando o teste de Hosmer Lemeshow e a discriminação mediante a curva ROC. Resultados: A mortalidade hospitalar foi de 4,6%. A calibração foi adequada no grupo geral com P=0,345; P=0,765; P=0,272 e P=0,062 para o STS, Eurosc1, Eurosc2 e IS, respectivamente. O poder discriminatório do STS score 0,649 (IC95% 0,529 P=0,2720,770, P=0,012), do Eurosc1 0,706 (IC95% 0,589 - 0,823, P 0,001), do Eurosc2 foi 0,704 (IC95% 0,590 - 0,818, P=0,001) e do InsCor 0,739 (IC95% 0,638 - 0,839, 3 0,001). Conclusão: 3RGHPRV D¿UPDU TXH QR JHUDO R ,QV&RU IRL melhor modelo, principalmente na discriminação da amostra estudada. O InsCor mostrou boa acurácia, além de ser efetivo e de fácil aplicação, principalmente por utilizar um menor número de variáveis comparado aos outros modelos.

Abbreviations, acronyms & symbols CCS Eurosc1 Eurosc2 NYHA ROC SPSS SP-SCORE STS

Canadian Cardiovascular Society The European system for cardiac operative risk evaluation The European system for cardiac operative risk evaluation II New York Heart Association Receiver Operating Characteristic Statistical Package for the Social Sciences São Paulo System for Cardiac Operative Risk Evaluation Society of Thoracic Surgeons score

Métodos: O estudo representa uma coorte. É prospectivo, observacional, analítico e unicêntrico. Foram analisados 562 pacientes consecutivos operados de revascularização do miocárdio e/ou cirurgia valvar, entre abril de 2011 e junho de 2013 na Santa Casa de Marília. A mortalidade foi calculada em cada paciente

Descritores: Fatores de Risco. Mortalidade Hospitalar. Procedimentos Cirúrgicos Cardíacos. Estudos de Validação.

INTRODUCTION

Among the most commonly used risk scores are the Society of Thoracic Surgeons score (STS score), The European system for cardiac operative risk evaluation (EuroSCORE) and the EuroSCORE II. Recently, Mejía et al.[6], created and validated internally at the Heart Institute of the Clinics Hospital, Faculty of Medicine, University of São Paulo (Incor/ HC-USP) a risk model, called InsCor, having meant to be a tool of easy implementation and good accuracy for prognostic analysis of patients undergoing valve replacement with or without CABG in our country. However this model has not been evaluated in any institution outside the place of origin. The aim of the study was to apply the InsCor in patients undergoing CABG and/or valve surgery at Santa Casa de Marília, a reference center for public patients in the state of São Paulo and compare its performance with the STS, EuroSCORE (Eurosc1) and EuroSCORE II (Eurosc2).

The search for quality excellence in the delivery of health services requires, in addition to technical and structural capacity, a broad knowledge of patients regarding the severity and complexity of their disease in order to identify the factors responsible for the results and long-term prognosis. Among medical specialties, cardiovascular surgery is one of the most complex. Its results are dependent of pre-, intra- and post-operative variables and are assessed by risk scores already developed that estimate the morbidity and mortality of surgical procedure. The use of performance indicators has emerged as an objective way to measure the quality of health services[1]. Risk VWUDWL¿FDWLRQ VHUYHV WR LQIRUP SDWLHQWV DQG KHDOWKFDUH SURIHVsionals about the potential risk of complications or death for WKH JURXS RI LQGLYLGXDOV ZLWK VLPLODU ULVN SUR¿OH ZKR KDG undergone the procedure proposed[2]. The creation and validation of local models become increasingly necessary for demographic, socio-economic and cultural differences found in our environment and the need for external validation of existing prognostic models is of paramount importance for their applicability in clinical practice situations[3]. For this, every proposed method should be calibrated and discriminated, or that is, presenting good accuracy and distinguish patients at low and high risk, respectively[4,5]. The importance of external validation of the risk model is not only limited in clinical application. It also serves to recognize the limitations DQG VWUXFWXUDO GH¿FLHQFLHV RI GLIIHUHQW PHGLFDO LQVWLWXWLRQV and strategies aiming to qualify these medical services.

METHODS The present study is a cohort. It is a prospective, observational, analytical, single-center study and performed at the Center for Cardiac Surgery in Marília. Between April 2011 and June 2013, patients older than 18 years undergoing coronary artery bypass grafting, valve surgery, and the association of the two procedures, including reoperations were included consecutively, totaling 562 patients. The exclusion criterion was patients under 18 years of age and surgical indication for any other reason. Of the 562 patients, 26 patients (4.63%) died. 368 (65.5%) CABG, 160 (28.5%) valve surgery and 34 (6%) associated coronary and valve were performed.

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Data were collected from an institutional database stored in an Excel software spreadsheet that already includes all variables of STS score, logistic EuroSCORE, EuroSCORE ,, DQG ,QV&RU UHVSHFWLQJ WKHLU GHÂżQLWLRQV &KDUW ZKLFK allowed the calculation of the EuroSCORE II and InsCor after their publications. The calculations of the STS score, Eurosc1 and Eurosc2 were performed by own application from a smartphone and in the case of InsCor from a graph with its own scoring system. The follow-up was limited to hospital phase, with the primary outcome of hospital mortality that included the period between surgery and discharge. The estimated mortality was calculated from the scores STS score, Eurosc1 and Eurosc2 and IS. The calibration was calculated using the Hosmer-Lemeshow test and the P YDOXH! LQGLFDWHV WKDW WKH PRGHO ÂżWV the data and predicts mortality appropriately. Discrimination distinguishes patients at low and high risk, and is measured by the area under the ROC curve (Receiver Operating Characteristics). Statistical analysis was performed using SPSS software version 16.0 for Windows (IBM Corporation Armonk, New York). The performance of models was measured by comparing observed and expected mortality in risk groups established by models. The Fisher exact test was used for

contingency tables. The P value <0.05 was considered significant. This study was approved by the Research Ethics Committee of the Faculty of Medicine of MarĂ­lia under number 767 329 on August 27, 2014. RESULTS Performance results of the STS score, EuroSCORE, EuroSCORE II and InsCor Calibration Results STS score In the analysis of the whole group, association was observed between the STS score and death (P<0.001). The +RVPHU /HPHVKRZ WHVW VKRZHG D JRRGQHVV RI ÂżW VWDWLVtic=8.9696 with 8 degrees of freedom and P=0.3449. For coronary surgeries, we observe that the STS score was not associated with death (P=0.182) but showed good calibration (P=0.210). For valve surgery, we found that it is associated with death (P=0.009) with good calibration (P=0.460). Associated surgeries (coronary and valve), was not associated with death (P=0.4078), but showed good calibration (P=0.2648).

Chart1. Description of variables used in the STS score, EuroSCORE, EuroSCORE II and InsCor. STS score

Surgical intervention, age, gender, ethnicity, peripheral disease, cerebrovascular disease and stroke, weight, height, diabetes mellitus, creatinine, dialysis, hypertension, endocarditis, pulmonary disease, immunosuppression, previous cardiac surgery or angioplasty, use of preoperative inotropic, cardiogenic shock, cardiac resuscitation, cardiac arrhythmia, myocardial infarction, coronary symptoms, NYHA functional class, number of coronary arteries involved, LMCD lesion, LV ejection fraction, associated valvular heart disease, number of previous surgeries, procedure status (elective, urgent, emergent), use of intra-aortic balloon.

Eurosc1

Age, gender, COPD, peripheral vascular disease, neurological dysfunction, creatinine, endocarditis, previous cardiac surgery, preoperative critical state (use of preoperative inotropic support, cardiogenic shock, cardiac resuscitation, use of intra-aortic balloon), unstable angina, recent myocardial infarction, left ventricular ejection fraction, pulmonary hypertension (PSAP greater than 60 mmHg), emergency, associated surgery, aortic surgery, post-infarction VSD.

Eurosc2

Age, gender, creatinine clearance, peripheral vascular disease, poor mobility, endocarditis, previous cardiac surgery, COPD, critical condition (use of preoperative inotropic, cardiogenic shock, cardiac resuscitation, use of intra-aortic balloon pump), insulin diabetes dependent, NYHA functional class, &&6 DQJLQD FODVVLÂżFDWLRQ SUHYLRXV P\RFDUGLDO LQIDUFWLRQ OHIW YHQWULFXODU HMHFWLRQ IUDFWLRQ GHJUHH of pulmonary hypertension, procedure status (elective, urgent, emergent), associated surgery, aortic surgery.

InsCor

Age over 70 years, female gender, associated surgery (coronary + valve), recent infarction, reoperation, aortic valve surgery, tricuspid valve surgery, creatinine greater than 2 mg/dl, LV ejection fraction less than 30%, preoperative events (use of preoperative inotropic support, cardiogenic shock, cardiac resuscitation, use of intra-aortic balloon, acute renal failure, cardiac massage, tracheal intuEDWLRQ WDFK\FDUGLD RU YHQWULFXODU ÂżEULOODWLRQ

STS=Society of Thoracic Surgeons; Eurosc1=EuroSCORE; Eurosc2=EuroSCORE II; NYHA=New York Heart Association; LMCD=Left Main Coronary Artery Disease; COPD=Chronic Obstructive Pulmonary Disease; PSAP=Pulmonary Artery Systolic Pressure; LV=Left ventricle; CCS=Canadian Cardiovascular Society; VSD=Ventricular Septal Defect

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observe that the area under the ROC curve was 0.649 (95% CI 0.529-0.770, P=0.012) (Table 1).

EuroSCORE In the analysis of the whole group, association was observed between Eurosc1 and death (P<0.001). The Hosmer-Lemeshow WHVW VKRZHG D JRRGQHVV RI ÂżW VWDWLVWLF ZLWK GHJUHHV of freedom and P=0.7656. For coronary procedures, we found that the EuroSCORE is associated with death (P=0.021) with good calibration (P=0.529). For valve surgery, we found that the model is associated with death (P=0.004) in addition to good calibration (P=0.893). For associated surgeries (coronary and valve), although the Eurosc1 was not associated with death (P=0.1033), it showed good calibration (P=0.2911).

EuroSCORE According to the discriminative power of Eurosc1, we observe that the area under the ROC curve was 0.706 (95% CI 0.589-0.823, 3”0.001) (Table 1). EuroSCORE II According to the discriminative power of Eurosc2, we observe that the area under the ROC curve was 0.704 (95% CI 0.590-0.818, P=0.001) (Table 1).

EuroSCORE II In the analysis of the whole group, association was observed between Eurosc2 and death (P<0.001). The HosPHU /HPHVKRZ WHVW VKRZHG D JRRGQHVV RI ÂżW VWDWLVWLF 9.8963 with 8 degrees of freedom and P=0.2724. For coronary procedures, we observed that Eurosc2 is associated with death (P=0.040) and demonstrates good calibration (P=0.250). For valve surgery, we found that the model is associated with death (P<0.001) and demonstrates good calibration (P=0.423). For associated surgeries (coronary and valve), although the Eurosc2 was not associated with death (P=0.5159), it showed good calibration (P=0.5659).

InsCor According to the discriminative power of InsCor, we observe that the area under the ROC curve was 0.739 (95% CI 0.638 to 0.839, 3”0.001) (Table 1).

InsCor In the analysis of the whole group, association was observed between InsCor and death (P<0.001). The HosPHU /HPHVKRZ WHVW VKRZHG D JRRGQHVV RI ¿W VWDWLVWLF 8.9533 with 4 degrees of freedom and P=0.0623. For coronary procedures, we observe that although the InsCor was not associated with death (P=0.059), it showed good calibration (P=0.110). For valve surgery, we observed that InsCor is associated with death (P=0.002) and good calibration (P=0.743). For associated surgeries (coronary and valve), the InsCor was associated with death (P=0.022) but the calibration was not adequate (3”0.001). Fig. 1 - ROC curve for the Eurosc1, Eurosc2, STS-score and InsCor. EuroSc1 ROC=ROC curve presented by EuroSCORE score; EuroSc2 ROC=ROC curve presented by EuroSCORE II score; STS ROC=ROC curve presented by STS-score score; InsCor ROC=ROC curve presented by InsCor score.

Discrimination results (Figure 1) STS score According to the discriminative power of STSscore, we

Table 1. Area under the ROC curve for the STS-score, Eurosc1, Eurosc2 and InsCor se Area CI 95% P STS-score 0.061 0.529 - 0.770 0.649 0.012 ES 0.060 0.589 - 0.823 0.706 < 0.001 ES II 0.058 0.590 - 0.818 0.704 0.001 InsCor 0.051 0.638 - 0.839 0.739 < 0.001 ROC=Receiver Operating Characteristic, STS-score=Society of Thoracic Surgeons score, (XURVF (XUR6&25( (XURVF (XUR6&25( ,, &, &RQÂżGHQFH LQWHUYDO VH 6WDQGDUG HUURU P=P value

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Table 2. Expected and observed mortality. Expected mortality (Median) Eurosc2 Observed mortality Eurosc1 STS 1.3% (0.5-32) 4.6% 3.0% (0.8-72) 3.7% (0.2-60) Global 1.0% (0.5-24) 3.2% 2.5% (0.8-72) 2.7% (0.2-60) CABG 1.8% (0.5-32) 6.2% 5.0% (0.8-44) 9.6% (0.9-59) Valve 5.8% (1.5-23) 2.8% (0.6-11) CABG + Valve 11.7% 12.5% (1.9-26) CABG=Coronary artery bypass grafting; STS-score=Society of Thoracic Surgeons score; Eurosc1=EuroSCORE; Eurosc2=EuroSCORE II

DISCUSSION

of 0.706 (95% CI 0.589 to 0.823, P”0.001). According to the analysis of discrimination by ROC curve we have a poor discrimination with ROC<0.70, acceptable with ROC<0.75, JRRG ZLWK 52& DQG YHU\ JRRG ZLWK 52&• On October 2011, Nashef et al. showed the remodeled EuroSCORE that became known as the EuroSCORE II, only logistical and started using new variables as: calculation of creatinine clearance, insulin dependent diabetes, 1<+$ FODVV DQG &&6 FODVV LQ DGGLWLRQ WR UHFODVVL¿cation of the following variables: ejection fraction, pulmonary hypertension, urgency of the procedure and type of procedure performed. In calibration, the observed mortality was 3.9% and the expected mortality by EuroSCORE II of 3.77%, compared to 4.6% of the original EuroSCORE[11]. Barili et al.[12] validated the EuroSCORE II from the retrospective analysis of the results of a database of three institutions containing 12,325 consecutive patients and reaching a hospital mortality rate of 2.2% and a high discriminative power with an area under the ROC of 0.82 (95% CI: 0.80-0.85) and good calibration curve to a mortality of 30% predicted. However, it did not appear WR VLJQL¿FDQWO\ LPSURYH WKH SHUIRUPDQFH RI ROGHU YHUVLRQV in the highest tertiles of risk. Paparella et al.[13], studied data on 6191 patients and found hospital mortality rate of 4.85% and EuroSCORE II of 4.40¹7.04%. The area under the ROC curve of 0.83 showed good discriminative ability. In the analysis of calibration, there was an underestimation of the expected mortality in high-risk patients[13]. In South America, Borracci et al.[14], performed the validation of the EuroSCORE II in 503 patients undergoing cardiac surgery and obtained a hospital mortality rate of 4.17% with predicted mortality of 3.18% (P=0.402). The area under the ROC curve was 0.85 (P=0.0001) and the model showed good calibration in predicting in-hospital mortality (Hosmer-Lemeshow, P=0.082). The EuroSCORE II showed a good overall discriminative ability and calibration in this population, however, the performed model underestimates in-hospital mortality of patients with lower risk[14] ,Q %UD]LO WKH ¿UVW YDOLGDWLRQ RI WKH (X-

7KH SUHVHQW VWXG\ LV WKH ÂżUVW DVVHVVLQJ WKH SHUIRUPDQFH RI InsCor outside the institution that developed it. We apply and compare the most current and popular scores worldwide and found little difference when comparing the EuroSCORE with EuroSCORE II, a result similar to other international studies. The good current medical practice requires doctors and hospitals proposing to perform cardiovascular surgery to assess their patients adequately and in a responsible manner. In this preoperative evaluation, calculation and estimation of complications or death are required and able to propose strategies in the search for better results. 7KH SURJQRVWLF PRGHOV IRU ULVN DQDO\VLV DUH LQHIÂżFLHQW LI they serve only to the population where they were developed, thus they must have good performance in other populations, or that is, they must be validated externally[4]. The EuroSCORE system that for nearly 15 years provides an estimate of postoperative mortality in cardiac surgery is widely used to have good accuracy and adequate discriminating power in different countries[2]. In our midst, Andrade et al.[7] analyzed 804 patients undergoing valve surgery at the +HDUW ,QVWLWXWH RI 3HUQDPEXFR DQG REWDLQHG D JRRG ÂżW ZLWK DQ area under the ROC curve of 0.731 (95% CI 0.660 to 0.793 P<0.001). This same effectiveness has been demonstrated by other authors who studied patients undergoing CABG and found good accuracy, estimated at 69.9% and 89.2%[8,9]. On the other hand, Carvalho et al. analyzed 546 patients undergoing CABG and observed underestimation of lethality expected, with notable differences between the predicted and observed with an area under the ROC curve estimated at 0.62 advising against the use of the model in our midst. This fact is explained by differences in prevalence among risk factors of the model and the differences found in the population studied. An adjustment to the weight of the factors that composes such model could correct its performance and make it an applicable tool[10]. In our study, we found that the EuroSCORE was associated with death, with good calibration for CABG and heart valve surgeries and proper ROC curve

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roSCORE II was performed by Lisboa et al.[15], from the analysis of 1000 consecutive patients undergoing coronary and/or valve surgery. In calibration, the Hosmer-Lemeshow test was inadequate (P=0.0003). However, in the discrimination, the area under the ROC curve was 0.81 [95% CI (0.76-0.85), P<0.001], concluding that the EuroSCORE II became more complex and similar to the international literature with respect to poor calibration to predict mortality in patients undergoing coronary and/or valve in our midst, reinforcing the importance of a local model[15]. In the present study, we found that the EuroSCORE II was associated with death, showing good calibration in CABG and valve surgery performed with proper ROC curve area of 0.704 (95% CI, 0.590 to 0.818, P=0.001). The model of surgical risk created by the American Society of Thoracic Surgeons (Society of Thoracic Surgeons-STS) allows the calculation of mortality and morbidity, including rates of complications such as the risk of prolonged hospitalization, stroke, prolonged intubation, renal failure, deep wound infection and reoperation in patients undergoing CABG, valve (replacement or repair) and the association between the two types of surgery[16]. In our environment, Ikeoka et al. evaluated the STS score and achieved good calibration and discrimination for mortality and morbidity with an area under the ROC curve of 0.76 and 0.75 (3”0.001) respectively in a group of patients undergoing CABG[17]. In study similar to ours, Wang et al.[18], Australia, analyzed four models of risk (EuroSCORE, EuroSCORE II, STS score, and a local score called AusScore) for patients undergoing CABG. The estimated 30-day mortality by EuroSCORE was 2.8% (1.6 to 5.2%), EuroSCORE II 1.6% (from 1.0 to 2.8%), STS Score of 2.3% (1.3 - 4.5%) and the AusScore 0.5% (0.2 to 1.1%). Regarding the EuroSCORE, the EuroSCORE II, the STS score and the AusScore showed a slight improvement in calibration but similar for 30-day mortality discrimination. In our study, although the STS score was not associated with death, it showed good calibration in division by groups and the ROC curve of 0.649 was poor (95% CI 0.529 to 0.770, P=0.012). In our study, we found overall hospital mortality of 4.6%. Regarding mortality and expected by the scores observed in the three groups the analysis shows an underestimation of mortality estimated by three international scores, especially Eurosc1 and Eurosc2. When comparing the study by Wang et al.[18], we observed a wide variation in the risk of patients seen in our service, which could be explained by delayed access to health care and/or late surgical indication of patients WR WKH VXUJLFDO SURFHGXUH D V\VWHP RI UHÀH[HV RI SRRU KHDOWK In patients undergoing CABG, mortality was 3.2%, ranging from 1.0% to 4% (0.8%-72%). In valve surgery, mortality was 6.2%, ranging from 1.8% to 9.6% (0.8% -59%). In the combined surgery group, mortality was 11.7%, ranging from 2.8% to 12.5% (from 0.6 to 26%) (Table 2).

In 2013, a model of national risk developed from the analysis of 3000 patients undergoing coronary artery bypass and/or valve at the Heart Institute of the Clinics Hospital, Faculty of Medicine, University of São Paulo, called of InsCor was proposed by Mejia et al.[5], a remodeling product of two models (2000 Bernstein-Parsonnet and EuroSCORE) validated and faced with our reality and has become an important tool for patients treated at InCor- HCFMUSP[19]. 10 variables were selected: age >70 years; female; surgical coronary revascularization + valve; myocardial infarction < 90 days; reoperation; surgical treatment of aortic valve; surgical treatment of tricuspid valve; creatinine > 2 mg/dL; ejection fraction < 30%; and events (use of preoperative inotropic support, cardiogenic shock, cardiac resuscitation, use of intra-aortic balloon, acute renal failure, cardiac masVDJH WUDFKHDO LQWXEDWLRQ WDFK\FDUGLD RU YHQWULFXODU ¿EULOlation). The Hosmer-Lemeshow test was 0.184, indicating excellent calibration and the area under the ROC curve was 0.79 (95% from 0.74 to 0.83, P<0.001 IC)[6]. In our study, the InsCor was not associated with mortality for CABG, presented good calibration for CABG and heart valve surgeries and had adequate ROC of 0.739 (95% CI, 0.638 – 0.839, 3”0,001). This study assessed and compared three scores of international risk, being an American and two European and one developed in our country. The Brazilian experience in creating risk scores nationwide is completing nearly a decade[20,21], but without external validation. The search for simple models containing few variables are of wider applicability, since they FRQWDLQ WKH VLJQL¿FDQW ULVN IDFWRUV DQG KDYH DQ DSSURSULDWH degree of prediction because they are easier to be incorporated in patient care[22-24] We can consider limitations of the study the fact that it is a single center and with a small sample. It is an ongoing multicenter study in referral hospitals in the state of São Paulo, aiming at reshaping the InsCor for creation of the SCORE-SP (São Paulo System for Cardiac Operative Risk Evaluation). This project will initiate the São Paulo State Registry of Cardiovascular Surgery, in order to improve the quality of results and the safety of patients undergoing cardiac surgery in the State of São Paulo[25]. CONCLUSION In conclusion, the InsCor was the best model to preGLFW WKH ¿QDO RXWFRPH RI VXUYLYDO RU PRUWDOLW\ IROORZHG E\ EuroSCORE. The EuroSCORE was the best model in adjusted mortality for CABG and InsCor, along with the EuroSCORE II for valve surgery. Therefore, the local model InsCor showed good accuracy, in addition to being effective and easy to apply, mainly by using a smaller number of variables compared to the other models, variables that represent relevant risk factors in our population.

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Lampreia D, et al. Avaliação do EuroSCORE como preditor de mortalidade em cirurgia de revascularização miocårdica no Instituto do Coração de Pernambuco. Rev Bras Cir Cardiovasc. 2006;21(1):29-34.

Authors’ roles & responsibilities 0*7

HAB MSS MHB MPBM SMF EAP RTB

$QDO\VLV DQG RU LQWHUSUHWDWLRQ RI GDWD ÂżQDO DSSURYDO RI the manuscript conception and study design, conduct of operations, and/or experiments, writing of the manuscript or revising it critically for its content Performing the procedures and/or experiments Performing the procedures and/or experiments Performing the procedures and/or experiments Performing the procedures and/or experiments Performing the procedures and/or experiments Final approval of manuscript Final approval of the manuscript, performing the operations and/or experiments, writing of the manuscript or review of its content

10. Carvalho MRM, Souza e Silva NA, Klein CH, Oliveira GMM. Aplicação do EuroSCORE na cirurgia de revascularização miocårdica em hospitais públicos do Rio de Janeiro. Rev Bras Cir Cardiovasc. 2010;25(2):209-17. 11. Nashef SA, Roques F, Sharples LD, Nilsson J, Smith C, GoldstoneAR, et al. EuroSCORE II. Eur J Cardiothorac Surg. 2012;41(4):734-44. 12. Barili F, Pacini D, Capo A, Rasovic O, Grossi C, Alamanni F, et al. Does EuroSCORE II perform better than its original versions? A multicentre validation study. Eur Heart J. 2013;34(1):22-9.

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practice and suggestions for improvement. Ann Thorac Surg. 2004;77(6):2232-7. 24. Ranucci M, Castelvecchio S, Menicanti L, Frigiola A, Pelissero G. Accuracy, calibration and clinical performance of the EuroSCORE: can we reduce the number of variables? Eur J Cardiothorac Surg. 2010;37(3):724-2.

22. Jones RH, Hannan EL, Hammermeister KE, DeLong ER, O’Connor *7 /XHSNHU 59 HW DO ,GHQWL¿FDWLRQ RI SUHRSHUDWLYH YDULDEOHV QHHGHG for risk adjustment of short-term mortality after coronary artery bypass graft surgery. The Working Group Panel on the Cooperative CABG Database Project. J Am Coll Cardiol. 1996;28(6):1478-87.

25. MejĂ­a OAV, Lisboa LAF, Dallan LAO, Pomerantzeff PMA, Trindade EM, Jatene FB, et al. Heart surgery programs innovation XVLQJ VXUJLFDO ULVN VWUDWLÂżFDWLRQ DW WKH 6mR 3DXOR 6WDWH 3XEOLF Healthcare System: SP-SCORE-SUS study. Rev Bras Cir Cardiovasc. 2013;28(2):263-9.

23. Omar RZ, Ambler G, Royston P, Eliahoo J, Taylor KM. Cardiac surgery risk modeling for mortality: a review of current

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Carvalho VO,ORIGINAL et al. - Determinants of peak VO2 in heart transplant recipients ARTICLE

Braz J Cardiovasc Surg 2015;30(1):9-15

Determinants of peak VO2 in heart transplant recipients Determinantes do pico de VO2 em transplantados cardĂ­acos

Vitor Oliveira Carvalho1, PhD; Guilherme Veiga GuimarĂŁes1, PhD; Marcelo Luiz Campos-Vieira1, PhD; Aparecida Maria Catai1, PhD; Vagner Oliveira-Carvalho1, MsC; Silvia Moreira Ayub-Ferreira1, PhD; Edimar Alcides Bocchi1, PhD

DOI 10.5935/1678-9741.20140055

RBCCV 44205-1608 Conclusion: The determinants of the peak VO2 in heart WUDQVSODQW UHFLSLHQWV ZHUH UHFHSWRU VH[ DJH %RG\ 0DVV ,QGH[ KHDUW UDWH UHVHUYH DQG OHIW DWULXP GLDPHWHU +HDUW UDWH reserve was the unique variable positively associated with peak VO2 7KLV GDWD VXJJHVW WKH LPSRUWDQFH RI WKH V\PSDWKHWLF reinnervation in peak VO2 in heart transplant recipients.

Abstract Objective: To establish the determinants of the peak VO2 in heart transplant recipients. Methods: Patient’s assessment was performed in two FRQVHFXWLYH GD\V ,Q WKH ¿UVW GD\ SDWLHQWV SHUIRUPHG WKH KHDUW rate variability assessment followed by a cardiopulmonary H[HUFLVH WHVW ,Q WKH VHFRQG GD\ SDWLHQWV SHUIRUPHG D UHVWLQJ HFKRFDUGLRJUDSK\ +HDUW WUDQVSODQW UHFLSLHQWV ZHUH HOLJLEOH if they were in a stable condition and without any evidence of WLVVXH UHMHFWLRQ GLDJQRVHG E\ HQGRP\RFDUGLDO ELRSV\ 3DWLHQWV ZLWK SDFHPDNHU QRQFDUGLRYDVFXODU IXQFWLRQDO OLPLWDWLRQV VXFK as osteoarthritis and chronic obstructive pulmonary disease were excluded from this study. Results: 6L[W\ SDWLHQWV PDOH \HDUV DQG PRQWKV IROORZLQJ KHDUW WUDQVSODQWDWLRQ ZHUH DVVHVVHG 0XOWLYDULDWH DQDO\VLV VHOHFWHG WKH IROORZLQJ YDULDEOHV UHFHSWRUœV JHQGHU (P UHFHSWRU DJH P UHFHSWRU %RG\ 0DVV ,QGH[ (P KHDUW UDWH UHVHUYH P OHIW DWULXP GLDPHWHU (P 0XOWLYDULDWH DQDO\VLV VKRZHG U DQG U ZLWK P (TXDWLRQ SHDN922 UHFHSWRU JHQGHU UHFHSWRU DJH UHFHSWRU %0, KHDUW UDWH UHVHUYH OHIW DWULXP GLDPHWHU

Descriptors: +HDUW 7UDQVSODQWDWLRQ ([HUFLVH ([HUFLVH Tolerance. Resumo Objetivo: Estabelecer os determinantes do VO2 pico em transplantados de coração. MÊtodos: Avaliação do paciente foi realizada em dois GLDV FRQVHFXWLYRV 1R SULPHLUR GLD RV SDFLHQWHV UHDOL]DUDP D DYDOLDomR GD YDULDELOLGDGH GD IUHTXrQFLD FDUGtDFD VHJXLGD GH XP WHVWH GH HVIRUoR FDUGLRSXOPRQDU 1R VHJXQGR GLD RV SDFLHQWHV UHDOL]DUDP HFRFDUGLRJUD¿D GH UHSRXVR 2V WUDQVSODQWDGRV IRUDP HOHJtYHLV VH HVWLYHVVHP HP XPD condição eståvel e sem qualquer evidência de rejeição GLDJQRVWLFDGD SRU ELySVLD HQGRPLRFiUGLFD 3DFLHQWHV FRP PDUFD SDVVR OLPLWDo}HV IXQFLRQDLV QmR FDUGLRYDVFXODUHV

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Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP (InCor HC-FMUSP), São Paulo, Brazil.

Correspondence address: Vitor Oliveira Carvalho Universidade Federal de Sergipe (UFS) Departamento de Fisioterapia/Hospital UniversitĂĄrio Rua ClĂĄudio Batista , sn - Aracaju, SE, Brazil - Zip code: 49060-000 E-mail vitor.ufs@gmail.com

This study was carried out at Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP (InCor HC-FMUSP), São Paulo, Brazil in association with Departamento de Fisioterapia da Universidade Federal de São Carlos - UFScar, São Carlos, SP, Brazil and Departamento de Fisioterapia da Universidade Federal de Sergipe (UFS), Aracaju, SE, Brazil.

Article received on December 3rd, 2013 Article accepted on February 24th, 2014

Financial suport: FAPESP (Fundação de Amparo a Pesquisa do Estado de São Paulo), protocol: 07137-3.

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Carvalho VO, et al. - Determinants of peak VO2 in heart transplant recipients

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sexo (P LGDGH P Ă‹QGLFH GH 0DVVD &RUSRUDO (P IUHTXrQFLD FDUGtDFD GH UHVHUYD P GLkPHWUR do ĂĄtrio esquerdo (P YDULiYHLV GR UHFHSWRU $ DQiOLVH PXOWLYDULDGD PRVWURX U H U FRP P (TXDomR VO2 VH[R UHFHSWRU LGDGH UHFHSWRU ,0& UHFHSWRU IUHTXrQFLD FDUGtDFD GH UHVHUYD GLkPHWUR GH iWULR HVTXHUGR ConclusĂŁo: Os determinantes do pico de VO2 em WUDQVSODQWDGRV GH FRUDomR IRUDP VH[R UHFHSWRU LGDGH Ă‹QGLFH GH 0DVVD &RUSRUDO IUHTXrQFLD FDUGtDFD GH UHVHUYD H GLkPHWUR do ĂĄtrio esquerdo. A frequĂŞncia cardĂ­aca de reserva foi a Ăşnica variĂĄvel positivamente associada com o pico de VO2. Estes GDGRV VXJHUHP D LPSRUWkQFLD GD UHLQHUYDomR VLPSiWLFD QR SLFR de VO2 em transplantados de coração.

$EEUHYLDWLRQV DFURQ\PV V\PEROV BMI BNP DT ECA IVRT LF/HF RRi VO2

Body mass index B-type Natriuretic Peptide Deceleration time Angiotensin conversor enzyme inhibitors Isovolumic relaxation time Low/high frequency domain in heart rate variability R-R intervals Oxygen consumption

tais como osteoartrite e doença pulmonar obstrutiva crônica foram excluídos deste estudo. Resultados: 6HVVHQWD SDFLHQWHV GR VH[R PDVFXOLQR DQRV H PHVHV DSyV R WUDQVSODQWH FDUGtDFR IRUDP DYDOLDGRV $ DQiOLVH PXOWLYDULDGD VHOHFLRQRX DV VHJXLQWHV YDULiYHLV

Descritores: 7UDQVSODQWH GH &RUDomR ([HUFtFLR $SWLGmR )tVLFD

VHFXWLYH GD\V ,Q WKH ÂżUVW GD\ SDWLHQWV SHUIRUPHG WKH KHDUW rate variability assessment followed by a cardiopulmonary exercise test. In the second day, patients performed a resting echocardiography.

INTRODUCTION Heart transplantation is a worldwide procedure indicated to patients with refractory heart failure. It is well known that heart transplant improves patient’s survival, quality of life and exercise capacity, when compared to pre-transplant condition[1,2]. Although heart transplant recipients have an exercise capacity greater than before the procedure, it is known that the physical capacity restoration to normal levels does not always occur[1,2]. This is attributed to physical deconditioning resulting from previous heart failure[3], a low chronotropic response (as a result of a cardiac denervation, also accessed by heart rate variability)[4] and, in many cases, impairment in cardiac function after transplantation[2]. The cardiac systolic function of the transplanted heart seems to be normal in most patients, while diastolic dysfunction appears to be present in most of the transplanted heart. Diastolic dysfuncWLRQ ZDV UHFHQWO\ LGHQWL¿HG DV RQH RI WKH IDFWRUV WKDW VHHP WR LQÀXHQFH QHJDWLYHO\ WKH PD[LPDO DQG VXEPD[LPDO H[HUFLVH capacity in heart transplant recipients[5,6]. Despite this, little is known about the determinants of exercise capacity in heart transplant recipients. The aim of this study was to establish the determinants of the peak VO2 in heart transplant recipients.

Study population Heart transplant recipients were eligible if they were in a stable condition (for, at least, 3 months) and without any evidence of tissue rejection diagnosed by endomyocardial biopsy. Patients with pacemaker, noncardiovascular functional limitations such as osteoarthritis and chronic obstructive pulmonary disease were excluded from this study. Patients were recruited from a tertiary cardiology hospital from September 2010 to November 2011. Subjects’ characteristics are listed in Table 1. This protocol was approved by the Ethical Committee of our institution. All patients provided informed consent prior to participation. Variables considered to be potentially associated with peak VO2 We considered to be potentially associated with peak VO2 as follows: donor and recipient age and body mass index (BMI), etiology of heart failure before transplantation (Chagas and non-Chagas), recipient heart rate reserve, gender, percentage of age-predicted peak heart rate, percentage of heart rate drop in the second minute of recovery in the cardiopulmonary test, left atrium diameter, cold ischemia time, time following heart transplantation, resting heart rate, VE/ VCO2 slope, right ventricle diameter, left ventricle diastolic diameter, left ventricle ejection fraction, E/E’ ratio and low/ high frequency domain in heart rate variability (LF/HF).

METHODS 6WXG\ GHVLJQ This study was performed in a tertiary cardiology hospital in Brazil. Patient’s assessment was performed in two con-

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Carvalho VO, et al. - Determinants of peak VO2 in heart transplant recipients

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Table 1. Characterization of study participants.

Variables Etiology: Chagas (%) Non-Chagas (%) Men (%) Recipients age (years) Donors age (years) Donors weight (kg) Recipients weight (kg) Donors height (cm) Recipients height (cm) Ischemic time (min) Recipients BMI (Kg/m2) Donors BMI (Kg/m2) Time following heart transplant (months) Resting heart rate (bpm) Recipients heart rate reserve (bpm) % of age-predicted peak heart rate % of heart rate drop in the second minute of recovery Left atrium diameter Cold ischemia time (min) VE/VCO2 slope Right ventricle diameter (mm) Left ventricle diastolic diameter (mm) Left ventricle ejection fraction (%) E/E’ ratio LF/HF Medication: Cyclosporine Diuretics ACE inhibitors (enalapril) Angiotensin receptor antagonist (losartan) Corticosteroids (prednisone) Azathioprine Mycophenolate Tacrolimus Sirolimus Everolimus Calcium channel blocker (diltiazem) Ezetimibe Simvastatin Hydralazine Metformin Fluoxetine Gabapentin Olanzapine Topiramate Bromazepam Insulin

Number of patients (%), dose(mg/day) 45% 55% 68% 48±15 31±11 76±9 68±13 176±7 166±10 206±115 25±4 25±2 64±54 82±12 49±17 77±12 8±8 44±10 207±115 30±6 22±3 48±4 62±5 6.8±2.3 6.9±8.9 71%, 174±58 mg/day 8.3% 10%, 23±14 mg/day 10%, 62±31 mg/day 30%, 5.2±3.4 mg/day 30%, 76±25 mg/day 37%, 1096±422 mg/day 25%, 7±4 mg/day 1.6%, 1 mg/day 3.3%, 1±0.35 mg/day 58%, 126±71 mg/day 1.6%, 10 mg/day 68.3%,11.4±4.4 mg/day 6.6%, 144±116 mg/day 6.6%,1700±00 mg/day 3.3%, 32±11 mg/day 1.6%, 400 mg/day 5%, 10 mg/day 3.3%, 125±106 mg/day 5%, 3 mg/day 7.5%, 69±53 mg/day

BMI=Body mass index, ECA=Angiotensin conversor enzyme inhibitors. LF/HF=Low/high frequency domain in heart rate variability

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&DUGLRSXOPRQDU\ H[HUFLVH WHVW All patients were asked to refrain from both strenuous physical activity and the consumption of any stimulants (e.g., coffee, tobacco, alcohol) for 24h prior to the cardiopulmonary exercise test. Patients’ last meal was ingested at least 2h before the test. Heart transplant recipients underwent the test on a programmable treadmill (TMX425 Stress Treadmill; TrackMaster, Newton, KS, USA) in a temperature-controlled room (21-23°C) between 10–12am with a standard 12-lead continuous ECG monitor (CardioSoft 6.5; GE Medical Systems IT, Milwaukee, WI, USA). Blood pressure monitoring was performed by an automatic device. Resting heart rate was considered the 20-min average in a supine position. Minute ventilation, oxygen uptake, carbon dioxide output and other cardiopulmonary variables were acquired breath-by-breath by a computerized system (Vmax Encore29; SensorMedics, Yorba Linda, CA, USA). 0HWDEROLF GDWD ZHUH FRPSXWHG DV WKH PHDQ RI WKH ÂżQDO 30 s of the resting period, whereas peak of VO2 and peak KHDUW UDWH ZHUH WKH PHDQ YDOXHV RI WKH ÂżQDO V RI HIIRUW before exhaustion. The respiratory exchange ratios were recorded as the averaged samples obtained during each stage RI D PRGLÂżHG 1DXJKWRQ SURWRFRO $ VDWLVIDFWRU\ FDUGLRSXOmonary exercise test was characterized by a peak of respiratory exchange ratio>1.05 and symptoms of maximum effort. +HDUW UDWH UHVHUYH >ESP@ ZDV GHÂżQHG DV PD[LPXP KHDUW UDWH achieved in the cardiopulmonary exercise test — average of 10-min resting heart rate in the supine position. Heart rate UHFRYHU\ ZDV DVVHVVHG GXULQJ WKH ÂżUVW DQG VHFRQG PLQXWHV after cardiopulmonary exercise test.

systole (S’ wave) at the septal ring, side ring, bottom ring, front ring of right ventricle. Measurement of E/E´ratio was performed in the left ventricular annulus, from the basal septal and lateral segments (considered mean values). +HDUW UDWH YDULDELOLW\ Experimental protocol: All the heart transplant recipients remained at rest for 10 minutes on the supine position and were instructed to breathe spontaneously. Then, instantaneous R-R intervals (RRi) were recorded for 10 min with a digital telemetry system, consisting of a transmitter placed on the patient’s chest and a HR monitor (PolarÂŁ RS800CX; Polar Electro Oy, Kempele, Finland) This system detects ventricular depolarization, corresponding to the R wave on the electrocardiogram, at a sampling rate of 500 Hz, which had been previously validated[8]. The signals were transmitted to a receiver and then to a computer for subsequent analysis. Data analysis: The RRi sequence of length n=256 beats was selected for each subject. The length of greatest stability was chosen from the central region of the time series. The mean and variance of the RRi were also calculated. HRV spectral analysis: The HRV frequency domain analysis was performed with an autoregressive model[9,10], on previously selected RRi sequences. Two main spectral components were considered: low frequency (LF - from 0.04 to 0.15 Hz) and high frequency (HF - from 0.15 to 0.50 Hz) that represent the sympathetic and vagal modulations, respectively[11]. The spectral components are reported as normalized units (LFun and HFun) and LF/HF ratio. Normalization consisted of dividing the power of a given spectral component (HF or LF) by the total power minus the power below 0.04 Hz, and multiplying the ratio by 100.9 All patients presented a respiratory rate in the frequency range of HF band of HRV.

(FKRFDUGLRJUDSK\ The assessment followed the recommendations of the American Society of Ecocardiography[7]. We used a commercially available equipment, model IE 33, Philips Medical Systems, Andover, MA, USA. The acquired data considered bidimensional echocardiography, pulsed Doppler, continuRXV ZDYH 'RSSOHU WLVVXH 'RSSOHU DQG FRORU ÀRZ PDSSLQJ It was obtained at least three measurements of each echocardiographic variable and the average was considered. We analyzed: left ventricle diameters and volumes, left ventricle ejection fraction (Simpson’s rule), left ventricle mass index, left ventricle diastolic assessment (pulsed Doppler of mitral LQÀRZ DQG WKH VWXG\ RI WKH ÀRZ RI SXOPRQDU\ YHLQV DQG 7LVsue Doppler). Thus, we analyzed with pulsed Doppler, E and A waves, E/A ratio, deceleration time (DT), isovolumic relaxation time (IVRT), systolic component of the pulmonary YHQRXV ÀRZV 6 ZDYH GLDVWROLF FRPSRQHQW RI WKH SXOPRQDU\ YHQRXV ÀRZ ' ZDYH 6 ' UDWLR 7KH DQDO\VLV ZLWK tissue Doppler was obtained in apical four and two chambers with sample volume of 1 to 2 mm. It was checked to the maximum rate of myocardial displacement at the beginning and end of the diastole (E’ and A’ wave respectively) and during

&XUUHQW PHGLFDWLRQ LQWDNH 0HGLFDWLRQ SURÂżOH LV VKRZQ LQ 7DEOH 3DWLHQWV WRRN DQgiotensin conversor enzyme inhibitors, losartan and isosorbide 5-mononitrate two times per day, one half of the daily dose in the morning (9:00 am) and the other half at night (9:00 pm). Diuretics were taken in the morning (9:00 am). All heart transplant recipients were receiving immunosuppressive therapy two times per day, one half of the daily dose in the morning and the other half at night. Antihypertensive drugs were taken, most of the times, in the morning. Statistical analysis Data are presented as mean and standard deviation. We evaluated the association of the variables collected in the 60 selected patients. For this, we used univariate analysis to select the variables to be used in the multivariate model. For WKH XQLYDULDWH DQDO\VLV D VLJQLÂżFDQFH OHYHO RI OHVV WKDQ (P<0.20) was considered. In multivariate analysis, the nonVLJQLÂżFDQW YDULDEOHV ZHUH H[FOXGHG IURP WKH PRGHO PDQXDO-

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ly, one at a time) following the criterion of greater “Pâ€? value. The model was determined when all the variables were SUHVHQWHG ZLWK D VLJQLÂżFDQFH OHYHO OHVV WKDQ P<0.05). The dependent variable used was the peak VO2[1,2,5]. After the analysis, we established an equation with variables associated with peak VO2. For all statistical analyzes, we used SPSS (Chicago IL, USA) version 13.0.

Multivariate analysis selected the following variables: receptor’s gender (P=0.001), receptor age (P=0.049), receptor BMI (P=0.005), heart rate reserve (P<0.0001), left atrium diameter (P=0.016). Multivariate analysis showed r=0.77 and r2=0.6 with P<0.001. Equation derived from the multivariate analysis: peak VO2=32,851 - receptor gender (3,708) - receptor age (0,067) - receptor BMI (0,318) + heart rate reserve (0,145) - left atrium diameter (0,111) Considering: peak VO2 in mL/Kg/min, gender (0=male and 1=female), age in years, BMI in Kg/m2, heart rate reserve in beats per minute and left atrium diameter in millimeters.

RESULTS Participants From 176 heart transplant recipients alive in our service, 109 were not found by phone calls or lived in another city that prevented the realization of the protocol. Seven patients were excluded due to refusal, pacemaker or sequel of stroke (Figure 1). Sixty patients (68% male, 48 years and 64 months following heart transplantation) were assessed (Table 1).

DISCUSSION 7KH PDLQ ÂżQGLQJ RI WKLV VWXG\ ZDV WKDW SHDN 922 of heart transplant recipients was determined by receptor gender, age, BMI, heart rate reserve and left atrium diameter. 2XU VWXG\ LV WKH ÂżUVW RQH WR LQYHVWLJDWH WKH GHWHUPLQDQWV of peak VO2 in heart transplant recipients using variables that are non-invasive and easy to be collected in clinical practice. In our study, we observed that the peak VO2 was negatively associated with gender, BMI and age of the recipient and the diameter of the left atrium of the allograft. Of these, gender and BMI seemed to be the determinants more strongly associated with exercise capacity. Moreover, the heart rate reserve was the unique variable positively associated to peak VO2. Our data strongly suggest that the sympathetic reinnervaWLRQ LV WKH PDLQ YDULDEOH WKDW SRVLWLYHO\ LQĂ€XHQFHV SHDN 922 in heart transplant recipients. Nevertheless, the parasymSDWKHWLF UHLQQHUYDWLRQ GRHV QRW VHHP WR LQĂ€XHQFH WKH H[HUcise capacity in heart transplant recipients. Previous studies showed that the parasympathetic reinnervation in adults is not consistent and may occur only from 5 to 10% of cases. Moreover, the sympathetic reinnervation occurs much more frequently and is related to exercise capacity in heart transplant recipients from 50 to 60% of cases in 3 years[1,12,13]. The study by Bernardi et al.[14] showed that exercise training can improve cardiovascular control in heart transplant recipients. 7KH QHJDWLYH LQĂ€XHQFH RI %0, DJH DQG JHQGHU LQ H[HUcise capacity is already well established in exercise physiolRJ\ ÂżHOG ,W LV NQRZQ WKDW ZRPHQ KDYH ORZHU SHDN 922 than men, as well as fatter people compared to skinny and older people compared to younger, when we keep all other variables (such as exercise training levels) constant[15]. A relatively new data appeared in our research: the negative LQĂ€XHQFH RI WKH OHIW DWULXP GLDPHWHU LQ SHDN 922 in heart transplant recipients. The study by Abdul-Waheed et al.[16] showed that the left atrium of adult heart transplant recipients increased in one year of follow-up. Moreover, this study showed an inverse association between left atrium and peak VO2. The authors K\SRWKHVL]HG WKDW WKH VXUJLFDO VFDU FRXOG EH QHJDWLYHO\ LQĂ€X-

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Outcome data/main results Univariate analysis selected the following variables: receptor’s age (P=0.042), receptor’s BMI (P=0.056), heart rate reserve (P<0.0001), percentage of age-predicted peak heart rate (P=0.052), percentage of heart rate drop in the second minute of recovery in the cardiopulmonary exercise test (P=0.067), slope VE/VCO2 (0.115), left atrium diameter (P=0.028), right ventricular diameter (P=0.079), E/E’ ratio (0.144), cold ischemia time (P=0.15), donor’s age (P=0.022), LF/HF (P=0.18) and receptor’s sex (P=0.003). The following variables were withdrawn from multivariate analysis model (in order of withdrawal): slope VE/VCO2 (P=0.957), percentage of heart rate drop in the second minute of recovery in the cardiopulmonary exercise test (P=0.937), percentage of age-predicted peak heart rate (P=0.771), right ventricle diameter (P=0.456), LF / HF (P=0.434), donor’s age (P=0.51), cold ischemia time (P=0.227) and E/E’ ratio (P=0.449).

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encing left atrium pumping. In agreement with Abdul-Waheed et al.[16], our study showed a similar relationship between left atrium and exercise capacity. Unfortunately, our study can not explain the mechanisms involved in this relationship, but the hypothesis raised by Abdul-Waheed at al.[16] seems to be relevant and deserves a deep investigation in future studies. 7KH ODFN RI LQĂ€XHQFH RI WKH WLPH RI WUDQVSODQW DQG WKH E/E’ ratio in peak VO2 found in this study is an important information and deserves some discussion. The E/E’ ratio is an important echocardiography index in the diagnosis of diastolic dysfunction and has been shown to be related to functional class, cardiac mortality and hospitalization in patients with heart failure[17,18]. The ratio above 15 is a strong indicator of heart failure with preserved left ventricle ejection fraction. The E/E’ ratio between 8 and 15 represents a “gray zoneâ€? for diagnosis of diastolic dysfunction. In these cases, B-type Natriuretic Peptide (BNP) seem to have a great importance for the differential diagnosis[19]. The prevalence of diastolic dysfunction in our study was 3.4%, which we consider low compared to 33% of the study by Roten et al.[5] We expected that the prevalence of diastolic dysfunction were higher and the E/E’ ratio increased along the segment after heart transplantation due to the increased incidence of co-morbidities such as hypertension. There are no data in the literature regarding diastolic function (E/E’ ratio) and time of cardiac transplantation. We believe the fact that our patients are well treated and compensated for comorbidities such as hypertension, the E/E’ ratio remained constant throughout the follow-up. In a curious way, our study showed no association between peak VO2 and the time of transplantation, but a positive association between peak VO2 and cardiac sympathetic reinnervation through heart rate reserve. These data are quite relevant for a deeper understanding of the behavior of exercise capacity over time of transSODQWDWLRQ ,W VHHPV WKDW WKH UHDO IDFWRU LQĂ€XHQFLQJ H[HUFLVH capacity is sympathetic reinnervation and not simply the time of transplantation. This information let us believe that for the same time following heart transplant, we will have more and less reinnervated patients. Consequently we will have patients with higher and lower exercise capacity. Finally, the study by Roten et al.[5] showed that the diastolic dysfunction was associated with exercise capacity limitation of heart transplant recipients. However, our study IRXQG QR VXFK DVVRFLDWLRQ %HFDXVH RI WKLV FRQĂ€LFWLQJ GDWD some considerations must be taken into account. In our study, the prevalence of diastolic dysfunction was much lower than in the study by Roten et al.[5] Perhaps if our study had shown a higher prevalence of diastolic dysfunction (and consequent higher E/E’ ratio), our data would have agreed to the study by Roten et al.[5] Therefore, further studies in this area are necessary for a deeper understanding of the relationship between peak VO2 and the E/E’ ratio. This study has some limitations. Patients only performed

resting echocardiography. Certainly, the assessment of the cardiac function during exercise would bring important information to the understanding of the relationship between E/E’ ratio and in exercise capacity of heart transplant recipients. In addition, further investigation of the left atrium would be relevant for a better understanding of the mechanisms involved in the limitation of exercise capacity. This study was also limited by not assessing the vascular function and peripheral muscle metabolism (oxygen extraction). Tests such as the kinetics of O2, would be useful in IXWXUH UHVHDUFK WR HYDOXDWH WKH LQĂ€XHQFH RI WKH ÂłSHULSKHU\´ LQ the exercise capacity of transplanted patients. CONCLUSION In this study, the determinants of the peak VO2 in heart transplant recipients were: receptor gender, age, BMI, heart rate reserve and left atrium diameter. Heart rate reserve was the unique variable that was positively associated with peak VO2. This data suggest the importance of the sympathetic reinnervation in peak VO2 in heart transplant recipients. $XWKRUVÂś UROHV UHVSRQVLELOLWLHV VOC

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REFERENCES 1. Bengel FM, Ueberfuhr P, Schiepel N, Nekolla SG, Reichart B, Schwaiger M. Effect of sympathetic reinnervation on cardiac performance after heart transplantation. N Engl J Med. 2001;345(10):731-8.

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2. Leung TC, Ballman KV, Allison TG, Wagner JA, Olson LJ, Frantz RP, et al. Clinical predictors of exercise capacity 1 year after cardiac transplantation. J Heart Lung Transplant. 2003;22(1):16-27.

11. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation. 1996;93(5):1043-65.

3. Renlund DG, Taylor DO, Ensley RD, O’Connell JB, Gilbert EM, Bristow MR, et al. Exercise capacity after heart transplantation: LQÀXHQFH RI GRQRU DQG UHFLSLHQW FKDUDFWHULVWLFV - +HDUW /XQJ Transplant. 1996;15(1 Pt 1):16-24.

12. Ramaekers D, Ector H, Vanhaecke J, van Cleemput J, van de Werf F. Heart rate variability after cardiac transplantation in humans. Pacing Clin Electrophysiol. 1996;19(12 Pt 1):2112-9.

4. Bengel FM, Ueberfuhr P, Schiepel N, Nekolla SG, Reichart B, Schwaiger M. Effect of sympathetic reinnervation on cardiac performance after heart transplantation. N Engl J Med. 2001;345(10):731-8.

13. Wilson RF, Laxson DD, Christensen BV, McGinn AL, Kubo SH. Regional differences in sympathetic reinnervation after human orthotopic cardiac transplantation. Circulation. 1993;88(1):165-71.

5. Roten L, Schmid JP, Merz F, Carrel T, Zwahlen M, Walpoth N, et al. Diastolic dysfunction of the cardiac allograft and maximal exercise capacity. J Heart Lung Transplant. 2009;28(5):434-9.

14. Bernardi L, Radaelli A, Passino C, Falcone C, Auguadro C, Martinelli L, et al. Effects of physical training on cardiovascular control after heart transplantation. Int J Cardiol. 2007;118(3):356-62.

6. Scott JM, Esch BT, Haykowsky MJ, Warburton DE, Toma M, Jelani A, et al. Cardiovascular responses to incremental and sustained submaximal exercise in heart transplant recipients. Am J Physiol Heart Circ Physiol. 2009;296(2):H350-8.

15. Fletcher GF, Balady GJ, Amsterdam EA, Chaitman B, Eckel R, Fleg J, et al. Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Circulation. 2001;104(14):1694-740.

7. Lang RM, Badano LP, Tsang W, Adams DH, Agricola E, Buck T, et al; American Society of Echocardiography; European Association of Echocardiography. EAE/ASE recommendations for image acquisition and display using three-dimensional echocardiography. Eur Heart J Cardiovasc Imaging. 2012;13(1):1-46.

16. Abdul-Waheed M, Yousuf M, Kelly SJ, Arena R, Ying J, Naz T, et al. Does left atrial volume affect exercise capacity of heart transplant recipients? J Cardiothorac Surg. 2010;5:113.

8. Loimaala A, Sievänen H, Laukkanen R, Pärkkä J, Vuori I, Huikuri H. Accuracy of a novel real-time microprocessor QRS detector for heart rate variability assessment. Clin Physiol. 1999;19(1):84-8.

17. Hamdan A, Shapira Y, Bengal T, Mansur M, Vaturi M, Sulkes J, et al. Tissue Doppler imaging in patients with advanced heart failure: relation to functional class and prognosis. J Heart Lung Transplant. 2006;25(2):214-8.

9. Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain. Circulation. 1991;84(2):482-92.

18. Galrinho A, Branco L, Soares R, Timóteo A, Abreu J, Leal A, et al. Prognostic implications of tissue Doppler in patients with dilated cardiomyopathy. Rev Port Cardiol. 2006;25(9):781-93.

10. Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, et al. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circulation Res. 1986;59(2):178-93.

19. Bocchi EA, Braga FG, Ferreira SM, Rohde LE, Oliveira WA, Almeida DR, et al. Sociedade Brasileira de Cardiologia. III Brazilian Guidelines on Chronic Heart Failure. Arq Bras Cardiol. 2009;93(1 Suppl 1):3-70.

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Lucinda LB, et al. - Stress and the acute myocardial infarction ORIGINAL ARTICLE

Braz J Cardiovasc Surg 2015;30(1):16-23

Evaluation of the prevalence of stress and its phases in acute myocardial infarction in patients active in the labor market Avaliação da prevalência do estresse e suas fases no infarto agudo do miocårdio em pacientes atuantes no mercado de trabalho

Luciane Boreki Lucinda1, MsC; Ana Claudia Merchan Giaxa ProsdĂłcimo1, MsC; Katherine Athayde Teixeira de Carvalho2, PhD; Julio Cesar Francisco1, PhD; Cristina Pellegrino Baena1, MD, PhD; Marcia Olandoski1, PhD;Vivian Ferreira do Amaral1, PhD; JosĂŠ Rocha Faria-Neto1, MD, PhD; Luiz CĂŠsar Guarita-Souza3, MD, MsC, PhD

DOI: 10.5935/1678-9741.20140068

RBCCV 44205-1609

Abstract Introduction: Acute myocardial infarction is a social health problem of epidemiological relevance, with high levels of morELGLW\ DQG PRUWDOLW\ 6WUHVV LV RQH RI WKH PRGL¿DEOH ULVN IDFWRUV that triggers acute myocardial infarction. Stress is a result of a set of physiological reactions, which when exaggerated in intensity or duration can lead to imbalances in one’s organism, resulting in vulnerability to diseases. Objective: To identify the presence of stress and its phases LQ KRVSLWDOL]HG DQG DFWLYH ODERU PDUNHW SDWLHQWV ZLWK XQVWDEOH myocardial infarction and observe its correlation with the life of this population with stress. Methods: The methodology used was a quantitative, descriptive and transversal research approach conducted with a total of SDWLHQWV ZKR ZHUH VWLOO DFWLYH LQ WKH ODERU PDUNHW SUHVHQWLQJ or not morbidities. Data collection occurred on the fourth day of their hospitalization and patients responded to Lipp’s Stress Symptom Inventory for adults.

Results: Thirty-one patients (72.1%) presented stress and WZHOYH GLG QRW ,Q SDWLHQWV ZLWK VWUHVV WKH LGHQWLÂżHG phases were: alert - one patient (3.2%); resistance -twenty-two patients (71.0%); quasi-exhaustion - six patients (19.4%) and exhaustion - two patients (6.5%). All women researched presented stress. Conclusion: The results suggest a high level of stress, especially in the resistance phase, in the male infarcted populaWLRQ KRVSLWDOL]HG DQG DFWLYH LQ WKH ODERU PDUNHW

1

Correspondence address: Luiz CĂŠsar Guarita-Souza PontifĂ­cia Universidade CatĂłlica do ParanĂĄ – PUCPR Rua Imaculada Conceição, 1155 – Prado Velho, Curitiba, PR, Brazil Zip code: 80215-901 E-mail: guaritasouzalc@hotmail.com

Descriptors: Stress. Myocardial infarction. Psychology. Resumo Introdução: O infarto agudo do miocårdio Ê um problema de saúde coletiva com altos índices de morbimortalidade com relevância epidemiológica. O estresse Ê um dos fatores de risco modL¿FiYHLV GHVHQFDGHDQWHV GR LQIDUWR DJXGR GR PLRFiUGLR 2 HVWUHVVH p FRPSRVWR SRU XP FRQMXQWR GH UHDo}HV ¿VLROyJLFDV TXH VH

PontifĂ­cia Universidade CatĂłlica do ParanĂĄ (PUCPR), Curitiba, PR, Brazil. Instituto de Pesquisa PelĂŠ Pequeno PrĂ­ncipe, Curitiba, PR, Brazil. 3 InCor-Hospital das ClĂ­nicas da Faculdade de Medicina da Universidade de SĂŁo Paulo(HCFMUSP), SĂŁo Paulo, SP, Brazil, PontifĂ­cia Universidade CatĂłlica do ParanĂĄ (PUCPR), Curitiba, PR, Brazil and Universidade Federal do ParanĂĄ (UFPR), Curitiba, PR, Brazil. 2

This study was carried out at PontifĂ­cia Universidade CatĂłlica do ParanĂĄ (PUCPR), Curitiba, PR, Brazil and Instituto de Pesquisa PelĂŠ Pequeno PrĂ­ncipe, Curitiba, PR, Brazil. 1R ÂżQDQFLDO VXSSRUW

Article received on April 8th, 2014 Article accepted on April 27th, 2014

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Resultados: A mÊdia de idade foi de 50,3 anos. A incidência de infarto agudo do miocårdio nos homens foi de 91% e nas mulheres de 9%. Em relação à escolaridade atÊ o segundo grau entre homens e mulheres foi de 16% e com segundo grau completo ou mais, de 84%. Apresentaram estresse 31 pacientes (72,1%), não apresentaram estresse 12 (27,9%). Nos pacientes FRP HVWUHVVH DV IDVHV LGHQWL¿FDGDV IRUDP DOHUWD SDFLHQWH (3,2%); resistência: 22 pacientes (71,0%); quase-exaustão: 6 pacientes (19,4%) e exaustão: 2 pacientes (6,5%). Todas as mulheres da pesquisa apresentaram estresse. Conclusão: Os resultados encontrados sugerem um elevado nível de estresse, principalmente na fase de resistência, na população de cardiopatas em infarto agudo do miocårdio ativos no mercado de trabalho.

Abbreviations, acronyms & symbols AMI CAD

Acute myocardial infarction Coronary artery disease

exageradas em intensidade ou duração, podem levar a um desequilíbrio do organismo, propiciando vulnerabilidade às doenças. Objetivo: ,GHQWL¿FDU D SUHVHQoD RX QmR GR HVWUHVVH H DV IDVHV do mesmo, em pacientes com infarto agudo do miocårdio, ativos no mercado de trabalho. MÊtodos: Pesquisa de abordagem quantitativa, descritiva e transversal que analisou 43 pacientes com diagnóstico de infarto agudo do miocårdio entre 21 e 65 anos, ativos no mercado de trabalho com ou sem comorbidades. A coleta de dados ocorreu no quarto dia de hospitalização; os pacientes responderam ao Inventårio de Sintomas de Stress para adultos de Lipp.

Descritores: Estresse. Infarto do miocĂĄrdio. Psicologia.

According to Shuterland & Cooper[7], the epidemiologiFDO VWXGLHV KDYH LGHQWL¿HG WKH H[LVWHQFH RI VHYHUDO ULVN IDFWRUV IRU FRURQDU\ KHDUW GLVHDVH DPRQJ WKHP JHQHWLF LQÀXHQFHV high blood pressure, high cholesterol and lipoprotein level, smoking, obesity, glucose intolerance, sedentary lifestyle and certain social-cultural and psychological factors. However, in a study with thousands of American men with high blood pressure, high cholesterol levels and smokers, just 14% presented a coronary heart disease during 10 years. These facts OHG VRPH VFLHQWLVWV WR FRQVLGHU WKH QHHG WR ¿QGLQJ RWKHU GHtermining etiological factors, most likely related to professional and psychosocial stress. Stress is composed of a set of metabolical responses that, if too intense or too long may lead to the organism’s imbalance, making it more vulnerable to diseases. The stress reaction is a biological attitude, necessary for the adaptation to new situations. They may manifest at a physical or psychological level. According to Lipp[8], increased sweating, gastric hyperacidity, muscular tension, high blood pressure, EUX[LVP DQG QDXVHDV PD\ EH LGHQWL¿HG DV FOLQLFDO PDQLIHVtations. The psychological manifestations may be anxiety, DQJXLVK DQG GRXEWV UHJDUGLQJ RQHVHOI FRQFHQWUDWLRQ GLI¿culties, excessive concern and hypersensitivity. The reaction to stress may be divided into phases, according to Selye: alert, resistance and exhaustion. Lipp[9] identi¿HG DQRWKHU SKDVH QDPHG DV TXDVL H[KDXVWLRQ 7R FODULI\ WKH process of stress development, it is necessary to consider that WKH V\PSWRPDWLF VWUHVV SUR¿OH YDULHV GHSHQGLQJ RQ LWV VWDJH.

INTRODUCTION Acute myocardial infarction (AMI) affects about 100,000 people each year, causing 35,000 deaths, corresponding to one third of the deaths caused by cardiovascular disease in Brazil. The cumulative mortality rate by ischemic cardiovascular disease for the Brazilian man, who is less than 65 years old, is 42%[1]. Cardiovascular diseases represent the ¿UVW FDXVH RI PRUWDOLW\ EHLQJ UHVSRQVLEOH IRU RI GHDWKV and the fourth reason of hospital admission, corresponding to 10.22% in 2007[2]. The AMI is a serious event that requires immediate care, hospitalization and is based on the parameters of the medical history, electrocardiographic analysis and tissue necrosis markers[3]. Some factor may trigger the AMI: acute emotional VWUHVV VLJQL¿FDQW HOHYDWLRQ RI WKH V\VWHPLF DUWHULDO SUHVVXUH obesity, sedentary lifestyle and smoking, among others[4]. According to deVries & Wilkerson’s studies[5], the World Health Organization and the World Bank estimate that neuro-psychiatric illnesses affect one in four people throughout the world, reaching 40% if we include disorders caused by stress. It is estimated that only 10% of cases are diagnosed and treated. The economic effects reach 120 billion of dollars in Europe and North America, with more than 60 million related to stress. The cardiovascular system has broad participation in stress adaptation, and because of this it suffers the consequences of its exacerbation. The suspicion that conditions of mental stress are risk factors for higher morbid-mortality by cardiovascular disease is an old one. However, the appropriDWH VFLHQWL¿F SURRI RI WKLV IDFW DQG LWV UHVSHFWLYH OHYHOV KDYH just recently been obtained. Many professionals still face this DVVRFLDWLRQ ZLWK D FHUWDLQ VNHSWLFLVP ¿QGLQJ LW GLI¿FXOW WR value in clinical practice, although mental stress is one of the main patients’ complaints[6].

Objective Thus, the aim of this study was to investigate the prevalence or not of stress in patients in acute myocardial infarct, active in labor market, and in which phase of stress the patient was in.

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to break; there are still some moments, in which the person gets to think clearly, make decisions, and laugh at jokes and work. All this, however, is done with great effort and these moments of normal functioning are interspersed with moments of total discomfort. There is much anxiety in this phase. The person experiences an emotional seesaw. The cortisol is produced in larger quantity and starts having negative effect, destroying the immunological defenses. In this phase, the illness process starts and the organs what have increased genetic or acquired vulnerability start revealing signs of deterioration. If there is no stress relief by removing the stressors or using confrontaWLRQ VWUDWHJLHV WKH VWUHVV UHDFKHV LWV ¿QDO SKDVH Phase III (Exhaustion) – This is the most negative phase RI VWUHVV ¹ WKH SDWKRORJLFDO RQH $ VLJQL¿FDQW LQQHU LPEDODQFH occurs at this moment. The person becomes depressed and he or she cannot concentrate or work. His or her decisions are, many times, thoughtless. Serious diseases may occur in the most vulnerable organs, such as infarction, psoriasis, ulcers, vitiligo, high blood pressure and others.

METHODS This research project was submitted to the Research Ethics Committee of the Hospital Erasto Gaertner and approved under the no. 1940 on December 15, 2009. This research was performed with through a quantitative and non-experimental approach, through cross-sectional studies with 43 patients aged between 21 and 65 years, admitted to the hospital with AMI, active in the labor market and with our without comorbities. All patients signed the Free Informed Consent Form (FICF). Diagnosis of AMI The diagnosis of AMI was performed through clinical evaluation of with the presence of typical angina, electrocardiographic alteration with ST-segment positive or negative GHÀHFWLRQ DQG DOWHUDWLRQ LQ WURSRQLQ YDOXHV Psychological evaluation The patients were addressed on the fourth day of their hospital admission. Within this scope, there was the intervention for the application of the Lipp’s Inventory proposed in this research. Two instruments were used for the evaluation: - Questionnaire of sociodemographic characterization: information on professional and personal data such as age, gender, marital status, education and profession was collected; - LIPP’s Inventory of Stress-Related Symptoms for Adults: evaluates the prevalence or not of stress in patients in phases I, II and III. The questionnaire consists of tables, divided into symptoms in temporal form[10]. Phase I (Alert) for symptoms experienced in the last 24 hours, which correspond to the phase of contact with the stress agent, its typical sensations, when the organism loses balance and prepares itself to face the situation in order to adapt and survive. This is the positive phase of stress, when the human being automatically prepares him or herself for action. This is characterized by the production of adrenaline that makes the person more attentive, stronger and more motivated, in other words, the survival is preserved and a sensation of wholeness is frequently reached. Phase II (Resistance) – if the alert phase continues for very long periods or if new stressors accumulate, the organism goes into action to hinder the total energy waste, which makes it to enter into the resistance phase, when it resists to stressors and it tries, inconsistently, to reestablish the inner balance (named homeostasis), which was broken during the alert phase. The productivity drops dramatically. This phase is characterized by the production of cortisol. The person’s vulnerability and bacteria are pronounced. If the stressing factors persist in frequency or intensity, there is a breakdown in the person’s resistance and he or she goes into the quasi-exhaustion phase. Phase II (Quasi-exhaustion) when the tension exceeds the manageable limit, the physical and emotional resistance start

Statistical analysis The results obtained in the study were expressed in averages, medians, maximum values and standard deviations (quantitative variables) or in percentages and frequencies (qualitative variables). To estimate the prevalence of patients with stress FRQ¿GHQFH LQWHUYDOV ZHUH FRQVWUXFWHG 7KH GDWD ZDV DQDlyzed with the software Statistica V.8.0. RESULTS )RUW\ WKUHH SDWLHQWV ZLWK $0, GH¿QHG IURP WKH FOLQLcal protocol, composed the sample. There was one death. The average age was 50.3 years. The AMI incidence in men was 91% and in women was 9%. In relation to schooling in both men and women: only 16% studied up to high school and the ones who completed high school or further totalized 84%. Figure 1 presents the distribution of participants according to their occupation. This was part of the research inclusion criteria, as all participants should be active in the labor market. The business people and technical assistants’ samples were the ones that presented higher incidence of stress. 50% of the sample were smokers and 50% were not. 2.5% declared themselves to be alcoholics and 97.5% declared themselves to be non-alcoholics. ZHUH VHGHQWDU\ DQG RQO\ FRQ¿UPHG WR SUDFtice physical exercises regularly (Figure 2). Regarding the body mass index (BMI), the average was 26.4 with standard deviation of ¹4.2. 72% of the patients presented criteria for inclusion in stress situations and 27% did not (Figure 3). For the phases of stress, the results indicated were: alert phase in 3%, resistance phase in 71%, quasi-exhaustion phase in 19% and exhaustion phase in 7% of the sample (Figure 4).

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Fig. 1 - Distribution of participants according to their occupation.

Fig. 2 - Graphic showing that 82.1% of the sample were sedentary and only 17.9% practice physical exercises regularly. Fig. 3 - Graphic showing that the percentage of the patients presented criteria for inclusion in stress situations.

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men aged under 65 years old, while in other countries (United States of America, Cuba and England) this proportion is around 25%[14]. Despite the lower female expressiveness, cardiovascular diseases are the main causes of death among women worldwide. In Brazil, there are three deaths caused by MAI for each death from breast cancer[15]. In our study, the age average of the studied population was 50.3 years old and it showed the MAI is manifesting itself in a population that is in the height of its professional productivity. As for smoking, the data of this research indicated that 50% of the patients were smokers. According to the studies “Interheartâ€? that were designed to assess the impact of conventional and emerging cardiovascular risk factors for MAI in several regions of the world, including South America, smoking was associated as high-risk factor[16]. In another study named Âł$ÂżUPDU´, smoking was also the risk factor of highest impact; a male smoker aged between 35 and 39 years KDG ÂżYH WLPHV PRUH SUREDELOLW\ RI KDYLQJ D KHDUW DWWDFN ZKHQ compared to non-smokers[17]. There was no correlation idenWLÂżHG EHWZHHQ DOFRKROLF SDWLHQWV DQG D KLJKHU ULVN RI P\RFDUdial infarction. 83% of the patients stated they did not exercise regularly DQG WKLV ZDV YHULÂżHG LQ WKH VWXGLHV ÂłInterheartâ€?, in analysis restricted to the Brazilian sample and in “Fricasâ€?, where no meaningful preventive differences of MAI were observed regarding the practice of physical activities[15-17]. 7KH ÂłInterheartâ€? study suggested that the risk of the population attributable to the relation waist-hip was higher than the risk attributable to the body mass index (BMI)[16]. The “Fricasâ€? VWXG\ FRQÂżUPHG WKH RYHUZHLJKW DV RQH RI WKH ULVN factors for the occurrence of MAI[17]. In our study, the BMI, the average found was 26.4, characterizing patients as overweight and who presented a higher tendency to MAI. Recent studies stated the relation waist-hip is better to analyze the cardiovascular risk factor than the BMI for the prognosis of heart attack risk for several ethnic groups. If obesity was reGHÂżQHG DFFRUGLQJ WR WKH UHODWLRQ ZDLVW KLS LQVWHDG RI XVLQJ BMI, the proportion of people with the risk of heart attack would triplicate. Regarding these patients’ education, the vast majority of the patients present a high intellectual level; the two categories with higher incidence were the businesspersons and the administrative assistants. It is possible to make an inference that these patients’ stress level is related to appointments and higher pressures is directly related to their professional activities. Regarding the stress analysis and its phases, the results LGHQWLÂżHG LQ WKLV VWXG\ ZHUH PHDQLQJIXO )URP WKH LQIDUFWed patients, 31 (72.1%) presented stress in one of its phases. In a stressful situation, the human body redistributes its energy sources, anticipating an imminent aggression. This adaptation mechanism is advantageous if there is an imminent

Fig. 4 - Phases of stress in the patients included in the study.

DISCUSSION Some symptoms of stress, such as palmar sudoresis, quick breath, tachycardia, gastric hyperacidity, lack of appetite or KHDGDFKH DUH HDV\ WR EH LGHQWL¿HG 2WKHU V\PSWRPV DUH PRUH VXEWOH VXFK DV LQWHUSHUVRQDO UHODWLRQVKLS GLI¿FXOWLHV ODFN RI interest in any activities that are not directly related to the reason of the cause of stress and the sensation of being sick, without the presence of any physical disturbances[11]. Emotionally, stress may produce a series of symptoms, such as apathy, depression, anger, emotive hypersensitivity, wrath, irritability, anxiety and it may cause psychotic disturbances in predisposed people. It is important to highlight that at a psychological level, the result of the stress response shall depend on individual, social and class differences and on cultural characteristics and adaptive behavior patterns[12]. The cardiovascular system is largely involved in adaptation to stress, therefore suffering, and the consequences from its exacerbation[6]. The cardiovascular system’s answer to stress is usually an increase and its objective is to deliver glucose and oxygen to the needy tissues. The main mediator of this answer is in the sympathetic nervous system that raises the heartbeat and the blood pressure. The cardiovascular answer, when this condition persists for too long or outside the context in which it is physiologically useful, affects the cardiac muscle and the blood vessels, as well as facilitates the accumulation of atherosclerotic plaques[13]. When performing the characterization of the studied group, we observe a higher incidence of MAI in men. It is worth remembering that, in Brazil, around 50% of male deaths caused by coronary artery disease (CAD) occur in

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risk. However, if this state persists for a long time, the damage will be irreversible[18]. Every meaningful change generates a need by the organism to adapt and this has an important role in the stress pathogenesis[19]. Drawin’s studies convinced Piaget, father of the genetic epistemology, regarding two basic points for the construction of his evolutionary theory of knowledge, which are: the answer to the problem should come from an evolutionary analysis and the mutant adaptation to the mean mutant demands should be one of the keys. According to Piaget’s theory, the adaptation is always the goal, which is, getting a suitable answer to the problems that the person faces at each moment, as he/she does not have the answer that allows him/ her to solve the problem, the organism is unbalanced with UHJDUG WR WKH HQYLURQPHQW WKH SURFHVV RI ¿QGLQJ QHZ DQswers tries to restore the balance and improve, this way, the adaptation to the environment’s demands. As the maturation opens new possibilities, the environment exploitation presents new challenges and education SUHVHQWV QHZ LVVXHV WKH SHUVRQ LQ GHYHORSPHQW ¿QGV KLPVHOI herself building new answers in order to get more and more HODERUDWHG DGDSWDWLRQ OHYHOV DQG EHQH¿WWLQJ IURP D FRQWLQXous and growing tendency to balance[20]. Man naturally seeks balance through a process of constant adaptation, aiming to develop cognitively and emotionally, which fundamentally contributes to the evolution of stress. As with adaptation, the stress is a component of human development, as we grow and mature, we improve the way we deal with the unexpected. We learn to adapt our attitudes in RXU EHKDYLRU WKURXJK WKH LGHQWL¿FDWLRQ RI VWUHVVIXO VLWXDWLRQV with the perception of physical and/or psychological answers DQG WKH YDORUL]DWLRQ RI WKH LGHQWL¿HG FRQWH[W 7KLV H[HUFLVH is dynamic, it happens all the time and varies from person to person; many times a situation may be stressful to one person and not stressful at all to another. Comprehension is the healthiest way to handle this process adequately, which is an individual one. In our study, the patients presented several levels of clinical manifestations of stress and we may infer the stress had a direct participation on AMI. In a stressful situation, the human body redistributes its energy sources, anticipating an imminent aggression. This adaptation mechanism is advantageous when there is real danger. However, if this state persists for a long time, the damage shall be irreversible. Every meaningful change generates a need to adapt from the body and this one has a significant role in the pathogenesis of stress[19]. 7KH ³Interheart� DQG ³$¿UPDU� studies recognize that, ZLWKLQ WKH QLQH ULVN IDFWRUV LGHQWL¿HG IRU WKH $0, SV\FKRsocial stress holds a prominent place. The main differences EHWZHHQ WKH GLVFRYHULHV IRXQG LQ WKH ³$¿UPDU� study and the SRSXODWLRQ VWXGLHG LQ ³Interheart� were that central obesity, high blood pressure and stress presented higher impacts on the genesis of myocardial infarction in Latin America[16]. In

both studies, the presence of psychosocial stressors is associated with increased risk of acute myocardial infarct, which suggests that approaches, which aim to control these factors suitably, should be developed. Literature data suggests that the manifestation of the myocardial infarct may occur with higher frequency in patients who are in the exhaustion phase. However, analyzing data from our study, there was a higher incidence at the resistance phase and this was the most important data in this sample[21]. 6LPLODU GDWD ZDV LGHQWL¿HG LQ D VWXG\ SHUIRUPHG E\ Bezerra[22] LQ ZKLFK WKH DXWKRU YHUL¿HG WKH SUHVHQFH RI VWUHVV in the cardiac population who would be submitted to revasFXODUL]DWLRQ VXUJHU\ DQG LGHQWL¿HG WKDW RI WKH SDWLHQWV evaluated presented stress symptoms and the most prevailing phase was the resistance one, with 84.6%. Other research performed with the same instrument of methodological analysis as our study, Lipp’s questionnaire, had as its objective to evaluate the stress level in two samples: people who lived in the capital and interior of the state of São Paulo; 79% presented meaningful symptoms of stress, independent of the groups. The stress level was concentrated in the second phase, the resistance one, which is considered moderate, but which causes an inner unbalance in the body. ,W LV IRXQG WR EH UHOHYDQW DV LW FRQ¿UPV WKH UHOLDELOLW\ RI WKH instrument in and outside of the hospital context[4]. Another study, performed by Santos et al.[23], with this same analysis questionnaire, evaluated patients who were submitted to cholecystectomy surgery; 73% of the cases showed to be stressed mainly in the resistance phase in 72% of the stressed patients. The resistance phase, in all research mentioned using the same measurement instrument, showed to be the most incidental one. This phase is characterized by the maintenance of the alert phase for longer periods. This is when the person resists to the stressors and tries, unconsciously, reestablishing the inner balance that was broken during the alert phase. The professional and intellectual productivity decreases VLJQL¿FDQWO\ ,W LV FKDUDFWHUL]HG E\ D KLJKHU SURGXFWLRQ RI cortisol. The person is there for more vulnerable to virus and bacteria. If the stressing factors persist in frequency or intensity, there is a break in the person’s resistance and he/she enters to the quasi-exhaustion phase. There is a huge effort of the body to recover its balance, as man’s natural condition seeks adaptation to the environment. The General Adaptation Syndrome, described by Selye, informs that initially the resistance is reduced as the ERG\ SUHSDUHV LWVHOI WR ¿JKW RU HVFDSH +RZHYHU WKH ERG\ ends up adapting itself and the resistance increases. Until the body is exhausted and the resistance falls rapidly[24]. The increase in the occurrences of acute and chronic disorders of the population’s circulatory system highlights the importance of the relation between diseases and work. Medical literature and media, for example, have highlighted the relation between the occurrence of acute myocardial infarc-

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tion, chronic coronary disease and high blood pressure, and stressful situations and unemployment, among others[25]. 7KH LQWHUYHQWLRQV RQ ZRUN RUJDQL]DWLRQV DUH PRUH HI¿FLHQW EXW PRUH FRPSOH[ DV WKH\ XVXDOO\ FRQÀLFW ZLWK WKH production demands. Health professionals and people who are in charge of Human Resources in companies have been challenged to reduce stress through changes in the forms of organization and work management. Having this in mind they propose: to give more autonomy to workers’ in their ways of working, reduce the pressure and demands on productivity, introducing pauses in suitable environments; establish rotation and enrichment of tasks in monotonous, isolated and repetitive jobs; reduce and/or adjust the work schemes and shifts; increase the workers’ participation in decision and management processes; improve interpersonal work relationships, replacing competition with collaboration. 3URFHGXUHV WKDW DLP DW HDUO\ LGHQWL¿FDWLRQ RI SUREOHPV or damage to health, derived from the exposure to risk factors and the development of actions to promote health, and healthier life habits are important. Nowadays, mainly in the framework of large cooperation, programs named Promotion of Health and Quality of Life have been implemented in order to act on the stress factors related to work[25]. Bourdieu reports that every social agent, who acts in ZLWKLQ D VSHFL¿F DUHD VHHNV WR DGMXVW KLV KHU WKRXJKWV SHUception and actions in order to meet the objective demands of that social space. For him, the motor of the action lies between habitus and area. Thus, it is within through adjustment SURFHVV WUDQVIRUPDWLRQ DQG DGDSWDWLRQ RI D VSHFL¿F DUHD WKDW the social agent builds up his/her practice. There is also a relation between these two structures and a third one identi¿HG DV GRPLQDWLRQ LQVWUXPHQWV ZKLFK DUH WKH UHVRXUFHV XVHG to legitimize the power of a certain social class, generating symbolic and political violence[26]. The patient that arrives at the hospital with chest pain and infarcted belongs to the environmental context described above. He tries to adapt to several demands, including symEROLF YLROHQFH VXIIHUHG DQG PRGL¿HG ULVN IDFWRUV LQVHUWHG LQ the universe of coronary diseases. The presence of physical and/or psychological stress FRQVWLWXWHV D PRGL¿DEOH FDUGLRYDVFXODU ULVN IDFWRU :H KLJKlight that the research related to stress also approaches other cardiovascular system diseases and we recommend that the promotion of educational health actions within the hospital context may help in the reorganization of infarcted patients’ life habits and in secondary prevention. In the pathology of stress in infarcted and hospitalized patients, the work of the hospital psychologist, who is part of a clinical team, is fundamental in accompanying the patient during the post-infarction period, helping to identify possible stress and its stressor agents, as well as allowing the patient and the doctor in charge to receive guidance regarding the need of psychotherapeutical follow-up upon hospital release,

in order to maintain suitable monitoring regarding the secondary prevention against acute myocardial infarction. Research performed by Pugliese et al.[27], which aims to assess WKH HIÂżFLHQF\ RI D SURJUDP GHVLJQHG WR SURPRWH FKDQJHV LQ lifestyle through psychological intervention, associated to the pharmacological therapy, in order to reduce coronary risk in patients with non-controlled high blood pressure, overweight and dyslipidemia, concluded that pharmacological treatment combined with psychological intervention aimed at reducing the stress level and changed the alimentary behavior resulted LQ DGGLWLRQDO EHQHÂżWV LQ UHGXFLQJ FRURQDU\ ULVN We face stress daily and as we grow and mature we learn how to deal with the unexpected, a reserve of information helps us in the adaptation process. However, there are more serious situations that also occur and we need to consider their impact on our lives, observing the physical and emotional reactions that are initiated, derived from this new experience and try to handle them in a proper way in order to reach balance and well-being. This exercise is dynamic, happens all the time and varies from person to person in a common situation. CONCLUSION The data of this study suggests that it was possible to establish a direct relation between stress and its resistance phase with a higher incidence of patients affected by myocardial infarct and active in labor market.

Authors’ roles & responsibilities LBL ACMGP KATC JCF CPB MO VFA -5)1 /&*6

Conception and study design, performing the procedures, and/or experiments conception and study design, performing the procedures, and/or experiments Final approval of manuscript Final approval of the manuscript, performing the procedures, and/or experiments Statistical analysis Statistical analysis Final approval of manuscript DQDO\VLV DQG RU LQWHUSUHWDWLRQ RI GDWD ÂżQDO DSSURYDO RI WKH manuscript conception and design of the study DQDO\VLV DQG RU LQWHUSUHWDWLRQ RI GDWD ÂżQDO DSSURYDO RI WKH manuscript conception and design of the study

REFERENCES 1. Brasil. MinistĂŠrio da SaĂşde [Online]. BrasĂ­lia: MinistĂŠrio da SaĂşde; 2008 [Acesso 6 Ago 2008]. DisponĂ­vel em: http://portal.saude. gov.br/saude

22 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

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deVries MW, Wilkerson B. Stress, work and mental health: a global perspective. Acta Neuropsychiatr. 2003;15(1):44-53.

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9. Lipp MEN. Manual do inventário de sintomas de stress para adultos de Lipp. São Paulo: Casa do Psicólogo; 2000. 10. Lipp MEN, Malagris LEN, Novais LE. Stress ao longo da vida. São Paulo: Ícone; 2007.

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24. Rezende Neto A. Gerenciamento do Stress: Controle da Ansiedade e das Alterações Fisiológicas. In: Lipp MEN, org. O stress no Brasi: Pesquisas avançadas. Campinas: Papirus; 2004.

12. Sparrenberger F, dos Santos I, Lima RC. Epidemiologia do distress psicológico: estudo transversal de base populacional. Rev. Saúde Pública. 2003;37(4):434-9.

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13. Gonzalez MAA. Stress: temas de psiconeuroendocrinologia. 2ª ed. São Paulo: Robe; 2001. 14. Avezum A, Guimarães HP, Berwanger O, Piegas L. Aspectos epidemiológicos do infarto agudo do miocárdio no Brasil. Rev Bras Clin Ter. 2005;31(2):93-6.

26. Coll C, Palacios J, Marchesi A. Desenvolvimento Psicológico e Educação. 2. ed. Porto Alegre: Artes Médicas; 2004. 27. Pugliese R, Zanella MT, Blay SL, Plavinik F, Andrade MA, *DOYmR 5 (¿FiFLD GH XPD LQWHUYHQomR SVLFROyJLFD QR HVWLOR de vida para a redução do risco coronariano. Arq Bras Cardiol. 2007;89(4):225-30.

15. Silva MAD, Sousa AGRM, Schargodsky H. fatores de risco para o infarto do miocárdio no Brasil: estudo FRICAS. Arq Bras Cardiol. 1998;71(5):667-75.

23 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Rodrigues CDA, et al. - RiskARTICLE factors for transient dysfunction of gas exchange ORIGINAL after cardiac surgery

Braz J Cardiovasc Surg 2015;30(1):24-32

Risk factors for transient dysfunction of gas exchange after cardiac surgery Fatores de risco para disfunção transitória da troca gasosa após a cirurgia cardíaca

Cristiane Delgado Alves Rodrigues1, MsC; Marcos Mello Moreira1, MsC, PhD; NĂşbia Maria Freire Vieira Lima1, MsC, PhD; Luciana Castilho de FigueirĂŞdo1, MsC, PhD; AntĂ´nio Luis Eiras FalcĂŁo1, MD, MsC, PhD; Orlando Petrucci Junior1, MD, MsC, PhD; Desanka Dragosavac1, MD, PhD

DOI 10.5935/1678-9741.20140103

RBCCV 44205-1610 Conclusion: Preoperative hypertension and cardiogenic shock were associated with the occurrence of postoperative transient dysfunction of gas exchange. The preoperative risk factors included hypertension, cardiogenic shock, and diabetes. Postoperatively, pneumonia, ventilator-associated pneumonia, renal replacement therapy, hemotherapy, and cardiac arrhythmia were associated with the appearance of some degree of transient dysfunction of gas exchange, which was a risk factor for reintubation, pneumonia, ventilator-associated pneumonia, and renal replacement therapy in the postoperative period of cardiac surgery and cardiac procedures.

Abstract Objective: A retrospective cohort study was preformed aiming to verify the presence of transient dysfunction of gas exchange in the postoperative period of cardiac surgery and determine if this disorder is linked to cardiorespiratory events. Methods: We included 942 consecutive patients undergoing cardiac surgery and cardiac procedures who were referred to the Intensive Care Unit between June 2007 and November 2011. Results: Fifteen patients had acute respiratory distress syndrome (2%), 199 (27.75%) had mild transient dysfunction of gas exchange, 402 (56.1%) had moderate transient dysfunction of gas exchange, and 39 (5.4%) had severe transient dysfunction of gas exchange. Hypertension and cardiogenic shock were associated with the emergence of moderate transient dysfunction of gas exchange postoperatively (P=0.02 and P=0.019, respectively) and were risk factors for this dysfunction (P=0.0023 and P=0.0017, respectively). Diabetes mellitus was also a risk factor for transient dysfunction of gas exchange (P=0.03). Pneumonia was present in 8.9% of cases and correlated with the presence of moderate transient dysfunction of gas exchange (P=0.001). Severe transient dysfunction of gas exchange was associated with patients who had renal replacement therapy (P=0.0005), hemotherapy (P=0.0001), enteral nutrition (P=0.0012), or cardiac arrhythmia (P=0.0451).

Descriptors: Thoracic Surgery. Postoperative Complications. Risk Factors. Intensive Care Units. Resumo Objetivo: Estudo de coorte retrospectivo com objetivo de YHULÂżFDU D SUHVHQoD GH GLVIXQomR WUDQVLWyULD GD WURFD JDVRVD QR SyV RSHUDWyULR GH FLUXUJLD FDUGtDFD H GHWHUPLQDU VH HVVH WUDQVWRUQR HVWi UHODFLRQDGR D HYHQWRV FDUGLRUUHVSLUDWyULRV MĂŠtodos: )RUDP LQFOXtGRV SDFLHQWHV FRQVHFXWLYRV VXEPHWLGRV j FLUXUJLD FDUGtDFD H SURFHGLPHQWRV FDUGtDFRV HQFDminhados para a Unidade de Terapia Intensiva, entre junho de 2007 e novembro de 2011.

1

Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.

Correspondence address: Cristiane Delgado Alves Rodrigues Universidade Estadual de Campinas (UNICAMP) Cidade UniversitĂĄria “Zeferino Vazâ€? Distrito de BarĂŁo Geraldo, Campinas, SP, Brazil – Zip code: 13083-970 E-mail: crist_rodrigues@yahoo.com.br

This study was carried out at Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.

Article received on December 28th, 2013 Article accepted on August 4th, 2014

1R ÂżQDQFLDO VXSSRUW

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WUDQVLWyULD GD WURFD JDVRVD PRGHUDGD QR SHUtRGR SyV RSHUDWyULR (P=0,02 e P=0,019, respectivamente) e foram considerados fatoUHV GH ULVFR SDUD HVVD GLVIXQomR P=0,0023 e P=0,0017, respectiYDPHQWH $ SUHVHQoD GH GLDEHWHV PHOOLWXV WDPEpP IRL FRQVLGHUDGD XP IDWRU GH ULVFR SDUD GLVIXQomR WUDQVLWyULD GD WURFD JDVRVD (P +RXYH FRUUHODomR HQWUH D SUHVHQoD GH SQHXPRQLD H D SUHVHQoD GH GLVIXQomR WUDQVLWyULD GD WURFD JDVRVD PRGHUDGD HP 8,9% dos casos (P $ SUHVHQoD GH GLVIXQomR WUDQVLWyULD GD troca gasosa grave foi associada a pacientes que necessitaram de hemodiĂĄlise (P=0,0005), hemoterapia (P QXWULomR HQWHral (P RX DUULWPLD FDUGtDFD P=0,0451). ConclusĂŁo: $ SUHVHQoD GH KLSHUWHQVmR DUWHULDO VLVWrPLFD SUp RSHUDWyULD H FKRTXH FDUGLRJrQLFR IRL DVVRFLDGD j RFRUUrQFLD GH GLVIXQomR WUDQVLWyULD GD WURFD JDVRVD SyV RSHUDWyULD 2V IDWRUHV GH ULVFR SUp RSHUDWyULRV IRUDP KLSHUWHQVmR DUWHULDO VLVWrPLFD FKRTXH FDUGLRJrQLFR H GLDEHWHV 1R SyV RSHUDWyULR SQHXPRQLD SQHXPRQLD DVVRFLDGD j YHQWLODomR KHPRGLiOLVH KHPRWHUDSLD H DUULWPLD FDUGtDFD IRUDP DVVRFLDGDV FRP FHUWR JUDX GH GLVIXQomR WUDQVLWyULD GD WURFD JDVRVD TXH IRL IDWRU GH ULVFR SDUD UHLQWXEDomR SQHXPRQLD SQHXPRQLD DVVRFLDGD j YHQWLODomR H KHPRGLiOLVH QR SyV RSHUDWyULR GH FLUXUJLD FDUGtDFD

Abbreviations, acronyms & symbols APACHE II ALI ARDS CH CPB FiO2 ICU PaO2 PCWP PEEP SD 6,56 TDGE UNICAMP VAP

Acute Physiology and Chronic Health Evaluation II Acute Lung Injury Acute Respiratory Distress Syndrome Clinics Hospital Cardiopulmonary Bypass Fraction of inspired oxygen Intensive Care Unit Partial pressure of oxygen Pulmonary capillary wedge pressure Positive end-expiratory pressure Standard deviation 6\VWHPLF LQĂ€DPPDWRU\ UHVSRQVH V\QGURPH Transient Dysfunction of Gas Exchange Universidade Estadual de Campinas Ventilator-Associated Pneumonia

Resultados: $ VtQGURPH GR GHVFRQIRUWR UHVSLUDWyULR DJXdo foi observada em 15 (2%) pacientes, 199 (27,75%) pacientes DSUHVHQWDUDP GLVIXQomR WUDQVLWyULD GD WURFD JDVRVD OHYH GLVIXQomR WUDQVLWyULD GD WURFD JDVRVD PRGHUDGD IRL REVHUYDGD HP SDFLHQWHV H GLVIXQomR WUDQVLWyULD GD WURFD JDVRVD JUDYH HP $ SUHVHQoD GH KLSHUWHQVmR DUWHULDO VLVWrPLFD H FKRTXH FDUGLRJrQLFR IRL DVVRFLDGD DR VXUJLPHQWR GH GLVIXQomR

Descritores: &LUXUJLD 7RUiFLFD &RPSOLFDo}HV 3yV 2SHUDWyrias. Fatores de Risco. Unidades de Terapia Intensiva.

INTRODUCTION

(ARDS) and acute lung injury (ALI) have been widely used in patients after cardiac surgery with CPB in recent decades. $FFRUGLQJ WR WKH FULWHULD RI WKH ÂżUVW FRQVHQVXV GHÂżQLWLRQV RI ARDS and ALI (1994), several studies reported the incidence of these disorders after such a procedure[4]. Recently, the criteria for the diagnosis of ARDS have been FKDQJHG 7KH FXUUHQW GHÂżQLWLRQ LV EDVHG RQ WKH GHJUHH RI K\poxemia, represented by the partial pressure of oxygen (PaO2)/ fraction of inspired oxygen (FiO2), namely, mild ARDS (PaO2/ FiO2 between 200 mmHg and 300 mmHg), moderate ARDS (PaO2/FiO2 between 100 mmHg and 200 mmHg), and severe ARDS (PaO2/FiO2<100 mmHg). In addition, four factors were included for the diagnosis of severe ARDS (refractory hypoxemia, radiographic severity, respiratory system compliance, and positive end-expiratory pressure)[7]. 7KH FULWHULD IRU GHÂżQLQJ '7*( WKLV VWXG\ ZHUH WKH VDPH ones used in the latest rankings of ARDS, described above. Therefore, the primary objective of the present study was to evaluate the presence of TDGE after cardiac surgery and to determine if there is an association between post-cardiac surgery TDGE and cardiorespiratory events. As a secondary objective, the presence of risk factors for the development of cardiorespiratory complications in the postoperative period was evaluated.

&DUGLDF VXUJHU\ KDV D GLUHFW LQĂ€XHQFH RQ WKH UHVSLUDWRU\ system in patients with heart disease, affecting the morbidity and mortality of patients postoperatively. Respiratory complications after cardiac surgery have been described in the literature since 1965[1]. Respiratory system dysfunction can occur due to general anesthesia, median sternotomy (which leads to instability of the upper chest), cardiopulmonary bypass (CPB), prolonged myocardial ischemia, manipulation during surgery, and number of chest tubes[1-4]. Changes in pulmonary function occurring in the postoperative period of cardiac surgery with CPB are secondary to the reaction of heparin with protamine complex, edema, congestion, and lung damage, in addition to microatelectasis. In most cases, there is an absence of mechanical ventilation during CPB, ZKLFK FRXSOHG ZLWK WKH LQĂ€DPPDWRU\ UHVSRQVH GXH WR VXUgical trauma, leads to changes in respiratory mechanics[2,5]. During CPB, blood contact occurs with non-endothelial surfaces, leading to blood clotting; this clotting occurs along ZLWK WKH DFWLYDWLRQ RI WKH LQĂ€DPPDWRU\ FDVFDGHV DQG FRQWULEutes to the increased weight of the pulmonary parenchyma and the additional breakdown of cellular units, further impairing gas exchange in these patients. Thus, the presence of postoperative hypoxemia is secondary to all these changes that impair the ventilation/perfusion ratio[6]. Due to the occurrence of transient dysfunction of gas exchange (called TDGE in this study) after surgery, the terms acute respiratory distress syndrome

METHODS Study design and ethical considerations The research project was approved by the ethics com-

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ICU protocols and procedures in the surgical center The heart surgeries and procedures were carried out by the same team for all patients. Surgical techniques and procedures complied with the standards described by the work-processes manuals of CH/UNICAMP. At the end of the surgery or termination of the procedure, patients presenting favorable clinical conditions were extubated in the surgical room. If the patient’s clinical conditions were not favorable, they were referred to the postoperative ICU, intubated, and mechanically ventilated. Postoperative ICU patients were admitted by the multidisciplinary team and were then processed using the admission protocol for surgical patients in the ICU. The patients were then under the care of the ICU staff, who DWWHQGHG WR WKH SDWLHQWV DFFRUGLQJ WR WKH VSHFL¿F SURWRFROV RI the unit.

mittee of the institution, under the assigned number 409,460/2013. During the research, the medical information DQG WKH SULYDF\ RI WKH SDWLHQWV ZHUH NHSW FRQÂżGHQWLDO 7KH data from this study were obtained from the database and charts of patients from the Clinics Hospital (CH) of the State University of Campinas (UNICAMP). Population Consecutive patients undergoing cardiac surgery and cardiac procedures referred to the ICU in between June 2007 and November 2011 were included in this study. The patients included males and females and over the age of 14 years. The initial observed sample included 942 patients, whose data were collected prospectively and consecutively and stored in the database of the ICU of Clinics Hospital at UNICAMP. Data collection was performed daily, at the bedside by specially trained professionals (1998/3432 Ordinance). The data from patients who had been readmitted and the data from patients with incomplete medical records were excluded from the statistical analysis. The demographic and clinical variables assessed in this study were as follows: 1) type of surgery or cardiac procedure performed; 2) occurrence of TDGE after surgery and cardiac procedures. TDGE represents changes in PaO2/FiO2 present up to 48 hours after surgery; 3) preoperative cardiorespiratory system background and its association with postoperative TDGE type; 4) presence of complications, infections, and post-operative interventions and their associations with postoperative TDGE type; 5) length of stay in the ICU, occurrence of death in the ICU, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, mortality provided by APACHE II, and their association with TDGE; 6) risk factors for developing cardiorespiratory complications in the postoperative period.

Phases of the retrospective study This study consisted of a data collection period followed by the assessment and review of the database and the medical records of patients. The tabulation of the data was revised, DQG ¿QDOO\ WKH VWDWLVWLFDO DQDO\VLV ZDV SHUIRUPHG )RU WKH statistical analysis, the program SAS System for Windows, version 9.2 was used. Continuous variables are presented as the mean ¹ SD. Categorical variables are expressed as absolute values and percentages. To verify an association, the chisquare test or Fisher’s exact test was used when necessary. To test the relationship between the disease preoperatively and TDGE, as well as the relationship between complications and interventions in the ICU and TDGE, the logistic regression model with proportional odds was used. ANOVA by ranks with transformation followed by the Tukey test was used to compare TDGE groups (no, mild, moderate, severe) with respect to the length of hospitalization in intensive care, APACHE II and predicted mortality. To verify a linear trend in proportions, the Cochran-Armitage test was applied. We used Cox regression analysis to identify factors associated with univariate complications and death. P<0.05 was considHUHG VLJQL¿FDQW IRU DOO WHVWV

Measuring instruments The APACHE II scores were calculated for the patient’s ¿UVW KRXUV LQ WKH ,&8 WKH SDWLHQWVœ PRUWDOLW\ ¿JXUHV ZHUH provided by that score[8].

RESULTS 2I WKH LQLWLDO VDPSOH SDWLHQWV IXOÂżOOHG WKH FULWHULD RI the study. Patients who were readmitted or had data missing from their charts were excluded from the study. There were 442 (61.6%) male and 275 (38.4%) female patients. The average age of the patients was 56.1 years (SD=13.7). The types of surgery and cardiac procedures performed are described in Table 1. In Table 2, the frequencies for TDGE are presented. In Table 3, the background and preoperative comorbidities and their correlations with postoperative TDGE are stated. TDGE was associated with age (P<0.0001), and age was also a risk factor (P<0.0001) for TDGE, as shown in Table 4.

&DOFXODWLRQ RI WKH UDWLR 3D22 )L22 7UDFNV RI WKH FXUUHQW FODVVLÂżFDWLRQ IRU GHÂżQLQJ $5'6 were employed to determine four patient groups with study TDGE: 1) absence of TDGE (PaO2/FiO2>300 mmHg), 2) mild TDGE (PaO2/FiO2 between 200 mmHg and 300 mmHg), 3) moderate TDGE (PaO2/FiO2 between 100 mmHg and 200 mmHg), and 4) severe TDGE (PaO2/ FiO2<100 mmHg). The values of PaO2/FiO2 were from the DUWHULDO EORRG JDV DQDO\VLV RQ WKH ÂżUVW SRVWRSHUDWLYH GD\ i.e., up to the 48th hour in the ICU.

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Table 1. Data of heart procedures.

Table 2. The impact of postoperative TDGE.

Procedures performed Myocardial revascularization Valve exchange Correction of aortic aneurysm Atrial septal defect or interventricular communication Coronary artery bypass grafting combined with valve replacement Resection of cardiac tumor Pacemaker implant Reconstruction of left ventricle Pericardial drainage Cardiac transplantation Other*

n 354 212 68

% 49.4% 29.5% 9.5%

35

4.9%

17 4 6 6 4 3 8 717

2.4% 0.6% 0.8% 0.8% 0.6% 0.4% 1.1% 100%

TDGE levels Absence Mild Moderate Severe

n % 77 10.7% 199 27.8% 402 56.1% 39 5.4% 717 100% TDGE=Transient Dysfunction of Gas Exchange. Absence of TDGE=PaO2/FiO2>300 mmHg; Mild TDGE=PaO2/FiO2 between 200 mmHg and 300 mmHg; Moderate TDGE=PaO2/FiO2 between 100 mmHg and 200 mmHg; Severe TDGE=PaO2/FiO2<100 mmHg

*Percentage of total group in parentheses

Table 3. Association of history and preoperative comorbidities with postoperative TDGE. Preoperative data Diabetes mellitus Hypertension Cardiogenic shock Cardiac arrhythmia Congestive heart failure Cardiopulmonary arrest Pneumopathy Pneumonia Deep vein thrombosis

Prevalence on Sample % n 19.5% 140 52.6% 377 2.1% 15 3.6% 26 8.8% 63 2.5% 17 9.5% 68 1.7% 12 0.3% 2

Absent n 7 34 0 2 7 1 5 3 0

TDGE levels Mild Moderate Severe n n n 39 83 11 224 26 93 11 3 1 1 7 16 3 19 34 5 8 3 17 40 6 2 7 0 1 1 0

Test for Association P-value* 0.057 0.022 0.019 0.098 0.966 0.172 0.442 0.373 -

Test for Risk Factor 6LJQL¿FDQFH 95% CI P-value** OR 1.49 1.03;2.14 0.035 1.56 1.17;2.07 0.002 5.67 1.92;16.75 0.001 1.14 0.53;2.45 0.738 0.89 0.54;1.46 0.645 1.68 0.63;4.46 0.297 1.44 0.88;2.37 0.15 0.64 0.22;1.85 0.405 -

TDGE= transient dysfunction of gas exchange; TDGE absent=PaO2/FiO2>300 mmHg; TDGE mild=PaO2/FiO2 between 200 mmHg and 300 mmHg; TDGE moderate=PaO2/FiO2 between 100 mmHg and 200 mmHg; severe TDGE=PaO2/FiO2<100 mmHg; Parentheses=percentage of the WRWDO JURXS 25 RGGV UDWLR &, FRQ¿GHQFH LQWHUYDO 3 YDOXH FKL VTXDUH WHVW 3 YDOXH ORJLVWLF UHJUHVVLRQ 'HHS YHLQ WKURPERVLV 7KHUH were not enough patients in the deep vein thrombosis group for statistical calculatios

Table 4. Association of age with TDGE (n=717). Age Classes 45-54 55-64 65-74

n 124 162 229 153 49 717

% 17.3% 22.6% 31.9% 21.4% 6.8% 100%

Absent n 26 16 21 8 6

TDGE levels Mild Moderate Severe n n n 42 49 7 55 86 5 139 52 17 91 45 9 5 37 1

Test for Association P-value* 0.0001 0.0001 0.0001 0.0001 0.0001

7HVW IRU 5LVN )DFWRU 6LJQL¿FDQFH OR 95%CI P-value** Reference class (baseline) 1.59 1.03;2.48 0.0001 2.62 1.72;3.99 0,0001 2.41 1.53;3.81 0.0001 3.00 1.56;5.78 0.0001

TDGE=transient dysfunction of gas exchange; TDGE absent=PaO2/FiO2 > 300 mmHg; TDGE mild= PaO2/FiO2 between 200 mmHg and 300 mmHg; TDGE moderate= PaO2/FiO2 between 100 mmHg and 200 mmHg; severe TDGE=PaO2/FiO2<100 mmHg; parentheses=percentage of total JURXS 25 RGGV UDWLR &, FRQ¿GHQFH LQWHUYDO 3 YDOXH FKL VTXDUH WHVW 3 YDOXH ORJLVWLF UHJUHVVLRQ RI ORZHU ULVN FRPSDUHG WR WKH \HDU JURXS

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Rodrigues CDA, et al. - Risk factors for transient dysfunction of gas exchange after cardiac surgery

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et al.[10]. The preoperative comorbidities diabetes mellitus (19.5%) and hypertension (52.6%) were prevalent. A previous study observed diabetes mellitus in 29.6% of cases[8]. Compared with other developed countries, Brazil has a higher incidence of hypertension (90.7% vs. 60%) and diabetes mellitus (37.2% vs. 29%)[9]. Diseases such as hypertension, autoimmune diseases, peripheral vascular disorders, and metabolic syndrome must be controlled and require great care in the immediate postoperative period[10]. Other studies report preoperative comorbidities of dyslipidemia in 48% of cases and a family background of coronary artery disease in 38% of cases but report hypertension in 75%[11] to 79%[2] of patients. In developed countries, cardiovascular diseases are the leading causes of death and are increasing in occurrence in developing countries[12]. Oliveira et al.[11] measured morbidity by measuring the occurrence of the postoperative complications described above and the mortality as the number of deaths. In our study, 0.84% of individuals died within 48 hours, and 9.21% died after 48 hours of intensive care. In Brazil, the mortality rate for myocardial revascularization is 6.2%. Several postoperative management protocols of cardiac surgery have been studied with the purpose of pre-

Interventions and complications in the ICU and their association with the appearance of TDGE are described in Table 5. The occurrence of death within 48 hours and after 48 hours are described in Table 6. The he average length of stay in the ICU and the mortality predicted by APACHE II are described in Figure 1 and Figure 2. 'HDWK ZLWKLQ WKH ÂżUVW KRXUV DIWHU VXUJHU\ DQG GHDWK in the ICU were associated with the APACHE II score (P=0.0105 and P<0.0001, respectively). Death within the ÂżUVW KRXUV DIWHU VXUJHU\ DQG GHDWK LQ WKH ,&8 ZHUH ERWK DVsociated with predicted mortality (P=0.0001, and P<0.0114, respectively). DISCUSSION Demographic variables, background, and preoperative comorbidities The majority of the study population was male (61.6%), ZLWK DQ DYHUDJH DJH RI \HDUV 7KLV ÂżQGLQJ LV FRQVLVWHQW with reports that the male population has a higher surgical incidence (70.1%) than females in the under-60 population[9]. In this study, myocardial revascularization surgery was the PRVW FRPPRQ FRUURERUDWLQJ WKH ÂżQGLQJV RI /DL]R

Table 5. Complications and interventions in the ICU and their associations with TDGE. Postoperative data Pneumonia VAP Non-invasive mechanical ventilation Reintubation Tracheostomy Renal replacement therapy Hemotherapy Cardiac arrhythmia

Prevalence on Sample % n 8.9% 64 0.6% 4 15 69 26 62 247 26

2.1% 9.6% 3.6% 8.6% 34.4% 3.6%

Absent n 4 0 0 4 3 6 21 2

TDGE levels Mild Moderate Severe n n n 11 37 12 2 2 0 4 15 6 10 60 7

10 45 15 36 139 12

1 5 2 10 27 5

Test for Association P-value* 0.0001 0.0420 0.5400 0.2250 0.8460 0.0005 0.0001 0.0450

Test for Risk Factor 6LJQLÂżFDQFH 95% CI P-value** OR 1.53;4.53 2.63 0.0005 19.51 2.75;138.45 0.003 0.247 0.042 0.651 0.002 0.0005 0.153

1.85 1.69 1.19 2.34 1.72 1.79

0.65;5.28 1.02;2.78 0.55;2.58 1.36;4.03 1.26;2.33 0.81;3.98

ICU=intensive care unit; TDGE=transient dysfunction of gas exchange; TDGE absent=PaO2/FiO2>300 mmHg; TDGE mild=PaO2/FiO2 between 200 mmHg and 300 mmHg; TDGE moderate=PaO2/FiO2 between 100 mmHg and 200 mmHg; severe TDGE=PaO2/FiO2<100 mmHg; 3DUHQWKHVHV SHUFHQWDJH RI WRWDO JURXS 9$3 PHFKDQLFDO YHQWLODWLRQ DVVRFLDWHG SQHXPRQLD 3 YDOXH FKL VTXDUH WHVW 3 YDOXH ORJLVWLF UHJUHVVLRQ &, FRQÂżGHQFH LQWHUYDO Table 6. The occurrence of death within 48 hours and after 48 hours after surgery. Postoperative data Death within 48 hours Death after 48 hours

Prevalence on Sample n % 6 0.8% 66 9,2%

Absent n 0 5

TDGE levels Mild Moderate Severe n n n 1 4 1 8 40 13

Test for Association P-value* 0.5420 0.0350

TDGE=transient dysfunction of gas exchange; TDGE absent=PaO2/FiO2>300 mmHg; TDGE mild=PaO2/ FiO2 between 200 mmHg and 300 mmHg; TDGE moderate=PaO2/FiO2 between 100 mmHg and 200 mmHg; severe TDGE=PaO2/FiO2 PP+J 3 YDOXH 7XNH\ WHVW IRU FRPSDULVRQ RI PHDVXUHV EHWZHHQ 7'*( groups

28 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Rodrigues CDA, et al. - Risk factors for transient dysfunction of gas exchange after cardiac surgery

Braz J Cardiovasc Surg 2015;30(1):24-32

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29 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Rodrigues CDA, et al. - Risk factors for transient dysfunction of gas exchange after cardiac surgery

Braz J Cardiovasc Surg 2015;30(1):24-32

dicting mortality[10]. In the study of Ribeiro et al.[13], especially in the postoperative period of cardiac surgery, 115,021 pulmonary complications contributed to the overall mortality rate of 8%. In Brazil, the mortality rate after cardiovascular VXUJHU\ LV DSSUR[LPDWHO\ LQ WKH 8QLÂżHG +HDOWK 6\VWHP[14]. $3$&+( ,, LV DQ LQGH[ WKDW FODVVLÂżHV FULWLFDO SDWLHQWV DFFRUGing to the severity of their condition[15]. Our patients had high APACHE II scores, similar to the study by FeijĂł et al.[16]. In a prospective trial of 520 patients lasting 13 months in the ICU of Hospital Sao Paulo, in which the APACHE II prognostic index was applied, scores > 25 were associated with a higher risk of death[15]. In our study, the APACHE II score (12.8 Âą 4.2 points) and predicted mortality (17.9Âą9.5 points) were correlated with the occurrence of severe TDGE (P=0.0001 for both), demonstrating that APACHE II score was effective to determine the severity of the patients in this study. Although mortality was high (10.5%), it was less than expected.

proposed: mild, moderate, and severe, based on the PaO2/ FiO2 UDWLR FKHVW ; UD\ FULWHULD ZHUH FODULÂżHG WR LPSURYH reliability between examiners; and the PCWP criterion was removed and clarity was added to improve the ability to rule RXW FDUGLDF FDXVHV RI ELODWHUDO LQÂżOWUDWHV[17] 7KH ODVW GHÂżQLtion includes the measurement of PEEP, limiting the possibilities of diagnosis for patients without mechanical ventilation, but the diagnosis of ARDS does not exclude these patients. 7R HYDOXDWH RXU SDWLHQWV XQGHU WKH QHZ FODVVLÂżFDWLRQ RI severity of the ARDS PaO2/FiO2 ratio, we found that 89.26% ÂżW WKLV FULWHULRQ IRU GLDJQRVLV VXJJHVWLQJ D KLJK LQFLGHQFH RI ARDS in this population. However, using only the PaO2/FiO2 UDWLR LV QRW VXIÂżFLHQW WR GHÂżQH WKH SUHVHQFH RI $5'6 2WKer factors are included in the dysfunctional gas exchange in the postoperative period of cardiac surgery, such as systemic LQĂ€DPPDWRU\ UHVSRQVH V\QGURPH 6,56 ZLWK SXOPRQDU\ UHpercussion, hyperdynamic frame, interstitial pulmonary edema, microatelectasis, and reduced surfactant. In most cases, the pulmonary radiological image is normal, undercommitted lung compliance, and patients recover from this dysfunction in a few hours, including extubation after a few hours in intensive care. In the present study, of 89.26% of patients who presented with TDGE, only 2% evolved with ARDS, according to the FULWHULD RI WKH ODVW FRQVHQVXV 7KH FODVVLÂżFDWLRQ RI $5'6 DV mild, moderate, and severe was used to determine the degree RI 7'*( %DVHG RQ WKHVH ÂżQGLQJV WKH WHUP $5'6 VKRXOG only be used for patients who meet all the diagnostic criteria. Therefore, we suggest that this acute and transient hypoxia that occurs in the postoperative period of cardiac surgery (within 48 hours) be called transient dysfunction of gas exchange, as we have in this work.

2FFXUUHQFH RI 7'*( DIWHU VXUJHU\ DQG FDUGLDF procedures Respiratory failure after heart surgery is an important factor of postoperative morbidity and mortality[4]. In this study, 15 (2%) patients had ARDS, 27.7% mild TDGE, 56.1% moderate TDGE, and 5.4% severe TDGE. In a study by Szeles et al.[5], the PaO2/FiO2 ratio was used to assess the impact of the seriousness of the hypoxemia in the immediate postoperative period. The patients were divided into three groups: PaO2/ FiO2>200 (45.8%); PaO2/FiO2 between 150 and 200 (26.9%) and PaO2/FiO2<150 (27.3%). That study reported that transient hypoxemia was not affected by an increase of mechanLFDO YHQWLODWLRQ WLPH DQG WKDW WKH LQĂ€DPPDWRU\ UHVSRQVH WR surgical trauma and CBP caused lung damage, explaining the transitional hypoxemia[5]. ARDS was present in 0.4% to 1.32% of the patients[4]. $5'6 ZDV ÂżUVW GHVFULEHG E\ $VKEDXJK 3HWW\ LQ with these common characteristics: tachypnea, hypoxemia, SHUVLVWHQW RSDFLÂżFDWLRQ RQ FKHVW ; UD\ GHFUHDVHG FRPSODFHQF\ DQG KLJK PRUWDOLW\ ,Q WKH ÂżUVW FRQVHQVXV IRU $5'6 ZDV SXEOLVKHG ZKLFK GHÂżQHG IRXU DVSHFWV DFXWH SUHsentation, presence of hypoxemia (PaO2/FiO2<200 mmHg), LQÂżOWUDWHG ELODWHUDO RQ FKHVW ; UD\ DQG SXOPRQDU\ FDSLOlary wedge pressure (PCWP) less than 18 cmH2O (to rule RXW KHDUW IDLOXUH $OVR GHÂżQHG LQ WKLV FRQVHQVXV VLPLODU WR $5'6 ZDV $/, GHÂżQHG DV EHLQJ SUHVHQW ZKHQ WKH 3D22/ FiO2 ratio is between 200 and 300 mmHg[17]. Over the years, the criteria for ARDS did not correspond to the manifestations of the syndrome. In 2012, the criteria ZHUH UHYLVHG XVLQJ WKH IROORZLQJ FODVVLÂżFDWLRQ WKH WHUP DFXWH ZDV GHÂżQHG DV WKH RFFXUUHQFH RI HYHQWV RI PDQLIHVWDtion in one week or less; the term ALI was abandoned; and the measurement of the PaO2/FiO2 relationship was amended to require a minimal amount of positive end-expiratory pressure (PEEP)[7]. In addition, three categories of ARDS were

$VVRFLDWLRQ RI 7'*( ZLWK SUHRSHUDWLYH DQG SRVWRSerative factors In our sample, increasing age was associated with increasing severity of TDGE, especially in patients older than 75 years, whose risk is three times higher than patients younger than 44 years. In the study of Oliveira et al.[9], age>70 years was sigQLÂżFDQWO\ DVVRFLDWHG ZLWK JUHDWHU PRUWDOLW\ P<0.002). In this study, the average length of stay in the ICU was 7.3Âą11.9 days, similar to the average of 4.16Âą3.76 days in the study by Laizo et al.[10]. There was a tendency for the prevalence of severe TDGE to increase from 2007 to 2011(P=0.01). Hypertension and cardiogenic shock were associated with the emergence of moderate TDGE postoperatively (P=0.022 and P=0.019, respectively) and were risk factors (P=0.001 and P=0.002, respectively) for the development of this dysfunction. Diabetes mellitus was a risk factor for TDGE (P=0.035). Diabetic patients have chronic vasculitis, and when associated ZLWK WKH SRVWRSHUDWLYH LQĂ€DPPDWRU\ SURFHVV WKLV FRQGLWLRQ worsens, altering the relative pulmonary ventilation/perfusion ratio, which corresponds to changes in gas exchange.

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Rodrigues CDA, et al. - Risk factors for transient dysfunction of gas exchange after cardiac surgery

Braz J Cardiovasc Surg 2015;30(1):24-32

7KH SRVWRSHUDWLYH FRPSOLFDWLRQV LQÀXHQFH WKH OHQJWK RI hospitalization of the patient, generating increased costs and hospital mortality[18]. In this study, pneumonia was present in 8.9% of cases and was associated with moderate TDGE (P=0.001), which was a risk factor (P=0.0005) for the occurrence of postoperative pneumonia. Ventilator-associated pneumonia (VAP) was present in 0.6% of the cases and was associated with severe TDGE (P=0.042), which in turn was a risk factor (P=0.003) for the development of VAP. The low incidence of VAP in the study may be explained by the implementation of prophylactic measures and the awareness of the professionals of the ICU at the beginning of 2007. In a previous study, lung infection was more common among the infectious complications (15.3%)[19]. In another study, 7332 patients undergoing cardiac surgery, infectious RXWEUHDNV ZHUH LGHQWL¿HG LQ SDWLHQWV RI WKHP SULmary infections[14]. However, there is no study reporting the occurrence of postoperative pulmonary complications[20]. Oliveira et al.[11] indicated the following as predictors of SRVWRSHUDWLYH LQIHFWLRQV ERG\ PDVV LQGH[ • NJ P2, preoperative hemodialysis, cardiogenic shock, preoperative age • \HDUV SUHRSHUDWLYH LPPXQRVXSSUHVVLYH WUHDWPHQW GLDEHWHV PHOOLWXV &3% • PLQXWHV DQG WKH UHYDVFXODUL]DWLRQ of three or more vessels. Among the complications encountered in the period after surgery, those that occur in the respiratory system contribXWH VLJQL¿FDQWO\ WR PRUELGLW\ DQG PRUWDOLW\ UHODWHG WR FDUGLDF surgery, as 3.5% to 10% of these morbidities and mortalities are caused by respiratory complications[21]. In large part, these complications are explained by the use of CPB, which FDXVHV DQ LQFUHDVH RI LQÀDPPDWRU\ PHGLDWRUV OHDGLQJ WR GHcreased ventricular contractility, which consequently increases vascular permeability and resistance of the organs. 6SHFL¿FDOO\ LQ WKH SXOPRQDU\ FLUFXODWLRQ LQÀDPPDWRU\ ÀXLG DFFXPXODWHV LQWHUVWLWLDOO\ OHDGLQJ WR WKH IRUPDWLRQ RI microatelectasis, hypoxemia, and hypoxic vasoconstriction. These conditions decrease the local production of pulmonary surfactant, which leads to worsening pressures, lung collapse, and pulmonary dysfunction, generating losses in respiratory mechanics and increased respiratory work[12,22]. This situation results in pneumonic complications in respiratory mechanics[23]. Morsch et al.[2] used pulmonary radiological changes as diagnostic criteria for unventilated areas and/or consolidation, pleural effusion, and collapsed lung. Diagnostic criteria of postoperative lung infections are not VWDQGDUG LQ WKH VFLHQWL¿F OLWHUDWXUH DQG DUH DVVRFLDWHG RU QRW with radiological changes, leukocytosis, body hyperthermia, and isolation of pathogens in culture or in microscopic analysis of[21]. Hypoxemia is among the leading pulmonary complications in the postoperative period of cardiac surgery; however, other complications, such as pleural effusion, pneumonia, SQHXPRWKRUD[ UHLQWXEDWLRQ DQG YHQWLODWRU\ LQVXI¿FLHQF\

are also observed[24]. We used non-invasive mechanical ventilation therapeutically in 2.1% of cases, reintubation in 9.6%, and tracheostomy in 3.6%. Reintubation was a risk factor (P=0.042) for only postoperative TDGE. Severe TDGE was associated with patients who had renal replacement therapy (P=0.0005), hemotherapy (P=0.0001), and cardiac arrhythmia (P=0.0450), with respective risk factors 2.34, 1.72, and 1.79. A large amount of information in this study was collected from patient records, so the loss of information is inexcusable. We sorted the information by category to extract the largest amount of available information. CONCLUSION We concluded that TDGE, in varying degrees, was present at the time of surgery and during postoperative cardiac procedures. Preoperative hypertension and cardiogenic shock were associated with the occurrence of postoperative TDGE. The preoperative risk factors included hypertension, cardiogenic shock, and diabetes. Postoperatively, pneumonia, VAP, renal replacement therapy, hemotherapy, and cardiac arrhythmia were associated with the appearance of a certain degree of TDGE, which was a risk factor for reintubation, pneumonia, VAP, and renal replacement therapy during the postoperative period from cardiac surgery and during cardiac procedures. ACKNOWLEDGMENTS 7KH DXWKRUV DFNQRZOHGJH WKH ZRUN GRQH E\ WKH 2IÂżFH RI Biostatistics, School of Medical Sciences, State University of Campinas. In particular, we would like to thank Cleide Aparecida Moreira Silva for his dedication to this work. We also appreciate nurse ClaudinĂŠia Muterle Logato Marmirolli for collecting data in the Intensive Care Unit of the Hospital of the State University of Campinas.

Authors’ roles & responsibilities &'$5

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$QDO\VLV DQG RU LQWHUSUHWDWLRQ RI GDWD ÂżQDO DSSURYDO RI WKH manuscript, study design, manuscript writing or critical review of its content Final approval of the manuscript Analysis and/or interpretation of data, statistical analysis, ÂżQDO DSSURYDO RI WKH PDQXVFULSW VWXG\ GHVLJQ PDQXVFULSW writing or critical review of its content Final approval of the manuscript Final approval of the manuscript Final approval of the manuscript $QDO\VLV DQG RU LQWHUSUHWDWLRQ RI GDWD ÂżQDO DSSURYDO RI WKH manuscript, study design, manuscript writing or critical review of its content

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Rodrigues CDA, et al. - Risk factors for transient dysfunction of gas exchange after cardiac surgery

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13. Ribeiro AL, Gagliardi SP, Nogueira JL, Silveira LM, Colosimo EA, Lopes do Nascimento CA. Mortality related to cardiac surgery in Brazil, 2000-2003. J Thorac Cardiovasc Surg. 2006;131(4):907-9.

REFERENCES 1. Guizilini S, Gomes WJ, Faresin SM, Carvalho ACC, Jaramillo JI, Alves FA, et al. Effects of the pleural drain site on the pulmonary function after coronary artery bypass grafting. Rev Bras Cir Cardiovasc. 2004;19(1):47-54.

14. Gomes WJ, Mendonça JT, Braile DM. Resultados em cirurgia cardiovascular: oportunidade para rediscutir o atendimento mÊdico e cardiológico no sistema público de saúde do país. Rev Bras Cir Cardiovasc. 2007;22(4):III-VI.

2. Morsch KT, Leguisamo CP, Camargo MD, Coronel CC, Mattos : 2UWL] /'1 HW DO 3HU¿O YHQWLODWyULR GRV SDFLHQWHV VXEPHWLGRV a cirurgia de revascularização do miocårdio. Rev Bras Cir Cardiovasc. 2009;24(2):180-7.

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16. FeijĂł CAR, Leite JĂşnior FO, Martins ACS, Furtado JĂşnior AH, Cruz LLS, Meneses FA. Gravidade dos pacientes admitidos j XQLGDGH GH WHUDSLD LQWHQVLYD GH XP KRVSLWDO XQLYHUVLWiULR brasileiro. Rev Bras Ter Intensiva. 2006;18(1):18-21.

4. Rodrigues CDA, Oliveira RARA, Soares SMTP, Figueiredo LC, Araújo S, Dragosavac D. Lesão pulmonar e ventilação mecânica em cirurgia cardíaca: revisão. Rev Bras Ter Intensiva. 2010;22(4):375-83.

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5. Szeles TF, Yoshinaga EM, Alencar W, Brudniewski M, Ferreira FS, Auler Jr JOC, et al. Hipoxemia após revascularização miocårdica: anålise dos fatores de risco. Rev Bras Anestesiol. 2008;58(2):124-36.

18. Piotto RF, Ferreira FB, Colósimo FC, Silva GS, Sousa AG, Braile DM. Fatores preditores independentes de ventilação PHFkQLFD SURORQJDGD HP SDFLHQWHV VXEPHWLGRV j FLUXUJLD de revascularização miocårdica. Rev Bras Cir Cardiovasc. 2012;27(4):520-8.

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20. Westerdahl E, Lindmark B, Almgren SO, Tenling A. Chest physiotherapy after coronary artery bypass graft surgery: a comparison of three different deep breathing techniques. J Rehabil Med. 2001;33(2):79-84.

8. Ledur P, Almeida L, Pellanda LC, Schaan BD. Preditores de infecção no pós-operatório de cirurgia de revascularização miocårdica. Rev Bras Cir Cardiovasc. 2011;26(2):190-6.

21. Brasher PA, McClelland KH, Denehy L, Story I. Does removal of deep breathing exercises from a physiotherapy program including pre-operative education and early mobilisation after cardiac surgery alter patient outcomes? Aust J Physiother. 2003;49(3):165-73.

9. Oliveira EL, Westphal GA, Mastroeni MF. Características FOtQLFR GHPRJUi¿FDV GH SDFLHQWHV VXEPHWLGRV j FLUXUJLD GH revascularização do miocårdio e sua relação com a mortalidade. Rev Bras Cir Cardiovasc. 2012;27(1):52-60.

22. Barbosa RAG, Carmona MJC. Avaliação da função pulmonar HP SDFLHQWHV VXEPHWLGRV j FLUXUJLD FDUGtDFD FRP FLUFXODomR extracorpórea. Rev Bras Anestesiol. 2002;52(6):689-99.

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23. Taylor GJ, Mikell FL, Moses HW, Dove JT, Katholi RE, Malik SA, et al. Determinants of hospital charges for coronary artery bypass surgery: the economic consequences of postoperative complications. Am J Cardiol. 1990;65(5):309-13.

12. Renault JA, Costa-Val R, Rossetti MB. Fisioterapia respiratória na disfunção pulmonar pós-cirurgia cardíaca. Rev Bras Cir Cardiovasc. 2008;23(4):562-9.

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32 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Sousa AG, etORIGINAL al. - Epidemiology of coronary artery bypass grafting at the ARTICLE +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD 6mR 3DXOR

Braz J Cardiovasc Surg 2015;30(1):33-9

Epidemiology of coronary artery bypass grafting at WKH +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD 6mR 3DXOR (SLGHPLRORJLD GD FLUXUJLD GH UHYDVFXODUL]DomR PLRFiUGLFD GR +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD GH 6mR 3DXOR

Alexandre Gonçalves de Sousa1 0' 0DULD =HQDLGH 6RDUHV )LFKLQR2 0' *LOPDUD 6LOYHLUD GD Silva3 )OiYLD &RUWH] &RORVLPR %DVWRV4 0' 3K' 5DTXHO )HUUDUL 3LRWWR5 3K'

DOI: 10.5935/1678-9741.20140062

RBCCV 44205-1611 PLD HVSHFLDOO\ DFXWH DWULDO ÂżEULOODWLRQ 3QHXPRQLD RFFXUUHG LQ RI SDWLHQWV DFXWH UHQDO IDLOXUH LQ PHGLDVWLQLWHV LQ VWURNH LQ DQG $0, LQ 7KH LQ KRVSLWDO PRUWDOLW\ ZDV DQG LQ LVRODWHG FRURQDU\ DUWHU\ E\SDVV JUDIW ZDV 7KH DYHUDJH KRVSLWDO VWD\ ZDV GD\V ZLWK D PHGLDQ RI HLJKW GD\V GD\V Conclusion: 7KH SURÂżOH RI SDWLHQWV XQGHUJRLQJ FRURQDU\ DUtery bypass graft surgery in this study is similar to other pubOLVKHG VWXGLHV

Abstract Introduction: The knowledge of the prevalence of risk factors and comorbidities, as well as the evolution and complications in patients undergoing coronary artery bypass graft allows comparison between institutions and evidence of changes LQ WKH SURÂżOH RI SDWLHQWV DQG SRVWRSHUDWLYH HYROXWLRQ RYHU WLPH Objective: 7R SURÂżOH ULVN IDFWRUV DQG FRPRUELGLWLHV DQG FOLQLFDO RXWFRPH FRPSOLFDWLRQV LQ SDWLHQWV XQGHUJRLQJ FRURnary artery bypass graft in a national institution of great surJLFDO YROXPH Methods: A retrospective cohort study of patients undergoLQJ FRURQDU\ DUWHU\ E\SDVV JUDIW LQ WKH KRVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD GH 6mR 3DXOR IURP -XO\ WR -XO\ Results: :H LQFOXGHG SDWLHQWV PHDQ DJH RI \HDUV DQG PDOH RI SDWLHQWV ZHUH K\SHUWHQVLYH GLDEHWLF KDG G\VOLSLGHPLD ZHUH VPRNHUV ZHUH RYHUZHLJKW REHVH KDG D IDPLO\ KLVWRU\ RI FRURQDU\ KHDUW GLVHDVH 7KH H[SHFWHG PRUWDOLW\ FDOFXODWHG E\ ORJLVWLF (XUR6&25( ZDV 7KH LVRODWHG &$%* RFFXUUHG LQ DQG VXUJHU\ ZDV SHUIRUPHG ZLWKRXW FDUGLRSXOPRQDU\ E\SDVV 7KH PRVW FRPPRQ FRPSOLFDWLRQ ZDV FDUGLDF DUUK\WK-

Descriptors: &RURQDU\ $UWHU\ %\SDVV (SLGHPLRORJ\ Risk )DFWRUV

Resumo Introdução: 2 FRQKHFLPHQWR GD SUHYDOrQFLD GRV IDWRUHV GH risco e comorbidades, bem como a evolução com complicaçþes nos pacientes submetidos à cirurgia de revascularização miocårdica, permite a comparação entre instituiçþes e a comprovação de PRGL¿FDo}HV QR SHU¿O GH SDFLHQWHV H QD HYROXomR SyV RSHUDWyULD DR ORQJR GR WHPSR

7KLV VWXG\ ZDV FDUULHG RXW DW +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD LQ 6mR 3DXOR 6mR 3DXOR 63 %UD]LO 1R ÂżQDQFLDO VXSSRUW

0HGLFDO VSHFLDOLVW LQ FDUGLRORJ\ DQG PHPEHU RI WKH %UD]LOLDQ &DUGLRORJ\ Society. &OLQLFDO 5HVHDUFK 3K\VLFLDQ DW WKH +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD LQ 6mR 3DXOR 6mR 3DXOR 63 %UD]LO 2 &DUGLRORJLVW DW WKH +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD LQ 6mR 3DXOR 6mR 3DXOR 63 %UD]LO 3 Research Nurse at the Center for Education and Research of the Hospital %HQHÂżFrQFLD 3RUWXJXHVD LQ 6mR 3DXOR 6mR 3DXOR 63 %UD]LO 4 &DQGLGDWH DW WKH 6FKRRO RI 1XUVLQJ 8QLYHUVLW\ RI 6mR 3DXOR 5HVHDUFK 1XUVH DW WKH &HQWHU IRU (GXFDWLRQ DQG 5HVHDUFK RI WKH +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD LQ 6mR 3DXOR 6mR 3DXOR 63 %UD]LO 5 Supervisor at the Center for Education and Research of the Hospital %HQHÂżFrQFLD 3RUWXJXHVD LQ 6mR 3DXOR 6mR 3DXOR 63 %UD]LO 1

Correspondence address: Alexandre Gonçalves de Sousa %HQH¿FrQFLD 3RUWXJXHVD GH 6mR 3DXOR 5XD 0DHVWUR &DUGLP %HOD 9LVWD 6mR 3DXOR 63 ¹ =LS FRGH E-mail: a.g.sousa@uol.com.br Article received on June 21st $UWLFOH DFFHSWHG RQ 0DUFK th

33 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Sousa AG, et al. - Epidemiology of coronary artery bypass grafting at the +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD 6mR 3DXOR

Braz J Cardiovasc Surg 2015;30(1):33-9

PRUWDOLGDGH PpGLD HVSHUDGD FDOFXODGD SHOR (XUR6&25( ORJtVWLFR IRL GH $ FLUXUJLD GH UHYDVFXODUL]DomR PLRFiUGLFD LVRODGD RFRUUHX HP H HP IRL UHDOL]DGD FLUXUJLD VHP FLUFXODomR H[WUDFRUSyUHD $ FRPSOLFDomR PDLV FRPXP IRL DUULWPLD FDUGtDFD HVSHFLDOPHQWH D ¿EULODomR DWULDO DJXGD 3QHXPRQLD RFRUUHX HP GRV SDFLHQWHV OHVmR UHQDO DJXGD HP PHGLDVWLQLWH HP DFLGHQWH YDVFXODU HQFHIiOLFR HP H LQIDUWR DJXGR GR PLRFiUGLR HP $ PRUWDOLGDGH LQWUD KRVSLWDODU IRL GH H QD FLUXUJLD GH UHYDVFXODUL]DomR PLRFiUGLFD LVRODGD IRL GH 2 WHPSR GH SHUPDQrQFLD KRVSLWDODU PpGLR IRL GH GLDV FRP PHGLDQD GH RLWR GLDV GLDV Conclusão: 2 SHU¿O GRV SDFLHQWHV VXEPHWLGRV à cirurgia de revascularização miocårdica neste estudo assemelha-se ao de RXWURV HVWXGRV SXEOLFDGRV

Abbreviations, acronyms & symbols CABG /9()

Coronary artery bypass graft 9HQWULFOH HMHFWLRQ IUDFWLRQ

Objetivo: &RQKHFHU R SHU¿O IDWRUHV GH ULVFR H FRPRUELGDGHV H D HYROXomR FOtQLFD FRPSOLFDo}HV QRV SDFLHQWHV VXEPHWLGRV à cirurgia de revascularização miocårdica em uma instituição naFLRQDO GH JUDQGH YROXPH FLU~UJLFR MÊtodos: (VWXGR GH FRRUWH UHWURVSHFWLYR GH SDFLHQWHV VXEmetidos ao procedimento de cirurgia de revascularização mioFiUGLFD QR +RVSLWDO %HQH¿FrQFLD 3RUWXJXHVD GH 6mR 3DXOR QR SHUtRGR GH MXOKR GH D MXOKR GH Resultados: Foram incluídos 3010 pacientes, com idade PpGLD GH DQRV H GR VH[R PDVFXOLQR GRV SDFLHQWHV HUDP KLSHUWHQVRV GLDEpWLFRV GLVOLSLGrPLFRV WDEDJLVWDV FRP VREUHSHVR REHVLGDGH H WLQKDP DQWHFHGHQWHV IDPLOLDUHV GH GRHQoD FRURQiULD $

Descritores: 5HYDVFXODUL]DomR 0LRFiUGLFD (SLGHPLRORJLD )DWRUHV GH 5LVFR

,1752'8&7,21

XQGHUJRLQJ &$%* VXUJHU\ DW WKH +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD LQ 6mR 3DXOR

The likelihood of patients undergoing coronary artery bypass graft (CABG) surgery with a short hospitalization period and no complications depends on the experience of the VXUJLFDO WHDP LQWHQVLYH WKHUDS\ FDUH WKH PXOWLGLVFLSOLQDU\ WHDP LQYROYHG DQG WKH SRVWRSHUDWLYH IROORZ XS SHULRG[1-3]. The success of this procedure is also dependent on the patient’s characteristics. In addition to the progress observed LQ WKH VXUJLFDO SURFHGXUH LWVHOI WKH SRSXODWLRQ XQGHUJRLQJ &$%* VXUJHU\ KDV DOVR EHHQ FKDQJLQJ DQG WKLV PD\ LQÀXHQFH WKH RXWFRPHV &XUUHQWO\ WKLV SRSXODWLRQ LV PXFKROGHU with a higher number of risk factors and associated comorbidities than the population undergoing CABG in the past[46] PRUHRYHU LQFUHDVHG XVH RI PHGLFDWLRQ GUXJV PRGL¿HV WKH GLVHDVHœV QDWXUDO FRXUVH VXFK DV VWDWLQV[7] DV GR D KLJK QXPEHU RI SUHYLRXV SHUFXWDQHRXV SURFHGXUHV ,Q %UD]LO WKH QXPEHU RI DQJLRSODVWLHV ZLWK RU ZLWKRXW VWHQWLQJ LQFUHDVHG from 27.5 per 100 thousand inhabitants in 2002 to 39 per 100 thousand inhabitants in 2010[8]. Several national studies have assessed the epidemiology of patients who underwent CABG[9-13] +RZHYHU PRVW RI WKRVH VWXGLHV IRFXVHG RQ VSHFL¿F RXWFRPHV RU KDYH D ORQJ GDWD FROOHFWLRQ SHULRG ZLWK D PHDQ GXUDWLRQ RI ¹ \HDUV GXULQJ ZKLFK WLPH FKDQJHV LQ WKH SUR¿OH RI WKH SDWLHQWV PD\ RFFXU FRQVHTXHQWO\ PDNLQJ WKHVH VWXGLHV ZHDN UHIHUHQFHV[6]. 7KHUHIRUH VWXGLHV ZLWK ODUJH VDPSOHV DQG VKRUW GDWD FROOHFtion periods are very important in order to assess the demoJUDSKLF SUR¿OH RI SDWLHQWV XQGHUJRLQJ &$%* LQ WKH SUHVHQW 7KH DLP RI WKLV VWXG\ ZDV WR GHWHUPLQH WKH FXUUHQW SUR¿OH (prevalence of risk factors) and clinical progress of patients

0(7+2'6 7KLV ZDV D UHWURVSHFWLYH FRKRUW VWXG\ LQIRUPDWLRQ RQ SDWLHQWV DJHG • \HDUV XQGHUJRLQJ WKH &$%* SURFHGXUH DW WKH +RVSLWDO %HQH¿FrQFLD 3RUWXJXHVD LQ 6mR 3DXOR EHWZHHQ -XO\ DQG -XO\ ZDV FROOHFWHG IURP DQ electronic database. This database contains data about 3010 SDWLHQWV ZKR XQGHUZHQW &$%* DFFRXQWLQJ IRU WKH GDWD UHgarding 69.6% of all surgeries performed at the institution over that period. The percentage of patients's loss includeGLQ WKH GDWDEDVH ZDV UDQGRP ZLWKRXW SUHIHUHQFH IRU GD\ WLPH SHULRG WHDP VXUJHRQ RU SDWLHQW FRQGLWLRQ 7KH GDWD collection form consisted of 243 variables with data from WKH SUHRSHUDWLYH LQWUDRSHUDWLYH DQG SRVWRSHUDWLYH SHULRGV (until hospital discharge or death). The CABG procedure with extracorporeal circulation (ECC) was performed with the patient under general anesthesia and orotracheal intubation in the supine horizontal SRVLWLRQ ZLWK PHGLDQ WUDQVWHUQDO ORQJLWXGLQDO WKRUDFRWRP\ IROORZHG E\ JUDIW UHPRYDO LQWHUQDO WKRUDFLF DUWHU\ VDSKHQRXV YHLQ UDGLDO DUWHU\ HWF DQG LQYHUWHG 7 SHULFDUGLRWRP\ $IWHU WKH EDJV IRU (&& ZHUH SUHSDUHG WKH SDWLHQW ZDV JLYHQ IXOO GRVH KHSDULQ PJ NJ ZLWK DUWHULDO FDQQXODWLRQ RI WKH DVFHQGLQJ DRUWD FDYRDWULDO FDQQXODWLRQ LQVHUWLRQ RI D * catheter in the ascending aorta to connect the aspiration pathZD\V DQG WR LQIXVH D FDUGLRSOHJLF VROXWLRQ FODPSLQJ RI WKH DVFHQGLQJ DRUWD DQG SUHSDUDWLRQ RI WKH GLVWDO DQG SUR[LPDO DQDVWRPRVHV LQ WKLV VHTXHQFH

34 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Sousa AG, et al. - Epidemiology of coronary artery bypass grafting at the +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD 6mR 3DXOR

Braz J Cardiovasc Surg 2015;30(1):33-9

5(68/76

$IWHU WKLV SURFHGXUH WKH (&& V\VWHP ZDV UHPRYHG DQG ÀXLG UHSODFHPHQW DQG SURWDPLQH LQIXVLRQ ZHUH SHUIRUPHG DORQJ ZLWK KHPRVWDVLV PRQLWRULQJ GUDLQLQJ RI WKH FKHVW FDYLW\ DQG PHGLDVWLQXP ¿[LQJ RI D SDFHPDNHU OHDG VWHUQDO VXWXULQJ DQG XVXDO FORVLQJ ,Q WKH SURFHGXUH ZLWKRXW (&& WKH SDWLHQW received general anesthesia with orotracheal intubation in the VXSLQH KRUL]RQWDO SRVLWLRQ 0HGLDQ WUDQVVWHUQDO ORQJLWXGLQDO thoracotomy was performed followed by graft removal (inWHUQDO WKRUDFLF DUWHU\ VDSKHQRXV YHLQ UDGLDO DUWHU\ HWF LQYHUWHG 7 SHULFDUGLRWRP\ KHSDULQ DGPLQLVWUDWLRQ WR PJ NJ DQG SUHSDUDWLRQ RI WKH GLVWDO DQG SUR[LPDO DQDVWRPRVHV LQ WKLV VHTXHQFH ZLWK WKH KHOS RI D FRURQDU\ DUWHU\ VWDELOL]HU $IWHU WKH SURFHGXUH WKH SDWLHQW ZDV JLYHQ D SURWDPLQH LQIXVLRQ DQG KHPRVWDVLV PRQLWRULQJ DQG GUDLQLQJ RI WKH FKHVW FDYLW\ DQG PHGLDVWLQXP ZHUH SHUIRUPHG DORQJ ZLWK ¿[LQJ RI D SDFHPDNHU OHDG VWHUQDO VXWXULQJ DQG XVXDO FORVLQJ

7KH SDWLHQWVÂś PHDQ DJH ZDV \HDUV ZLWK WKH SURSRUWLRQ RI PHQ EHLQJ RI WKH SDWLHQWV ZHUH VPRNHUV K\SHUWHQVLYH DQG GLDEHWLF 5HJDUGLQJ WKH ÂżQDQFLDO DVSHFW RI WKH VXUJHULHV ZHUH IXQGHG E\ WKH 1+6 E\ SULYDWH KHDOWK LQVXUDQFH DQG E\ SHUVRQDO UHVRXUFHV 7KH SDWLHQWVÂś clinical-demographic characteristics are shown in Table 1. 2I WKH SDWLHQWV LQFOXGHG LQ WKLV VWXG\ had the result of their coronary angiography (catheterization) stated on their patient records. Coronary obstructions larger than 50% were considered serious when located in the left coronary WUXQN DQG ODUJHU WKDQ LQ DOO RWKHU EORRG YHVVHOV 6LPLODUO\ RQO\ RI WKH SDWLHQWV KDG WKH OHIW YHQWULFOH HMHFWLRQ IUDFWLRQ /9() PHQWLRQHG RQ WKHLU UHFRUGV ,Q WKLV VDPSOH WKH PHWKRG XVHG IRU HVWLPDWLRQ RI WKH /9() ZDV HFKRFDUGLRJUDSK\ IRU SDWLHQWV YHQWULFXORJUDSK\ IRU P\RFDUGLDO VFLQWLJUDSK\ IRU SDWLHQWV DQG QXFOHDU PDJnetic resonance imaging for 4 patients (0.3%) (Table 2). The preoperative risk score (logistic EuroSCORE) was inGLYLGXDOO\ FDOFXODWHG IRU DOO SDWLHQWV ZLWK WKH PHDQ VFRUH EHLQJ

3RVWRSHUDWLYH FRPSOLFDWLRQV ZHUH GH¿QHG DV ‡ 3HULRSHUDWLYH P\RFDUGLDO LQIDUFWLRQ SURORQJHG SDLQ for more than 20 minutes/typical pain not improved with niWUDWHV DQG RU VHULDWHG HOHFWURFDUGLRJUDPV DW OHDVW VKRZLQJ new changes to the ST/T segment or new Q waves of at least 0.03 sec or more than a third of the QRS (in at least 2 contiguous leads) plus elevation of cardiac enzyme (creatine kiQDVH 0% RU WURSRQLQ WLPHV KLJKHU WKDQ WKH QRUPDO XSSHU OLPit) and/or a new hypokinetic area found on echocardiography. ‡ 6WURNH PRWRU GH¿FLW SHUVLVWHQW IRU PRUH WKDQ KRXUV or coma >24 hours. ‡ $FXWH NLGQH\ LQMXU\ VHUXP FUHDWLQLQH OHYHO KLJKHU WKDQ 2.0 mg/dL or 2 times higher than that in the preoperative peULRG RU WKH QHHG IRU GLDO\VLV DQ\ PHWKRG ‡ 0HGLDVWLQLWLV GHHS LQIHFWLRQ LQYROYLQJ WKH PXVFOHV ERQHV DQG RU WKH PHGLDVWLQXP ZLWK WKH IROORZLQJ FRQGLWLRQV RSHQ ZRXQG ZLWK WLVVXH H[FLVLRQ SRVLWLYH FXOWXUH UHVXOWV DQG WUHDWPHQW ZLWK DQWLELRWLFV ‡ 3QHXPRQLD GLDJQRVHG RQ WKH EDVLV RI SRVLWLYH VSXWXP EORRG RU SOHXUDO ÀXLG FXOWXUH UHVXOWV HPS\HPD RU UDGLRJUDSK\ VKRZLQJ QHZ LQ¿OWUDWHV ‡ $UUK\WKPLD DQ\ DUUK\WKPLD DWULDO ¿EULOODWLRQ DWULDO ÀXWWHU SDUR[\VPDO VXSUDYHQWULFXODU WDFK\FDUGLD EUDG DUUK\WKPLD RU RWKHU UHTXLULQJ LQWHUYHQWLRQ

Table 1. Clinical-demographic characteristics of 3010 patients who XQGHUZHQW FRURQDU\ DUWHU\ E\SDVV JUDIWLQJ 6mR 3DXOR Variable n % Demographic variables 62.2 Âą 9.49 years Age (meanÂąstandard deviation) 0DOH 2105 69.9 Cardiovascular risk factors Hypertension 2491 82.8 Overweight (n=2921) 1319 45.1 Obesity (n=2921) 601 20.6 Dyslipidemia 1338 44.5 Diabetes 1102 36.6 )DPLO\ KLVWRU\ RI &$' 881 29.3 3UHYLRXVO\ D VPRNHU TXLW VPRNLQJ

1203 39.9 Smoking (presently a smoker) 462 15.3 3UHYLRXV FRURQDU\ FDUGLDF DQJLRSODVW\ 3UHYLRXV P\RFDUGLDO LQIDUFWLRQ 1411 46.9 3UHYLRXV WKURPERO\VLV 26 0.8 3UHYLRXV DQJLRSODVW\ 261 8.7 3UHYLRXV &$%* 47 1.6 3UHYLRXV YDOYH VXUJHU\ 8 0.3 Other previous cardiac surgery 4 0.1 Other morbidities Chronic obstructive pulmonary disease 209 6.9 3UHYLRXV VWURNH 168 5.6 &KURQLF NLGQH\ LQMXU\ 170 5.7 3HULSKHUDO DUWHULDO GLVHDVH 146 4.9 &KURQLF DWULDO ÂżEULOODWLRQ 81 2.7 Carotid disease 54 1.8

The study was approved by the Ethics Committee of the +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD LQ 6mR 3DXOR XQGHU RSLQion number 663-10. Statistical considerations The variables were descriptively analyzed. Regarding WKH TXDQWLWDWLYH YDULDEOHV WKH DQDO\VLV ZDV SHUIRUPHG E\ determining the minimum and maximum values and/or the PHDQ VWDQGDUG GHYLDWLRQ DQG PHGLDQ YDOXHV 5HJDUGLQJ WKH TXDOLWDWLYH YDULDEOHV DEVROXWH DQG UHODWLYH IUHTXHQFLHV ZHUH determined.

CAD=coronary artery disease; CABG=coronary artery bypass graft chronic kidney disease=serum creatinine > 2.0 mg/dL or dialysis (whether hemodialysis or peritoneal dialysis)

Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Sousa AG, et al. - Epidemiology of coronary artery bypass grafting at the +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD 6mR 3DXOR

Braz J Cardiovasc Surg 2015;30(1):33-9

“ IRU WKH JURXS UDQJLQJ IURP WR 7KH median score was 1.81% (Table 2). Table 3 shows the characteristics of the surgical procedure. 7KH IUHTXHQF\ RI WKH PDLQ SRVWRSHUDWLYH FRPSOLFDWLRQV LV described in Table 4. 7KH OHQJWK RI WKH KRVSLWDO VWD\ ZDV GD\V ZLWK D PHGLDQ RI GD\V UDQJH ¹ GD\V ,QWUD KRVSLWDO PRUWDOLW\ RFFXUUHG LQ SDWLHQWV :LWK UHJDUG WR LVRODWHG &$%* the intra-hospital mortality was 3.5%. Intraoperative death occurred in 7 patients (0.2%).

7DEOH $QJLRJUDSKLF FKDUDFWHULVWLFV YHQWULFXODU IXQFWLRQ DQG EuroSCORE of patients who underwent coronary artery bypass JUDIWLQJ 6mR 3DXOR n % Variable Result from the previous hemodynamic study (n=1947) 400 20.5 Severe lesion in 1 artery 41.2 802 Severe lesion in 2 arteries 36.1 703 Severe lesion in 3 arteries 2.2 42 No lesion 10.5 203 Severe lesion in LCT 40.5 788 Lesion in proximal third of AD Ventricular function (n=1331) 76.0 1011 1RUPDO HMHFWLRQ IUDFWLRQ •

14.5 193 0LOG G\VIXQFWLRQ HMHFWLRQ IUDFWLRQ Âą

8.5 0RGHUDWH G\VIXQFWLRQ HMHFWLRQ IUDFWLRQ Âą 113 6HYHUH G\VIXQFWLRQ HMHFWLRQ IUDFWLRQ

1.0 14 2.70Âą3.09 0HDQ ORJLVWLF (XUR6&25(

',6&866,21 The continuous assessment of CABG surgery outcomes using records and large databases is a reality in several countries. The oldest coronary surgery database dates back to DQG WKH PRVW ZLGHO\ SXEOLFL]HG RQH LV WKH 8QLWHG 6WDWHV Society of Thoracic Surgeons’ database - STS National DataEDVH ZKLFK KDV EHHQ FROOHFWLQJ GDWD VLQFH DQG LQYROYHV more than 800 sites across the country contributing every \HDU ZLWK LQIRUPDWLRQ RQ DSSUR[LPDWHO\ SDWLHQWV XQdergoing coronary surgery[14]. ,Q %UD]LO DOWKRXJK &$%* VXUJHULHV KDYH EHHQ SHUIRUPHG IRU DOPRVW KDOI D FHQWXU\ WKH\ KDYH QRW EHHQ UHFRUGHG RQ D ODUJH VFDOH 7KLV VWXG\ DOWKRXJK QRW UHSUHVHQWDWLYH RI WKH QDWLRQDO VLWXDWLRQ SUHVHQWV WKH LPPHGLDWH UHDOLW\ RI DQ LQVWLtution with high representativeness at the national level and involving several independent teams. The results of this study show that men account for the maMRULW\ RI WKH RSHUDWHG SDWLHQWV LQ OLQH ZLWK RWKHU VWXGLHV that show a proportion of men ranging from 60.0%[15] to 70.0%[16]. 5HJDUGLQJ DJH DQ LQFUHDVH LQ WKH QXPEHU RI SDWLHQWV EHORQJLQJ to more advanced age groups was observed as opposed to in a study performed at the beginning of the previous decade[17]. This is probably the result of an increasingly aging population and the LQFUHDVHG VDIHW\ LQ SHUIRUPLQJ WKH VXUJHU\ RQ HOGHUO\ SDWLHQWV thereby leading to good results in this population. 7KH SUHYDOHQFH RI FDUGLRYDVFXODU ULVN IDFWRUV ZDV KLJK ZLWK WKH PRVW IUHTXHQW ¿QGLQJ EHLQJ K\SHUWHQVLRQ A high prevalence of hypertension is usually found in studies ZLWK WKLV W\SH RI SRSXODWLRQ UHDFKLQJ OHYHOV XS WR [17]. Diabetes and obesity showed prevalence rates similar to WKRVH UHSRUWHG LQ WKH SUHYLRXVO\ PHQWLRQHG VWXG\ ZKHUHDV the presence of dyslipidemia was relatively lower. It is noteworthy that there is a lower prevalence of smoking in our UHVXOWV WKDQ LQ WKH UHVXOWV RI WKH RWKHU VWXG\ ZLWK GDWD FROOHFWHG EHWZHHQ DQG ZKHUH WKH UHSRUWHG UDWH UHDFKHV 63%[18]. This may be the result of numerous awareness and anti-smoking campaigns that took place over the last years. +RZHYHU WKH FXUUHQW VPRNLQJ UDWH VPRNLQJ LQ WKH SUHYLRXV 4 weeks) was 15.3% in our study. The number of patients with previous percutaneous coroQDU\ DQJLRSODVW\ KDV EHHQ JURZLQJ RYHU WKH ODVW \HDUV KLJK-

LCT=left coronary trunk; AD=anterior descending coronary; EuroSCORE=assessment of the risk of death following cardiac surgery

Table 3. Operative characteristics of 3010 patients who underwent FRURQDU\ DUWHU\ E\SDVV JUDIWLQJ 6mR 3DXOR n % Variable 2982 99.1 Elective surgery 2688 89.3 Isolated CABG 2653 88.1 8VLQJ (&& 46.7Âą22.9 min Clamping time (mean Âą standard deviation) 141 4.7 Associated valve surgery 80 2.6 Aortic valve 63 2.1 0LWUDO YDOYH 9 0.3 Tricuspid valve 173 5.7 Other associated cardiac procedure 31 1.0 Associated non-cardiac procedure 2637 87.6 Graft use in internal thoracic artery CABG=coronary artery bypass grafting; ECC=extracorporeal circulation

7DEOH 0DLQ SRVWRSHUDWLYH FRPSOLFDWLRQV RI SDWLHQWV ZKR XQGHUZHQW FRURQDU\ DUWHU\ E\SDVV JUDIWLQJ 6mR 3DXOR Variable n % Cardiac arrhythmia 564 18.7 $FXWH DWULDO ÂżEULOODWLRQ 429 14.3 3QHXPRQLD 187 6.2 $FXWH NLGQH\ LQMXU\ 134 4.4 In need of dialysis 50 1.6 Heart failure 99 3.3 Reoperation for any reason 92 3.1 0HGLDVWLQLWLV 64 2.1 Stroke 53 1.8 3HULRSHUDWLYH P\RFDUGLDO LQIDUFWLRQ 35 1.2

36 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Sousa AG, et al. - Epidemiology of coronary artery bypass grafting at the +RVSLWDO %HQH¿FrQFLD 3RUWXJXHVD 6mR 3DXOR

Braz J Cardiovasc Surg 2015;30(1):33-9

• &$%* \HDU WKH PHDQ PRUWDOLW\ ZDV UDQJLQJ between 1.9% and 19%[11].

lighting the increased indication for this procedure[8]. In our VHULHV RI WKH SDWLHQWV KDG D KLVWRU\ RI SHUFXWDQHRXV FRURQDU\ DQJLRSODVW\ $ VWXG\ FRPSDULQJ WKH SUR¿OH RI SDWLHQWV operated in 2 different time periods (early 1990s versus early 2000s) reported a history of coronary angioplasty in 6.5% of SDWLHQWV LQ WKH ¿UVW SHULRG DQG LQ WKH VHFRQG SHULRG 0RUHRYHU SDWLHQW UHSRUWHG SUHYLRXV VWHQW XVH LQ WKH ¿UVW PRPHQW ZDV QRQH LQ WKH ¿UVW SHULRG DQG LQ WKH VHFRQG PRPHQW[18]. Regarding the 1099 patients who underwent CABG surgery at WKH ,QVWLWXWR GR &RUDomR +HDUW ,QVWLWXWH LQ 6mR 3DXOR EHWZHHQ 0D\ DQG -XQH KDG XQGHUJRQH SUHYLRXV FRURnary angioplasty[19]. Coronary angiography showed that 77.3% RI WKH SDWLHQWV KDG VHYHUH REVWUXFWLYH OHVLRQV LQ RU DUWHULHV a proportion that was practically identical to that reported in a recent study conducted in southern Brazil[20]. Severe left corRQDU\ WUXQN OHVLRQV KRZHYHU ZHUH IRXQG LQ RXU VHULHV DW D lower percentage (10.5%) than that reported in other national VWXGLHV L H [15] [19] and 21.6%[20]. :LWK UHJDUG WR VXUJHU\ LQWHUQDO WKRUDFLF DUWHU\ XVH ZDV VHHQ LQ RI FDVHV DQG WKLV PLUURUV WKH FRQFHUQ RI WKH surgery teams for ensuring the implantation of superior grafts whose superiority has been well supported in studies and FRQVLGHUHG DV D TXDOLW\ LQGLFDWRU LQ &$%* VXUJHU\ 5HJDUGLQJ (&& XVH RQO\ RI WKH VXUJHULHV ZHUH SHUIRUPHG ZLWKRXW (&& VXSSRUW +RZHYHU WKLV SHUFHQWDJH YDULHG JUHDWO\ EHWZHHQ WHDPV UDQJLQJ EHWZHHQ DQG for different teams. Data from other national services show that 18.6% of the surgeries were performed without ECC in the southern region[16] and 39.5% of isolated bypass grafting VXUJHULHV ZHUH SHUIRUPHG DW WKH ,QVWLWXWR GR &RUDomR ORFDWHG LQ WKH FLW\ RI 6mR 3DXOR IURP WR [21]. The mean length of hospital stay in this study (11 days) shows a progressive decrease from the length of hospital stay LQ SUHYLRXV VWXGLHV %HWZHHQ DQG WKH PHDQ ZDV 14.5 days[22] DQG EHWZHHQ DQG GD\V[11]. &RPSDULVRQ RI WKH IUHTXHQF\ RI SRVWRSHUDWLYH FRPSOLFDtions between this study and other national data was impossible because of the lack of studies including all the compliFDWLRQV 6HYHUDO VWXGLHV DGGUHVV WKLV VXEMHFW E\ IRFXVLQJ RQ D VSHFL¿F FRPSOLFDWLRQ DQG QRW RQ DOO RWKHU FRPSOLFDWLRQV ,Q RUGHU WR VWUDWLI\ WKH RSHUDWLYH PRUWDOLW\ ULVN WKH (XURpean Cardiac Surgery Risk Assessment Score (EuroSCORE) ZDV XVHG D PRGHO WKDW ZDV LQLWLDOO\ YDOLGDWHG LQ VLWHV across Europe[23]. This tool was easy to use and accessible RYHU WKH ,QWHUQHW DQG VKRZHG JRRG DFFXUDF\ LQ QRQ (XURSHDQ SRSXODWLRQV DV ZHOO ,Q %UD]LO DOWKRXJK VRPH DXWKRUV KDYH demonstrated good applicability of the EuroSCORE[24-26] some health services have developed scoring models of their RZQ EHWWHU VXLWHG WR WKHLU SRSXODWLRQ[27]. ,Q WKLV VWXG\ WKH LVRODWHG &$%* PRUWDOLW\ ZDV $ EURDG VXUYH\ XVLQJ WKH '$7$686 GDWDEDVH HQFRPSDVVLQJ 175 hospitals of the NHS showed a mean hospital mortality of 6.22%. Among the hospitals with high volume of surgeries

Advantages and limitations of the study 7KLV VWXG\ VKRZHG WKH SUR¿OH RI WKH SRSXODWLRQ ZKR UHcently underwent CABG surgery at an institution with high volume of surgeries. Several previous publications have DVVHVVHG WKH SUR¿OH RI SDWLHQWV XQGHUJRLQJ &$%* VXUJHU\ +RZHYHU VXFK VWXGLHV ZHUH PRVWO\ UHWURVSHFWLYH ZLWK D ORQJ GDWD FROOHFWLRQ SHULRG WR REWDLQ D VLJQL¿FDQW VDPSOH 7KLV type of data collection may lead to accumulation of several ELDVHV DULVLQJ IURP FKDQJHV LQ WKH SUR¿OH RI SDWLHQWV RYHU WKH data collection period as well as from changes in the funcWLRQLQJ RI WKH KHDOWK VHUYLFH LWVHOI ,Q WKLV VWXG\ D VLJQL¿FDQW VDPSOH ZDV REWDLQHG LQ RQO\ \HDU RI GDWD FROOHFWLRQ WKHUHby minimizing the mentioned effects. The expressive volume of data and the abundance of variables contributed towards WKH XQGHUWDNLQJ RI VHYHUDO VFLHQWL¿F VWXGLHV LQ IXWXUH DV ZHOO as improvements in the procedure. The variables representLQJ FRURQDU\ VXUJHU\ TXDOLW\ OHG WR WKH VHWXS RI DQ LQGLFDWRU EDVHG TXDOLW\ LPSURYHPHQW SURFHGXUH DW WKH LQVWLWXWLRQ with all the involved surgical team members taking part of it. The main limitation of this study was the fact that the GDWDEDVH XVHG ZDV WKDW RI D VLQJOH LQVWLWXWLRQ VLQJOH FHQWHU DOWKRXJK FRPSULVLQJ GLIIHUHQW VXUJLFDO WHDPV ZLWK LQGHpendent procedures. In spite of the broad experience and the KLJK YROXPH RI SURFHGXUHV LW FDQQRW EH VWDWHG WKDW WKH UHVXOWV DUH UHSUHVHQWDWLYH RI WKH QDWLRQDO VFHQDULR HVSHFLDOO\ RI institutions with low volume of surgery. Another limitation was the fact that the data were collected from patient medical UHFRUGV WKH TXDOLW\ DQG FRPSOHWHQHVV RI ZKLFK LV GHSHQGHQW on the note-taking skills of the health care team. &21&/86,21 7KH FOLQLFDO GHPRJUDSKLF SUR¿OH RI D W\SLFDO SDWLHQW XQGHUJRLQJ &$%* VXUJHU\ DW WKH +RVSLWDO %HQH¿FrQFLD 3RUWXJXHVD LQ 6mR 3DXOR LV VLPLODU WR WKDW LGHQWL¿HG LQ RWKHU VWXGLHV and mirrors the changes caused by demographic changes and the availability of other therapeutic options. Authors’ roles & responsibilities $*6 0=6) GSS )&&% 5)3

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Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Sousa AG, et al. - Epidemiology of coronary artery bypass grafting at the +RVSLWDO %HQHÂżFrQFLD 3RUWXJXHVD 6mR 3DXOR

Braz J Cardiovasc Surg 2015;30(1):33-9

2. Guidelines and indications for coronary artery bypass graft surgery: a report of the American College of Cardiology/American +HDUW $VVRFLDWLRQ 7DVN )RUFH RQ $VVHVVPHQW RI 'LDJQRVWLF DQG 7KHUDSHXWLF &DUGLRYDVFXODU 3URFHGXUHV 6XEFRPPLWWHH RQ Coronary Artery Bypass Graft Surgery). J Am Coll Cardiol.

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Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Sousa AG, et al. - Epidemiology of coronary artery bypass grafting at the +RVSLWDO %HQH¿FrQFLD 3RUWXJXHVD 6mR 3DXOR

Braz J Cardiovasc Surg 2015;30(1):33-9

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39 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Winkelmann ORIGINAL ER, et al. - Analysis of steps adapted protocol in cardiac ARTICLE rehabilitation in the hospital phase

Braz J Cardiovasc Surg 2015;30(1):40-8

Analysis of steps adapted protocol in cardiac rehabilitation in the hospital phase Análise do protocolo adaptado de steps na reabilitação cardíaca na fase hospitalar

Eliane Roseli Winkelmann1, PhD; Fernanda Dallazen2, Angela Beerbaum Steinke Bronzatti3, Juliara Cristina Werner Lorenzoni4, Pollyana Windmöller5

DOI: 10.5935/1678-9741.20140048

RBCCV 44205-1612 evolving in achieving the Steps, where Step 3 was the most used during the rehabilitation phase I. Conclusion: This evolution program by steps can to guide the physical rehabilitation at the hospital in patients after cardiac surgery.

Abstract Objective: To analyze a cardiac rehabilitation adapted protocol in physical therapy during the postoperative hospital phase of cardiac surgery in a service of high complexity, in aspects regarded to complications and mortality prevalence and hospitalization days. Methods: This is an observational cross-sectional, retrospective and analytical study performed by investigating 99 patients who underwent cardiac surgery for coronary artery bypass graft, heart valve replacement or a combination of both. Step program adapted for rehabilitation after cardiac surgery was analyzed under the command of the physiotherapy professional team. Results: In average, a patient stays for two days in the Intensive Care Unit and three to four days in the hospital room, totalizing six days of hospitalization. Fatalities occurred in a higher percentage during hospitalization (5.1%) and up to two years period (8.6%) when compared to 30 days after hospital discharge (1.1%). Among the postoperative complications, the hemodynamic (63.4%) and respiratory (42.6%) were the most prevalent. 36-42% of complications occurred between the immediate postoperative period and the second postoperative GD\ 7KH KRVSLWDO GLVFKDUJH VWDUWHG IURP WKH ¿IWK SRVWRSHUDWLYH day. We can observe that in each following day, the patients are

Descriptors: Thoracic Surgery. Rehabilitation. Hospital Service of Physiotherapy.

Resumo Objetivo: Analisar o protocolo adaptado de reabilitação carGtDFD QD ¿VLRWHUDSLD GXUDQWH D IDVH KRVSLWDODU SyV RSHUDWyULD de cirurgia cardíaca em um serviço de alta complexidade, nos aspectos complicações e prevalência de mortalidade e dias de internação. Métodos: Estudo observacional transversal, retrospectivo, analítico. Realizado por meio da investigação de 99 prontuários de pacientes submetidos à cirurgia cardíaca de revascularização do miocárdio, troca de valva cardíaca ou associadas. Foi analisado um programa de step DGDSWDGR SDUD UHDELOLWDomR SyV RSHUDWyULD GH FLUXUJLD FDUGtDFD H[HFXWDGR SHOD HTXLSH GH )LVLRWHUDSLD

1

Physiotherapist, in Health Sciences: Cardiovascular Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil, Master of Biological Sciences: Physiology, UFRGS, Specialist in Cardiorespiratory Physiotherapy and Acupuncture, Teacher of Physiotherapy Course at Universidade Regional do Noroeste do Estado do Rio Grande do Sul (UNIJUÍ), Master in Comprehensive Health Care Scrictu Sensu Program (UNIJUI/ UNICRUZ). Ijuí, RS, Brazil. 2 Physiotherapist, Master Degree in Gerontology from the Federal University of Santa Maria (UFSM), Post graduate in Physiotherapy in Intensive Care Faculty Inspire - Porto Alegre. Member of the Cardiology Institute of Hospital de Caridade de Ijuí, Ijuí, RS, Brazil. 3 Physical Therapy Student from UNIJUÍ, Ijuí, RS, Brazil. 4 Physiotherapist and Specialist Hospital Physiotherapy by UNIJUÍ, Ijuí, RS, Brazil. 5 Physiotherapist and Specialist Hospital Physiotherapy by UNIJUÍ. Member of the Cardiology Institute of Hospital de Caridade de Ijuí, Ijuí, RS, Brazil.

This study was carried out at the Universidade Regional do Noroeste do Estado do Rio Grande do Sul (UNIJUÍ), Ijuí, RS, Brazil. 1R ¿QDQFLDO VXSSRUW Correspondence address: Eliane Roseli Winkelmann DCVida/ UNIJUÍ Rua do Comércio 3000 - Bairro Universitário – Ijuí, RS, Brazil - Zip Code: 98700-000 - PO Box 383 E-mail: elianew@unijui.edu.br

Article received on November 12th, 2013 Article accepted on February 24th, 2014

40 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Winkelmann ER, et al. - Analysis of steps adapted protocol in cardiac rehabilitation in the hospital phase

Braz J Cardiovasc Surg 2015;30(1):40-8

DQRV TXDQGR FRPSDUDGR DR SHUtRGR GH GLDV SyV DOWD KRVSLWDODU 'HQWUH DV FRPSOLFDo}HV QR SyV RSHUDWyULR DV KHPRGLQkPLFDV H UHVSLUDWyULDV IRUDP DV PDLV predominantes. De 36% a 42% das complicaçþes ocorreram enWUH R SyV RSHUDWyULR LPHGLDWR H R VHJXQGR GLD SyV RSHUDWyULR $ DOWD KRVSLWDODU WHYH LQtFLR D SDUWLU GR TXLQWR GLD SyV RSHUDWyULR 3RGHPRV REVHUYDU TXH FRP R SDVVDU GRV GLDV RV SDFLHQWHV YmR evoluindo na realização dos steps VHQGR TXH R PDLV XWLOL]DGR durante a reabilitação na fase I foi o Step 3. Conclusão: Este programa de evolução por steps pode norWHDU D UHDELOLWDomR ¿VLRWHUDSrXWLFD QRV SDFLHQWHV QR SyV RSHUDWyULR GH FLUXUJLD FDUGtDFD QD IDVH KRVSLWDODU

Abbreviations, acronyms & symbols AMI CABG CCU COPD CVD DM HVR PO SAH WHO

Acute myocardial infarction Coronary artery bypass graft Coronary care unit Chronic obstructive pulmonary disease Cardiovascular disease Diabetes mellitus Heart valve replacement Postoperative Systemic Arterial Hypertension World Health Organization

Resultados: Em mĂŠdia, o paciente permanece dois dias na 8QLGDGH GH 7HUDSLD ,QWHQVLYD H GH WUrV D TXDWUR GLDV QR TXDUWR ÂżFDQGR HP PpGLD VHLV GLDV LQWHUQDGR QR KRVSLWDO 2 yELWR RFRUreu em maior percentual no perĂ­odo hospitalar (5,1%) e atĂŠ dois

Descritores: Cirurgia Toråcica. Reabilitação. Serviço Hospitalar de Fisioterapia.

INTRODUCTION

The program aims at this stage that the patient is discharged with the best possible physical and psychological conditions, with all the possible information regarding healthy lifestyle. Phase 2 starts after discharge and lasts three to six months, during this period the exercise program is individualized in terms of intensity, duration, frequency, type of training and progression, as well as constant monitoring, aiming to return to social and professional activities. The third phase lasts 6 to 24 months and may or may not be following the previous phase. The improvement of the physical condition is the main purpose, as well as improved quality of life. The phase 4, following long-term programs, with the main objective of increasing and maintaining physical ÂżWQHVV $FWLYLWLHV DUH QRW QHFHVVDULO\ VXSHUYLVHG DQG VKRXOG adequate time availability for the maintenance of physical exercise program and preference for recreational sporting activities. In this study, we discuss the phase I of cardiac rehabilitation in patients in the postoperative period (PO) of cardiac surgery. In the Literature it becomes clear protocols for cardiac UHKDELOLWDWLRQ GXULQJ KRVSLWDOL]DWLRQ GHÂżFLW 7KHUH DUH SURtocols that demonstrate a progression in which individuals go through stages (steps) that evolve according to their recovery[8,9] and others as a daily rehabilitation, adopting different therapeutic strategies in PO, both in cardiac rehabilitation after acute myocardial infarction as in the postoperative period of cardiac surgery[10,11]. An example for postoperative care of cardiac surgery is proposed by Umeda[8] protocol that works as developing global Steps exercises, daily progression involving large muscle groups and stretches developed in 5 days. Other authors have also highlighted in phase I cardiac rehabilitation in other cardiac pathologies and similar to

Currently cardiovascular disease (CVD) is a public health problem. According to the World Health Organization (WHO), about 17 million people die annually from cardiovascular diseases[1]. Coronary artery bypass grafting is an effective alternative for the treatment of CVD, optimizing the prevention of acute myocardial infarction (AMI), improved quality of life and delay death. Likewise, surgical intervention is the treatment of degenerative rheumatic valvular heart disease[2,3]. However, cardiac VXUJHU\ LV D FRPSOH[ SURFHGXUH WKDW FDUULHV VLJQL¿FDQW LPplications, both organic, and changes the patient’s physiological mechanism, resulting in a higher incidence of comSOLFDWLRQV WKDW WHQG WR VLJQL¿FDQWO\ GHFUHDVH WKH SRWHQWLDO for recovery[4]. Moreover, physiotherapy participates in the process of cardiac rehabilitation, pre and postoperative FDUGLDF VXUJHU\ WR FRQWULEXWH VLJQL¿FDQWO\ WR EHWWHU SURJnosis, acting in the preoperative period with techniques aimed at the prevention and minimization of pulmonary complications, and in the postoperative period, with hygiene maneuvers and pulmonary expansion, to contribute on reducing the effects of time spent in bed and decrease the length of hospital stay[5,6]. Thus, cardiac surgery requires the work of a multidisciplinary team, and the physiotherapist is one of the professionals involved and of great importance in the rehabilitation process. According to the Guidelines for Cardiopulmonary and Metabolic Rehabilitation[7] cardiac rehabilitation should take place LQ SKDVHV 3KDVH DSSOLHV WR LQSDWLHQWV EHLQJ WKH ¿UVW VWHS WRward an active and productive life, which should predominate the combination of low-intensity exercise, techniques for stress management and education programs in relation to risk factors.

41 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Winkelmann ER, et al. - Analysis of steps adapted protocol in cardiac rehabilitation in the hospital phase

Braz J Cardiovasc Surg 2015;30(1):40-8

Through an analysis of patient records, data collection ZDV SHUIRUPHG XVLQJ D VSHFL¿FDOO\ GHVLJQHG IRUP IRU WKLV purpose, containing the variables for identifying individuals, clinical variables: family history of cardiovascular disease (CVD), hypertension (SAH) diabetes mellitus (DM), dyslipidemia, smoking, physical inactivity and stress and comorbid conditions: acute myocardial infarction (AMI), chronic obstructive pulmonary disease (COPD) and surgical history. The analyzed variables were intraoperative time of surgical procedure, duration of cardiopulmonary bypass (CPB) time, aortic clamping, recovery rate (spontaneous or shock) and type of drain used. In the postoperative period, the variables analyzed were duration of mechanical ventilation (MV), length of stay in the coronary care unit (CCU), days of hospital stay and total hospital days. The Cardiology Institute of Hospital de Caridade de Ijuí opened its cardiology unit in 2010 and since its inception, the physiotherapy team entered in the cardiac rehabilitation in order to prevent and minimize pulmonary complications, reduce the effects of time spent in bed and shorten hospitalization. Thus, physical therapy along with the team of professionals, adopted and adapted a cardiac rehabilitation program through steps (Chart 1) from the protocol of cardiac rehabilitation after myocardial infarction[9]. The protocol is composed of seven progressive stages, with low intensity activities starting at 2 METs and reaching around 4 METs in the last step. It begins with early mobilization, followed by sedestation and active assisted or free standing position. The progression of the intensity is made individually, following the program steps in which each Step is equivalent to a set of exercises at an intensity and repetition, wherein the energy consumption of each group are related in accordance with oxygen consumption required by the body for the task. The physiotherapist opted by Step after performing the assessment to the bedside, observing the general condition of the patient and performed the medical record entries. By the time the analysis was performed physiotherapy twice a day. The adoption of this protocol by physiotherapy was performed at the time the service began and professionals performed the standardization of care, as well as a detailed record of the protocol in the medical record. This allowed the holding of a protocol analysis of cardiac rehabilitation, as well as it was possible to verify the postoperative complications, mortality and length of hospital stay in postoperative cardiac surgery. It is noted that the present study performed the analysis for a range of time of application. Data were stored and analyzed using the Statistical Package for Social Sciences (SPSS, version 18.0) software. The variables were presented as absolute and relative, average, standard deviation and percentage frequencies.

the postoperative cardiac surgical actions. The protocol Babu et al.[11] worked with three levels of evolution and ZLWK ORZHU LQWHQVLW\ H[HUFLVH GXULQJ ¿YH GD\V ,Q UHKDELOitation in post-AMI, Regenga[9] adapted its protocol from the Emory University School of Medicine, occurring progression of 7 Steps to simultaneous work of motor and respiratory therapy. Currently, studies bring the effectiveness of physiotherapy techniques in phase I in the Literature, cardiac rehabilitation individualized[10] having so few studies that are directed to protocols with progression to hospital discharge in cardiac rehabilitation in postoperative cardiac surgery[8,9]. Thus, the physiotherapy team, along with staff health professionals of the Heart Institute of the Hospital de Caridade de Ijuí (General Hospital of IV status), cardiology reference in the countryside of the State of Rio Grande do Sul, by the occasion of the opening service of cardiac surgery and cardiac rehabilitation process chose to adapt the Regenga[9] protocol. This protocol is intended for patients after acute myocardial infarction[9] and adapted by the team to be performed in patients in the postoperative period of cardiac surgery. The adoption of a protocol ensured that the team could standardize care among professionals and conduct the registration of a comprehensive and systematic way activity. Therefore, the aim of this study was to analyze the adapted protocol for cardiac rehabilitation in physical therapy during the postoperative hospital stay (PO) of cardiac surgery in a service of high complexity, prevalence and complications in aspects of mortality and hospitalization days. METHODS Study of cross observational, retrospective and analytical form, approved by the Ethics Research Committee of the Regional University of the Northwestern of Rio Grande do Sul, - UNIJUÍ under Opinion No. 201 602, and it is in accordance with the Guidelines and Standards Regulating Research Involving Human beings, according to the Resolution of the National Health Council (CNS) No. 466/2012. Data collection was conducted through research into patient charts, so it does not have any risk of damage, being subject to the secrecy of information. A total of 111 records analyzed, 12 were eliminated from the sample because they belonged to individuals who died more than a year before the data collection, and they were in a position to inactive ¿OH RU E\ QRW UHSRUWLQJ RQ WKH SURJUDP RI 6WHSV LQ KRVSLtal rehabilitation. It is the sample of 99 patients undergoing heart bypass surgery (CABG) or heart valve replacement (HVR), in the Cardiology Institute of Hospital de Caridade de Ijuí, Brazil (General Hospital of status IV from the Northwest of Rio Grande do Sul). Data were analyzed from April to September 2012.

42 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Winkelmann ER, et al. - Analysis of steps adapted protocol in cardiac rehabilitation in the hospital phase

Braz J Cardiovasc Surg 2015;30(1):40-8

Chart 1. Cardiac Rehabilitation Program consists of Steps adapted to postoperative cardiac surgery for patients in hospital phase I. STEP 1 - Calories = 2 METs Patient lying Diaphragmatic breathing exercises + ventilatory patterns Active exercises of the extremities Active assisted exercises - elbow and knees Milking drains STEP 2 - Calories 2 METs Patient sitting Diaphragmatic breathing exercises + ventilatory pattern Exercises with ventilatory incentive + Flutter Active exercises of the extremities Active exercises of the lower limbs (quadriceps) Milking drains STEP 3 - Calories 3-4 METs Patient standing Active exercises of the elbow and ends Active stretching of lower limbs (quadriceps, adductors, hamstrings and triceps) Mark steps with knee Ambulation: 35 meters Exercises with ventilatory incentive STEP 4 - Calories 3-4 METs Patient standing Passive stretching of active upper and lower limbs Active exercises of the extremities $FWLYH H[HUFLVHV RI WKH ORZHU OLPEV ÀH[LRQ H[WHQVLRQ DQG DEGXFWLRQ DGGXFWLRQ Exercises with incentive spirometry Ambulation: 60 meters Walking downstairs training (1st ÀRRU

STEP 5 Calories = 3-4 METs Patient standing Passive stretching and active upper and lower limb Active exercises of the extremities $FWLYH H[HUFLVHV RI WKH ORZHU OLPEV ÀH[LRQ H[WHQVLRQ DQG DEGXFWLRQ DGGXFWLRQ Exercises with incentive spirometry Ambulation: 100 meters Walking downstairs training (1st ÀRRU

STEP 6 Calories = 3-4 METs Patient standing Passive stretching of upper and lower limb active Active exercises of the extremities $FWLYH H[HUFLVHV RI WKH ORZHU OLPEV ÀH[LRQ H[WHQVLRQ DQG DEGXFWLRQ DGGXFWLRQ Breathing exercises encouraged Ambulation: 160 meters :DONLQJ GRZQVWDLUV WUDLQLQJ ÀRRUV

STEP 7 Calories = 3-4 METs Patient standing Passive stretching of upper and lower limb active Active exercises of the extremities $FWLYH H[HUFLVHV RI WKH ORZHU OLPEV ÀH[LRQ H[WHQVLRQ DQG DEGXFWLRQ DGGXFWLRQ Exercises with incentive spirometry Ambulation: 200 meters :DONLQJ GRZQVWDLUV WUDLQLQJ ÀRRUV

Steps program adapted to patients in the postoperative period of cardiac surgery in phase I or hospital adapted from the Steps of Regenga program[9]

43 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Winkelmann ER, et al. - Analysis of steps adapted protocol in cardiac rehabilitation in the hospital phase

Braz J Cardiovasc Surg 2015;30(1):40-8

RESULTS

analysis of the implementation of the step, at each postoperative day, most of the time: the PO immediately was step 1, RQ WKH ÂżUVW SRVWRSHUDWLYH GD\ VWHS DQG LQ WKH VHFRQG DQG WKLUG 32 WKH VWHS DQG WKH IRXUWK ÂżIWK VL[WK DQG VHYHQWK PO the step 3 and 4; and some patients already managed to evolve step 5 and 6 from the fourth postoperative day. Most patients were discharged on postoperative day 5. Each postRSHUDWLYH GD\ VWDUWLQJ IURP WKH ÂżUVW SRVWRSHUDWLYH GD\ RQ average 3.4% of patients did not undergo physiotherapy for being unable or refusing to perform such activity. Seventeen patients remained hospitalized. Seventeen patients were hospitalized for a prolonged period of eight days or more, and of these, ten were male and seven females. We performed a comparison between the overall average values of the sample (99 patients) with the values of these patients (17 patients) who were hospitalized for eight days or longer. The results were respectively for the following variables: duration of MV (654.46Âą312.48 and 734.53Âą313.611 min); hospitalization time in CCU (61.69Âą26.86 and 97.47Âą41.25 hours), stay in the room (90.43Âą50.08 and 139.76Âą65.85 hours), and total length of stay of patients (151.23Âą51.73 and 238.59Âą63.19 hours). The death rate of the patients who remained for a long time was 2 patients (11.8%) from 30 days to a year after the PO.

The study consisted of 99 patients undergoing cardiac surgery, with an average age of 59.7Âą10.3 years, 60 (60.6%) were male and 39 (39.4%) were female. The predominant type of surgery was CABG (53.5%), followed by aortic valve replacement (22.2%), mitral valve replacement (11.1%), exchange of pulmonary valve (1.0%), CRM associated with aortic valve replacement (3.0%), CRM associated with mitral valve replacement (1.0) and aortic valve replacement associated with mitral valve (7.1%), aortic valve replacement associated with pulmonary (1.0%). The presence of cardiovascular risk factors and comorbidities have a high prevalence of cardiac patients. Thus, it is observed that family history (67.7%), hypertension (65.7%), physical inactivity (55.6%) and history of smoking (49.5%) are the most occurring in this sample. Among the comorbidities, AMI (32.3%) was more prevalent followed by several surgical history (23.2%) and chronic obstructive pulmonary disease (4.0%). Table 1 shows the analysis of intraoperative and postoperative factors of patients undergoing cardiac surgery. It is observed in most patients that the recovery rate was spontaneous, ejection fraction was above 55%, average duration of mechanical ventilation was three times greater than the time of cardiac surgery, most did not require blood transfusion and when it did, it was through erythrocytes. On average it is two days in the ICU and three to four days in the room, with an average of six days in hospital. The PO mortality had a higher percentage in hospital and two years compared to 30 days after hospital discharge. To facilitate analysis, the complications of PO were divided into seven groups, they are the neurological complications (psychomotor agitation, confusion and syncope), cardiovascular complications (hypotension, tachycardia and cardiogenic shock), respiratory (hemoptysis, pleural effuVLRQ SOHXUDO ÂżVWXOD SQHXPRWKRUD[ DWHOHFWDVLV DQG UHLQWXbation), vascular complications (ischemia and bleeding); hemodynamic complications (bleeding and thrombocytopenia), gastrointestinal complications (nausea and vomiting), renal (aerodynamics evaluation and oliguria). Respiratory complications such as atelectasis and pleural effusion in small proportions were found in 100% of patients after surgery. Table 2 shows all the complications that occurred in each PO, and hemodynamic and respiratory complications were the most prevalent. Complications occur in about 3642 % between the immediate postoperative periods, until the VHFRQG SRVWRSHUDWLYH GD\ 7KH GLVFKDUJH VWDUWHG IURP WKH ÂżIWK to the seventh postoperative day, 80.2% of patients were sent home, while 17 still remaining hospitalized (17.7%). Table 3 describes the steps performed on each postoperative day. It is observed that by each passing day, the patients were progressing in achieving Steps, and the step most used during the rehabilitation phase I, it was the Step 3. In the

Table 1. Description of intraoperative and postoperative factors of patients undergoing cardiac surgery. Âą/n (%) Intraoperative factors 73.77Âą26.38 Aortic clamping (min) 92.33Âą29.86 CPB time (min) Heartbeat Recovery (n/%) 60 (60.6) Spontaneous 37 (37.4) Shock 2 (2.0) Cardiogenic shock 654.46Âą312.48 V M Time (min) 222.55Âą83.65 Surgical Time (min) 64.78Âą11.07 Ejection Fraction (%) Blood Transfusion (n/%) 26 (26.5) Erythrocytes (mllions/mmÂł) 2 (2.0) Plasma (ml/kg) 6 (6.1) Erythrocytes (millions/mmÂł)+ plasma (ml/kg) 8 (8.2) Bleeding (ml/kg) 1 (1.0) Bleeding + RBCs 56 (56.6) Not Blood Transfusion 61.69Âą26.86 UCOR Stay (hs) 90.43Âą50.08 Room Stay (hs) 151.23Âą51.73 Hospital Stay (hs) 5 (5.1) In-Hospital Death (n/%) 1 (1.1) 30 day Death (n/%) 5 (8.6) Death within 2 years (n/%) 99 Total patients Data presented as median and minimum-maximum or absolute and relative frequency, CPB=cardiopulmonary bypass; VM=Mechanical ventilation; CCU=Coronary Care Unit; n=number of subjects analyzed

44 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Winkelmann ER, et al. - Analysis of steps adapted protocol in cardiac rehabilitation in the hospital phase

Braz J Cardiovasc Surg 2015;30(1):40-8

Table 2. Characterization of postoperative complications in cardiac surgery according to the days of hospitalization (n = 96). 3° PO 2° PO PO I Postoperative 6° PO 5° PO 7° PO 4° PO 1° PO n (%) n (%) n (%) complications n (%) n (%) n (%) n (%) n (%) 1 (1.1) 3 (3.2) 4 (4.2) Neurological 0 (0) 0 (0) 0 (0) 1 (1.1) 3 (3.1) 1 (1.1) 2 (2.1) 3 (3.1) Cardiac 1 (1.9) 1 (1.1) 1 (3.6) 1 (1.1) 2 (2.1) 6 (6.3) 5 (5.3) 11 (11.5) Respiratory 2 (2.1) 1 (1.9) 2 (7.1) 2 (2.1) 6 (6.3) 0 (0) 3 (3.2) 2 (2.1) Vascular 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 5 (5.3) 13 (13.5) 16 (16.7) 17 (17.9) Hemodynamic 2 (2.1) 0 (0) 1 (3.6) 4 (4.3) 0 (0) 1 (1.1) 1 (1.0) Digestive 0 (0) 0 (0) 0 (0) 2 (2.1) 2 (2.1) 0 (0) 0 (0) 0(0) Renal 1 (1.9) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.1) 3 (3.2) 1 (1.0) Resp. + Hemod. 1 (1.1) 1 (1.9) 1 (3.6) 1 (1.1) 4 (4.2) 0 (0) 0 (0) 2 (2.1) Vasc + Hemod. 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (2.1) Neurol+ Hemod. 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.0) 1 (1.1) 0 (0) 1 (1.0) Neurol + Resp. 0(0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.1) 0 (0) Hemod. + Digestive 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.1) 0 (0) Hemod. + Card. 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.1) 1 (1.1) 0 (0) Hemod+Neurol+Resp. 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.1) 0 (0) Hed+Cardio+Resp+Renal 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Digestive + Resp 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.0) 0 (0) 0 (0) 0 (0) Resp + Card 0 (0) 1 (1.1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) )2 'H¿FLHQF\ 2 (2.1) 0 (0) 0 (0) 0 (0) 0 (0) Total patients with 40 (41.6) 35 (36.4) 37 (39.3) 17 (17.9) 12 (12.9) complications 8 (8.6) 4 (7.6) 5 (19.2) Total patients without 56 (58.4) 60 (62.5) 58 (60.7) 77 (81.1) 82 (87.1) 43 (45.7) 22 (44.3) complications 12(46.1) 0 (0) 0 (0) 0 (0) Discharge 43 (45.7) 25 (48.1) 0 (0) 9 (34.6) 0 (0) 0 (0) 1 (1.0) 0 (0) Death 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.1) 95 95 96 Total 94 94 26 51 96

Total n (%) 12 (12.7) 12 (16.1) 35 (42.6) 5 (5.3) 58 (63.4) 6 (6.3) 1 (1.9) 13 (17.2) 2 (2.1) 3 (3.1) 2 (2.1) 1 (1.1) 1 (1.1) 2 (2.2) 1 (1.1) 1 (1.0) 1 (1.1) 2 (2.1)

77 (80.2) 2 (2.1)

Data are presented as absolute and relative frequencies. Resp=respiratory; Hemod=hemodynamic; Card=heart; n=number of patients with postoperative complications; POI=immediate postoperative; PO=postoperatively discharge Table 3. Description of the Steps program used in the postoperative period of cardiac surgery (n = 96). 3° PO 2° PO Step used IPO 4° PO 5° PO 1° PO n (%) n (%) n (%) n (%) n (%) n (%) 4 (4.2) 13 (13.7) Step 1 92 (95.8) 1 (1.1) 2 (2.1) 29 (30.2) 21 (22.1) 42 (44.2) Step 2 0 (0) 10 (10.6) 5 (5.4) 61 (63.5) 46 (48.4) 35 (36.8) Step 3 0 (0) 31 (33.0) 19 (20.4) 3 (3.1) 18 (18.9) 1 (1.1) Step 4 0 (0) 14 (15.1) 34 (36.2) 0 (0) 1 (1.1) 0 (0) Step 5 0 (0) 12 (12.8) 8 (8.6) 0 (0) 0 (0) 0 (0) Step 6 0 (0) 2 (2.1) 3 (3.2) 0 (0) 4 (4.2) 4 (4.2) Do not PST 4 (4.2) 2 (2.1) 3 (3.2) 2 (2.1) 0 (0) 0 (0) Discharge 0 (0) 40 (43.0) 1 (1.1) 0 (0) 1 (1.1) 0 (0) Death 0 (0) 0 (0) 0 (0) 1 (1.1) 94 95 Inpatient 96 93 53 95 95 95 Total 96 94 93 96

6° PO n (%) 1 (1.9) 2 (3.8) 12 (23.1) 10 (19.2) 2 (3.8) 2 (3.8) 2 (3.8) 22 (40.6) 0 (0) 31 53

7° PO n (%) 1 (3.2) 0 (0) 3 (9.7) 6 (19.4) 4 (12.9) 3 (9.7) 0 (0) 14 (45.1) 0 (0) 17 31

Data are presented as absolute and relative frequencies; IPO=immediate post-operative; PO=Postoperatively discharge; Do not PST=do not undergo physiotherapy

The cardiac rehabilitation programs aim at physical, social and psychological improvement of the individuals, and studies show the reduction of anxiety and depression[14], beyond patients expressing who believe in physical therapy as a possibility of improved health status[15]. At this hospital physiotherapy rehabilitation phase aims to avoid the negative effects of prolonged bed rest, stimulates a fast return to daily activities, maintains functional capacity, develops the

DISCUSSION Over the years, cardiac rehabilitation programs have been evolving and gaining in importance as a result of their social relevance and effectiveness in the rehabilitation of patients[12] $OWKRXJK WKH EHQH¿WV RI FDUGLDF UHKDELOLWDWLRQ IRU patients who underwent CABG, HVR are known[13], still require larger scale studies, especially in phase I.

45 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Winkelmann ER, et al. - Analysis of steps adapted protocol in cardiac rehabilitation in the hospital phase

Braz J Cardiovasc Surg 2015;30(1):40-8

SDWLHQWœV FRQ¿GHQFH UHGXFHV WKH SV\FKRORJLFDO LPSDFW VXFK as anxiety and depression), maximizes chance of early discharge and provides the basis for a home program[9]. In the hospital, physiotherapy also acts preoperatively, aiding the team in the instruction and guidance of ventilatory physiotherapy exercises and pre –operative hospital routines, which leads to reduced levels of anxiety in these patients[16]. Several studies have been done showing the effectiveness of cardiac rehabilitation as Herdy et al.[6], adopted the procedures of Phase I with breathing exercises, Stein et al.[17] using EPAP mask, bronchial hygiene, progressive walking and calistemic exercises. Hirschhorn et al.[18] with physiotherapy and moderate walking and Ferreira et al.[19] with incentive therapy associated with expiratory positive airway pressure. Although the therapy is effective, there is still need for more VWXGLHV VKRZLQJ WKH VFLHQWL¿F HYLGHQFH IRU PRVW SK\VLRWKHUapy techniques[20]. There are questions about the cardiac rehabilitation protocols applied during the in-hospital phase (phase I) presenting subjectiveness, and its results were contested when evaluated considering that they must follow the WKUHH EDVLF SULQFLSOHV RI H[HUFLVH SUHVFULSWLRQ VSHFL¿FLW\ overload and reversibility[21]. This study performed an analysis of a protocol for cardiac rehabilitation AMI[9] patients, it was adapted for patients in postoperative cardiac surgery which proposes the progression to exercise through stages, individualized treatment because selection step is performed and executed after evaluating the bedside. They follow a pattern of evolution 2-4 MET from the beginning of rehabilitation until discharge. 7KH XVH RI VSHFL¿F SURWRFROV IRU SDWLHQWV UHFHLYLQJ SRVWRSerative cardiac surgery physiotherapy services, since there is a standardization of the adoption of procedures for patients and also their attention to evaluate the effectiveness of their procedures. A simple evolution of the physical therapy procedures that are performed in the records does not guarantee this, as well as the loss of information, they are not standardized and there is an adoption of the techniques performed in ZD\V RI PHDVXULQJ WKH VDPH TXDOL¿FDWLRQ %XW XQIRUWXQDWHO\ this is the adoption by most physical therapy services during hospitalization. The role of physiotherapy in rehabilitation Phase I, according Herdy et al.[6] leads to a reduced rate of postoperative complications (reducing the incidence of pleural effusion, atelecWDVLV SQHXPRQLD DQG DWULDO ¿EULOODWLRQ 7KH DQDO\VLV RI WKLV study revealed that the most frequent complications were also hemodynamic and respiratory, and these were also the complications that increased the length of stay in the intensive care unit due to cardiac surgery, according to Lazio et al.[22]. It is noteworthy that most of these complications occurred until the third postoperative day. Physiotherapy also provides a shorter hospital stay[6]. The hospitalization was 151.23 hours, in other ZRUGV WKH PDMRULW\ ZDV GLVFKDUJHG RQ WKH ¿IWK SRVWRSHUDWLYH day, and this average hospital stay was lower than that found

in other studies as Fernandes et al.[23]. This analysis of hospital stay shows that the role of physiotherapy is important in the health service for these patients while minimizing the costs of hospitalization. A literature review[5] showed that the preoperative therapy reduces postoperative pulmonary complications (atelectasis and pneumonia) and decreases the length of hospitalization in patients after elective cardiac surgery. But it also noted that there is a gap of evidence on the role of physiotherapy in reducing preoperative pneumothorax, prolonged mechanical ventilation or mortality from all causes. During the protocol analysis, we found out that by each passing day, patients are evolving in achieving the Steps, and the most used during the rehabilitation phase I was the Step 3. Cardiac rehabilitation through the introduction of standardized exercise protocol reduces the deleterious effects of immobility during hospitalization, allowing the professional physiotherapist inserted in the multidisciplinary team, take care of the functional health of the patient immediately after surgery. That is, the therapist guides and monitors the physical and hemodynamic parameters of the patient that is undergoing exercises after surgery. This helps to prevent the perpetuation of the myth experienced by many patients bedrest after surgery. In our study, two sessions of physical therapy were held daily, which is consistent with the literature in which the supervised exercise sessions are recommended at least twice a day, with an average duration of 15 to 20 minutes, including time for education and informal conversation[9]. It is worth noting that the work of therapy should be initiated in the preoperative period[24], with patient education about the work of breathing and motor to be performed before and after surgery. The protocol of this study did not include these activities, but they should be included in physiotherapy routine. Physical therapy provides early rehabilitation which allows the patient to have a social inclusion and reduced costs for the healthcare system. But still, there is need for further studies and therapeutic proposals that seek to shorten the period of hospitalization, provide the patient with early and safe social inclusion and hence lower costs for the healthcare system. CONCLUSION This study investigated an adapted protocol of cardiac rehabilitation in the postoperative period of cardiac surgery during hospitalization in a service of high complexity checking postoperative complications, mortality and length of hospitalization. It was observed that the most common complications were respiratory and hemodynamic, with the most of these complications occuring until the third postoperative day. Regarding the type of surgical procedure performed was the predominance of CRM and hospitalization time was 151.23 hours, and death during hospital stay was 5.1%. The step program was an important to guide the work of therapy, and the steps have

46 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Winkelmann ER, et al. - Analysis of steps adapted protocol in cardiac rehabilitation in the hospital phase

Braz J Cardiovasc Surg 2015;30(1):40-8

been evolving over the days postoperatively until hospital discharge and the most used step during the rehabilitation phase I was the Step 3. Therefore, this program can guide evolution by physical therapy rehabilitation in patients after cardiac surgery during hospitalization. The limitation of this study lies in being a retrospective study. We suggest further studies with a prospective design and randomized clinical trials in order to show the effectiveness of cardiac rehabilitation program in postoperative cardiac surgery.

4. Smetana GW. Postoperative pulmonary complications: an update on risk assessment and reduction. Cleve Clin J Med. 2009;76(Suppl 4):S60-5. 5. Hulzebos EH, Smit Y, Helders PP, van Meeteren NL. Preoperative physical therapy for elective cardiac surgery patients. Cochrane Database Syst Rev. 2012;11:CD010118. 6. Herdy AH, Marcchi PL, Vila A, Tavares C, Collaco J, Niebauer J, et al. Pre- and postoperative cardiopulmonary rehabilitation in hospitalized patients undergoing coronary artery bypass surgery: a randomized controlled trial. Am J Phys Med Rehabil. 2008;87(9):714-9.

ACKNOWLEDGMENT We thank the support granted by the Foundation for Research Support from the State of Rio Grande do Sul (Fapergs), the NaWLRQDO &RXQFLO IRU 6FLHQWL¿F DQG 7HFKQRORJLFDO 'HYHORSPHQW (CNPq) and the Regional Northwest University of Rio Grande do Sul (UNIJUÍ) through the scholarship undergraduates.

7. Sociedade Brasileira de Cardiologia. Guidelines for cardiopulmonary and metabolic rehabilitation: practical aspects and responsibilities. Arq Bras Cardiol. 2006;86(1):74-82. 8. Umeda IIK. Manual de Fisioterapia na Reabilitação Cardiovascular. São Paulo: Manole, 2005. 9. Regenga MM. Fisioterapia em Cardiologia: da Unidade de Terapia Intensiva à Reabilitação. São Paulo: Roca; 2000. 417p.

Authors’ roles & responsibilities (5:

FD ABSB JCWL PW

10. Dias CM, Vieira Rde O, Oliveira JF, Lopes AJ, Menezes SL, Guimarães FS. Three physiotherapy protocols: effects on pulmonary volumes after cardiac surgery. J Bras Pneumol.2011;37(1):54-60.

$QDO\VLV DQG RU LQWHUSUHWDWLRQ RI GDWD VWDWLVWLFDO DQDO\VLV ¿nal approval of the manuscript; conception and design of the study; completion of experiments; drafting and review of the manuscript Data collection, analysis and interpretation of data, manuscript draft Data collection, analysis and interpretation of data, manuscript draft Study design, data collection Study design, data collection

11. Babu AS, Noone MS, Haneef M, Naryanan SM. Protocol-Guided Phase-1 Cardiac Rehabilitation in Patients with ST-Elevation Myocardial Infarction in A Rural Hospital. Heart Views. 2010;11(2):52-6. 12. Pasquina P, Tramèr MR, Walder B. Prophylactic respiratory physiotherapy after cardiac surgery: systematic review. BMJ. 2003;327(7428):1379. 13. Stewart KJ, Badenhop D, Brubaker PH, Keteyian SJ, King M. Cardiac rehabilitation following percutaneous revascularization, heart transplant, heart valve surgery, and for chronic heart failure. Chest. 2003;123(6):2104-11.

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AP, Costantini CR, et al. Phase I of cardiac rehabilitation: A new challenge for evidence based physiotherapy. World J Cardiol. 2011;3(7):248-55.

18. Hirschhorn AD, Richards D, Mungovan SF, Morris NR, Adams L. Supervised moderate intensity exercise improves distance walked at hospital discharge following coronary artery bypass graft surgery--a randomised controlled trial. Heart Lung Circ. 2008;17(2):129-38.

22. Laizo A, Delgado FEF, Rocha GM. Complicaçþes que DXPHQWDP R WHPSR GH SHUPDQrQFLD QD XQLGDGH GH WHUDSLD intensiva na cirurgia cardíaca. Rev Bras Cir Cardiovasc. 2010;25(2):166-71. )HUQDQGHV $06 0DQVXU $- &DQrR /) /RXUHQoR '' 3LFFLRQL MA, Franchi SM, et al. Redução do período de internação e de GHVSHVDV QR DWHQGLPHQWR GH SRUWDGRUHV GH FDUGLRSDWLDV FRQJrQLWDV submetidos à intervenção cirúrgica cardíaca no protocolo da via råpida. Arq Bras Cardiol. 2004;83(1):18-26.

19. Ferreira GM, Haeffner MP, Barreto SS, Dall’Ago P. Incentive spirometry with expiratory positive airway pressure brings EHQH¿WV DIWHU P\RFDUGLDO UHYDVFXODUL]DWLRQ $UT %UDV &DUGLRO 2010;94(2):230-5. %UDQVRQ 5' 7KH VFLHQWL¿F EDVLV IRU SRVWRSHUDWLYH UHVSLUDWRU\ care. Respir Care. 2013,58(11):1974-84.

24. Olmos SC, Granço BM, Oliveira SP, Figueiredo LC, Sasseron AB, Cardoso AL, et al. Tempo de internação hospitalar relacionado j ¿VLRWHUDSLD UHVSLUDWyULD QR SUp RSHUDWyULR GH FLUXUJLD FDUGtDFD eletiva. Arq Med ABC. 2007;32(Supl 2):S23-5.

21. de Macedo RM, Faria-Neto JR, Costantini CO, Casali D, Muller

48 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Pretto P, et al.ORIGINAL - Perioperative myocardial infarction in patients undergoing ARTICLE myocardial revascularization surgery

Braz J Cardiovasc Surg 2015;30(1):49-54

Perioperative myocardial infarction in patients undergoing myocardial revascularization surgery Infarto do miocårdio perioperatório em pacientes submetidos à cirurgia de revascularização miocårdica

Pericles Pretto1, MD; Gerez Fernandes Martins2, MD, MsC, PhD; Andressa Biscaro3, MD; Dany David Kruczan4, MD, MsC, PhD; Barbara Jessen5, MD

DOI: 10.5935/1678-9741.20140059

RBCCV 44205-1613 WLHQWV ZLWK DQG ZLWKRXW WKLV FRPSOLFDWLRQ KRZHYHU SDWLHQWV ZLWK perioperative myocardial infarction progressed with worse left ventricular function and more death cases. Conclusion: The frequency of perioperative myocardial infarction found in this study was considered high and as a conVHTXHQFH WKH VDPH REVHUYHG DYHUDJH KLJKHU WURSRQLQ , PRUH cases of worsening left ventricular function and death.

Abstract Introduction: Perioperative myocardial infarction adversely affects the prognosis of patients undergoing coronary artery bypass graft and its diagnosis was hampered by numerous GLIÂżFXOWLHV EHFDXVH WKH SDWKRSK\VLRORJ\ LV GLIIHUHQW IURP WKH WUDGLWLRQDO LQVWDELOLW\ DWKHURVFOHURWLF DQG WKH FOLQLFDO GLIÂżFXOW\ to be characterized. Objetive: To identify the frequency of perioperative myocardial infarction and its outcome in patients undergoing coronary artery bypass graft. Methods: Retrospective cohort study performed in a tertiaU\ KRVSLWDO VSHFLDOL]HG LQ FDUGLRORJ\ IURP 0D\ WR $SULO ZKLFK LQFOXGHG DOO UHFRUGV FRQWDLQLQJ FRURQDU\ DUWHU\ E\SDVV JUDIW UHFRUGV 7R FRQÂżUP WKH GLDJQRVLV RI SHULRSHUDWLYH P\RFDUGLDO LQIDUFWLRQ FULWHULD WKH 7KLUG 8QLYHUVDO 'HÂżQLWLRQ RI 0\RFDUGLDO ,QIDUFWLRQ ZDV XVHG Results: :H DQDO\]HG FDVHV 3HULRSHUDWLYH P\RFDUGLDO LQIDUFWLRQ ZDV GLDJQRVHG LQ SDWLHQWV 1XPEHU RI JUDIWV and use and cardiopulmonary bypass time were associated with WKLV GLDJQRVLV DQG WKH PHDQ DJH ZDV VLJQLÂżFDQWO\ KLJKHU LQ WKLV JURXS 7KH GLDJQRVWLF FULWHULD HOHYDWHG WURSRQLQ , ZKLFK ZDV SRVLWLYH LQ RI FDVHV UHJDUGOHVV RI GLDJQRVLV RI SHULRSHUDWLYH P\RFDUGLDO LQIDUFWLRQ 1R VLJQLÂżFDQW GLIIHUHQFH ZDV IRXQG between length of hospital stay and intensive care unit in pa-

Descriptors: 0\RFDUGLDO ,QIDUFWLRQ 0\RFDUGLDO 5HYDVFXlarization. 3RVWRSHUDWLYH &RPSOLFDWLRQV 7URSRQLQ ,

Resumo Introdução: O infarto do miocårdio perioperatório afeta negativamente o prognóstico dos pacientes submetidos à cirurgia de revascularização do miocårdio e seu diagnóstico esbarra em LQ~PHUDV GL¿FXOGDGHV SRLV D ¿VLRSDWRORJLD p GLIHUHQWH GD WUDGLcional instabilidade aterosclerótica e o quadro clínico de difícil caracterização. Objetivo: ,GHQWL¿FDU D IUHTXrQFLD GH LQIDUWR GR PLRFiUGLR perioperatório e seu desfecho em pacientes submetidos à cirurgia de revascularização do miocårdio. MÊtodos: Coorte retrospectiva realizada em hospital terciåULR HVSHFLDOL]DGR HP FDUGLRORJLD GH GH PDLR GH D GH

1

This study was carried out at Instituto Estadual de Cardiologia Aloysio De Castro (IECAC), Rio de Janeiro, RJ, Brazil.

Hospital SĂŁo JosĂŠ, CriciĂşma, SC, Brazil, Instituto Estadual de Cardiologia Aloysio de Castro(IECAC), Rio de Janeiro, RJ, Brazil e Instituto Nacional de Cardiologia (INC), Rio de Janeiro, RJ, Brazil. 2 Universidade Federal do Rio de Janeiro (UFRJ) , Rio de Janeiro, RJ, Brazil e Instituto Estadual de Cardiologia Aloysio de Castro (IECAC), Rio de Janeiro, RJ, Brazil. 3 Universidade do Extremo Sul Catarinense (UNESC), CriciĂşma, SC, Brazil. 4 Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil, PontifĂ­cia Universidade CatĂłlica do Rio de Janeiro(PUC/RJ), Rio de Janeiro, RJ, Brazil e Instituto Estadual de Cardiologia Aloysio de Castro(IECAC), Rio de Janeiro, RJ, Brazil. 5 Universidade Gama Filho Curso (UGF), Rio de Janeiro, RJ, Brazil.

1R ÂżQDQFLDO VXSSRUW Correspondence address: Pericles Pretto Instituto Estadual de Cardiologia Aloysio de Castro (IECAC). Rua David Campista, 326, Humaita - Rio de Janeiro, RJ, Brazil - Zip code: 22281-100 E-mail: periclescolorado@bol.com.br Article received on October 10th, 2013 Article accepted on March 24th, 2014

49 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Pretto P, et al. - Perioperative myocardial infarction in patients undergoing myocardial revascularization surgery

Braz J Cardiovasc Surg 2015;30(1):49-54

Resultados: )RUDP DQDOLVDGRV FDVRV )RL GLDJQRVWLFDGR LQIDUWR GR PLRFiUGLR SHULRSHUDWyULR HP SDFLHQWHV 1~PHUR GH HQ[HUWRV H XWLOL]DomR H WHPSR GH FLUFXODomR H[WUDFRUSyUHD IRUDP IDWRUHV DVVRFLDGRV D HVWH GLDJQyVWLFR H D PpGLD GH LGDGH IRL VLJQL¿FDWLYDPHQWH PDLV HOHYDGD QHVWH JUXSR 2 FULWpULR GLDJQyVWLFR HOHYDomR GH WURSRQLQD , IRL SRVLWLYR HP GRV FDVRV LQGHSHQGHQWHPHQWH GR GLDJQyVWLFR GH LQIDUWR GR PLRFiUGLR SHULRSHUDWyULR 1mR IRL HQFRQWUDGD GLIHUHQoD VLJQL¿FDWLYD entre tempo de internação hospitalar e em unidade de terapia LQWHQVLYD QRV JUXSRV FRP H VHP HVWD FRPSOLFDomR SRUpP SDcientes com infarto do miocårdio perioperatório evoluíram com pior função ventricular esquerda e mais casos de óbito. Conclusão: $ IUHTXrQFLD GH LQIDUWR GR PLRFiUGLR SHULRSHUDtório encontrada neste trabalho foi considerada alta e como conVHTXrQFLD GR PHVPR REVHUYRX VH PpGLD PDLV HOHYDGD GH WURSRQLQD , PDLV FDVRV GH SLRUD GD IXQomR YHQWULFXODU HVTXHUGD H yELWR

$EEUHYLDWLRQV DFURQ\PV V\PEROV AMI CABG CAD CLAMP CPB ECG IECAC LBBB LV LVEF PMI

Acute myocardial infarction Coronary artery bypass graft Coronary artery disease Coronary lesion, surgical time and length of clamping Cardiopulmonary bypass Electrocardiogram Instituto Estadual de Cardiologia Aloysio de Castro Left bundle branch block Left ventricle Left ventricle ejection fraction Perioperative myocardial infarction

DEULO GH TXH LQFOXLX WRGRV RV SURQWXiULRV FRQWHQGR UHJLVWURV GH FLUXUJLD GH UHYDVFXODUL]DomR GR PLRFiUGLR 3DUD FRQÂżUPDomR GLDJQyVWLFD GR LQIDUWR GR PLRFiUGLR SHULRSHUDWyULR IRUDP XWLOL]DGRV RV FULWpULRV GD 7KLUG 8QLYHUVDO 'HÂżQLWLRQ RI 0\RFDUGLDO Infarction.

Descritores: ,QIDUWR GR 0LRFiUGLR 5HYDVFXODUL]DomR 0LRFiUGLFD &RPSOLFDo}HV 3yV 2SHUDWyULDV 7URSRQLQD ,

tracheal intubation, present changes in cognition by residual anesthetic effect or confuse it with the pain generated by the chest wall incision, through drains or pericardium with ischemic pain[5]. This cohort study aims to identify the frequency of PMI and its outcome in patients undergoing CABG surgery in a hospital specialized in cardiology.

INTRODUCTION The coronary artery bypass graft (CABG) is very frequent. It aims to relieve symptoms caused by coronary artery disease (CAD), protect the ischemic myocyte, improve ventricular function, prevent acute myocardial infarction (AMI) and prolong life as well as its quality[1]. In the last three decades, a better understanding of the pathophysiology of atherosclerotic disease and advances in technology and surgical technique, promoted the reduction of the consequent complications to CABG. It was observed that even small atherosclerotic plaques can evolve into important DQG OLPLWLQJ OHVLRQV RI WKH FRURQDU\ ÀRZ DQG WKDW DQ\ ERDUG can suffer rupture and can cause an acute event. Considering the operating framework, to perform procedures without cardiopulmonary bypass (CPB) and use of arterial grafts are the most relevant contribution[1,2]. Despite these improvements, the surgical treatment of coronary disease have been performed in patients with increasingly complex lesions and with more comorbidities, which has resulted in increased incidence of postoperative complications[3]. In cardiovascular surgery, perioperative myocardial infarction (PMI) is a complication that adversely affects the prognosis of patients, and their pathophysiology may be different from the traditional instability of atherosclerotic plaque[4,5]. In general, it happens secondary to hypotension, inadequate myocardial protection during surgery, technical factors related to anastomosis and hypovolemia during procedures and in the postoperative period[3]. The diagnosis of PMI has its particularities. Its characterizaWLRQ PD\ EH GLI¿FXOW HVSHFLDOO\ LQ WKH ¿UVW KRXUV DIWHU VXUJHU\ when you cannot get the patient’s report, which may be under

METHODS This is a retrospective cohort study conducted at the Instituto Estadual de Cardiologia Aloysio de Castro (IECAC), in the city of Rio de Janeiro, developed between May 1, 2011 and April 30, 2012. $OO UHFRUGV RI PHGLFDO ÂżOHV FRQWDLQLQJ LVRODWHG RU DVVRciated cardiac surgeries performed in the period described above were included. Patients who did not have a recorded echocardiogram, and those who performed pre and postoperative electrocardiogram (ECG), preoperative troponin I and seriated on the postoperative period, and those with illegible or incomplete records were excluded from the study. 7R FRQÂżUP WKH GLDJQRVLV RI 30, WKH IROORZLQJ FULWHULD were adopted: elevated troponin greater than ten times the 99th percentile in patients with normal baseline; associating to a new pathological Q wave or new left bundle branch block (LBBB) on ECG or coronary angiography showing occluded graft or native vessel or image test showing loss of viable myocardium or new abnormal segmental movement[6]. Paradoxical septal motion on echocardiography was not considered an element belonging to the previous criteria as it happens after cardiac surgery without necessarily being secondary to ischemic response[7].

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Pretto P, et al. - Perioperative myocardial infarction in patients undergoing myocardial revascularization surgery

Braz J Cardiovasc Surg 2015;30(1):49-54

skal-Wallis test to compare the means. They were considered VWDWLVWLFDOO\ VLJQLÂżFDQW ZKHQ P<0.05.

The test used to determine the level of troponin I in serum or plasma was VIDASŽ Ultra Troponin I (TNIU) by ELFA technique (EnzymeLinked Fluorescent Assay). The value was considered normal when less than 0.01 ¾g/L (as bull test) [8] . The dosage, for all patients, was performed before CABG (basal troponin) at the time of admission at the intensive care unit, 12 and 24 hours after the procedure. The results of echocardiographic studies used for the analysis of global and segmental function of the left ventricle (LV), performed at times by different and experienced examiners, were transferred to individual spreadsheets and divided into seventeen segments, as requested by the Comittee of Cardiological Images from the Council on Clinical Cardiology of the American Heart Association[9]. The left ventricle ejection fraction (LVEF) was considered normal if greater than 55% and abnormal when between 54 and 45% (mild dysfunction), between 44 and 30% (moderate dysfunction) and less than 30% (severe dysfunction) according to the Guidelines recommendations for quantifying cardiac chambers[10]. All patients underwent surgical treatment with a technique involving median sternotomy transsternal. CPB was SHUIRUPHG ZLWK PRGHUDWH FRUH K\SRWKHUPLD Û& Û& and myocardial protection was established by means of hySRWKHUPLF EORRG FDUGLRSOHJLD Û& LQIXVHG LQWR WKH DRUWLF root or directly into the coronary sinus. All patients received a balanced closed loop absorber veno inhalationed general anesthesia, with CO2 (Soda Lime) absorber and mechanical YHQWLODWLRQ 7KH LQKDODWLRQDO DJHQW LVRÀXUDQH ZLWK R[\gen mixed with nitrous oxide was used as an inhaler agent. As venous drugs, the hipnotics etomidate and midazolam; as opiod, fentanyl; and as muscle relaxant, pancuronium bromide were used[11]. This study was approved by the IECAC Research Ethics Committee, registered in Brazil under the Platform number 0328411112.0.0000.5265. Data were stored and analyzed using Epi Info™ version 3.5.3 program. It was used the Fisher exact test to demonstrate association between qualitative variables and the Kru-

RESULTS A hundred and thirty-eight CABG procedures were listHG LQ WKH PHGLFDO ÂżOHV RI ZKLFK ZHUH H[FOXGHG RQH E\ treating it exclusively of valve surgery, 10 due to incomplete UHFRUGV DQG UHFRUGV ZHUH QRW ORFDWHG ZLWK D ÂżQDO VDPSOH comprised of 116 cases. PMI was diagnosed in 28 (24.1%) patients and the variable PHDQ DJH ZDV VLJQLÂżFDQWO\ KLJKHU LQ WKLV JURXS 7KH RYHUDOO SURÂżOH RI WKH VDPSOH VHSDUDWHG E\ JURXSV ZLWK DQG ZLWKRXW PMI) and its epidemiological characteristics, are in Table 1. The reoperation occurred in one patient and he did not receive a diagnosis of PMI. The number of grafts, usage and CPB time were factors associated with a diagnosis of PMI. However, incomplete revascularization, emergency surgery, cardiac surgery associated, type of coronary lesion, surgical time and length of clamping (CLAMP) of the aorta were similar between groups (Table 2). A new Q wave on the electrocardiogram was observed in 11 cases (9.5%) and LBBB in 10 (8.6%). The paradoxical interventricular septum movement was reported in 25% of echocardiograms performed after CABG. In the comparison between the groups with and without D GLDJQRVLV RI 30, QR VLJQLÂżFDQW GLIIHUHQFH ZDV IRXQG UHgarding the hospitalization time and intensive care unit after CABG (Table 3). The elevation of the troponin I level above ten times the 99th percentile was demonstrated in 99.1% of the measurePHQWV SHUIRUPHG DIWHU &$%* 7KHLU OHYHOV ZHUH VLJQLÂżFDQWly higher in patients undergoing surgery with CPB (P<0.00) and in those who died (P=0.01). Mean troponin I in patients who died was 11.3 Âľg/L and those who survived 2.9Âľg/L. When analyzing the mean troponin I in the group with and without PMI, it was found 1.1Âľg/L in the former and 7.4 Âľg/L in the latter.

7DEOH 3URÂżOH RI WKH VDPSOH DQG HSLGHPLRORJLFDO FKDUDFWHULVWLFV Total sample (n=116)

With PMI (n=28)

Without PMI (n=88) P value

Variables Female Age Hypertension DM Current smoking Dyslipidemia Severe dysfunction of the LV

n 33 98 41 35 44 8

meanÂąSD 60.8Âą8.9 -

% 28.4 84.5 35.3 30.2 37.9 6.8

n 10 25 12 11 11 0

meanÂąSD 65.2Âą7.6 -

% 35.7 89.3 42.9 39.3 39.3 0

n 23 73 29 24 33 8

meanÂąSD 59.4Âą8.9 -

% 26.1 83 33 27.3 37.5 9.1

0.22* 0.00†0.31* 0.23* 0.19* 0.51* 0.10*

PMI= perioperative myocardial infarction; DM=type 2 diabetes mellitus; LV=left ventricle; SD=standard deviation; (*) Fisher exact test; (†) Kruskal-Wallis test

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Pretto P, et al. - Perioperative myocardial infarction in patients undergoing myocardial revascularization surgery

Braz J Cardiovasc Surg 2015;30(1):49-54

Table 2. Surgical characteristics of the sample. Total sample (n=116)

With PMI (n = 28)

Without PMI (n=88) P value

Variables Emergency surgery Cardiac surgery associated Triple vessel coronary lesion Lesions of the LMCA Number of grafts Use of CPB CPB time* Length of aortic clamping* Surgical time*

n 11 8 56 20 100 -

meanÂąSD 2.8Âą1.0 86.3Âą26.7 61.5Âą22.7 237.4Âą63.7

% 9.5 6.9 48.3 17.2 86.2 -

n 2 2 18 3 28 -

meanÂąSD 3.3Âą0.9 96.5Âą27.2 67.2Âą24.7 260.6Âą71.7

% 7.1 7.1 64.3 10.7 100 -

n 9 6 38 17 72 -

meanÂąSD 2.7Âą1.0 82.4Âą25.6 59.3Âą21.7 230.1Âą59.6

% 10.2 6.8 43.2 19.3 81.8 -

0.47†0.45†0.04†0.22†0.01‥ 0.00†0.01‥ 0.19‥ 0.20‥

PMI=perioperative myocardial infarction; LMCA=left main coronary artery; CPB=cardiopulmonary bypass; SD=standard deviation; (*) time in minutes; (†) Fisher exact test; (‥) Kruskal-Wallis test Table 3. Variables related to perioperative myocardial infarction. Total sample (n=116)

With PMI (n=28)

Without PMI (n=88) P value

Variables Mean troponina I (¾g/L) Time on ICU* Surgery – hospital discharge Deterioration in LV function postoperative Intra aortic balloon Deaths

n -

meanÂąSD 3.1Âą4.4 5.3Âą4.2 14.8Âą11.0

% -

n -

meanÂąSD 7.4Âą6.8 5.2Âą2.7 16.0Âą10.4

% -

n -

meanÂąSD 1.8Âą1.8 5.3Âą4.6 14.4Âą11.3

% -

0.00‥ 0.66‥ 0.26‥

20 3 3

-

17.2 2.6 2.6

14 2 3

-

50 7.1 10.7

6 1 0

-

6.8 1.1 0

0.00†0.14†0.01â€

PMI=perioperative myocardial infarction; LV= left ventricle; ICU=Intensive Care Unit; SD=standard deviation; (*) time in days; (†) Fisher exact test; (‥) Kruskal-Wallis test

al.[12] described in their study fewer smokers and more dyslipidemia regarding the data from this sample. This study found 24.1% of PMI, above the value found by Jagger et al.[14] - 14%; and by DĂ­az Arrieta et al.[5] - 15%; but within 2 to 30% in the literature. This difference can be attributed to different criteria used in the diagnosis, as quoted by DĂ­az Arrieta et al.[5]. The average length of hospitalization of patients in this work contributed negatively to the means of the county and state of Rio de Janeiro (Table 4)[15]. This greater permanence can be explained, at least partially, by the fact that IECAC have undergone renovations in June and July 2011, during which there was a CABG per month, a very small number when compared to the 11.4 procedures done in the months in which there was not this impediment. Mohammed et al.[12] reported that after CABG, 98% of patients had elevation more than 10 times the 99 percentile of troponin T, a fact that made them question the value arbitrarily assigned to this criterion for diagnosis of PMI. In the present study, while dosing troponin I, the same data ZDV UHSURGXFHG E\ ÂżQGLQJ WKHVH OHYHOV LQ RI WKH UHvascularized patients.

Amongst the complications related to the PMI, we can QDPH ÂżYH GHJUHH DWULRYHQWULFXODU EORFNV D PXUDO WKURPEXV in LV and a vascular ischemic brain (associated with carotid endarterectomy combined with CABG), without any statisWLFDO VLJQLÂżFDQFH 6LJQV RI ORZ FDUGLDF RXWSXW UHTXLULQJ LQtra-aortic balloon pump were observed in three cases, two (7.1%) in a group with PMI and one (1.1%) in the group without PMI (Table 3). All deaths (3; 10.7%) occurred in the group with PMI, PDNLQJ WKLV D VLJQLÂżFDQW ÂżQGLQJ P=0.01) compared to patients without this complication. DISCUSSION The epidemiological characteristics of age and gender were similar to those described by Mohammed et al.[12]. According to Houlind et al.[13], age is an independent factor of serious complications after CABG, which is in agreement ZLWK WKH GDWD RI WKLV VWXG\ RQFH ZH IRXQG VLJQLÂżFDQWO\ KLJKHU age in the group with PMI. In this cohort the prevalence of hypertension and diabetes was high, as well as that described by Jagger et al.[14]. Mohammed et

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Pretto P, et al. - Perioperative myocardial infarction in patients undergoing myocardial revascularization surgery

Braz J Cardiovasc Surg 2015;30(1):49-54

Table 4. Length of hospital stay and hospital mortality by place of occurrence, May 2011 to April 2012. Place IECAC Rio de Janeiro city* Rio de Janeiro*

Number of hospitalizations 116 534 1241

Average length of stay 40.6 26.1 18.3

Days of stay 4711 13920 22682

Deaths 2.5 8.2 7.3

IECAC – Instituto Estadual de Cardiologia Aloysio de Castro; (*) source: www.datasus.com.br

The high levels in the CABG postoperative troponin do not always represent myocardial ischemia and may be caused by mechanical damage related to the procedure. However, it is known that its levels are linearly related to worse prognosis[16]. In this study’s sample, the mean serica dosage of troponin, both the PMI group and for the group WKDW HYROYHG WR GHDWK ZDV VLJQL¿FDQWO\ KLJKHU 7KHUH LV HYLGHQFH LQ WKH OLWHUDWXUH WKDW ELRPDUNHUV DUH VLJQL¿FDQWO\ higher in surgery with CPB[6,17], and it is consistent with that found in this research. It is estimated that about 25% of CABG in the United States do not use CPB, value above the one found in this sample (13.8%)[17]. Evidences show that patients operated with CPB have a higher incidence of this complication and IMP is also directly related to the duration of CPB[14,18]. These ¿QGLQJV ZHUH DOVR REWDLQHG LQ WKLV UHVHDUFK In the sample analyzed, when compared the anatomical alterations, it was found that both the three-vessel disease (sigQL¿FDQWO\ PRUH FRPPRQ LQ WKH JURXS ZLWK 30, DV WKH GLVHDVH of the left main coronary artery (LMCA) are not independent predictors of PMI. However, it could be argued that injury in LMCA is related to the higher prevalence of PMI[14]. It may be noted that in this study there was a direct relationship between high number of grafts and the prevalence of PMI, a correlation previously reported by other authors[14]. 7KLV IDFW FDQ EH MXVWL¿HG E\ D GLUHFW WUDXPD WR WKH P\RFDUdium, heart manipulation and surgical time, factors that may be related to myocardial injury and necrosis after CABG[6]. According to Pomerantzeff et al.[18], PMI is more common in patients who did not undergo elective surgery, unlike the data analyzed in this study, where this diagnosis was proportionately lower. Despite being reported a higher incidence of PMI in CABG combined with other cardiac surgery[19], this association was not found in this study. 7KH LQFRPSOHWH UHYDVFXODUL]DWLRQ ZDV QRW VLJQL¿FDQWO\ PRUH FRPPRQ LQ WKH JURXS ZLWK 30, RSSRVLQJ WKH ¿QGLQJV by Pomerantzeff et al.[18]. As reported by López Mora & Fiscal López[3], it was observed in this study that developed heart failure in post CABG is related to the PMI. Brick et al.[1] reported increased risk of death in patients ZLWK 30, ,Q WKLV VWXG\ GHDWK ZDV VLJQL¿FDQWO\ PRUH SUHYDlent in the group with this complication.

Concerning the mortality rate, at the IECAC it was 2,5%, what positively stands out in comparison to the municipal and state rates, that have approximately three times higher indices (Table 4). The retrospective study has limitations such as the inability to standardize the echocardiographic analysis and loss of patients due to lack of data in the medical records. Despite of the inclusion of patients with procedures associated with CRM having the potential to contaminate the sample, it was thought to observe whether these cases were associated with the outcome of CABG. CONCLUSION The frequency of PMI found in this study (24.1%) was high since, in the literature, this rate varies from 2 to 30% depending on the diagnostic criteria used. As a consequence of PMI it was observed that when the average of troponin is higher, more cases of worsening of the left ventricular function and death occur.

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REFERENCES 1. Brick AV, Souza DSR, Braile DM, Buffolo E, Lucchese FA, Silva FPV, et al. Diretrizes da cirurgia de revascularização miocårdica valvopatias e doenças da aorta. Arq Bras Cardiol. 2004;82(Suppl 5):1-20. 2. Cantero MA, Almeida RMS, Galhardo R. Anålise dos resultados imediatos da cirurgia de revascularização do miocårdio com e sem circulação extracorpórea. Rev Bras Cir Cardiovasc. 2012;27(1):38-44. 3. López Mora GE, Fiscal López O. Infarto miocårdico perioperatorio. Arch Cardiol MÊx. 2009;79(3):173-4.

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Braz J Cardiovasc Surg 2015;30(1):49-54

)RUFH 7 +LEEHUG 3 :HHNV * .HPSHU $- %ORRPÂżHOG 3 7RZ D, et al. Perioperative myocardial infarction after coronary DUWHU\ E\SDVV VXUJHU\ &OLQLFDO VLJQLÂżFDQFH DQG DSSURDFK WR ULVN VWUDWLÂżFDWLRQ &LUFXODWLRQ

12. Mohammed AA, Agnihotri AK, van Kimmenade RR, Martinez-Rumayor A, Green SM, Quiroz R, et al. Prospective, comprehensive assessment of cardiac troponin T testing after coronary artery bypass graft surgery. Circulation. 2009;120(10):843-50.

5. DĂ­az-Arrieta G, RincĂłn-Salas JJ, Reyes-SĂĄnchez ME, UrzuaZamarripa M, Mendieta-Tapia JC, Mendoza-HernĂĄndez ME, et al. DiagnĂłstico de infarto miocĂĄrdico perioperatorio dentro de las primeras 72 horas posteriores a la cirugĂ­a cardiaca. Arch Cardiol MĂŠx. 2009;79(3):189-96.

13. Houlind K, Kjeldsen BJ, Madsen SN, Rasmussen BS, Holme SJ, Nielsen PH, et al.; DOORS Study Group. On-pump versus offpump coronary artery bypass surgery in elderly patients: results from the Danish on-pump versus off-pump randomization study. Circulation. 2012;125(20):2431-9.

6. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al.; Joint ESC/ACCF/AHA/WHF Task Force IRU WKH 8QLYHUVDO 'HÂżQLWLRQ RI 0\RFDUGLDO ,QIDUFWLRQ 7KLUG universal definition of myocardial infarction. Circulation. 2012;126(16):2020-35.

14. Jaeger CP, Kalil RAK, Guaragna JCVC, Petraco JB. Fatores preditores de infarto do miocårdio no período perioperatório de cirurgia de revascularização miocårdica. Rev Bras Cir Cardiovasc. 2005;20(3):291-5.

7. Choi SH, Choi SI, Chun EJ, Chang HJ, Park KH, Lim C, et al. Abnormal motion of the interventricular septum after coronary artery bypass graft surgery: comprehensive evaluation with MR imaging. Korean J Radiol. 2010;11(6):627-31.

15. Brasil. MinistÊrio da Saúde. Departamento de Informåtica do SUS – DATASUS. Procedimentos hospitalares do SUS - por gestor - Rio de Janeiro. [Acesso 25 Nov 2012]. Available from: http://tabnet.datasus.gov.br/cgi/deftohtm.exe?sih/cnv/qgrj.def

8. VidasŽ Troponin I Ultra [bula de remÊdio]. Marcy-IÉtoile: bioMÊrieux SA.

16. UpToDate. Troponins and creatine kinase as biomarkers of cardiac injury. [Acess Aug 15, 2012]. Available from: http:// www.uptodate.com/contents/troponins-and-creatine-kinase-asbiomarkers-of-cardiac-injury?source=search_result&search=Tr oponins+and+creatine+kinase+as+ biomarkers+of+cardiac+inj ury&selectedTitle=1~150

9. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK et al.; American Heart Association Writing Group on Myocardial Segmentation and Registration for Cardiac Imaging. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation. 2002,105(4):539-42.

17. Selvanayagam JB, Petersen SE, Francis JM, Robson MD, Kardos A, Neubauer S, et al. Effects of off-pump versus on-pump coronary surgery on reversible and irreversible myocardial injury: a randomized trial using cardiovascular magnetic resonance imaging and biochemical markers. Circulation. 2004;109(3):34550.

10. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA et al.; American Society of Echocardiography’s Nomenclature and Standards Committee; Task Force on Chamber Quantification; American College of Cardiology Echocardiography Committee; American Heart Association; European Association of Echocardiography, European Society RI &DUGLRORJ\ 5HFRPPHQGDWLRQV IRU FKDPEHU TXDQWL¿FDWLRQ Eur J Echocardiogr. 2006;7(2):79-108.

18. Pomerantzeff PMA, Auler Jr. JOC, CĂŠsar LAM. Isquemia miocĂĄrdica pĂłs-operatĂłria. In: Ramirez JAF, Oliveira SA, eds. Cuidados PrĂŠ e PĂłs-Cirurgia CardĂ­aca. SĂŁo Paulo: Editora Roca; 2004. p.204-5. 19. UpToDate. Early cardiac complications of coronary artery bypass graft surgery. [Acess Aug 15, 2012]. Available from: http://www. uptodate.com/contents/early-cardiac-complications-of-coronaryartery-bypass-graft-surgery?source=search_result&search=Earl y+cardiac+complications+of+coronary+artery+bypass+graft+su rgery&selectedTitle=1~150

11. Martins GF, Siqueira Filho AG, Santos JBF, Assunção CRC, Bottino F, Carvalho KG, et al. Trimetazidina na injúria de isquemia e reperfusão em cirurgia de revascularização do miocårdio. Arq Bras Cardiol. 2011;97(3):209-16.

54 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Compostella L, et al. - HRV and postoperative atrial fibrillation 25,*,1$/ $57,&/(

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Abnormal heart rate variability and atrial ÂżEULOODWLRQ DIWHU DRUWLF VXUJHU\ 9DULDELOLGDGH DQRUPDO GD IUHTXrQFLD FDUGtDFD H ÂżEULODomR DWULDO DSyV FLUXUJLD DyUWLFD

Leonida Compostella1, MD; Nicola Russo1,2 0' $XJXVWR 'Âś2QRIULR2, MD; Tiziana Setzu1, MD; Caterina Compostella3, MD; Tomaso Bottio2, MD; Gino Gerosa2, MD; Fabio Bellotto1, MD

DOI 10.5935/1678-9741.20140100

RBCCV 44205-1614

$EVWUDFW ,QWURGXFWLRQ Complete denervation of transplanted heart H[HUWV SURWHFWLYH HIIHFW DJDLQVW SRVWRSHUDWLYH DWULDO ÂżEULOODWLRQ various degrees of autonomic denervation appear also after transection of ascending aorta during surgery for aortic aneurysm. 2EMHFWLYH This study aimed to evaluate if the level of cardiac GHQHUYDWLRQ REWDLQHG E\ UHVHFWLRQ RI DVFHQGLQJ DRUWD FRXOG H[HUW DQ\ HIIHFW RQ SRVWRSHUDWLYH DWULDO ÂżEULOODWLRQ LQFLGHQFH 0HWKRGV We retrospectively analysed the clinical records of SDWLHQWV VXEPLWWHG WR JUDIW UHSODFHPHQW RI DVFHQGLQJ DRUWD JURXS $ DQG ZLWK DRUWLF YDOYH UHSODFHPHQW JURXS % DOO HSLVRGHV RI SRVWRSHUDWLYH DWULDO ÂżEULOODWLRQ RFFXUUHG GXULQJ WKH PRQWK IROORZ XS KDYH EHHQ UHSRUWHG +HDUW 5DWH 9DULDELOLW\ SDUDPHWHUV ZHUH REWDLQHG IURP D K +ROWHU UHFRUGLQJ FOLQLcal, echocardiographic and treatment data were also evaluated. 5HVXOWV 2YHUDOO RI SDWLHQWV JURXS $ JURXS % SUHVHQWHG DW OHDVW RQH HSLVRGH RI SRVWRSHUDWLYH DWULDO ÂżEULOODWLRQ 2OGHU DJH EXW QRW JHQGHU DEQRUPDO JOXFRVH WROHUDQFH ejection fraction, left atrial diameter) was correlated with inciGHQFH RI SRVWRSHUDWLYH DWULDO ÂżEULOODWLRQ 2QO\ DPRQJ D VXEJURXS of patients with aortic transection and signs of greater autonomic GHUDQJHPHQW KHDUW UDWH YDULDELOLW\ SDUDPHWHUV EHORZ WKH PHGLan and mean heart rate over the 75th SHUFHQWLOH SRVVLEO\ LQGLcating more profound autonomic denervation, a lower incidence RI SRVWRSHUDWLYH DWULDO ÂżEULOODWLRQ ZDV REVHUYHG YV

&RQFOXVLRQ Transection of ascending aorta for repair of an DRUWLF DQHXU\VP GLG QRW FRQIHU DQ\ VLJQLÂżFDQW SURWHFWLYH HIIHFW IURP SRVWRSHUDWLYH DWULDO ÂżEULOODWLRQ LQ FRPSDULVRQ WR SDWLHQWV ZLWK LQWDFW DVFHQGLQJ DRUWD ,W FRXOG EH VSHFXODWHG WKDW D OLPLWHG DQG KHWHURJHQHRXV FDUGLDF GHQHUYDWLRQ ZDV SURGXFHG E\ WKH LQWHUYHQWLRQ FUHDWLQJ DQ HOHWURSK\VLRORJLFDO VXEVWUDWH IRU WKH KLJK LQFLGHQFH RI SRVWRSHUDWLYH DWULDO ÂżEULOODWLRQ REVHUYHG

1

Correspondence address: Leonida Compostella Ist. Codivilla-Putti, Riabilitazione Cardiologica Via Codivilla, 1 32043 Cortina d’Ampezzo (BL), Italy ( PDLO l.compostella@alice.it

'HVFULSWRUV $XWRQRPLF 1HUYRXV 6\VWHP $WULDO )LEULOODWLRQ $RUWLF $QHXU\VP +HDUW 5DWH 5HVXPR ,QWURGXomR Denervação completa do coração transplantado H[HUFH HIHLWR SURWHWRU FRQWUD D ¿EULODomR DWULDO QR SyV RSHUDWyULR YiULRV JUDXV GH GHQHUYDomR DXWRQ{PLFD DSDUHFHP WDPEpP DSyV D WUDQVHFomR GD DRUWD DVFHQGHQWH GXUDQWH D FLUXUJLD GH aneurisma da aorta. 2EMHWLYR (VWH HVWXGR WHYH FRPR REMHWLYR DYDOLDU VH R QtYHO GH GHQHUYDomR FDUGtDFD REWLGD SRU UHVVHFomR GD DRUWD DVFHQGHQWH SRGHULD H[HUFHU DOJXP HIHLWR VREUH D LQFLGrQFLD GH ¿EULODomR DWULDO QR SyV RSHUDWyULR 0pWRGRV )RUDP DQDOLVDGRV UHWURVSHFWLYDPHQWH RV SURQWXiULRV GH SDFLHQWHV VXEPHWLGRV D HQ[HUWR GH VXEVWLWXLomR GH DRUWD WRUiFLFD JUXSR $ H FRP D VXEVWLWXLomR GD YDOYD DyU-

Preventive Cardiology and Rehabilitation, Inst. Codivilla-Putti, Cortina d’Ampezzo, (BL), Italy. 2 'SW &DUGLDF 7KRUDFLF DQG 9DVFXODU 6FLHQFHV 8QLYHUVLW\ RI 3DGXD 3DGRYD ,WDO\ 3 'SW 0HGLFLQH 6FKRRO RI (PHUJHQF\ 0HGLFLQH 8QLYHUVLW\ RI 3DGXD 3DGRYD ,WDO\ This study was carried out Preventive Cardiology and Rehabilitation, Inst. Codivilla-Putti, Cortina d’Ampezzo, (BL), Italy. 1R ¿QDQFLDO VXSSRUW 1R FRQÀLFW RI LQWHUHVW

Article received on May 7nd, 2014 Article accepted on August 4nd, 2014

55 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Braz J Cardiovasc Surg 2015;30(1):55-62

Compostella L, et al. - HRV and postoperative atrial fibrillation

EULODomR DWULDO QR SyV RSHUDWyULR ,GDGH PDLV DYDQoDGD PDV QmR JrQHUR WROHUkQFLD j JOLFRVH DQRUPDO IUDomR GH HMHomR GLkPHWUR GR iWULR HVTXHUGR IRL FRUUHODFLRQDGD FRP D LQFLGrQFLD GH ¿EULODomR DWULDO SyV RSHUDWyULD $SHQDV HP XP VXEJUXSR GH SDFLHQWHV FRP WUDQVHFomR DyUWLFD H VLQDLV GH PDLRU GHVDUUDQMR DXWRQ{PLFR SDUkPHWURV GH YDULDELOLGDGH GD IUHTXrQFLD FDUGtDFD DEDL[R GD PHGLDQD H D PpGLD GH IUHTXrQFLD FDUGtDFD acima do percentil 75), indicando possivelmente denervação DXWRQ{PLFD PDLV SURIXQGD IRL REVHUYDGD PHQRU LQFLGrQFLD GH ¿EULODomR DWULDO SyV RSHUDWyULD YV &RQFOXVmR Transecção da aorta ascendente para correção GH XP DQHXULVPD GD DRUWD QmR FRQIHUH TXDOTXHU HIHLWR SURWHWRU VLJQL¿FDWLYR GH ¿EULODomR DWULDO QR SyV RSHUDWyULR HP FRPparação com pacientes com aorta ascendente intacta. Pode-se HVSHFXODU TXH XPD GHQHUYDomR FDUGtDFD OLPLWDGD H KHWHURJrQHD IRL SURGX]LGD SHOD LQWHUYHQomR FULDQGR XP VXEVWUDWR HOHWUR¿VLROyJLFR SDUD D HOHYDGD LQFLGrQFLD GH ¿EULODomR DWULDO SyV RSHUDWyULD REVHUYDGD

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56 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Braz J Cardiovasc Surg 2015;30(1):55-62

Compostella L, et al. - HRV and postoperative atrial fibrillation

2Q WKH GD\ RI WUDQVIHUUDO WR &5 DOO SDWLHQWV ZHUH VXEPLWWHG WR K +ROWHU UHFRUGLQJ FDUGLDF DXWRQRPLF IXQFWLRQ was evaluated by time-domain heart rate variability (HRV) RQ WKLV UHFRUGLQJ )RU WKH SXUSRVHV RI WKLV VWXG\ PHDQ KHDUW UDWH PHDQ +5 VWDQGDUG GHYLDWLRQ RI DOO QRUPDO 55 LQWHUYDOV 6'11 DQG VWDQGDUG GHYLDWLRQ RI WKH PLQ DYHUDJH RI QRUPDO 55 LQWHUYDOV 6'$11 KDYH EHHQ FRQVLGHUHG During the whole hospitalization in cardiac surgery and GXULQJ DW OHDVW WKH ¿UVW ¿YH GD\V RI &5 DOO SDWLHQWV ZHUH maintained under continuous telemetry monitoring; all epiVRGHV RI $) KDYH EHHQ UHFRUGHG /HIW YHQWULFOH HMHFWLRQ IUDFWLRQ /9() ZDV DVVHVVHG E\ PHDQV RI WZR GLPHQVLRQDO WUDQVWKRUDFLF HFKRFDUGLRJUDP (Simpson’s method in patients with good quality echo windows; area-length method in the other cases); standard atrial GLPHQVLRQV DQG YROXPH KDYH EHHQ UHFRUGHG KRZHYHU IRU WKLV VWXG\ RQO\ DQWHUR SRVWHULRU OHIW DWULDO GLDPHWHU KDV EHHQ FRQVLGHUHG DEVROXWH OHQJWK DQG LQGH[HG E\ ERG\ VXUIDFH DUHD [19].

&RQWLQXRXV YDULDEOHV KDYH EHHQ HYDOXDWHG E\ PHDQV RI WKH 6WXGHQW W WHVW IRU XQSDLUHG VDPSOHV &DWHJRULFDO YDULables were compared using the Pearson chi-square test Ȥ2 6WDWLVWLFDO VLJQL¿FDQFH ZDV VHW DW D SUREDELOLW\ YDOXH RI 8QLYDULDWH DQDO\VLV ZDV SHUIRUPHG WR DVVHVV WKH DVVRFLDWLRQ EHWZHHQ RFFXUUHQFH RI 32$) GHSHQGHQW YDULable) and demographic, clinical and HRV variables; all variables with a P YDOXH ” LQ WKH XQLYDULDWH DQDO\sis were entered into a multivariate logistic regression model, in which variables were selected by step-wise, backward elimination; a P value <0.05 was considered VLJQLILFDQW Statement $OO SDUWLFLSDQWV ZHUH LQIRUPHG DERXW WKH SURFHGXUHV WKH\ ZHUH XQGHUJRLQJ 7KH XVXDO GLDJQRVWLF DQG IROORZ XS URXWLQH IRU WKH &5 KDG EHHQ DSSOLHG QR VSHFLDO WHVW RU WUHDWPHQW ZDV SHUIRUPHG QR VSHFL¿F DSSURYDO RI WKH 3URYLQFLDO (WKLFV &RPPLWWHH ZDV QHHGHG IRU WKH VWXG\

Statistical analysis 6366 6WDWLVWLFV 3DFNDJH IRU 6RFLDO 6FLHQFHV 6366 ,QF &KLFDJR ,OOLQRLV 86$ ZDV XVHG IRU WKH DQDO\VLV 'Hscriptive statistics are expressed as mean ± standard deviaWLRQ IRU FRQWLQXRXV YDULDEOHV FDWHJRULFDO YDULDEOHV DUH SUHsented as absolute values with percentages.

5(68/76 7DEOH SUHVHQWV WKH FOLQLFDO FKDUDFWHULVWLFV RI WKH SDWLHQWV while the main results are summarized in Table 2.

Table 1. Patients characteristics.

Patients’ characteristics Age, years *HQGHU PDOH Q

'D\V IURP LQWHUYHQWLRQ WR &5 'XUDWLRQ RI &5 GD\V Total observation period, days 3UHYDOHQFH RI 'LDEHWHV Q

3UHYDOHQFH RI DEQRUPDO JOXFRVH PHWDEROLVP Q

Hb level, g/l /HIW 9HQWULFXODU (MHFWLRQ )UDFWLRQ /HIW DWULDO GLDPHWHU PP /HIW DWULDO GLDPHWHU LQGH[HG PP P 6LPXOWDQHRXV &$%* Q RI FDVHV

3UHYLRXV FRURQDU\ UHYDVFXODUL]DWLRQ &$%* RU 3&, Q RI FDVHV

6LPXOWDQHRXV LQWHUYHQWLRQ RQ PLWUDO YDOYH Q

Amiodarone treatment during Holter monitor test ‡ Q RI FDVHV

• average dosage, mg Metoprolol treatment during Holter monitor test ‡ Q RI FDVHV

‡ RI WDUJHW GRVDJH

Group A (n=67)

Group B (n=132)

P

59.0±14.3 50 (75) 15.3±11.0 14.4±4.3 29.8±11.1 12 (18) 18 (27) 10.0±1.0 59±7 41±6 22.2±3.4 10 (15) 2 (3) 3 (4)

68.1±12.3 85 (64) 12.9±8.9 15.4±3.6 28.3±9.5 26 (20) 54 (41) 10.4±1.1 57±8 43±7 23.5±4.2 36 (27) 8 (6) 11 (8)

<0.001 (0.000) ns (0.144) ns (0.101) ns (0.110) ns (0.295) ns (0.762) ns (0.051) <0.02 (0.015) ns (0.308) ns (0.148) <0.05 (0.038) ns (0.051) <0.05 (0.034) ns (0.315)

17 (25) 235±79

31 (23) 232±75

ns (0.769) ns (0.895)

35 (52) 45±21

66 (50) 38±20

ns (0.765) ns (0.112)

Group A=patients with grafting of ascending aorta/aortic arch; Group B=patients with aortic valve replacement without DRUWLF UHSDLU 3 OHYHO RI VLJQL¿FDQFH EHWZHHQ *URXSV $ DQG % &5 &DUGLDF 5HKDELOLWDWLRQ +E KDHPRJORELQ &$%* FRURQDU\ DUWHU\ E\ SDVV JUDIW 3&, SHUFXWDQHRXV FRURQDU\ LQWHUYHQWLRQ

57 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Braz J Cardiovasc Surg 2015;30(1):55-62

Compostella L, et al. - HRV and postoperative atrial fibrillation

7DEOH 0DLQ UHVXOWV RI WKH VWXG\

HRV parameters mean-HR, bpm SDNN, ms SDANN, ms ,QFLGHQFH RI $WULDO )LEULOODWLRQ LQ ZKROH JURXSV Q

LQ SDWLHQWV DJHG • Q

LQ SDWLHQWV DJHG Q

LQ SDWLHQWV ZLWK PHDQ +5 • ESP - in patients with mean-HR <93 bpm LQ SDWLHQWV ZLWK 6'11 ” th percentile - in patients with SDNN >75th percentile

Group A (n=67)

Group B (n=132)

P

86.0±14.3 60.1±22.0 53.6±19.6

83.3±11.5 70.8±37.7 63.0±32.7

ns (0.157) <0.05 (0.050) <0.05 (0.048)

29 (43) 17 (77) 12 (27) P<0.001 5 (22) P<0.01 24 (54) 2 (12) P<0.05 17 (43)

61 (46) 44 (55) P<0.02 17 (33) 11 (37) ns 50 (49) 6 (23) ns 38 (43)

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Group A=patients with grafting of ascending aorta/aortic arch; group B=patients with aortic valve replacement without DRUWLF UHSDLU 3 OHYHO RI VLJQL¿FDQFH EHWZHHQ *URXSV $ DQG % PHDQ +5 PHDQ KHDUW UDWH UHFRUGHG DW K +ROWHU ESP EHDWV SHU PLQXWH 6'11 VWDQGDUG GHYLDWLRQ RI DOO QRUPDO 55 LQWHUYDOV GXULQJ WKH ZKROH K +ROWHU UHFRUGLQJ SHULRG 6'$11 VWDQGDUG GHYLDWLRQ RI WKH PLQ DYHUDJH RI QRUPDO 55 LQWHUYDOV GXULQJ WKH ZKROH K +ROWHU UHFRUGLQJ period; Ms=milliseconds

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58 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Braz J Cardiovasc Surg 2015;30(1):55-62

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RI $) KDG EHHQ SXW RQ DPLRGDURQH RXW RI WKH SDWLHQWV WKDW SUHVHQWHG RQH RU PRUH HSLVRGHV RI $) ZHUH on amiodarone treatment at admission to CR and 12 more patients received amiodarone during the remaining hospiWDOL]DWLRQ SHULRG 2I WKH FDVHV ZLWKRXW HSLVRGHV RI $) GXULQJ WKH REVHUYDWLRQ WLPH RQO\ ZHUH RQ SURSK\ODFtic treatment with amiodarone at admission to CR. Among patients treated with amiodarone that presented AF, an equal SHUFHQWDJH RI FDVHV KDG XQGHUJRQH WUDQVHFWLRQ RI DVFHQGLQJ DRUWD RU DRUWLF YDOYH VXEVWLWXWLRQ Ȥ2 0.000, P=1.000). DISCUSSION ,Q WKLV VWXG\ IURP D UHDO ZRUOG SRSXODWLRQ DOPRVW D SDWLHQW HYHU\ WZR SUHVHQWHG RQH RU PRUH HSLVRGHV RI $) DIWHU DQ LQWHUYHQWLRQ RI PDMRU FDUGLDF VXUJHU\ QRW SULPDULO\ LQYROYLQJ OHIW DWULXP RU PLWUDO YDOYH VXFK LQFLGHQFH RI 32$) LV RQH RI WKH PRVW HOHYDWHG UHSRUWHG LQ WKH OLWHUDWXUH IRU FDUGLDF surgery cases[1-3]. It must be said that our patients underwent a rather long clinical observation, they have been evaluated also by a 24-h Holter and submitted to prolonged telemetry PRQLWRULQJ DQG DOO HSLVRGHV RI $) LQFOXGLQJ DV\PSWRPDWLF DQG VHOI OLPLWHG HSLVRGHV KDYH EHHQ UHFRUGHG &RPSDULQJ WKH ZKROH JURXS RI SDWLHQWV WKDW XQGHUZHQW JUDIW VXEVWLWXWLRQ RI DVFHQGLQJ DRUWD JURXS $ ZLWK WKH JURXS RI SDWLHQWV LQ ZKLFK DVFHQGLQJ DRUWD ZDV OHIW LQWDFW JURXS % QR VLJQL¿FDQW SURWHFWLYH HIIHFW DJDLQVW 32$) FRXOG EH H[HUWHG E\ WKH UHVHFWLRQ RI SHULDRUWLF QHUYH WHUPLQDWLRQV LQ WKH SDWLHQWV RI JURXS $ .QRZLQJ WKDW ÀXFWXDWLRQV RI DFWLYLW\ RI WKH cardiac autonomic nervous system precede the development RI 32$) LQ SDWLHQWV XQGHUJRLQJ PDMRU FDUGLDF RU WKRUDFLF surgery[7,8], it could be expected that altering the autonomic tone by surgical cardiac denervation could lead to reduction RI WKH LQFLGHQFH RI DWULDO DUUK\WKPLDV LQ WKH SRVWRSHUDWLYH SHULRG 7KLV ZDV QRW WKH FDVH LQ RXU SDWLHQWV LQGHHG FRQÀLFWLQJ results are reported in literature with techniques that aimed to alter cardiac autonomic control, by removing the epicarGLDO DQWHULRU IDW SDG[20-24] or all the nerves around the great YHVVHOV DW WKH YHQWUDO VXUIDFH RI WKH EDVH RI WKH KHDUW[25-28]. 'LIIHUHQWO\ IURP WKHVH VXUJLFDO WHFKQLTXHV DRUWLF WUDQVHFWLRQ OHDGV WR FRPSOHWH UHPRYDO RI SHULDRUWLF QHUYHV DQG SOH[XVHV DV ZHOO DV RI DRUWLF PHFKDQLFDO VWUHVV UHFHSWRUV ZKLOH QHUYHV and plexuses surrounding venae cavae and pulmonary artery DUH XVXDOO\ OHIW LQ VLWX $ SURIRXQG FDUGLDF DXWRQRPLF GHQHUvation is hence achieved[12-15] DQG VXFK OHYHO RI GHQHUYDWLRQ alters the sympatho-vagal balance in the heart and could exHUW PDMRU LQÀXHQFH RQ DWULDO HOHFWULFDO SURSHUWLHV DQG VXVFHSWLELOLW\ WR ¿EULOODWH[29,30]. :KLOH LQ RXU SDWLHQWV RI JURXS $ QR UHGXFWLRQ RI 32$) is apparent compared to group B, the situation is somehow GLIIHUHQW LQ D VXEJURXS RI WKHP $ VLJQL¿FDQWO\ ORZHU LQFLGHQFH RI $) YV ZDV REVHUYHG LQ D PLQRULW\ RI FDVHV IURP WKH JURXS RI DRUWLF WUDQVHFWLRQ WKDW VHHPLQJO\

59 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Braz J Cardiovasc Surg 2015;30(1):55-62

Compostella L, et al. - HRV and postoperative atrial fibrillation

H[SHULHQFHG D PRUH DGYDQFHG DXWRQRPLF GHUDQJHPHQW DIWHU UHVHFWLRQ RI DVFHQGLQJ DRUWD WKLV LV WKH VXEJURXS RI JURXS $ patients with more altered HRV parameters (SDNN below median; mean-HR over the 75th SHUFHQWLOH ,I WKH PRUH GHpressed HRV parameters in this subgroup express a more extensive surgical denervation is unknown. In any manner, no VLJQL¿FDQW UHGXFWLRQ RI LQFLGHQFH RI $) YV ZDV REVHUYHG LQ WKH VXEJURXS RI SDWLHQWV IURP JURXS % WKDW DOVR SUHVHQWHG D VLPLODUO\ PDUNHG GHSUHVVLRQ RI +59 SDUDPHWHUV This observation could support the hypothesis that the possiEOH SURWHFWLYH IDFWRU DJDLQVW DSSHDUDQFH RI $) LV QRW WKH OHYHO RI SRVWRSHUDWLYH GHSUHVVLRQ RI +59 SDUDPHWHUV E\ LWVHOI H[SUHVVLRQ RI WKH DXWRQRPLF GHUDQJHPHQW XVXDOO\ SUHVHQW DIWHU FDUGLDF VXUJHU\ DQG DWWULEXWDEOH WR D YDULHW\ RI PHFKDQLVPV

[31,32] , but an advanced autonomic blockade obtained by exWHQVLYH KHDUW GHQHUYDWLRQ DV DIWHU UHVHFWLRQ RI DVFHQGLQJ DRUWD 7KLV VLWXDWLRQ VRPHKRZ UHVHPEOHV WKH SURWHFWLYH HIIHFW given by the marked denervation-dysautonomia that occurs DIWHU KHDUW WUDQVSODQW ,W PXVW EH LQ VRPH ZD\ DFNQRZOHGJHG WKDW WKH VPDOO QXPEHU RI FDVHV LQ WKH VXEJURXSV FRXOG OHDYH WKH GRXEW WKDW WKH UHVXOWV FRXOG VLPSO\ EH DQ HIIHFW RI FKDQFH We must also remember that when cardiac autonomic nervous system is irregularly altered by surgical intervention, or only a partial or patchy cardiac autonomic denervation is DFKLHYHG DV LW FRXOG KDYH EHHQ WKH FDVH LQ VRPH RI RXU JURXS $ SDWLHQWV QR SURWHFWLRQ DJDLQVW HSLVRGHV RI SRVWRSHUDWLYH AF can be expected; this consideration is based on studies WKDW GHPRQVWUDWH QR LPSDFW RQ LQFLGHQFH RI SRVWRSHUDWLYH $) IURP LQWHUYHQWLRQV VXFK DV DQWHULRU IDW SDG UHPRYDO WKDW SURGXFH RQO\ SDUWLDO GHQHUYDWLRQ RI WKH KHDUW DQG GR QRW DFKLHYH WKH FRPSOHWH UHPRYDO RI QHUYH WHUPLQDOV REVHUYHG LQ KHDUW WUDQVSODQW 1R SURWHFWLYH HIIHFW DJDLQVW SRVWRSHUDWLYH $) KDV EHHQ GHVFULEHG DOVR LQ SDWLHQWV DIWHU OXQJ WUDQVSODQW LQ ZKLFK WKH VXWXUHV RI GRQRU¶V SXOPRQDU\ YHLQV WR UHFLSLHQWV OHIW DWULXP OHDG RQO\ WR LQFRPSOHWH KHDUW GHQHUYDWLRQ[33]. ,QVWHDG RI EHLQJ SURWHFWLYH DQ KHWHURJHQHRXV DXWRQRPLF GHnervation in most cases could have contributed to the rather KLJK LQFLGHQFH RI $) LQ ERWK JURXSV RI RXU SDWLHQWV WKURXJK D SRVVLEOH LUUHJXODULW\ LQ WKH UHVLGXDO LQQHUYDWLRQ RI WKH DWULD As reported in previous studies[2,34], older patients presentHG D JUHDWHU LQFLGHQFH RI SRVWRSHUDWLYH $) RQ WKH FRQWUDU\ QR VLJQL¿FDQW FRUUHODWLRQ ZDV IRXQG ZLWK SUHVHQFH RI GLDEHtes or impaired glucose metabolism, or with linear measures RI DWULDO GLPHQVLRQV RU OHIW YHQWULFXODU HMHFWLRQ IUDFWLRQ 3URSK\ODFWLF DGPLQLVWUDWLRQ RI GUXJV VXFK DV DPLRGDURQH RU EHWD EORFNHUV KDYH GHPRQVWUDWHG WR EH HIIHFWLYH DW SUHYHQWLQJ WKH LQFLGHQFH RI $) DIWHU FDUGLDF VXUJHU\[35,36], even though not all studies were able to demonstrate that commonly used preventive agents were associated with lower UDWHV RI $) LQ KLJK ULVN SRSXODWLRQ[37]. Our study was not DLPHG DW YHULI\LQJ WKH HIIHFWV RI GUXJV RQ LQFLGHQFH RI SRVWRSHUDWLYH $) DPLRGDURQH ZDV DGPLQLVWHUHG DIWHU WKH ¿UVW HSLVRGH RI SRVWRSHUDWLYH $) QR FRUUHODWLRQ ZDV IRXQG EHWZHHQ

beta-blocker treatment or individual beta-blocker dosage and LQFLGHQFH RI $) LQ DQ\ RI WKH WZR JURXSV Limitations of the study This is a retrospective study; no details were available DERXW WKH VXUJLFDO WHFKQLTXH XVHG LQ VSHFL¿F SDWLHQWV DQG LQ SDUWLFXODU LI DQWHULRU IDW SDG KDG EHHQ UHPRYHG RU LQMXUHG during aortic valve substitution (group B); even though this ZDV WKH FDVH SDWLHQWV RI JURXS % GLG QRW JDLQ DQ\ DGYDQWDJH LQ WHUPV RI LQFLGHQFH RI SRVWRSHUDWLYH $) 7KH WRWDO QXPEHU RI HSLVRGHV RI $) WKDW RFFXUUHG ERWK in cardiac surgery and in cardiac rehabilitation has been reFRUGHG WKH VWXG\ GLG QRW FROOHFW GDWD DERXW GXUDWLRQ RI WKH VLQJOH HSLVRGHV $OWKRXJK D SDUW RI SDWLHQWV ZDV XQGHU WUHDWment with amiodarone and/or beta-blockers during the study, they were equally distributed among the two groups; thus, WUHDWPHQW VKRXOG QRW KDYH LQÀXHQFHG WKH UHVXOWV $ OLPLWHG QXPEHU RI FDVHV ZDV VWXGLHG 1HYHWKHOHVV WKH QXPEHU RI SDWLHQWV WKDW XQGHUZHQW WUDQVHFWLRQ RI DVFHQGLQJ aorta in our study (67 cases; 132 controls) is not dissimilar IURP WKDW RI VXEMHFWV VXEPLWWHG WR DQWHULRU IDW SDG UHPRYDO RU ventral cardiac denervation in other studies (Davis et al.[20] 73 cases, 58 controls; Cummings et al.[22] 29 cases, 26 controls; Alex et al.[28] 70 cases, 70 controls; AFIST-III study[23]: 88 cases, 92 controls; Breda et al.[26] 25 cases, 25 controls); only in the study by Melo et al.[25] D JUHDWHU QXPEHU RI FDVHV ZDV recruited (207 cases, 219 controls). +59 ZDV QRW DQDO\]HG LQ RXU SDWLHQWV EHIRUH VXUJHU\ LW LV already known that heart surgery leads to cardiac autonomic G\VIXQFWLRQ ZKLOH WKH DLP RI WKLV VWXG\ ZDV WR FRPSDUH LQÀXHQFH RI DXWRQRPLF GLVWXUEDQFHV RQ 32$) LQ WZR GLIIHUHQW W\SHV RI KHDUW VXUJHU\ 7KH +59 DQDO\VLV ZDV SHUIRUPHG RQ DYHUDJH GD\V DIWHU VXUJHU\ DEQRUPDOLWLHV RI +59 SHUVLVW GXULQJ DW OHDVW VRPH ZHHNV DIWHU FDUGLDF VXUJHU\[38], so that the WLPH RI +59 VWXG\ LQ RXU SDWLHQWV VKRXOG QRW KDYH DIIHFWHG RXU ¿QGLQJV :H ZHUH XQDEOH WR SHUIRUP IUHTXHQF\ GRPDLQ +59 DQDO\VHV WKDW FRXOG KDYH DOORZHG D PRUH VSHFL¿F GHWHUPLQDWLRQ RI WKH YDULDWLRQV RI YDJDO WRQH DQG RI WKH V\PSDWKR YDJDO balance. In any manner, previous studies have determined that time-domain HRV indices measured over a 24-h period are ZHOO FRUUHODWHG ZLWK IUHTXHQF\ GRPDLQ LQGLFHV LQ JHQHUDO SRSulation[39] and in thoracic surgery patients[8]. CONCLUSIONS $ KLJK LQFLGHQFH RI $) ZDV REVHUYHG LQ WKH SRVWRSHUDWLYH SHULRG RI SDWLHQWV VXEPLWWHG WR VXUJHU\ RI WKH DRUWLF YDOYH DQG DVFHQGLQJ DRUWD 7UDQVHFWLRQ RI DVFHQGLQJ DRUWD IRU VXUJLFDO UHSDLU RI DQ DRUWLF DQHXU\VP GLG QRW FRQIHU D VLJQL¿FDQW SURWHFWLYH HIIHFW WRZDUGV 32$) LQ FRPSDULVRQ WR UHIHUHQFH SDWLHQWV LQ ZKLFK DVFHQGLQJ DRUWD ZDV OHIW LQWDFW $ UHGXFHG LQFLGHQFH RI 32$) ZDV REVHUYHG RQO\ LQ D PLQRULW\ RI FDVHV with aortic transection, that presented a probably greater au-

60 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Braz J Cardiovasc Surg 2015;30(1):55-62

Compostella L, et al. - HRV and postoperative atrial fibrillation

tonomic denervation indicated by markedly depressed HRV parameters and elevated mean-HR; in the remaining cases, it could be hypothesized that a likely heterogeneous cardiac denervation, secondary to limited or patchy nervous lesions, PD\ KDYH FUHDWHG WKH HOHFWURSK\VLRORJLFDO VXEVWUDWH IRU WKH REVHUYHG KLJK LQFLGHQFH RI 32$)

circulation in man. J Thorac Cardiovasc Surg. 1983;86(5):718-26. .DSD 6 9HQNDWDFKDODP ./ $VLUYDWKDP 6- 7KH DXWRQRPLF QHUYRXV system in cardiac electrophysiology: an elegant interaction and emerging concepts. Cardiol Rev 2010;18(6):275-84. 7. Dimmer C, Tavernier R, Gjorgov N, Van Nooten G, Clement '/ -RUGDHQV / 9DULDWLRQV RI DXWRQRPLF WRQH SUHFHGLQJ RQVHW RI DWULDO ¿EULOODWLRQ DIWHU FRURQDU\ DUWHU\ E\SDVV JUDIWLQJ $P - Cardiol. 1998;82:22-5.

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62 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

GĂłmez FA, etORIGINAL al. - Morphological description of great cardiac vein in pigs ARTICLE compared to human hearts

Braz J Cardiovasc Surg 2015;30(1):63-9

Morphological description of great cardiac vein in pigs compared to human hearts Descrição morfológica da grande veia cardíaca em suínos em comparação com coraçþes humanos

Fabian Alejandro GĂłmez1; Luis Ernesto Ballesteros2, PhD; Luz Stella CortĂŠs1

DOI 10.5935/1678-9741.20140101

RBCCV 44205-1615 tomosis between the great cardiac vein and the middle cardiac vein was found in 59 (49%) specimens. Conclusion: The morphological and biometric characteristics of the great cardiac vein and its tributaries had not been reported in prior studies, and due to their similitude with those of the human heart, allows us to propose the pig model for procedural and hemodynamic applications.

Abstract Introduction: In spite of its importance as an experimental model, the information on the great cardiac vein in pigs is sparse. Objective: To determine the morphologic characteristics of the great cardiac vein and its tributaries in pigs. Methods: 120 hearts extracted from pigs destined to the slaughterhouse with stunning method were studied. This descriptive cross-over study evaluated continuous variables with 7 WHVW DQG GLVFUHWH YDULDEOHV ZLWK 3HDUVRQ Ȥ VTXDUH WHVW $ OHYHO RI VLJQL¿FDQFH P<0.05 was used. The great cardiac vein and its tributaries were perfused with polyester resin (85% Palatal and 15% Styrene) and then subjected to potassium hydroxide infusion to release the subepicardial fat. Calibers were measured, and trajectories and relations with adjacent arterial structures were evaluated. Results: The origin of the great cardiac vein was observed at the heart apex in 91 (76%) hearts. The arterio-venous trigone was present in 117 (97.5%) specimens, corresponding to the open expression in its lower segment and to the closed expression in the upper segment in the majority of the cases (65%). The caliber of the great cardiac vein at the upper segment of the paraconal interventricular sulcus was 3.73¹ PP $Q DQDV-

Descriptors: Cardiovascular System. Models, Cardiovascular. Heart/anatomy & histology. Coronary Disease. Resumo Introdução: $SHVDU GH VXD LPSRUWkQFLD FRPR XP PRGHOR experimental, a informação sobre a grande veia cardíaca em suínos Ê esparsa. Objetivo: Determinar as características morfológicas da grande veia cardíaca e suas tributårias em suínos. MÊtodos: Foram estudados 120 coraçþes extraídos de suínos destinados para o matadouro com mÊtodo de atordoamento. Este estudo descritivo cross-over avaliou variåveis contínuas FRP WHVWH 7 H YDULiYHLV GLVFUHWDV FRP WHVWH Ȥ TXDGUDGR GH 3HDUVRQ 2 QtYHO GH VLJQL¿FkQFLD P IRL XVDGR $ JUDQGH YHLD

1

Correspondence address: Luis Ernesto Ballesteros Universidad Industrial de Santander Departamento de Ciencias BĂĄsicas, Facultad de Salud Cra 32 # 29-31 - Bucaramanga, Colombia. E-mail: lballest56@yahoo.es

Universidad Cooperativa de Colombia, BogotĂĄ, Colombia. Universidad Industrial de Santander, Bucaramanga, Colombia.

2

This study was carried out at Universidad Industrial de Santander Bucaramanga, Colombia and Universidad Cooperativa de Colombia, BogotĂĄ, Colombia.

Article received on June 24th, 2014 Article accepted on August 4th, 2014

1R ÂżQDQFLDO VXSSRUW

63 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

GĂłmez FA, et al. - Morphological description of great cardiac vein in pigs compared to human hearts

Braz J Cardiovasc Surg 2015;30(1):63-9

Resultados: $ RULJHP GD JUDQGH YHLD FDUGtDFD IRL REVHUYDGD no åpice do coração em 91 (76%) espÊcimes. O trígono arteriovenoso estava presente em 117 (97,5%) espÊcimes, correspondente à expressão aberta no seu segmento inferior e para a expressão fechada no segmento superior na maioria dos casos (65%). O calibre da grande veia cardíaca no segmento superior do sulco interventricular paraconal foi de 3,73¹0,79 mm. Uma anastomose entre a grande veia cardíaca e da veia cardíaca mÊdia foi encontrada em 59 (49%) espÊcimes. Conclusão: $V FDUDFWHUtVWLFDV PRUIROyJLFDV H ELRPpWULFDV GD grande veia cardíaca e suas tributårias não haviam sido relatadas em estudos anteriores e, devido à sua semelhança com as do coração humano, nos permite propor o modelo porcino para SURFHGLPHQWRV H DSOLFDo}HV KHPRGLQkPLFDV

$EEUHYLDWLRQV DFURQ\PV V\PEROV AIB AVT &%; CS GCV LAVS LCA LMV MCV OVLA PLCV RMV

Anterior interventricular branch Arterio-venous trigone of the heart &LUFXPĂ€H[ EUDQFK Coronary sinus Great cardiac vein Left atrioventricular sulcus Left coronary artery Left marginal vein Middle cardiac vein Oblique vein of the left atrium Posterior left cardiac vein Right marginal vein

cardíaca e suas tributårias foram perfundidas com resina de poliÊster (85% palatal e estireno de 15%) e, em seguida, submetidas à infusão de hidróxido de potåssio para remover a gordura subepicardal. Os calibres foram medidos e trajetórias e relaçþes com estruturas arteriais adjacentes foram avaliadas.

Descritores: Sistema Cardiovascular. Modelos Cardiovasculares. Coração/anatomia & histologia. Doença das Coronårias.

INTRODUCTION

Knowing the cardiac vein system of the pig is useful for experimental anatomic models to train hemodynamists, cardiologists and surgeons[2,3,15,17]. The aim of this study was analyze anatomy of pig cardiac vein and discuss the similarities between these and human cardiac veins.

Since prior studies have indicated few morphological differences between pigs and humans and since the information available on the venous drainage of the heart is poor, these anatomic characteristics of the pig need to be enriched. The few works conducted on this subject have made vary basic descriptions and have used a limited number of specimens, so the statistic robustness of their ÂżQGLQJV LV GHEDWDEOH[1-3]. The great cardiac vein (GCV) in humans drains into the coronary sinus (CS), the territories irrigated by the left coronary artery (LCA). This vein originates at the lower third of the anterior interventricular sulcus (AIS) or even at the heart apex, and continues its course along said sulcus in parallel to the anterior interventricular branch (AIB) to the upper portion of that artery[4-8]. Then it crosses to the left until it reaches the left atrioventricular sulcus (LAVS) forming the basis of the arterio-venous trigone of the heart (AVT) together with WKH $,% DQG WKH FLUFXPĂ€H[ EUDQFK &[% ,WV WUDMHFWRU\ LV PRVWO\ VXSHUÂżFLDO ZLWK UHVSHFW WR WKH DUWHU\ LW UXQV DORQJ with. After a short run through the LAVS, the GCV, receives the drainage of the left posterior veins (PLCV) and gives origin to the SC[4,5,8-15] 7KH FRQÂżJXUDWLRQ RI WKH $97 RI WKH KHDUW has been based on its crossing or not the GCV to the AIB and the CxB, which determines closed trigones when there is a crossing, or open trigones if the vein does not cross through these arterial branches. The expression of the open AVT in its lower segment and closed AVT in the upper segment have been reported as most frequent (50-73%)[5,8,14,16].

METHODS This descriptive cross-over study evaluated the characteristics and main tributaries of the GCV in 120 hearts pigs of commercial breeds destined to the slaughterhouse with stunning method, with a mean age of 5 months. This study was supported by the Bioethics Committee of the Cooperative University of Colombia. The organs were subjected to an exsanguination process in a water source for 6 hours. An arciform plicature ZDV PDGH ZLWK VLON DURXQG WKH &6 RULÂżFH DQG D QXPEHU catheter was installed, through which semisynthetic polyester resin was perfused (palatal GP40L to the 85%; styrene to the ZLWK PLQHUDO EOXH G\H 6LPLODUO\ SULRU LGHQWLÂżFDWLRQ RI the ostium and application of a reference point with 2.0 silk, the LCA was perfused with red-stained resin. Later, the hearts were subjected to a partial corrosion process with 15% potassium hydroxide (KOH) in order to remove the subepicardial fat situated on the bottom of the interventricular and atrioventricular sulci. Then, the GCV and its tributaries were dissected from their origin to their distal segment. The caliber of the GCV was measured with an electronic calibrator (MitutoyoÂŽ), at its upper interventricular and atrio-ventricular segments and at its end. The GCV tributaries were measured at their medium and distal segments. The

64 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

GĂłmez FA, et al. - Morphological description of great cardiac vein in pigs compared to human hearts

Braz J Cardiovasc Surg 2015;30(1):63-9

presence of a venous communication of the GCV with other YHQRXV EUDQFKHV ZDV GHWHUPLQHG 7KH VXSHUÂżFLDO RU GHHS UHlation of the GCV with respect to the paraconal interventricular branch (PIB) was established, as well as the trajectories parallel to the right or left and the proximal or distal crossLQJV RI WKH *&9 ZLWK UHVSHFW WR WKH 3,% 7KH FRQÂżJXUDWLRQ RI the AVT of the heart determined by the relation of the GCV ZLWK WKH EUDQFKHV RI WKH /&$ 3,% DQG &[% ZHUH FODVVLÂżHG according to Pejkovic & Bogdanovic[10] criteria; as opened in its lower segment and closed in its upper segment; both lower and upper opened; both lower and upper closed; lower closed and upper opened. The data thus obtained were recorded in a physical matrix and were consigned in digital media using Excel tables. Photographs were taken to each one of the pieces evaluated with digital camera. Continuous variables were described with means and standard deviation, nominal variables with proportions.

upper portions in 15 (13%) hearts (Figure 4), and closed at its lower portion and open at its upper portion in 6 (5%) specimens (Figure 5). The caliber of the GCV at the paraconal interventricular sulcus was 3.73Âą0.79 mm; at the LAVS it was 4.99Âą1.04 mm, and at the site of drainage into the coronary sinus was 5.3Âą0.98 mm. The GCV received on average the drainage of 3.5 right anterior ventricular branches and 5.5 left anterior ventricular branches and in 99% of the cases it was superÂżFLDO ZLWK UHVSHFW WR WKH 3,% $ YHQRXV FRPPXQLFDWLRQ EHtween the GCV and the MCV was found in 59 (49%) specimens (Figure 6) and with the right marginal vein (RMV) in 2 (1.5%) cases.

RESULTS One hundred and twenty hearts were evaluated, 101 (84.2%) of which were from male pigs and 19 (15.8%) from female pigs. The mean weight of the hearts was 375Âą78.12 g. The specimens were obtained from pigs with a mean weight of 90 kg and between 4 and 5 months of age. In 91 (76%) hearts the GCV originated at the heart apex and in 29 (24%) at the lower third of the sternocostal surface of the heart. This vessel showed a left parallel course with respect to the PIB in 87 (72.5%) specimens and a right parallel trajectory with distal crossing in 1 (0.8%) case (Table 1). The AVT was present in 117 (97.5%) specimens. In the cases in which it was absent, the GCV took an ascending course crossing the proximal segment of the CxB, going then WR WKH OHIW RI WKH DVFHQGLQJ DRUWD DQG ÂżQDOO\ GUDLQLQJ LQWR WKH right atrium above the outlet of the CS (2.5%). In these 3 cases the CS received the drainage of the left marginal vein (LMV), of the PLCV and the middle cardiac vein (MCV) (Figure 1). $Q RSHQ FRQÂżJXUDWLRQ RI WKH $97 DW WKH ORZHU SRUWLRQ and closed at the upper portion was observed in 76 (65%) cases (Figure 2); closed in both its lower and upper segments in 20 (17%) especimens (Figure 3); open in its lower and

Fig. 1 - Left surface of the heart. LA=Left Atrium; LV=Left Ventricle; RV=Right Ventricle; GCV=Great cardiac vein draining directly into the right atrium; PIB=Paraconal interventricular branch; &[% &LUFXPĂ€H[ EUDQFK

Table 1. Course of the great cardiac vein (GCV) with respect to the interventricular paraconal branch (PCIB), by gender. Males n (%) 73 (72.3) 10 (9.9) 11 (10.9) 6 (5.9) 1 (1) 101

Course Parallel left Parallel left, crossed proximal Parallel left, crossed distal Parallel right, crossed proximal Parallel right, crossed distal Total

65 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Females n (%) 14 (73.7) --4 (21) 1 (5.3) --19

Total sample n (%) 87 (72.5) 10 (8.4) 15 (12.5) 7 (5.8) 1 (0.8) 120 (100)

Gรณmez FA, et al. - Morphological description of great cardiac vein in pigs compared to human hearts

Braz J Cardiovasc Surg 2015;30(1):63-9

Fig. 2 - Left surface of the heart. LA=Left Atrium; LV=Left Ventricle; RV=Right Ventricle; GCV=Great cardiac vein; PIB=Paraconal LQWHUYHQWULFXODU EUDQFK &[% &LUFXPร H[ EUDQFK $UWHULRYHQRXV triangle, open at the lower end and closed at the top

Fig. 3 - Left surface of the heart. LA=Left Atrium; LV=Left Ventricle; RV=Right Ventricle; GCV=Great cardiac vein. PIB: Paraconal interventricular branch; CxB=Circumflex branch, LDB=Left GLDJRQDO EUDQFK $UWHULRYHQRXV WULDQJOH FORVHG DW WKH ORZHU end and top

Fig. 4 - Left surface of the heart. LA=Left Atrium; LV=Left Ventricle; RV=Right Ventricle; GCV=Great cardiac vein; PIB=Paraconal LQWHUYHQWULFXODU EUDQFK &[% &LUFXPร H[ EUDQFK $UWHULRYHQRXV triangle, open at the lower end and top

Fig. 5 - Left surface of the heart. LA=Left Atrium; LV=Left Ventricle, RV=Right Ventricle; GCV=Great cardiac vein; PIB=Paraconal LQWHUYHQWULFXODU EUDQFK &[% &LUFXPร H[ EUDQFK $UWHULRYHQRXV triangle, closed at the lower end and open at the top

66 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

GĂłmez FA, et al. - Morphological description of great cardiac vein in pigs compared to human hearts

Braz J Cardiovasc Surg 2015;30(1):63-9

The PLCVs had a caliber of 1.61Âą0.61 mm and drained into the GCV in 58% of the cases, and into the CS in 42% (Figure 7). One to four branches drained into each one of these structures, with a predominance of the expression of a single branch (Table 2).

Fig. 6 - Venous communication between middle and great cardiac veins. LV=Left Ventricle; RV=Right Ventricle; MCV=Middle cardiac YHLQ *&9 *UHDW FDUGLDF YHLQ 9HQRXV FRPPXQLFDWLRQ QHDU the apex of the heart

The LMV was originated at the heart apex in 54 (46%) specimens, and at the middle third of the obtuse edge of the heart in 30%; whereas in 16 (14%) hearts this structure was originated at the lower third and was very short, having its origin at the upper third in 12 (10%) cases. The LMV drained into the distal segment of the GCV in 116 (97%) specimens and into the proximal segment of the CS in 3 (2.5%) specimens; in one case it drained into an anterior ventricular branch (0.5%). The mean caliber of the LMV was 1.53Âą0.51 mm and the distal caliber was 2.61Âą0.75 mm. DISCUSSION There are no data from pigs on the caliber and length of the GCV; most prior studies have only limited to describe its qualitative characteristics[1,2]. With respect to the GCV origLQDWLQJ PRVWO\ DW WKH KHDUW DSH[ RXU ÂżQGLQJV DUH FRQVLVWHQW with reports in humans, but while the frequency in our series is of 76%, in humans it has been reported in a range of 27-57.4%[6,8,18,19]. In 24% of the cases the GCV originated at

Fig. 7 - Right surface of the heart. RV=Right ventricle; LV=Left ventricle; RA=Right atrium; CS=Cylindrical coronary sinus, 0&9 0LGGOH FDUGLDF YHLQ &[% &LUFXPĂ€H[ EUDQFK *&9 *UHDW cardiac vein; AV=Azygos vein; LPV=Left posterior vein

Table 2. Number of branches of the left posterior veins (PLCV) draining into the great cardiac vein (GCV) or the coronary sinus (CS). Number of branches PLCV One branch Two branches Three branches Four branches Total

Drainage into the GCV % Total sample 61 44 19 26 8 11 1 2 72 100

67 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Drainage into the CS % Total sample 58.3 28 29.2 14 8.3 4 4.2 2 100 48

GĂłmez FA, et al. - Morphological description of great cardiac vein in pigs compared to human hearts

Braz J Cardiovasc Surg 2015;30(1):63-9

tive because in certain pathophysiologic conditions allow to attenuate or prolong the history of the cardiovascular disease by providing alternative routes for venous drainage[8]. The caliber of the LMV reported in prior studies in humans[5,8,11,21] LV VLPLODU WR RXU ÂżQGLQJV PP &RQFHUQing the drainage of the LMV, our results are consistent with reports in humans indicating this vascular structure draining into the GCV in the majority of the cases, but there is some controversy about the frequency of its drainage into the CS, which was found in our study in 2.5%, whereas in humans it has been reported within a range of 5-19%[5,8,11] 7KH ÂżQGLQJV about the qualitative and morphometric characteristics of the LMV are new knowledge that had not been previously described in the literature. The drainage of the PLCV in the GCV had been described in humans in a range of 28-35%, whereas in our study we obVHUYHG LQ RI WKH VSHFLPHQV 6LPLODUO\ RXU ÂżQGLQJV DUH consistent with those of prior studies conducted in humans, with respect to the caliber and the prevalent expression of one or two PLCV at their turn receiving small tributaries that drained the lateral and posterior surface of the left ventricle, then to drain into the GCV or into the CS[7,8,13,15]. The large variations in number of the PLCV should be taken into account for the insertion of devices in the management of arrhythmias; the absence of the lateral veins or the small number of PLCV, may virtually limit the possibility of going into the left ventricle through a venous access. The dimensions of the PLCV, have a negative correlation with its number, which leads to the high number of tributaries, the lower the accessibility with the available catheters, so that these characteristics become relevant in the practice of intravenous approaches to the heart[5,6]. Interventionist cardiologists consider that the minimum diameter of these vessels for an appropriate manipulation with an intracoronary mapping catheter should be 1.3 mm, because the diameter of the devices is 1.1 mm[3,4]. The mean caliber of the PLCV found in our series (1.61 mm) allows us to propose to the young adult pig model as a good training scenario for the application of intravenous devices through the GCV and its left posterior ventricular tributaries.

the lower third of the paraconal interventricular sulcus coinciding with some studies in humans[6,19]. Some other authors have reported the origin of the GCV at this level with a greater frequency, within a range of 57-74%[5,9,11]. When this anatomic expression occurs, the venous drainage is compensated ZLWK WKH ÂżQGLQJ RI D ORQJ 0&9 RULJLQDWLQJ DW WKH ORZHU WKLUG of the anterior ventricular surface. The location of the GCV to the left of the PIB of the LCA observed in our series in 93% of the specimens exceeds what has been reported in humans[8], with this characteristic being determinant for the high percentage of open forms of the lower segment of the AVT. The characterization of the trajectory of the GCV in parallel to the PIB, together with the proximal or distal crossings of the vein over the artery where it runs along with, is new information on anatomy of the GCV in pigs and are useful for procedures using this animal model. In our study a few specimens of the GCV ran along the PIB until the vicinity to the point of division of the LCA, without giving place to the formation of the cardiac AVT as classically described. The high incidence of the AVT in our series (97.5%) is considerably greater than that reported in humans (59-80%) [5,8,11,12,16,20] . The absence of an AVT could hamper the pass of electrodes during radiofrequency ablation procedures utilized for the management of heart failure due to foci of arrhythmia[9]. 6LPLODUO\ RXU ÂżQGLQJV DUH FRQVLVWHQW ZLWK WKRVH UHSRUWHG LQ KXman heartsindicating an open expression of the TAV inferiorly as the most frequent, although the frequency observed in our sample was slightly higher (65%)[5,8,16]. In our series the incidence of the open form of the upper and lower segments of cardiac AVT (13%) was similar to the study by Ortale et al.[5], and slightly higher than the reports by other authors[8,16]. ,Q KXPDQV WKH VXSHUÂżFLDO ORFDWLRQ RI WKH *&9 ZLWK UHspect to the AIB of the LCA has been reported within a range RI EHWZHHQ FRQVLVWHQW ZLWK RXU ÂżQGLQJV ZKHUH WKH YHLQ UXQV VXSHUÂżFLDOO\ WR WKH 3,% EXW LWV IUHTXHQF\ is superior to what has been reported in humans[8,9,11,12]. This situation in humans has been considered relevant because in the presence of occlusive coronary heart disease cases where the GCV runs deeply in the AVT this vessel could be compressed by rigid arteries that would alter the venous return of the heart and would worsen the disease[16,20]. The mean calibers of the GCV found in our study at the interventricular sulcus and at the distal segment (3.73 mm and 5.3 mm, respectively), are consistent with the majority of the reports from studies in humans[4,9,16,21,22]. The venous communication found between the GCV and the MCV at the heart apex (49%) in our study, is considerably more numerous than those reported in humans indicating ranges between 15-34%[5,8,9,11,14,16]. Melo et al.[4], in a study conducted in humans, reported venous communication of these veins in 90% of the cases, although they do not discriminate where these venous communication occurred. This morphological characteristic has been considered as protec-

CONCLUSION The morphological and biometric characteristics of the GCV and its tributaries in pigs had not been reported in prior studies, similitudes of GCV anatomy in pigs enable the use of pig hearts as models for surgical and hemodynamics procedures. ACKNOWLEDGEMENTS 7R )ULJRUtÂżFR 9LMDJXDO LQ WKH FLW\ RI %XFDUDPDQJD Âą &Rlombia for the donation of pieces to conduct this investigation and to the students Diana Reyes and Jairo Rivera, for their participation in the preparation of the study specimens.

68 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

GĂłmez FA, et al. - Morphological description of great cardiac vein in pigs compared to human hearts

Braz J Cardiovasc Surg 2015;30(1):63-9

$XWKRUVÂś UROHV UHVSRQVLELOLWLHV FAG

LEB

LSC

9. Mochizuki S. Vv. Cordis. In: Adachi B, eds. Das venensystem der Japaner. Kyoto: Kenkyusha; 1933. p.41-64.

Analysis and/or interpretation of data, statistical analysis, ÂżQDO DSSURYDO RI WKH PDQXVFULSW FRQFHSWLRQ DQG GHVLJQ RI the study, implementation of operations and/or experiments, manuscript writing or critical review of its content Analysis and/or interpretation of data, statistical analysis, ÂżQDO DSSURYDO RI WKH PDQXVFULSW FRQFHSWLRQ DQG GHVLJQ RI the study, implementation of operations and/or experiments, manuscript writing or critical review of its content Conception and design of the study, implementation of operations and/or experiments, manuscript writing or critical review of its content

10. Pejkovic B, Bogdanovic D. The great cardiac vein. Surg Radiol Anat. 1992;14(1):23-8. 11. Mahmud E, Raisinghani A, Keramati S, Auger W, Blanchard DG, DeMaria AN. Dilation of the coronary sinus on echocardiogram: SUHYDOHQFH DQG VLJQLÂżFDQFH LQ SDWLHQWV ZLWK FKURQLF SXOPRQDU\ hypertension. J Am Soc Echocardiogr. 2001;14(1):44-9. 12. Liu DM, Zhang FH, Chen L, Zheng HP, Zhong SZ. Anatomy RI WKH FRURQDU\ VLQXV DQG LWV FOLQLFDO VLJQLÂżFDQFH IRU UHWURJUDGH cardioplegia. Di Yi Jun Yi Da Xue Xue Bao. 2003;23(4):358-60. 13. Piffer CR, Piffer MI, Zorzetto NL. Anatomic data of the human coronary sinus. Anat Anz. 1990;170(1):21-9.

REFERENCES 1. Kato T, Yasue T, Shoji Y, Shimabukuro S, Ito Y, Goto S, et al. Angiographic difference in coronary artery of man, dog, pig and monkey. Acta Pathol Jpn. 1987;37(3):361-73.

14. Kaczmarek M, Czerwinski F. Assessment of the course of the great cardiac vein in a selected number of human hearts. Folia Morphol (Warsz). 2007;66(3):190-3.

2. Crick SJ, Sheppard MN, Ho SY, Gebstein L, Anderson RH. Anatomy of the pig heart: comparisons with normal human cardiac structure. J Anat. 1998;193( Pt 1):105-19.

15. Schlesinger MJ. Relation of anatomic pattern to pathologic conditions of the coronary arteries. Arch Pathol. 1940;30:403-15. 16. von LĂźdinghausen M. Clinical anatomy of cardiac veins, Vv. cardiacae. Surg Radiol Anat. 1987;9(2):159-68.

3. Sahni D, Kaur GD, Jit H, Jit I. Anatomy & distribution of coronary arteries in pig in comparison with man. Indian J Med Res. 2008;127(6):564-70.

17. Lee MS, Shah AP, Dang N, Berman D, Forrester J, Shah PK, et al. Coronary sinus is dilated and outwardly displaced in patients with mitral regurgitation: quantitative angiographic analysis. Catheter Cardiovasc Interv. 2006;67(3):490-4.

4. Melo DS, Prudencio LA, Kusnir CE, Pereira AL, Marques V, Vieira MC, et al. Angiography of the coronary venous system. Use in clinical electrophysiology. Arq Bras Cardiol. 1998;70(6):409-13.

6FKDIĂ€HU *- *URHOO 5 3HLFKHO .+ 5LHQPÂ OOHU 5 ,PDJLQJ WKH coronary venous drainage system using electron-beam CT. Surg Radiol Anat. 2000;22(1):35-9.

5. Ortale JR, Gabriel EA, Iost C, MĂĄrquez CQ. The anatomy of the coronary sinus and its tributaries. Surg Radiol Anat. 2001;23(1):15-21. 6. El-Maasarany S, Ferrett CG, Firth A, Sheppard M, Henein MY. The coronary sinus conduit function: anatomical study (relationship to adjacent structures). Europace. 2005;7(5):475-81.

19. Christiaens L, Ardilouze P, Ragot S, Mergy J, Allal J. Prospective evaluation of the anatomy of the coronary venous system using multidetector row computed tomography. Int J Cardiol. 2008;126(2):204-8.

7. Sousa-Rodrigues CF, Alcântara FS, Olave E. Topografía y biometría del sistema venoso coronario y de sus tributarias. Int J Morphol. 2005;23:177-84.

20. Kawashima T, Sato K, Sato F, Sasaki H. An anatomical study of the human cardiac veins with especial reference to the drainage of the great cardiac vein. Ann Anat. 2003;185(6):535-42.

8. Ballesteros LE, RamĂ­rez LM, Forero PL. Study of the coronary sinus and its tributaries in Colombian subjects. Rev Colomb Cardiol. 2010;17(1):9-15.

21. Gilard M, Mansourati J, Etienne Y, Larlet JM, Truong B, Boschat J, et al. Angiographic anatomy of the coronary sinus and its tributaries. Pacing Clin Electrophysiol. 1998;21(11 Pt 2):2280-4.

69 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Antonio EL, etORIGINAL al. - Are thereARTICLE gender differences in left ventricular remodeling after myocardial infarction in rats?

Braz J Cardiovasc Surg 2015;30(1):70-6

Are there gender differences in left ventricular remodeling after myocardial infarction in rats? Hå diferenças entre os gêneros no remodelamento ventricular esquerdo após infarto do miocårdio em ratos?

Ednei Luiz Antonio1, MD; Andrey Jorge Serra2, MsC, PhD; Alexandra Alberta dos Santos3, MD; Stella Sousa Vieira3, MD; Jairo Montemor Augusto Silva3, MD; Amanda Yoshizaki4, MD; 5HQDWR 5RGULJXHV 6RÂżD5, MD; Paulo JosĂŠ Ferreira Tucci3, MD, PhD

DOI: 10.5935/1678-741.20140093

RBCCV 44205-1616 “ YV 0$ “ FP V@ ZDYH $ >)( “ YV 0$ “ FP V@ ( $ >)( “ YV 0$ “ @ ZHHN Conclusion: *HQGHU GRHV QRW LQÀXHQFH OHIW YHQWULFOH UHPRGeling post-MI in rats.

Abstract Objective: $Q XQFOHDU LVVXH LV ZKHWKHU JHQGHU PD\ LQÀXHQFH DW cardiac remodeling after myocardial infarction (MI). We evaluated left ventricle remodeling in female and male rats post-MI. Methods: Rats were submitted to anterior descending coronary occlusion. Echocardiographic evaluations were performed RQ WKH ¿UVW DQG VL[WK ZHHN SRVW RFFOXVLRQ WR GHWHUPLQH P\Rcardial infarction size and left ventricle systolic function (FAC, fractional area change). Pulsed Doppler was applied to analyze left ventricle diastolic function using the following parameters: E wave, A wave, E/A ratio. Two-way ANOVA was applied for comparisons, complemented by the Bonferroni test. A P” ZDV FRQVLGHUHG VLJQL¿FDQW Results: 7KHUH ZHUH QR VLJQL¿FDQW GLIIHUHQFHV EHWZHHQ JHQGHUV IRU PRUSKRPHWULF SDUDPHWHUV RQ ¿UVW 0, >)HPDOH )( “ YV 0DOH 0$ “ @ GLDVWROLF >)( “ YV 0$ “ PP J@ DQG V\VWROLF >)( “ YV 0$ “ PP J@ GLDPHWHUV RI OHIW YHQWULFOH DQG VL[WK 0, >)( “ YV 0$ “ @ GLDVWROLF >)( “ YV 0$ “ PP J@ DQG V\VWROLF >)( “ YV 0$ “ PP J@ RI /9 ZHHN 6LPLODU ¿QGLQJV ZHUH UHSRUWHG IRU OHIW YHQWULFOH IXQFWLRQDO SDUDPHWHUV RQ ¿UVW )$& >)( “ YV 0$ “ @ ZDYH ( >)( “ YV 0$ “ FP V@ ZDYH $ >)( “ YV 0$ “ FP V@ ( $ >)( “ YV 0$ “ @ DQG VL[WK )$& >)( “ YV 0$ “ @ ZDYH ( >)(

Descriptors: Gender and Health. Myocardial Infarction. Ventricular Remodeling. Resumo Objetivo: $ LQĂ€XrQFLD GR JrQHUR QR UHPRGHODPHQWR FDUGtDFR apĂłs o infarto do miocĂĄrdio ĂŠ uma questĂŁo em intenso debate. NĂłs avaliamos o remodelamento ventricular esquerdo em ratos LQIDUWDGRV GH DPERV RV JrQHURV MĂŠtodos: O infarto do miocĂĄrdio foi induzido por oclusĂŁo da DUWpULD FRURQiULD GHVFHQGHQWH DQWHULRU IrPHDV >)0@ PDFKRV >0&@ $ HFRFDUGLRJUDÂżD IRL UHDOL]DGD QD SULPHLUD H VH[WD VHPDna pĂłs-oclusĂŁo para determinar o tamanho do infarto do miocĂĄrdio e a função sistĂłlica do ventricular esquerdo (mudança na iUHD IUDFLRQDO >)$&@ $ IXQomR GLDVWyOLFD GHULYRX GRV VHJXLQWHV SDUkPHWURV RQGD ( RQGD $ UD]mR ( $ $129$ GXDV YLDV FRP pĂłs-teste de Bonferroni foi aplicado nas comparaçþes (P” Resultados: Todas variĂĄveis morfomĂŠtricas foram similares (P! HQWUH RV JrQHURV FRP XPD LQIDUWR GR PLRFiUGLR >)0 “ vs 0& “ @ GLkPHWUR GLDVWyOLFR >)0 “ vs 0& “ PP J@ H VLVWyOLFR >)0 “ vs 0& “ PP J@ GR 9( H VHLV ,0

1

Correspondence address: Andrey Jorge Serra Postgraduate Program in Biophotonics Applied Health Sciences, Universidade Nove de Julho (UNINOVE) Rua Vergueiro, 235 - SĂŁo Paulo, SP, Brazil Zip code: 01504-001 E-mail: andreyserra@gmail.com

Laboratório de Fisiologia e Fisiopatologia Cardíacas da Disciplina de Cardiologia da Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil. 2 Docente da Universidade Nove de Julho (Uninove), São Paulo, SP, Brazil. 3 Laboratório de Fisiologia e Fisiopatologia Cardíacas da Disciplina de Cardiologia da Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil. 4 Programa de Pós-graduação em Ciências da Reabilitação da Universidade Nove de Julho (Uninove), São Paulo, SP, Brazil. 5 Universidade Nove de Julho (Uninove), São Paulo, SP, Brazil.

Financial support: Grant number 2009/54225-8, SĂŁo Paulo Research Foundation (FAPESP).

This study was carried out at Universidade Federal de SĂŁo Paulo (Unifesp), SĂŁo Paulo, SP, Brazil and Universidade Nove de Julho (Uninove), SĂŁo Paulo, SP, Brazil.

Article received on September 26th, 2013 Article accepted on June 2nd, 2014

70 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Antonio EL, et al. - Are there gender differences in left ventricular remodeling after myocardial infarction in rats?

Braz J Cardiovasc Surg 2015;30(1):70-6

>)0 “ vs 0& “ @ RQGD ( >)0 “ vs. 0& “ FP V@ RQGD $ >)0 “ vs 0& “ FP V@ ( $ >)0 “ vs 0& “ @ H VHLV )$& >)0 “ vs 0& “ @ RQGD ( >)0 “ vs. MC: “ FP V@ RQGD $ >)0 “ vs 0& “ FP V@ ( $ >)0 “ vs 0& “ @ VHPDQDV Conclusão: 2 JrQHUR QmR p GHWHUPLQDQWH SDUD R UHPRGHODmento ventricular esquerdo pós-infarto do miocårdio em ratos.

Abbreviations, acronyms & symbols FE LV MA MI

Female Left ventricle Male Myocardial infarction

>)0 “ vs 0& “ @ GLkPHWUR GLDVWyOLFR >)0 “ vs 0& “ PP J@ H VLVWyOLFR >)0 “ vs 0& “ PP J@ GR YHQWULFXODU HVTXHUGR VHPDQDV Achado similar ocorreu para os dados funcionais com uma (FAC

Descritores: *rQHUR H 6D~GH ,QIDUWR GR 0LRFiUGLR 5HPRdelação Ventricular.

stitutes of Health (National Institutes of Health publication number 96-23, revised, 1996; http://bioethics.od.nih.gov/animals.html)â€?. The MI was induced in three-month-old female Wistar-EPM rats weighing between 180 to 220g. The animals were housed at regular temperature (22°-24°C) on a 12h dark/ light cycle with food and water provided ad libitum. Rats were anesthetized with ketamine (50 mg/kg) plus xylazine (10 mg/ kg) intraperitoneally, intubated, and ventilated with room air (rate: 90 breaths/minute; tidal volume: 2.5 ml on a Harvard rodent respirator [model 683, Harvard Apparatus Co., South Natik, MA, USA]). After thoracotomy, the MI was produced by ligation of the left descending coronary artery as previously described[17,18]. Sham surgery was performed with a similar process except the suture was tied loosely around the coronary artery. Afterward MI or Sham surgery, the rats returned to their plastic boxes and were kept under observation without any drug therapy. Survivor animals were assigned to the following groups: (1) Female sham (n=8); (2) Female MI (n=11); (3) Male sham (n=9); (4) Male MI (n=12).

INTRODUCTION Myocardial infarction (MI) is an important cause of heart failure and mortality among adults. A number of factors can determine a worsening in prognosis such as infarct expansion, hypertrophy of the non-infarcted myocardium, increased collagen deposition in the infarcted and non-infarcted areas, progressive dilatation, geometric changes in chamber shape, and eventual progression to chronic heart failure. It is well known that premenopausal women are less likely to develop coronary heart disease than men. Previous studies have also shown that gender can be a key factor in cardiac remodeling post-MI. Thus, studies show gender as a risk factor of unfavorable prognostic[1,2]. Although valuable, these ÂżQGLQJV FDQQRW EH FRQVLGHUHG DV DEVROXWH WUXWK 6HYHUDO LVsues such as age heterogeneity, drug therapy, associated risk factors, and hemodynamics (e.g., pre- and afterload; blood YROXPH PD\ FDXVH GLIÂżFXOWLHV LQ HQVXULQJ WKDW WKH WKHUH LV differential cardiac remodeling between genders post-MI[2,3]. Moreover, some researchers have found higher survival rates in women[4,5] while others show higher mortality in women due to higher severity of MI[6]. Since possible gender differences in post-MI left ventricle (LV) remodeling are not clear, we conducted the current study using a rat MI model. The MI model by coronary ocFOXVLRQ UHSUHVHQWHG D VLJQLÂżFDQW DGYDQFH WR SURYLGH DFFXUDWH control of bias[7-13]. Moreover, coronary occlusion is the most commonly used experimental model to induce MI in rats and VRPHZKDW UHSURGXFHV WKH ÂżQGLQJV LQ KXPDQV ZLWK FDUGLDF decompensation[14]. We performed paired time evaluations in the LV with transthoracic echocardiography. This approach has been shown to be readily reproducible in longitudinal assessment of morphology and function of LV in rodents[15,16].

Echocardiographic measurements Echocardiography has been shown accurate in evaluating cardiac remodeling post-MI[16,19-20]. Echocardiographic analyVLV ZDV DSSOLHG RQ WKH ¿UVW DQG VL[WK ZHHN SRVW 0, 7KH UDWV were anesthetized as described above and measurements were performed using a 12-MHz transducer connected to an HP Sonos-5500 echocardiograph (Hewlett-Packard, California, USA)[11]. MI size was evaluated by transversal LV two-dimensional view on the basal, mid-transversal, and apical planes. In the diastolic phase, measurements of the endocardial perimeter (EP) and length of the infarcted segment (ISe) for each view were taken. MI size for each segment (ISi), expressed as the proportion of the LV perimeter for each view, was calculated by the following equation: ISi (%) = ISe/EP x 100. MI was de¿QHG DV D VHJPHQW ZLWK LQFUHDVHG HFKRJHQLFLW\ DQG RU FKDQJH in myocardial thickening or systolic movement. 2QO\ UDWV ZLWK ODUJH LQIDUFWLRQV • RI /9 ZHUH LQFOXGed for evaluation since this is the group that shows the highest severity of the disease[8]. The diastolic (DA) and systolic (SA) transverse areas of the LV were measured by two-dimensional

METHODS Animal MI model The study was approved by the Committee on Ethics from the Federal University of SĂŁo Paulo and use the “Principles of Laboratory Animal Care formulated by the National In-

Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Antonio EL, et al. - Are there gender differences in left ventricular remodeling after myocardial infarction in rats?

Braz J Cardiovasc Surg 2015;30(1):70-6

RESULTS

images on the basal, middle and apical parasternal transverse SODQHV 7KH ¿QDO YDOXH ZDV WKH DULWKPHWLF PHDQ RI WKH PHDsurements of the three views. Systolic function was analyzed by the fractional area change (FAC=DA - SA/DA, %) in the three transverse planes (basal, middle, and apical). Pulsed 'RSSOHU DW WKH /9 VLGH RI WKH PLWUDO YDOYH SURYLGHG WKH ÀRZ velocity curve to analyze the diastolic function parameters (E and A waves and E/A ratio). Echocardiographic images for cardiac effects of MI are shown in Figure 1.

To characterize the MI repercussions in both genders, echocardiography analyses were taken into account over six weeks after coronary occlusion. LV morphology and funcWLRQ ZHUH HYDOXDWHG LQ WKH ÂżUVW DQG VL[WK ZHHN DIWHU LVFKHPLF insult. The sham group was evaluated at the same time. LV morphology data are shown in Table 1. None of the evaluated parameters changed for female and male sham-operated rats during follow-up. MI size was similar between female and male rats, and we did not see expansion of MI in either gender GXULQJ IROORZ XS /HIW DWULXP VL]H ZDV VLJQLÂżFDQWO\ KLJKHU LQ the infarcted rats regardless of gender; moreover, there was not difference in the left atrium size between female and male rats on any assessment time. There was LV dilatation with only a week post-MI; therefore, female and male rats showed a sigQLÂżFDQW LQFUHDVH LQ GLDVWROLF DQG V\VWROLF /9 GLDPHWHU ZKHQ FRPSDULQJ WKH ÂżUVW DQG VL[WK ZHHN )RU DOO IROORZ XSV /9 GLOatation level was similar between genders. When LV diameters were indexed by body weight, LV dilation post-MI was similar FRPSDULQJ ÂżUVW WR VL[WK ZHHN IRU ERWK JHQGHUV The LV performance data are shown in Table 2.

6WDWLVWLFDO DQDO\VLV Data were analyzed with GraphPad Prism software 4.0 (San Diego, CA, USA) and values are expressed as mean Âą S.D. The Shapiro-Wilk and Levene tests were applied to verify normal statistic distributions and error variances, respectively. To determine the effect of time and infarction on the echocardiographic parameters of respective genders, twoway analysis of variance (ANOVA) with repeated measures was performed. To evaluate the difference between genders at each respective time point, regular two-way ANOVA was performed. The Bonferroni post-hoc was carried out for all DQDO\VHV DQG OHYHO RI VLJQLÂżFDQFH ZDV VHW DW

Table 1. Echocardiographic morphology parameters for female and male rats post-MI. Female Week 6 Week 1 Week 1 Sham MI Sham ---44Âą5 ---MI size(%) 4Âą0.2 4.9Âą1* 4Âą0.5 SLA (mm) SLA/BW(mm/g) 0.02Âą 0.001 0.02Âą0.0005* 0.02Âą0.002 5Âą1 8Âą0.5* 5Âą0.5 LVDD(mm) LVDD/BW(mm/g) 0.03Âą 0.002 0.04Âą0.003* 0.03Âą0.001 3Âą1 6Âą1* 2Âą0.3 LVSD(mm) LVSD/BW(mm/g) 0.02Âą 0.002 0.03Âą0.0004* 0.02Âą0.0001

Week 6 MI 42Âą9 6Âą1*# 0.03Âą0.003* 9Âą1*# 0.04Âą0.01* 7Âą1*# 0.03Âą0.01*

Male Week 6 Week 1 Week 1 Sham MI Sham ---42Âą3 ---3Âą0.4 5Âą1* 3Âą0.5 0.01Âą0.002 0.02Âą0.0005* 0.01Âą0.0003 5Âą1 9Âą1* 4Âą1 0.03Âą0.001 0.04Âą0.005* 0.03Âą0.002 3Âą1 7Âą0.3* 2Âą1 0.02Âą0.0001 0.03Âą0.005* 0.02Âą0.0002

Week 6 MI 42Âą7 6Âą1*# 0.02Âą0.002* 10Âą0.01*# 0.03Âą0.005* 8Âą0.3*# 0.03Âą0.005*

MI=myocardial infarction; BW=body weight; SLA=left atrium size; LVDD=left ventricle diastolic diameter; LVSD=left ventricle systolic diameter. Data are shown as meansÂąSD. Two-way ANOVA and Bonferroni tests were applied for comparisons. 3 YV 6KDP RQ ÂżUVW DQG VL[WK ZHHN 3 YV 0, RQ ÂżUVW ZHHN

Table 2. Echocardiographic functional parameters for female and male rats post-MI.

FAC (%) E (cm/s) A (cm/s) E/A ratio

Week 1 Sham 63Âą4 69Âą2 24Âą1 3Âą1

Week 1 MI 34Âą6* 70Âą2 20Âą1 5Âą3

Female Week 6 Sham 67Âą3 73Âą6 29Âą5 3Âą1

Male Week 6 MI 29Âą7* 85Âą2* 20Âą1 6Âą4*

Week 1 Sham 66Âą7 59Âą2 30Âą5 1Âą0.5

Week 1 MI 32Âą4* 73Âą1 28Âą1 3Âą2

Week 6 Sham 63Âą4 67Âą4 30Âą6 2Âą0.2

Week 6 MI 31Âą7* 87Âą2* 28Âą2 5Âą3*

FAC=fractional area change; E=E wave; A=A wave; Data are shown as meansÂąSD. Two-way ANOVA and Bonferroni tests were applied for comparisons. 3 YV 6KDP RQ ÂżUVW DQG VL[WK ZHHN

Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

)LJ ,OOXVWUDWLYH H[DPSOH RI WZR GLPHQVLRQDO PRGH WUDFHV RI WKH OHIW YHQWULFOH /9 RI WKH IHPDOH DQG PDOH UDWV ,PDJHV IRU PLWUDO LQÀRZ YHORFLW\ SUR¿OH GHWHUPLQHG E\ SXOVHG wave Doppler are also shown. Sham rats are placed on the left, and infarcted rats are placed on the right

Antonio EL, et al. - Are there gender differences in left ventricular remodeling after myocardial infarction in rats? Braz J Cardiovasc Surg 2015;30(1):70-6

Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Antonio EL, et al. - Are there gender differences in left ventricular remodeling after myocardial infarction in rats?

Braz J Cardiovasc Surg 2015;30(1):70-6

7KH 0, UHVXOWHG LQ D VLJQL¿FDQW UHGXFWLRQ RI /9 V\VWROLF function within a week of coronary occlusion. The systolic G\VIXQFWLRQ OHYHO ZDV QRW VLJQL¿FDQWO\ GLIIHUHQW FRPSDUHG WR WKH VL[WK ZHHN SRVW 0, 2XU ¿QGLQJV LQGLFDWH WKDW JHQGHU GLG QRW LQÀXHQFH WKH GHOHWHULRXV 0, HIIHFWV RQ /9 V\VWROLF IXQFWLRQ %RWK JHQGHUV VKRZHG VLJQL¿FDQW LQFUHDVHV LQ ( ZDYH in the sixth week post-MI, whereas the A wave remained unchanged. Thus, female and male rats had a restrictive LV ¿OOLQJ SDWWHUQ GH¿QHG DV DQ LQFUHDVHG UDWLR RI HDUO\ ( WR ODWH $ ¿OOLQJ YHORFLWLHV DQG UDSLG GHFHOHUDWLRQ RI WKH HDUO\ ¿OOLQJ ZDYH ZLWK VL[ ZHHNV SRVW 0, 7KHUH ZHUH QR VLJQL¿FDQW differences between genders for these parameters (Table 2).

apoptosis[31] and increasing angiogenesis in female[32]. It is also possible that sexual hormones may indirectly regulate myocardial adaptation by vascular or endocrine effects. For example, cardiac preload or afterload may be different between males and females with MI as a result of differences in blood volume regulation, venous or arterial tone[13]. The female rats used in this study were young adults with normal ovaries. This study was not designed to assess the role of sex hormones in post-MI LV remodeling, and we did not monitor the serum hormone changes. Although we can not exclude that there were minor effects of sex hormones on LV functional and echocardiographic parameters, our data do not support the view that the positive effects of the sexual KRUPRQHV PD\ VSUHDG IRU D EHQH¿FLDO /9 UHPRGHOLQJ LQ IHmale rats with MI.

DISCUSSION We performed this study to evaluate if there are gender-related differences in the LV remodeling post-MI. Echocardiography serial analyses were performed including sham non-operated rats for paired comparisons. We have included in the study only animals with large infarcts, and this was based on the issue that large infarcts are representative of notable cardiac remodeling[8,21]. The current study showed that several indicators for poor prognosis were seen with only one week of coronary occlusion[22-25] ([FHSW IRU UHVWULFWLYH /9 ¿OOLQJ SDWWHUQ LQFUHDVHG LQ the sixth week), the left atrium size, LV end-systolic and end-diastolic dimensions as well as depressed LV systolic function ZHUH LQFUHDVHG 7KHVH ¿QGLQJV DUH FRQVLVWHQW ZLWK SUHYLRXV studies in rats on similar MI sizes and follow-up analysis[3]. As the main interest was the comparison between genders, we directly compared male and female rats with similar infarction sizes. The negative effects of MI on LV morphology and function were similar for both genders. Therefore, gender was not decisive for LV remodeling post-MI. In respect to LV dilatation and systolic dysfunction, we have shown similar results to other studies[3]. On the other hand, our results do not corroborate results reported by Litwin et al.[3] LQ UHJDUGV WR UHVWULFWLYH /9 ¿OOLQJ SDWWHUQ $OWKRXJK /LWwin et al.[3] showed a higher increase of E wave and E/A ratio in male rats, we have shown that there was a similar increase in these variables for both genders. In terms of gender as a determinant of LV remodeling after MI, the reasons for the different patterns in male and female are not clear. Better remodeling of noninfarcted regions in female than in male animals can result in lower operating chamber stiffness; thus female rats may have attenuated the GHYHORSPHQW RI D UHVWULFWLYH /9 ¿OOLQJ SDWWHUQ[3]. Lines of evidence have attributed a key role for sex hormones. This is based, for example, in observations that testosterone is a potent inducer of LV hypertrophy while estradiol has an inhibitory action[26,27]. There is evidence that estrogen reduces collagen content[28,29] as well as wall stress in late MI[30]. Moreover, studies showed that estrogen may favor remodeling by preventing

CONCLUSION The current study had a preset end point of 6 weeks in which male and female rats showed similar morphological and functional abnormalities. Therefore, we cannot draw conclusions about gender differences in the LV remodeling post-MI. It should be noted that the rats were young adults with no atherosclerotic disorder. It is unlikely that humans would have MI at such a young age. However, this experimental model has been widely accepted in studying post-MI LV remodeling. ACKNOWLEDGMENTS This study was funded by grant number 2009/54225-8, São Paulo Research Foundation (FAPESP).

Authors’ roles & responsibilities ELA AJS AAS SSV JMAS AY RRS PJFT

Data collection and analysis, experimental design and manuscript writing Experimental design, statistical analysis and manuscript writing Collection and analysis of data Collection and analysis of data Collection and analysis of data Collection and analysis of data Study design and manuscript writing Experimental design, getting funding for research, critical review of the manuscript

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74 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

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19. Nozawa E, Kanashiro RM, Murad N, Carvalho AC, Cravo SL, Campos O, et al. Performance of two-dimensional Doppler echocardiography for the assessment of infarct size and left ventricular function in rats. Braz J Med Biol Res. 2006;39(5):687-95.

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20. dos Santos L, Mello AF, Antonio EL, Tucci PJF. Determination of myocardial infarction size in rats by echocardiography and WHWUD]ROLXP VWDLQLQJ FRUUHODWLRQ DJUHHPHQWV DQG VLPSOLÂżFDWLRQV Braz J Med Biol Res. 2008;41(3):199-201.

8. Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ, Spadaro J, Kloner RA, et al. Myocardial infarct size and ventricular function in rats. Circ Res. 1979;44(4):503-12.

21. Jain M, Liao R, Podesser BK, Ngoy S, Apstein CS, Eberli FR. ,QĂ€XHQFH RI JHQGHU RQ WKH UHVSRQVH WR KHPRG\QDPLF RYHUORDG after myocardial infarction. Am J Physiol Heart Circ Physiol. 2002;283(6):H2544-50.

9. Fletcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E. Left ventricular diastolic pressure-volume. Relations in rats with healed myocardial infarction. Effects on systolic function. Circ Res. 1981;49(3):618-26.

22. White HD, Norris RM, Brown MA, Brandt PW, Whitlock RM, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation, 1987;76(1):44-51.

10. Baily RG, Lehman JC, Gubin SS, Musch TI. Non-invasive assessment of ventricular damage in rats with myocardial infarction. Cardiovasc Res. 1993;27(5):851-5.

23. St John Sutton M, Pfeffer MA, Plappert T, Rouleau JL, MoyĂŠ LA, Dagenais GR, et al. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril. Circulation. 1994;89(1):68-75.

11. MoisĂŠs VA, Ferreira R, Nozawa E, Kanashiro RM, Campos O, Andrade JL, et al. Structural and functional characteristics of rat hearts with and without myocardial infarct. Initial experience with Doppler echocardiography. Arq Bras Cardiol. 2000;75(2):125-36. 12. Kanashiro RM, Nozawa E, Murad N, Gerola LR, MoisĂŠs VA, Tucci PJ. Myocardial infarction scar plication in the rat. Cardiac mechanics in an animal model for surgical procedures. Ann Thorac Surg. 2002;73(5):1507-13.

24. Xie GY, Berk MR, Smith MD, Gurley JC, DeMaria AN. Prognostic value of Doppler transmitral flow patterns in patients with congestive heart failure. J Am Coll Cardiol. 1994;24(1):132-9.

13. Cavasin MA, Tao Z, Menon S, Yang XP. Gender differences in cardiac function during early remodeling after acute myocardial infarction in mice. Life Sci. 2004;75(18):2181-92.

25. Meris A, Amigoni M, Uno H, Thune JJ, Verma A, Køber L, et al. Left atrial remodelling in patients with myocardial infarction

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complicated by heart failure, left ventricular dysfunction, or both: the VALIANT Echo study. Eur Heart J. 2009; 30(1):56-65.

estradiol, its metabolites, and progesterone inhibit cardiac ÂżEUREODVW JURZWK +\SHUWHQVLRQ 3W

26. Cabral AM, Vasquez EC, MoysĂŠs MR, Antonio A. Sex hormone modulation of ventricular hypertrophy in sinoaortic denervated rats. Hypertension. 1988;11(2 Pt 2):I93-7.

30. Smith PJ, Ornatsky O, Stewart DJ, Picard P, Dawood F, Wen WH, et al. Effects of estrogen replacement on infarct size, cardiac remodeling, and the endothelin system after myocardial infarction in ovariectomized rats. Circulation. 2000;102(24):2983-9.

27. Pelzer T, Loza PA, Hu K, Bayer B, Dienesch C, Calvillo L, et al. Increased mortality and aggravation of heart failure in estrogen receptor-beta knockout mice after myocardial infarction. Circulation. 2005;111(12):1492-8.

31. Patten RD, Pourati I, Aronovitz MJ, Baur J, Celestin F, Chen X, et al. 17beta-estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling. Circ Res. 2004;95(7):692-9.

28. Fischer GM, Swain ML. Effect of sex hormones on blood pressure and vascular connective tissue in castrated and noncastrated male rats. Am J Physiol. 1977;232(6):H617-21.

32. Chen Q, Williams R, Healy CL, Wright CD, Wu SC, O’Connell TD. An association between gene expression and better survival in female mice following myocardial infarction. J Mol Cell Cardiol. 2010;49(5):801-11.

29. Dubey RK, Gillespie DG, Jackson EK, Keller PJ. 17Beta-

Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Aydin MS, et ORIGINAL al. - Thymoquinone protects end organs from abdominal aorta ARTICLE ischemia/reperfusion injury in a rat model

Braz J Cardiovasc Surg 2015;30(1):77-83

Thymoquinone protects end organs from abdominal aorta ischemia/reperfusion injury in a rat model Timoquinona protege ĂłrgĂŁos terminais da isquemia/reperfusĂŁo da aorta abdominal em modelo com ratos

Mehmet Salih Aydin1, MD; Aydemir Kocarslan1, MD; Sezen Kocarslan2, MD; Ahmet Kucuk4, MD; øUIDQ Eser4, MD; Hatice Sezen5 0' (YUHQ %X\XN¿UDW3, MD; Abdussemet Hazar1, MD

DOI 10.5935/1678-9741.20140066

RBCCV 44205-1617

Abstract Introduction: Previous studies have demonstrated that thymoquinone has protective effects against ischemia reperfusion injury to various organs like lungs, kidneys and liver in different experimental models. Objective: We aimed to determine whether thymoquinone has favorable effects on lung, renal, heart tissues and oxidative stress in abdominal aorta ischemia-reperfusion injury. Methods: Thirty rats were divided into three groups as sham (n=10), control (n=10) and thymoquinone (TQ) treatment group (n=10). Control and TQ-treatment groups underwent abdominal aorta ischemia for 45 minutes followed by a 120-min period of reperfusion. In the TQ-treatment group, thymoquinone was given 5 minutes. before reperfusion at a dose of 20 mg/kg via an intraperitoneal route. Total antioxidant capacity, total oxidative status (TOS), and oxidative stress index (OSI) in blood serum were measured and lung, kidney, and heart tissue histopathology were evaluated with light microscopy. Results: Total oxidative status and oxidative stress index activity in blood samples were statistically higher in the control group compared to the sham and TQ-treatment groups (P<0.001 for TOS and OSI). Control group injury scores were

statistically higher compared to sham and TQ-treatment groups (P<0.001 for all comparisons). Conclusion: Thymoquinone administered intraperitoneally was effective in reducing oxidative stress and histopathologic injury in an acute abdominal aorta ischemia-reperfusion rat model.

1

This study was carried out at Harran Univercity Faculty of Medicine, Department of Cardiovascular Surgery, Sanliurfa, Turkey.

Descriptors: Aorta, Abdominal. Ischemia-Reperfusion Injury. Oxidative Stress.

Resumo Introdução: Estudos prÊvios demonstraram que a timoquinona tem efeitos protetores contra a lesão de isquemia/reperfusão em vårios órgãos como pulmão, rins e fígado em diferentes modelos experimentais. Objetivo: Determinar se timoquinona tem efeitos positivos em tecidos do pulmão, rim e coração e no estresse oxidativo em lesão de isquemia/perfusão da aorta abdominal. MÊtodos: Trinta ratos foram divididos em três grupos: sham (n=10), controle (n=10) e tratamento com timoquinona (TQ) (n=10). Os grupos controle e de tratamento com TQ foram

Harran Univercity Faculty of Medicine, Department of Cardiovascular Surgery, Sanliurfa, Turkey. 2 Harran Univercity Faculty of Medicine, Department of Pathology, Sanliurfa, Turkey. 3 Harran Univercity Faculty of Medicine, Department of Anesthesiology and Reanimation, Sanliurfa, Turkey. 4 Harran Univercity Faculty of Medicine, Department of Thoracic Surgery, Sanliurfa, Turkey. 5 Harran Univercity Faculty of Medicine, Department of Biochemistry, Sanliurfa, Turkey.

Correspondence address: 0HKPHW 6DOLK $\GĂ•Q Department of Cardiovascular Surgery, Harran Univercity Faculty of Medicine 63000 Sanliurfa, Turkey E-mail: drmsalihaydin@gmail.com

Article received on February 19th, 2014 Article accepted on March 31st, 2014

1R ÂżQDQFLDO VXSSRUW

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Aydin MS, et al. - Thymoquinone protects end organs from abdominal aorta ischemia/reperfusion injury in a rat model

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do sangue foram medidos, e a histopatologia dos tecidos do pulmão, rim e coração foram avaliados com microscopia de luz. Resultados: Estado oxidativo e índice de estresse oxidativo total em amostras de sangue foram estatisticamente mais altos no grupo controle em relação aos grupos sham e tratamento com TQ (P<0,001 para TOS e OSI). Escores de lesþes no grupo controle foram estatisticamente mais altos em relação aos grupos sham e tratamento com TQ (P<0,001 para todas as comparaçþes). Conclusão: A timoquinona administrada por via intraperitoneal IRL H¿FD] QD UHGXomR GR HVWUHVVH R[LGDWLYR H OHVmR KLVWRSDWROyJLFD HP modelo de rato de isquemia/reperfusão aguda da aorta abdominal.

Abbreviations, acronyms & symbols I/R OSI ROS TAC TOS TQ

Ischemia-Reperfusion Oxidative Stress Index Reactive Oxygen Species Total Antioxidant Capacity Total Oxidant Status Thymoquinone

submetidos Ă isquemia da aorta abdominal durante 45 minutos, seguido por um perĂ­odo de 120 minutos de reperfusĂŁo. No grupo de tratamento com TQ, a timoquinona foi administrada 5 minutos antes da reperfusĂŁo, dose de 20 mg/kg atravĂŠs da via intraperitoneal. A capacidade total antioxidante, estado oxidativo total (TOS) e o Ă­ndice de estresse oxidativo (OSI) no soro

Descritores: Aorta Abdominal. Isquemia TraumĂĄtica por ReperfusĂŁo. Estresse Oxidativo.

INTRODUCTION

METHODS

Acute abdominal aorta ischemia followed by reperfusion may be encountered in several clinical circumstances, such as abdominal aortic aneurysm or dissection repair, acute thromboembolism with aortic atherosclerosis, or trauma surgery being brought to the emergency room. Such clinical scenarios are associated with high mortality and morbidity rates GXH WR D V\VWHPLF LQĂ€DPPDWRU\ UHVSRQVH DQG PXOWLSOH RUJDQ dysfunction occurring during the reperfusion phase. Reperfusion of an acutely ischemic aorta may, paradoxically, lead to V\VWHPLF FRPSOLFDWLRQV WKDW DFFRXQW IRU VLJQLÂżFDQW PRUELGLW\ and mortality[1,2]. Overproduction of reactive oxygen species 526 DQG SURLQĂ€DPPDWRU\ PROHFXOHV DQG WKH VXEVHTXHQW LQĂ€DPPDWRU\ UHVSRQVH LV RQH RI WKH PRVW FUXFLDO XQGHUO\LQJ mechanisms[2] that initiates injury, especially in the lungs and vital organs, such as kidney and heart, with a subsequent high morbidity[1-4]. Thymoquinone (TQ; 2-isopropyl-5-methyl-1, 4-benzoquinone), the active constituent of Nigella sativa seeds, is a pharmacologically active quinone that has been shown to have pharmacological actions, such as antibacterial[5], antihypertensive[6], antidiabetic[7], neuroprotective[8] DQWL LQĂ€DPPDWRU\[9] and antiapoptotic[10] as well as, in some studies, apoptotic[11,12]. It has been reported that TQ prevents oxidative injury in various in vitro and in vivo studies[13,14]. TQ possesses strong antioxidant properties through its ability to scavenge different free radicals[15,16]. It has also been reported that TQ attenuated several organ injuries (lung, renal, hepatic) in different ischemia-reperfusion (I/R) models (renal, hepatic). However, no studies have evaluated the protective effects of TQ in an aorta I/R model[17-20]. 7KH SXUSRVH RI WKLV VWXG\ ZDV WR GHWHUPLQH WKH HIÂżFDF\ of TQ in preventing injury in vital organs (lung, heart and kidney) in an acute abdominal aorta ischemia-reperfusion model in rats.

The experimental study was performed on a total of 30 three-month-old Wistar-albino rats weighing 200–250 g. All animals were maintained under standard conditions and treated in compliance with National Institutes of Health guidelines. They were housed on a 12-h dark/light cycle schedule with lights on at 06.00 h. Rats were deprived of food, though not water, for 12 hours before surgery. Experiments were done in the Harran University Experimental Research Center. The rats were randomly assigned to three experimental groups: sham operation, control (I/R; non-treated), and TQ-treated I/R. Rats were anesthetized using ketamine hydrochloride (0.2mL/100 g) in all experiments. The abdomen was explored through a midline incision after shaving and disinfection. In the sham group, only laparotomy was performed. In the control group, I/R injury was induced by clamping the aorta under renal vascular pedicles for 45 minutes, followed by 2 hours of reperfusion. In the TQ-treated I/R group, I/R injury was also induced by clamping the aorta under renal vascular pedicles for 45 minutes and TQ was given 5 minutes before reperfusion at a dose of 20 mg/kg via the intraperitoneal route, and again reperfusion was established for 2 hours. Heparin was not used due to possibility of affecting histopathological or biochemical UHVXOWV $W WKH HQG RI WKH SURFHGXUHV WKH UDWV ZHUH VDFUL¿FHG after blood sampling, and then kidney, lung, and heart tissues were obtained from all rats. TQ were purchased from Sigma–Aldrich (St. Louis, MO). 7KH SXULW\ *& RI 74 ZDV • DV SHU WKH PDQXIDFWXUHUœV VSHFL¿FDWLRQ DQG ZDV GLVVROYHG LQ GLPHWK\O VXOSKR[LGH Biochemical Analyses Measurement of Total Antioxidant Capacity TAC of supernatant fractions was determined using a novel automated measurement method developed by Erel[21].

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Aydin MS, et al. - Thymoquinone protects end organs from abdominal aorta ischemia/reperfusion injury in a rat model

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HRVLQ 0DJQLÂżFDWLRQ RI ĂŽ ZDV XVHG 2O\PSXV %; TF, USA). Samples were then graded histologically according to the severity of injury using a predetermined scoring system[24]. The predetermined scoring system, from Solez et al.[24], included tubular necrosis, interstitial edema, loss of brush border, and cast formation, in which the score was 0 for absent; 1 for mild to moderate; and 2 for marked renal involvement. The histological parameters for lung evaluation were alveolar congestion, intra-alveolar hemRUUKDJH DQG LQWHUVWLWLDO SHULYDVFXODU LQÂżOWUDWLRQ RI QHXWURphils, in which the assessment score was 0 for absent; 1 for mild focal; 2 for moderate focal; and 3 for severe marked OXQJ LQYROYHPHQW ,QWHUVWLWLDO HGHPD LQĂ€DPPDWRU\ FHOO LQÂżOWUDWLRQ DQG FRDJXODWLRQ QHFURVLV ZHUH DVVHVVHG IRU KHDUW examination, in which the score was 0 for absent; 1 for mild focal; 2 for moderate focal; and 3 for severe marked heart involvement. Histological analysis was performed by a blinded expert.

Hydroxyl radicals, the most potent biological radicals, are produced in this method. In the assay, the ferrous ion solution present in Reagent 1 is mixed with hydrogen peroxide, which is present in Reagent 2. The subsequently produced radicals, such as brown-colored dianisidinyl radical cations produced by the hydroxyl radicals, are also potent radicals. Using this method, the antioxidative effect of the sample was measured against the potent-free radical reactions initiated by the produced hydroxyl radicals. The assay has excellent precision, ZLWK YDOXHV ORZHU WKDQ 7KH UHVXOWV DUH H[SUHVVHG DV QPRlTrolox Equiv./mg protein. Measurement of Total Oxidant Status TOS of supernatant fractions was determined using a novel automated measurement method developed by Erel[22]. Oxidants present in the sample oxidize the ferrous ion–o-dianisidine complex to ferric ion. The oxidation reaction is enhanced by glycerol molecules, which are abundant in the reaction medium. The ferric ion produces a colored complex with xylenol orange in an acidic medium. The color intensity, which can be measured spectrophotometrically, is related to the total amount of oxidant molecules present in the sample. The assay was calibrated with hydrogen peroxide, and the results are expressed in terms of nmol H2O2 Equiv/mg protein.

Statistical Analysis Statistical analyses were performed using SPSS 11.5 (SPSS for Windows 11.5, Chicago, IL). Continuous data are expressed as meanÂąSD whereas categorical variables are presented as number (count) and percentage. Distribution of continuous variables was assessed with one-sample Kolmogorov-Smirnov test and indicated that all variables were abnormally distributed. Therefore, nonparametric independent group comparisons were made: for multiple comparisons, the Kruskal-Wallis test was used, and for comparisons between groups, the Mann-Whitney test was used if any statistical VLJQLÂżFDQFH ZDV IRXQG $ WZR VLGHG P value of <0.05 was FRQVLGHUHG VWDWLVWLFDOO\ VLJQLÂżFDQW

Oxidative Stress Index 7KH SHUFHQW UDWLR RI 726 OHYHO WR 7$& OHYHO ZDV GHÂżQHG as OSI. OSI values were calculated according to the following formula[23]: OSI (arbitrary unit) = TOS (nmol H2O2 Equiv/mg protein)/TAC (nmolTroloxEquiv/mg protein). Histopathological Evaluation The kidney, lung, and heart of each animal were obtained for histological evaluation. Samples of these organs were placed in formalin and embedded in wax according to standard protocols. They were subsequently sectioned DW Č?P VOLFH WKLFNQHVV DQG VWDLQHG ZLWK KHPDWR[\OLQ DQG

RESULTS All animals survived through the experimental protocol. 7$& DFWLYLW\ LQ EORRG VDPSOHV ZHUH VLJQLÂżFDQWO\ KLJKHU LQ the sham group than in the treatment and control groups

Table 1. Oxidative and antioxidative parameters and histopathological evaluation in Sham, Control and TQ + I/R rats.

TAC (nmolTroloxEqv./mg protein) TOS (nmol H2O2 Eqv./ mg protein) OSI (arbitrary units) Renal Pathology score Lung Pathology score Heart Pathology score

Sham (n=10) 1.39Âą0.18* 28.3Âą8.5 2.0Âą0.44 1.7Âą1.25 1.7Âą1.15 0.3Âą0.48

Control (n=10) 0.53Âą0.12 44.1Âą8.1+ 8.35Âą1.23+ 4.4Âą0.69+ 4.6Âą0.51+ 1.5Âą0.52+

TQ+I/R (n=10) 0.65Âą0.12 25.8Âą2.3 1.30Âą0.41 2.1Âą1.37 3.0Âą1.24 0.9Âą0.73

TAC=Total Antioxidant Capacity; TOS=Total Oxidant Status; OSI=Oxidative Stress Index 3 ZDV FRQVLGHUHG DV VWDWLVWLFDOO\ VLJQLÂżFDQW * P<0.001 (for all comparisons) compared with I/R and TQ+I/R + P<0.001 (for all comparisons) compared with sham and TQ+I/R

79 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

P P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 P<0.001

Aydin MS, et al. - Thymoquinone protects end organs from abdominal aorta ischemia/reperfusion injury in a rat model

Braz J Cardiovasc Surg 2015;30(1):77-83

(P<0.001; for all comparisons) but there were no statisticalO\ VLJQLÂżFDQW GLIIHUHQFHV EHWZHHQ WKH WUHDWPHQW JURXS DQG control group for TAC activity (P>0.05). TOS and OSI activity in blood samples were statistically higher in the control group than in the sham and thymoquinone group (P<0.001 for all comparisons). Histopathologic injury scores of renal, lung and heart tissues are summarized in Table 1. Control group injury scores were statistically increased compared to sham and thymoquinone groups (P<0.001 for all comparisons). The results are summarized in Figures1, 2, and 3.

Fig. 3 - OSI levels in sham, control, and thymoquinine groups. +P<0.001 (for all comparisons) compared with sham and thymoquinine groups

Upon histopathological evaluation, renal, lung and heart tissues were found to be normal with no pathological changes in the sham group (Figures 4A and 4D). Histopathological examination of the tissues in the control group revealed severe lesions, such as tubular damage characterized by cast formation, the loss of brush border and interstitial edema in the kidney. Histopathological examination of the tissues in WKH FRQWURO JURXS UHYHDOHG QHXWURSKLO DQG OHXNRF\WH LQÂżOWUDtion with alveolar congestion in the lung. Histopathological examination of the tissues in the control group revealed interstitial edema in the heart (Figures 4B and 4E). In rats receiving TQ intraperitoneally, these lesions were less severe than in the control group (Figures 4C and 4F).

Fig. 1 - TAC levels for sham, control, and thymoquinine groups. * P<0.001 (for all comparisons) compared with I/R and I/R+TQ

DISCUSSION In our experimental study, we hypothesized that abdominal aorta ischemia for 45 minutes followed by reperfusion for 2 hours would cause renal, lung, and heart pathology and we have found that (i) abdominal aorta ischemia for 45 minutes followed E\ UHSHUIXVLRQ IRU KRXUV FDXVHG VLJQL¿FDQW SDWKRORJ\ LQ OXQJ renal, and heart tissues (ii) TOS and OSI levels were increased in the control group and (iii) TOS, OSI, and histopathological injury scores were decreased in sham and TQ+IR groups. It has been recognized that multiple organ dysfunction syndrome is a major cause of morbidity and mortality after abdominal aortic surgery and contributes to approximateO\ RI DOO GHDWKV LQ HOHFWLYH DEGRPLQDO DRUWD UHSDLU ,W is postulated that aortic cross-clamping during open repair may cause ischemia–reperfusion (I/R) injury of the intestine and subsequently result in the translocation of bacteria and

Fig. 2 - TOS levels in sham, control, and thymoquinine groups. + P<0.001 (for all comparisons) compared with sham and thymoquinine groups

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Aydin MS, et al. - Thymoquinone protects end organs from abdominal aorta ischemia/reperfusion injury in a rat model

Braz J Cardiovasc Surg 2015;30(1):77-83

Fig. 4 - A and D show renal and lung tissues samples of the sham group and there were no pathological changes. B) VKRZV OXQJ WLVVXHV VDPSOHV RI FRQWURO JURXS DQG QHXWURSKLO DQG OHXNRF\WH LQÂżOWUDWLRQ ZLWK DOYHRODU FRQJHVWLRQ ZHUH observed. E) shows renal tissues samples of control group and tubular damage characterized by cast formation; the loss of brush border and interstitial edema were observed. C and F show lung and renal tissues samples of thymoquinine treated group and there were less severe lesions than in the control group.

endotoxin across the intestinal mucosal barrier, leading to the V\VWHPLF UHOHDVH RI UHDFWLYH R[\JHQ VSHFLHV 526 DQG LQĂ€DPmatory cytokines, which not only damage the gut itself but also harm distant organs, including heart, kidney, and lung[25]. Nigella sativa (NS), also known as black seed or black cumin, has long been used in folk medicine. NS contains PRUH WKDQ RI D Âż[HG RLO DQG Z Z RI D YRODWLOH RLO 7KH YRODWLOH RLO KDV EHHQ VKRZQ WR FRQWDLQ WK\PRTXLQRQH 74 DQG PRQRWHUSHQHV[7]. NS has been UHSRUWHG WR H[KLELW DQWL LQĂ€DPPDWRU\ LPPXQRPRGXODWRU\ and anti-neoplastic effects in many experimental and clinical studies[26-28]. TQ, the active constituent of Nigella sativa seeds similar to NS, also showed favorable effects with respect to R[LGDWLYH VWUHVV DQG LQĂ€DPPDWLRQ 7KXV 74 KDV DWWUDFWHG the attention of scientists to investigate its molecular mechanisms and potential use in the treatment of different diseasHV ,W KDV EHHQ VKRZQ WR KDYH DQWLR[LGDQW DQWL LQĂ€DPPDWRU\ effects in several diseases, including experimental allergic encephalomyelitis, colitis, arthritis encephalomyelitis, diabetes, asthma, and carcinogenesis[10]. TQ attenuated lipid peroxidation and increased antioxidant enzyme activities. It has been reported to have strong antioxidant potential through its ability to scavenge different free radicals, its scavenging power being as effective as SOD against superoxide anions[16-18]. It acts as a scavenger of superoxide, hydroxyl radicals and singlet molecular oxygen[29]. Furthermore, recent studies have demonstrated that TQ supplementation increases

the expression of antioxidant genes, SOD, catalase and glutathione peroxidase in rat liver. Thus, TQ may reduce oxidative stress through a direct antioxidant effect as well as through the induction of endogenous antioxidant enzymes[30]. TQ also inhibited inducible nitric oxide synthase mRNA expression in rat lipopolysaccharide-stimulated peritoneal macrophage cells[31,32], which has been attributed to its ability to reduce R[LGDWLYH VWUHVV LQGXFHG LQĂ€DPPDWLRQ OHDGLQJ WR WKH SUHYHQWLRQ of inducible NOS (nitric oxide synthase) upregulation. Several studies reported protective effects in the lung in different situations with different mechanisms. Suddek et al. showed that TQ produces a protective mechanism against cysplatin-induced pulmonary damage with anti-oxidant and DQWL LQĂ€DPPDWRU\ SURSHUWLHV DQG LQ DGGLWLRQ 74 KDV EHHQ IRXQG WR KDYH SRWHQWLDO DQWLÂżEURWLF HIIHFWV EHVLGHV LWV DQWLR[LGDQW DFWLYLW\ ZKLFK FRXOG EH WKURXJK 1) Č›% LQKLELWLRQ LQ bleomycin-induced oxidative stress of rat lungs[20,33]. Renal protective effects of TQ have also been discussed in several studies, including vancomycin induced nephrotoxicity, inorganic mercury intoxication, and gentamicin-induced acute renal toxicity. These studies highlight the importance of reactive oxygen species in renal pathophysiology and the intriguing possibility of TQ play a role in the prevention of and/ or protection from renal injury in humans[17,34-36]. Myocardial protective effects of TQ have also been demonstrated in injury induced by isoproterenol, cyclophosphamide-induced cardiotoxicity, and doxorubicin-induced cardiotoxicity[37-39]. TQ

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Aydin MS, et al. - Thymoquinone protects end organs from abdominal aorta ischemia/reperfusion injury in a rat model

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has also been widely studied in different ischemia reperfusion models and reported to have favorable effects with different potential mechanisms, including primarily antioxidant mechanisms[18,40]. In this study we also found protective effects of TQ in the lung, kidney, and heart with histopathologLF HYDOXDWLRQ 6LJQLÂżFDQW R[LGDWLYH VWUHVV LQ WKH FRQWURO JURXS compared to sham and TQ groups also emphasizes that the anti-oxidant properties of TQ might be the probable protective mechanism in the acute abdominal aorta ischemia-reperfusion model in the rat. :H EHOLHYH WKDW WKHUH DUH VXIÂżFLHQW SUHFOLQLFDO UHVHDUFK results with a considerable amount of information about TQ UHJDUGLQJ LWV PROHFXODU DQWLR[LGDQW DQWL LQĂ€DPPDWLRQ DQWLcancer activity, drug toxicity, bioavailability and pharmacokinetics, and novel drug delivery approaches, to encourage the use of TQ in clinical settings[41]. However, the clinical implications and appropriate pathophysiological mechanisms RI WKH ÂżQGLQJV RI WKH SUHVHQW VWXG\ UHPDLQ WR EH HOXFLGDWHG with further large-scale clinical studies. Several limitations of this study should be considered. One of the potential limitations is the absence of oral administration of TQ versus an intraperitoneal route. Another limitation is the absence of biochemical analysis of different biochemical markers, including urea, creatinine, creatinine phosphokinase and creatinine kinase MB for the heart. Further studies focusing on IR injury of other end organs, such as intestine, brain and medulla spinalis injury are needed.

REFERENCES <DVVLQ 00 +DUNLQ ': %DUURV 'Âś6D $$ +DOOLGD\ 0, 5RZODQGV BJ. Lower limb ischemia-reperfusion injury triggers a systemic LQĂ€DPPDWRU\ UHVSRQVH DQG PXOWLSOH RUJDQ G\VIXQFWLRQ :RUOG - Surg. 2002;26(1):115-21. 2. Carvalho AC, Guillaumon AT, Cintra EdeA, Figueiredo LC, Moreira MM, AraĂşjo S. Plasmatic vasopressin in patients undergoing conventional infra-renal abdominal aorta aneurysm repair. Rev Bras Cir Cardiovasc 2011;26(3):404-12 +DUNĂ•Q ': %DUURV 'ÂśVD $$ 0FFDOOLRQ . +RSHU 0 +DOOĂ•GD\ MI, Campbell FC. Circulating neutrophil priming and systemic LQĂ€DPPDWLRQ LQ OLPE LVFKDHPLD UHSHUIXVLRQ LQMXU\ ,QW$QJLRO 2001;20(1):78-89. *URHQHYHOG $% 5DĂ•MPDNHUV 3* 5DXZHUGD -$ +DFN &( 7KH LQĂ€DPPDWRU\ UHVSRQVH WR YDVFXODU VXUJHU\ DVVRFLDWHG LVFKDHPLD DQG reperfusion in man: effect on postoperative pulmonary function. Eur J Vasc Endovasc Surg 1997;14(5):351-9. 5. Hanafy MS, Hatem ME. Studies on the antimicrobial activity of Nigella sativa seed (black cumin). J Ethnopharmacol. 1991;34(23):275-8. 6. el-Tahir K, Ashour M, al-Harbi M. The cardiovascular actions of the volatile oil of the black seed (Nigella sativa) in rats: elucidation of the mechanism of action. Gen Pharmacol 1993;24(5):1123-31. 7. Kanter M. Effects of Nigella sativa and its major constituent, thymoquinone on sciatic nerves in experimental diabetic neuropathy. Neurochem Res. 2008;33(1):87-96.

CONCLUSION

8. Al-Majed AA, Al-Omar FA, Nagi MN. Neuroprotective effects of thymoquinone against transient forebrain ischemia in the rat hippocampus. Eur J Pharmacol. 2006;543(1-3):40-7.

In conclusion, TQ administered intraperitoneally was effective in reducing oxidative stress and histopathologic injury in an acute abdominal aorta I/R rat model. Oxidative stress indices and WLVVXH LQMXULHV PLJKW EH PRGLÂżHG ZLWK 74 WUHDWPHQW LQ GLIIHUHQW clinical settings. However, further large scale studies are needed WR GHÂżQH WKH SRVVLEOH IDYRUDEOH HIIHFWV RI 74 LQ FOLQLFDO VHWWLQJV

0XWDEDJDQL $ (O 0DKG\ 6$ 6WXG\ RI WKH DQWL LQĂ€DPPDWRU\ DFtivity of Nigella sativa L. and thymoquinone in rats. Saudi Pharm J. 1997;5(2-3):110-3. 10. Woo CC, Kumar AP, Sethi G, Tan KH. Thymoquinone: potential FXUH IRU LQĂ€DPPDWRU\ GLVRUGHUV DQG FDQFHU %LRFKHP 3KDUPDFRO 2012;83(4):443-51.

Authors’ roles & responsibilities 06$

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$QDO\VLV DQG RU LQWHUSUHWDWLRQ RI GDWD VWDWLVWLFDO DQDO\VLV Âżnal approval of the manuscript conception and study design, conduct of procedures, and/or experiments, writing of the manuscript or review of its content $QDO\VLV DQG RU LQWHUSUHWDWLRQ RI GDWD ÂżQDO DSSURYDO RI manuscript Statistical analysis, conception and study design, conduct of procedures, and/or experiments Conduct of procedures and/or experiments, writing of the manuscript or review of its content 6WDWLVWLFDO DQDO\VLV ÂżQDO DSSURYDO RI PDQXVFULSW 6WDWLVWLFDO DQDO\VLV ÂżQDO DSSURYDO RI WKH PDQXVFULSW FRQFHSWLRQ and study design, conduct of procedures, and/or experiments 6WDWLVWLFDO DQDO\VLV ÂżQDO DSSURYDO RI WKH PDQXVFULSW GUDIWLQJ the manuscript or revising it critically for its content Drafting of the manuscript or review of its content

11. Wirries A, Breyer S, Quint K, Schobert R, Ocker M. Thymoquinone hydrazone derivatives cause cell cycle arrest in p53-competent colorectal cancer cells. Exp Ther Med. 2010;1(2):369-75. 12. Roepke M, Diestel A, Bajbouj K, Walluscheck D, Schonfeld P, Roessner A, et al. Lack of p53 augments thymoquinone-induced apoptosis and caspase activation in human osteosarcoma cells. Cancer Biol Ther. 2007;6(2):160-9. 13. Suguna P, Geetha A, Aruna R, Siva GV. Effect of thymoquinone on ethanol and high fat diet induced chronic pancreatitis--a dose response study in rats. Indian J Exp Biol. 2013;51(4):292-302. 14. Rifaioglu MM, Nacar A, Yuksel R, Yonden Z, Karcioglu M, Zorba 28 HW DO $QWLR[LGDWLYH DQG DQWL LQĂ€DPPDWRU\ HIIHFW RI WK\PR-

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Braz J Cardiovasc Surg 2015;30(1):77-83

quinone in an acute pseudomonas prostatitis rat model. Urol Int. 2013;91(4):474-81.

28. Yildiz F, Coban S, Terzi A, Savas M, Bitiren M, Celik H, et al. Protective effects of Nigella sativa against ischemia-reperfusion injury of kidneys. Ren Fail. 2010;32(1):126-31.

15. Selçuk CT, Durgun M, Tekin R, Yolbas L, Bozkurt M, Akçay C, et al. Evaluation of the effect of thymoquinone treatment on wound healing in a rat burn model. J Burn Care Res. 2013;34(5):e274-81.

29. Mansour MA, Nagi MN, El-Khatib AS, Al-Bekairi AM. Effects of thymoquinone on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase in different tissues of mice: a possible mechanism of action. Cell Biochem Funct. 2002;20(2):143-51.

16. Badary OA, Taha RA, Gamal el-Din AM, Abdel-Wahab MH. Thymoquinone is a potent superoxide anion scavenger. Drug Chem Toxicol. 2003;26(2):87-98.

30. Ismail M, Al-Naqeep G, Chan KW. Nigella sativa thymoquinone-rich fraction greatly improves plasma antioxidant capacity and expression of antioxidant genes in hypercholesterolemic rats. Free Radic Biol Med. 2010;48(5):664-72.

17. Fouda AM, Daba MH, Dahab GM, Sharaf El-Din OA. Thymoquinone ameliorates renal oxidative damage and proliferative response induced by mercuric chloride in rats. Basic Clin Pharmacol Toxicol. 2008;103(2):109-18.

31. Nagi MN, Almakki HA, Sayed-Ahmed MM, Al-Bekairi AM. Thymoquinone supplementation reverses acetaminophen-induced oxidative stress, nitric oxide production and energy decline in mice liver. Food Chem Toxicol. 2010;48(8-9):2361-5.

18. Awad AS, Kamel R, Sherief MA. Effect of thymoquinone on hepatorenal dysfunction and alteration of CYP3A1 and spermidine/spermine N-1-acetyl-transferase gene expression induced by renal ischaemia reperfusion in rats. J Pharm Pharmacol. 2011;63(8):1037-42.

32. El-Mahmoudy A, Matsuyama H, Borgan MA, Shimizu Y, El-Sayed MG, Minamoto N, et al. Thymoquinone suppresses expression of inducible nitric oxide synthase in rat macrophages. Int Immunopharmacol. 2002;2(11):1603-11.

19. Abd El-Ghany RM, Sharaf NM, Kassem LA, Mahran LG, Heikal OA. Thymoquinone triggers anti-apoptotic signaling targeting death ligand and apoptotic regulators in a model of hepatic ischemia reperfusion injury. Drug Discov Ther. 2009;3(6):296-306.

33. El-Khouly D, El-Bakly WM, Awad AS, El-Mesallamy HO, El-DePHUGDVK ( 7K\PRTXLQRQH EORFNV OXQJ LQMXU\ DQG ÂżEURVLV E\ attenuating bleomycin-induced oxidative stress and activation of nuclear factor Kappa-B in rats. Toxicology. 2012;302(2-3):106-13.

20. Suddek GM, Ashry NA, Gameil NM. Thymoquinone attenuates F\FORSKRVSKDPLGH LQGXFHG SXOPRQDU\ LQMXU\ LQ UDWV ,QĂ€DPPRpharmacology. 2013;21(6):427-35.

34. Basarslan F, Yilmaz N, Ates S, Ozgur T, Tutanc M, Motor VK, et al. Protective effects of thymoquinone on vancomycin-induced nephrotoxicity in rats. Hum Exp Toxicol. 2012;31(7):726-33.

21. Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem. 2004;37(2):112-9.

35. Ragheb A, Attia A, Eldin WS, Elbarbry F, Gazarin S, Shoker A. The SURWHFWLYH HIIHFW RI WK\PRTXLQRQH DQ DQWL R[LGDQW DQG DQWL LQĂ€DPmatory agent, against renal injury: a review. Saudi J Kidney Dis Transpl. 2009;20(5):741-52.

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38. Nagi MN, Al-Shabanah OA, Hafez MM, Sayed-Ahmed MM. Thymoquinone supplementation attenuates cyclophosphamide-induced cardiotoxicity in rats. J Biochem Mol Toxicol. 2011;25(3):135-42.

/L & /L <6 ;X 0 :HQ 6+ <DR ; :X < HW DO /LPE UHPRWH ischemic preconditioning for intestinal and pulmonary protection during elective open infrarenal abdominal aortic aneurysm repair: a randomized controlled trial. Anesthesiology. 2013;118(4):842-52.

39. Randhawa MA, Alghamdi MS, Maulik SK. The effect of thymoquinone, an active component of Nigella sativa, on isoproterenol induced myocardial injury. Pak J Pharm Sci. 2013;26(6):1215-9.

26. Ammar el-SM, Gameil NM, Shawky NM, Nader MA. Comparative HYDOXDWLRQ RI DQWL LQĂ€DPPDWRU\ SURSHUWLHV RI WK\PRTXLQRQH DQG curcumin using an asthmatic murine model. Int Immunopharmacol. 2011;11(12):2232-6.

40. GÜkçe A, Oktar S, Koc A, Gonenci R, Yalcinkaya F, Yonden Z, Duru M. Protective effect of thymoquinone in experimental testicular torsion. Urol Int. 2010;85(4):461-5.

27. Keyhanmanesh R, Boskabady MH, Khamneh S, Doostar Y. Effect of thymoquinone on the lung pathology and cytokine levels of ovalbumin-sensitized guinea pigs. Pharmacol Rep. 2010;62(5):910-6.

41. Abukhader MM. Thymoquinone in the clinical treatment of cancer: )DFW RU ÂżFWLRQ" 3KDUPDFRJQ 5HY

83 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Evora PRB, et REVIEW al. - TwentyARTICLE years of vasoplegic syndrome treatment in heart surgery. Methylene blue revised

Braz J Cardiovasc Surg 2015;30(1):84-92

Twenty years of vasoplegic syndrome treatment in heart surgery. Methylene blue revised Vinte anos de tratamento da sĂ­ndrome vasoplĂŠgica em cirurgia cardĂ­aca. Azul de metileno revisado

Paulo Roberto Barbosa Evora1, MD, PhD; Lafaiete Alves Junior1, MD; Cesar Augusto Ferreira1, MD, PhD; AntĂ´nio Carlos Menardi1, MD, PhD; Solange Bassetto1, MD; Alfredo JosĂŠ Rodrigues1, MD, PhD; Adilson Scorzoni Filho1, MD; Walter Vilella de Andrade Vicente1, MD, PhD

DOI 10.5935/1678-9741.20140115

RBCCV 44205-1618 DQG 7KH QHHG IRU WKH HVWDEOLVKPHQW RI WKH 0% WKHUDSHXWLF window in humans. Conclusion: MB action to treat vasoplegic syndrome is time-dependent. Therefore, the great challenge is the need, for the establishment the MB therapeutic window in humans. This ZRXOG EH WKH ÂżUVW VWHS WRZDUGV D V\VWHPDWLF JXLGHOLQH WR EH IROlowed by possible multicenter studies.

Abstract Objective: This study was conducted to reassess the concepts established over the past 20 years, in particular in the last 5 years, about the use of methylene blue in the treatment of vasoplegic syndrome in cardiac surgery. Methods: A wide literature review was carried out using the data extracted from: MEDLINE, SCOPUS and ISI WEB OF SCIENCE. Results: 7KH UHDVVHVVHG DQG UHDIÂżUPHG FRQFHSWV ZHUH 0% LV VDIH LQ WKH UHFRPPHQGHG GRVHV WKH OHWKDO GRVH LV PJ NJ 0% GRHV QRW FDXVH HQGRWKHOLDO G\VIXQFWLRQ 7KH 0% HIIHFW DSSHDUV LQ FDVHV RI 12 XS UHJXODWLRQ 0% LV QRW D YDVRFRQstrictor, by blocking the cGMP pathway it releases the cAMP SDWKZD\ IDFLOLWDWLQJ WKH QRUHSLQHSKULQH YDVRFRQVWULFWRU HIIHFW 7KH PRVW XVHG GRVDJH LV PJ NJ DV ,9 EROXV IROORZHG E\ the same continuous infusion because plasma concentrations VKDUSO\ GHFUHDVH LQ WKH ÂżUVW PLQXWHV DQG 7KHUH LV D SRVVLble “window of opportunityâ€? for MB’s effectiveness. In the last ÂżYH \HDUV PDMRU FKDOOHQJHV ZHUH 2EVHUYDWLRQV DERXW VLGH HIIHFWV 7KH QHHG IRU SURSK\ODFWLF DQG WKHUDSHXWLF JXLGHOLQHV

Descriptors: 0HWK\OHQH EOXH 9DVRSOHJLF V\QGURPH 9DVRSOHJLD Circulatory shock. Cardiac surgery. Nitric oxide.

Resumo Objetivo: 2 SUHVHQWH HVWXGR IRL UHDOL]DGR FRP D ¿QDOLGDGH de reavaliar conceitos estabelecidos em 20 anos, com ênfase nos últimos 5 anos, sobre a utilização do azul de metileno no tratamento da síndrome vasoplÊgica em cirurgia cardíaca. MÊtodos: Foram considerados dados da literatura utilizando-se três bases de dados (MEDLINE, SCOPUS e ISI Web of 6FLHQFH

1

Correspondence address: Paulo Roberto Barbosa Evora Rua Rui Barbosa, 367, apt. 15 - Centro, RibeirĂŁo Preto, SP, Brazil. Zip code: 14015-120 E-mail: prbevora@fmrp.usp.br

Department of Surgery and Anatomy, Faculdade de Medicina de RibeirĂŁo Preto da Universidade de SĂŁo Paulo (FMRP-USP), RibeirĂŁo Preto, SP, Brazil . This study was carried at Faculdade de Medicina de RibeirĂŁo Preto da Universidade de SĂŁo Paulo (FMRP-USP), RibeirĂŁo Preto, SĂŁo Paulo, Brazil. Financial support: CNPq, FAEPA, FAPESP

Article received on April 24th, 2014 Article accepted on October 12th, 2014

1R FRQĂ€LFW RI LQWHUHVW

84 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Evora PRB, et al. - Twenty years of vasoplegic syndrome treatment in heart surgery. Methylene blue revised

Braz J Cardiovasc Surg 2015;30(1):84-92

HIHLWR GR $0 Vy DSDUHFH HP FDVR GH VXSUD QLYHODPHQWR GR 12 2 $0 QmR p XP YDVRFRQVWULWRU SHOR EORTXHLR GD YLD *03F ele libera a via do AMPc, facilitando o efeito vasoconstritor da QRUHSLQHIULQD $ GRVDJHP PDLV XWLOL]DGD p GH PJ NJ FRPR EROXV (9 VHJXLGD GH LQIXVmR FRQWtQXD SRUTXH DV FRQFHQWUDo}HV SODVPiWLFDV GHFDHP IRUWHPHQWH QRV SULPHLURV PLQXWRV H ([LVWH XPD ³MDQHOD GH RSRUWXQLGDGH´ SUHFRFH SDUD HIHWLYLGDGH GR $0 1RV ~OWLPRV FLQFR DQRV RV SULQFLSDLV GHVD¿RV IRUDP 2EVHUYDo}HV GH HIHLWRV FRODWHUDLV $ QHFHVVLGDGH GH GLUHWUL]HV H $ QHFHVVLGDGH GD GHWHUPLQDomR GH XPD MDQHOD WHUDSrXWLFD para o uso do AM em humanos. Conclusão: 2 HIHLWR GR $0 QR WUDWDPHQWR GD 69 p GHSHQGHQWH GR WHPSR SRUWDQWR R JUDQGH GHVD¿R DWXDO p D QHFHVVLGDGH GR HVWDEHOHFLPHQWR GD MDQHOD WHUDSrXWLFD GR $0 HP KXPDQRV Esse seria o primeiro passo para a sistematização de uma diretriz a ser seguida por possíveis estudos multicêntricos.

Abbreviations, acronyms & symbols ARDS cAMP BBB CPB GC IE iNOS LVAD MB NO RVEDP sGC VHS VS

Acute respiratory distress syndrome Cyclic adenosine monophosphate Blood-brain barrier Cardiopulmonary bypass Guanylate cyclase Infective endocarditis Inducible nitric oxide synthase Left ventricular assist device Methylene blue Nitric oxide Right ventricle end diastolic pressure Soluble guanylate cyclase Valvular heart surgery Vasoplegic syndrome

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reported the incidence of 8.8% of VS in 638 patients. Among the 56 vasoplegic patients randomly receiving MB or placebo, there was no mortality in the group treated with MB, and it was possible to discontinue vasoconstrictors in a short period time, with less consequential morbidity and mortality. In contrast, in the placebo group two deaths occurred and the use of amines lasted in average 48 hours, with a higher incidence of respiratory and renal problems. 3) From the prevention point of view, Ozal et al.[13], in Turkey, showed in a prospective and randomized study that MB was associated to with lower incidence of vasoplegia and amines use. In 2009, targeting MB for VS treatment in heart surgery, ZH SXEOLVKHG D SHUVRQDO VWDWHPHQW LQFOXGLQJ ÂżIWHHQ \HDUV RI questions, answers, doubts and certainties. Some observations can be applied to VS: 1) MB is safe in the recommended doses (the lethal dose is 40 mg/kg). 2) The use of MB does not cause endothelial dysfunction. 3) The MB effect appears in cases of NO up-regulation. 4) MB is not a vasoconstrictor, by blocking the cGMP pathway it releases the cAMP pathway, facilitating the epinephrine vasoconstrictor effect. 5) It is possible that MB acts through this “crosstalkâ€? mechanism DQG LWV XVH DV D GUXJ RI ÂżUVW FKRLFH PD\ QRW EH ULJKW 7KH most used dosage is 2 mg/kg as IV bolus followed by the same continuous infusion because the plasma concentrations VKDUSO\ GHFUHDVH LQ WKH ÂżUVW PLQXWHV $OWKRXJK WKHUH DUH QR GHÂżQLWLYH PXOWLFHQWULF VWXGLHV WKH 0% XVHG WR WUHDW KHDUW surgery VS, at the present time, is the best, safest and cheapest option. 8) But there is a possible 'window of opportunity’ for the MB’s effectiveness[14]. The above observations, dranw from 15 years, of use of MB, were presented in the introduction of this text as a

INTRODUCTION The vasoplegic syndrome (VS) concepts are a valuable Brazilian contribution to cardiac surgery. Gomes[1-3] described the syndrome and the MB treatment was proposed by Evora et al.[4-8]. VS is a constellation of signs and symptoms: hypotension, high cardiac index, low systemic YDVFXODU UHVLVWDQFH ORZ ÂżOOLQJ SUHVVXUHV GLIIXVH EOHHGLQJ tendency, and sustained hypotension despite the use of high doses of vasoconstrictor amines. There is experimental and clinical evidence to show that the pathophysiology of VS is associated with endothelial dysfunction caused by systemLF LQĂ€DPPDWLRQ 7KH PRVW LPSRUWDQW PHGLDWRU LV QLWULF R[ide (NO) produced from L-arginine by polymorphonuclear blood cells. NO release is dependent on the expression of inducible nitric oxide synthase (iNOS). It has been demonstrated along the years, that the blockade of NO synthesis is associated with prohibitive morbidity and mortality by microcirculation impairment. This has led to the proposition of using MB, a blocking of soluble guanylate cyclase (sGC), an enzyme whose expression is related to the forPDWLRQ RI F*03 ZKLFK LV WKH ÂżQDO PHVVHQJHU RI WKH 12 pathway responsible for vasoplegia. Although MB has been used for over 20 years in the treatment of VS, there are few quality clinical studies that would allow the treatment to become a protocol. Three studies involving a higher number of patients deserve to be cited: 1) In 2003, Leyh et al.[9] reported, in Germany, 54 cases of cardiac surgery patients not carrying bacterial endocarditis who had been treated with MB, with over 90% of the patients responding to the treatment. 2) Levin et al.[10-12], in Argentina,

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UHDI¿UPDWLRQ RI FRQFHSWV +RZHYHU WKH XOWLPDWH DLPV ZLOO EH FHQWHUHG LQ WKH VXEVHTXHQW ¿YH \HDUV The relevant literature review (1994-2008) will be updated, emphasizing that the great majority of the articles are letters and case reports as well as and some excellent reviews. Most of the present discussion is based on our letters motiYDWHG DJDLQVW WKH FRQFHSW WKDW 0% LV D UHVFXH DQG QRW D ¿UVW line therapy. This study was carried out to critically examine the use of MB in treating cardiac surgery VS, based on literature data and 20 years of clinical and experimental experience, highlighting what has been going in the last 5 years. It was presented on the 22nd Annual Meeting of the Asian Society for Cardiovascular and Thoracic Surgery (Istanbul – April 2014). The text will discuss the following points that address why the use of MB to treat cardiac surgery VS remains questionable: 1) Observations about side effects; 2) Restrictions in using MB in cases of pulmonary hypertension and acute respiratory distress syndrome (ARDS); 3) The need for prophylactic and therapeutic guidelines, and; 4) The need for the establishment of the MB therapeutic window in humans.

were adopted: 1) “Methylene blue and heart surgeryâ€? or; 2) “Methylene blue and cardiac surgeryâ€?. This combination of MB with rather generic keywords was intentional in the sense obtaining a wider view of the subject. RESULTS 7KH SUHYLRXV ÂżIWHHQ \HDUV ELEOLRJUDSKLFDO VXUYH\ 2009) on the therapeutic use of MB, based on MEDLINE and SCOPUS database searches, revealed a total of 58 publications directly related to VS in cardiac surgery. Approximately 30 more SXEOLFDWLRQV ZHUH DGGHG RQ WKH ODVW ÂżYH \HDUV Concerning the number of publications, there are about 70 publications, showing an increasing trend in the number of publications and citations (Figure 1). Concerning the type of articles, there is prevalence of article reports (50-70%), reviews (21%), and letters (1118%) (Figure 2). The country of origin of the publications is shown on Figure 3. DISCUSSION

METHODS It is crucial to emphasize the increasing number of ciWDWLRQV 7KH SUHYDOHQFH RI DUWLFOHV NHSW WR WKH SURÂżOH FDVH reports, letters, and reviews). Regarding the country of origin of the publications, Brazil has been the sixth place in the last ÂżYH \HDUV GURSSLQJ IRXU SRVLWLRQV LQ WKH UDQN

A wide review of literature and the authors' documented observations over a period of 20 years was carried out using the data extracted from: MEDLINE, SCOPUS and ISI WEB OF SCIENCE. The following combinations of key words

Fig. 1 - Published items and citations per year.

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Fig. 2 - Types of articles.

Fig. 3 - Country of origin of publications.

0HWK\OHQH EOXH VLGH HIIHFWV ELQRPLDO HIÂżFLHQF\ VDIHW\

Methylene blue administration may also result in worsening of arterial oxygenation. The pathophysioloJ\ WKRXJKW WR EH UHVSRQVLEOH IRU WKLV ¿QGLQJ LV WKDW 0% leads to systemic vasoconstriction as well as pulmonary vasoconstriction. Impaired gas exchange in the lung and pulmonary hypertension are caused by this pulmonary vasoconstriction. The adverse pulmonary effects of MB may limit its use in patients with adult respiratory distress syndrome. In addition, high-doses of MB may also result in PHVHQWHULF EHG FRQVWULFWLRQ DQG FRPSURPLVH EORRG ÀRZ LQ mesenteric vessels[16]. More recently, MB has been shown to cause a serotonin

Conceptual aspects One problem still present when describing VS is the lack RI FRQVLVWHQF\ LQ LWV GH¿QLWLRQ 7KHUH LV QHLWKHU D FOHDU GH¿nition, nor a single biomarker, and even the determination of nitrite/nitrate (NOx) failed to characterize the syndrome[15]. $W SUHVHQW FOLQLFDO PDQDJHPHQW RI LQÀDPPDWRU\ YDsoplegia associated to sepsis or anaphylaxis is symptomDWLF 9ROXPH LV H[SDQGHG E\ DGPLQLVWUDWLRQ RI ÀXLGV DQG low blood pressure is managed by administering positive inotropes and vasoconstrictors. This therapeutic approach is mainly associated with cyclic AMP (cAMP) and, many times the circulatory shock is refractory to high amines concentrations.

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Methylene blue and endocarditis Infective endocarditis is a life-threatening condition that occasionally necessitates emergency valve replacement. PaWLHQWV ZLWK DQ RQJRLQJ V\VWHPLF LQĂ€DPPDWRU\ UHVSRQVH DV D result of infective endocarditis and those who require CPB for emergency valve replacement may demonstrate resistant hypotension related to vasoplegia. It has a spectrum of clinical SUHVHQWDWLRQ DQG LV DVVRFLDWHG ZLWK D V\VWHPLF LQĂ€DPPDWRU\ response and the release of nitric oxide. Hemodynamically, it is characterized by arterial vasodilation, high cardiac output despite myocardial depression, and a decreased sensitivity of the heart and peripheral vessels to sympathomimetic agents. Grayling et al.[20] GHVFULEHG WKH ÂżUVW FDVH RI PHWK\OHQH EOXH used in the CPB prime and in the context of refractory hypotension in a patient undergoing valve replacement surgery for infective endocarditis, suggesting that methylene blue should be added to the CPB prime (2 mg/kg), and as a continuous infusion (0.25-2 mg/kg Ă— h) to ameliorate the hypotension. In a prospective, randomized, controlled, open-label, pilot study to evaluate the effects of continuous infusion of methylene blue (MB), on hemodynamics and organ functions in human septic shock, Kirov et al.[21] concluded that, in human septic shock, continuously infused MB counteracts myocardial depression, maintains oxygen transport, and reduces concurrent adrenergic support. Infusion of MB appears WR KDYH QR VLJQLÂżFDQW DGYHUVH HIIHFWV RQ WKH VHOHFWHG RUJDQ function variables. Ozal et al.[13] prospectively studied whether preoperative MB administration would prevent vasoplegic syndrome in these high-risk patients. Angiotensin-converting enzyme inhibitors, calcium channel blockers, and preoperative intravenous heparin use are independent risk factors for cardiac surgery VS. They did not include septic endocarditis as a risk factor. The results suggested that preoperative MB administration reduces the incidence and severity of vasoplegic syndrome in high-risk patients, thus ensuring adequate systemic vascular resistance in both operative and postoperative periods and shortening both intensive care unit and hospital VWD\V 7KLV UHSRUW PD\ EH WKH ÂżUVW VXJJHVWLRQ RI WKH SURSK\lactic use of MB prior to CPB. The accentuated NO release that is induced by the sysWHPLF LQĂ€DPPDWRU\ UHVSRQVH DVVRFLDWHG ZLWK LQIHFWLYH HQGRcarditis (IE) and cardiopulmonary bypass (CPB) may result in catecholamine refractory hypotension (vasoplegia) and increased transfusion requirement due to platelet inhibition. Cho et al.[22] aimed to evaluate the effect of prophylactic MB administration before CPB on vasopressor and transfusion requirements in patients with IE undergoing valvular heart surgery (VHS). Forty-two adult patients were randomly assigned to receive 2 mg/kg of MB (MB group, n=21) or saline (control group, n=21) for 20 min before the initiation of CPB. According Cho et al.[22], "the primary end points were comparisons of vasopressor requirements serially assessed after

syndrome reaction in patients who are concomitantly taking serotonergic agents such as serotonin reuptake inhibitors. This is attributable to an inhibitory action of MB on monoamine oxidase. MB’s monoamine oxidase-inhibiting property and its ability to display anxiolytic and antidepressant activity are likely the reason it was used to treat neuropsychiatric illnesses as early as 1989. The syndrome only occurs in a small percentage of patients and it is treatable with benzodiazepines and supportive care. Its incidence is less impeditive than the risk of untreated vasoplegia and potential end-organ injury and graft loss[17]. Weiner et al.[18] hypothesized that patients with vasoplegia who were treated with MB were more likely to show increased postoperative morbidity and mortality. A multiple logistic regression model demonstrated that receiving MB was an independent predictor of in-hospital mortality. A propensity score matching the association with morbidity was also seen, but the relationship with mortality was not IRXQG 7KH VWXG\ LGHQWL¿HG WKH XVH RI 0% WUHDWPHQW ZDV independently associated with poor outcomes. The authors concluded that, while further studies are required, a thorRXJK ULVN EHQH¿W DQDO\VLV VKRXOG EH DSSOLHG EHIRUH XVLQJ MB and, perhaps, it should be relegated to rescue use and QRW DV ¿UVW OLQH WKHUDS\[18]. It is remarkable that the risks are taking into more conVLGHUDWLRQ WKDQ WKH OLIHVDYLQJ EHQH¿WV $V WR WKH VDIHW\ DQG HWKLFDO DVSHFWV RI 0%�V FOLQLFDO XVH LW FDQ EH DI¿UPHG WKDW in recommended doses it is a safe drug (the lethal dose is 40 mg/kg). The accumulation of clinical experience has testHG WKH ELQRPLDO HI¿FLHQF\ VDIHW\ 7KHVH UHVXOWV VKRZ WKDW LQWUDYHQRXV LQIXVLRQ RI 0% VHHPV WR EH VDIH 7KH ¿QGLQJV support clinical trials where MB was used to treat VS afWHU FRURQDU\ DUWHU\ E\SDVV JUDIWLQJ ZLWK &3% RQ LQÀDPPDtory response syndrome patients - SIRS and anaphylaxis. These results are not unexpected, especially when analyzed LQ KHDOWK\ DQLPDOV LQ ZKLFK KHPRG\QDPLFV SUHVHQW ¿QH but not total regulation under the control of NO. In these conditions, no action is expected when there is inhibition of guanylate cyclase by MB. Methylene blue injection in a non VS carrier individual does not have hemodynamic effects in normal conditions. The MB effect appears only in the case of NO supra-regulation, and thus, spasm occurrence in coronary arterial grafts is unlikely. The risk of vasospasm and thrombosis of these JUDIWV UHTXLUH FRQ¿UPDWLRQ in vivo. The perception of safety is fully grounded in data set in studies in healthy animals that received MB in vivo. Although ischemic events were not evidenced in the ECG monitoring, normal endothelium-dependent and endothelium-independent vascular reactivity was determined by in vitro studies. With a wide safety range, these data support the assumption that, unlike the NO (L-NAME) synthesis inhibition, the injection in vivo does not cause endothelial dysfunction[4,14,19].

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weaning from CPB and hemodynamic parameters serially recorded before and after CPB. The secondary endpoint was the comparison of transfusion requirements". The results of WKH VXG\ VKRZHG WKDW WKHUH ZHUH QR VLJQLÂżFDQW GLIIHUHQFHV LQ vasopressor requirements and hemodynamic parameters between the two groups. The mean number of units of packed HU\WKURF\WHV WUDQVIXVHG SHU SDWLHQW ZDV VLJQLÂżFDQWO\ OHVV LQ the MB group. The numbers of patients transfused with fresh frozen plasma and platelet concentrates were lesser in the MB group". The authors concluded that in IE patients undergoing VHS, prophylactic MB administration before CPB did not FRQIHU VLJQLÂżFDQW EHQHÂżWV LQ WHUPV RI YDVRSUHVVRU UHTXLUHments and hemodynamic parameters, but it was associated ZLWK D VLJQLÂżFDQW UHGXFWLRQ LQ WUDQVIXVLRQ UHTXLUHPHQW[22]. Taylor & Holtby[23] have presented a case of refractory hypotension in a child with native mitral valve endocarditis with cerebral complications in whom MB was less effective than previously described. Although these authors seemed disappointed with the effect of the MB on blood pressure, we believe that their case had an impressive evolution despite its severity. We disagree that obvious clinical improvement using MB was not evident in this case since most of the pharmacologic support to the circulation was necessary for a short time. In our opinion, the controversy about the use of MB to treat similar cases arises when one uses MB merely as a “last-minute vasopressorâ€?. MB sometimes seems to work for this purpose and sometimes it does not, perhaps due the fact that, unlike many vasopressors, MB does not act through a membrane receptor. We believe that the pivotal action of MB is not exclusively the guanylyl cyclase blockage, resulting in a cGMP release decrease. This blockage also enhances the “crosstalkâ€? between cyclic adenosine monophosphate (cAMP) and cGMP pathways, which facilitates the effect of the cAMP-dependent vasopressors. Many clinical reports in the medical literature, including sepsis treatment, substantiate that the guanylyl cyclase blockage seems to improve the effect of the vasopressors, shortening the length of pharmacologic cardiovascular support. Another quite advantageous effect of MB is its capacity to reduce vascular permeability. We operated on a drug-addicted young man with native DRUWLF YDOYH HQGRFDUGLWLV 7KH SDWLHQW UHFHLYHG D ELOHDĂ€HW valve prosthesis (St Jude Medical, Inc, St Paul, Minn). A high dose of norepinephrine was necessary to maintain a reasonable blood pressure during CPB. After weaning from CPB, he was hypotensive and had high cardiac output, low systemic vascular resistance, and pulmonary edema. The arterial oxygen saturation was below 80%, even though he was being ventilated with 100% oxygen and positive end-expiratory pressure. We started MB in a continuous infusion in a way quite similar to that used by Taylor & Holtby[23], followed by a bolus of 3 mg/kg (in 100 mL of 5% glucose in water) twice a day. Even though the mean arterial pressure did not increase, even with norepinephrine, the cardiac output gradually

decreased, and the systemic vascular resistance increased. In addition, the rapid resolution of lung edema, improving arterial oxygen saturation, was astonishing[19]. Methylene blue and heart transplant. Grubb et al.[17] reported a case of a 60-year-old male with history of nonischemic cardiomyopathy and end-stage heart failure who underwent placement of a left ventricular assist device (LVAD), replacement of a mechanical aortic valve with a porcine prosthesis complicated by multiple driveline infections. Heart transplantation was the last option. During the operation, the authors reported: “episodes of hypotension during the extensive lysis of adhesions for LVAD removal. Intermittent boluses of phenylephrine were administered to maintain a VXIÂżFLHQW PHDQ DUWHULDO SUHVVXUH 6XEVHTXHQWO\ D 0% PJ NJ bolus followed by continuous infusion of 0.5 mg/kg per hour was administered. In the postoperative, the patient presented signals of serotonergic syndrome assumed as a consequence of the association of MB with antidepressants"[17]. This report has two crucial points 1) the alert to the possibility of serotonergic syndrome triggered by the association of MB with antidepressants, and; 2) the routine use of MB to KDQGOH YDVRSOHJLD LQ WKH PLOLHX RI KHDUW WUDQVSODQW .RÂżGLV et al.[24] UHSRUWHG WKH ÂżUVW H[SHULHQFH RI YDVRSOHJLD WUHDWPHQW with MB after heart transplantation and pointed that this drug deserves attention because of its catecholamine-saving effect, thus preventing possible malperfusion. When searching 0('/,1( .RÂżGLVÂśV UHSRUW LV WKH RQO\ UHIHUHQFH RQ WKH XVH of MB to treat vasoplegia associated to heart transplant. To prevent morbidity and mortality associated with VS, Grubb et al.[18] implemented an intraoperative protocol that includes administration of MB for VS resistant to vasopressor drugsâ€?. It is clear that they trusted the MB treatment since they concluded for it use while weighing the risks of serotonin syndrome[25]. Methylene blue as rescue therapy Blacker & Whaler[26] reported a distributive shock case during an on pump coronary artery bypass grafting with no response to MB. A possible explanation, was given based on Fernandes academic thesis using a mouse sepsis model, that evidenced three eight-hour windows of guanylate cyclase (GC) activity[27] ,Q WKH ÂżUVW HLJKW KRXUV WKHUH ZDV LQFUHDVHG nitric oxide synthase (NOS) activity and GC upregulation. In the second eight hours, there was absence of GC expression and a downregulation of NOS. In the third eight hour window, there is an upregulation of GC and NOS. The authors emphasized two practical and educational fundamental aspects: 1) The disclosure in using the MB treatment considering the window opportunity, and; 2) The need for the establishment of this window in humans, perhaps choosing cGMP as biomarker since our attempt to use nitrite/nitrate, measured by chemiluminescence, was frustrating[15]. In conclusion, MB use as a last

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rescue therapeutic option is against the above mentioned concepts, and it is possible that MB does not act (second window), or acts too late (third window) when the circulatory shock is metabolically irreversible, presenting high lactate levels and intractable metabolic acidosis. It might be more sensible to consider MB not as a late rescue treatment, but as an adjuvant drug to be used precociously (window 1)[28,29].

model of experimental cardiac arrest. The main physiological effects during reperfusion include systemic circulation VWDELOL]DWLRQ ZLWKRXW VLJQL¿FDQWO\ LQFUHDVLQJ WRWDO SHULSKHUDO resistance and moderately increasing cerebral cortical blood ÀRZ D UHGXFWLRQ RI OLSLG SHUR[LGDWLRQ DQG LQÀDPPDWLRQ DQG less anoxic brain and heart tissue damage[34,35]. One intriguing investigation studied the effects of cardiac arrest and CPR on BBB permeability and consequent neurological injury. In addition, this investigation studied the MB effects on the maintenance of BBB integrity, and NO release in the cerebral cortex. In a piglet model of 12 minutes of cardiac arrest, the authors demonstrated a time-dependent increase of necrotic neurons, caused by ischemia and reperfusion. Moreover, the immunohistochemistry analysis indicated less blood brain barrier disruption in the animals receiving MB, evidenced by decreased albumin leakage, water content and potassium, and less neuronal injury[34,35]. Similarly, MB treatment reduced nitrite/nitrate ratio, iNOS expression, and nNOS expression. In summary, MB markedly reduced BBB disruption and subsequent neurologic injury. In addition to these cerebral morphologic effects, the exposure to MB was associated with a decrease of NO as measured by nitrate/nitrite content and partial inhibition of NOS activity[34,35]. Induced mild hypothermia and administration of MB proved to have neuroprotective effects in CPR. However, induction of hypothermia is time consuming. A study was conducted to determine if the MB administered during CPR can enhance the neuroprotective effect of hypothermia. A piglet model of cardiac arrest with variable duration of CPR showed that the neuroprotective effect of MB in combination with hypothermia was sigQL¿FDQWO\ JUHDWHU WKDQ WKH GHOD\HG K\SRWKHUPLD DORQH[36]. Effects of MB in cardiac arrest and CPR were investigated. A pig model of cardiac arrest, comparing 12 min without CPR and 8 min of CPR, was employed to assess the addition of MB to a hypertonic saline-dextran solution. Hemodynamic variables were slightly improved at 15 min, and MB, co-administered with a hypertonic-hyperoncotic solution, increased 4-hr survival, reducing neurologic injury[36]. MB could be used in association with hypertonic sodium chloride, but it precipitates. However, an alternative mixture of MB in hypertonic sodium lactate was developed and investigated, using the same piglet model, during and after CPR. This association could be used against reperfusion injury during experimental cardiac arrest, presenting similar effects as MB plus hypertonic saline-dextran[36]. There are no publications considering MB, VS and neuroprotection, but the above concepts would be relevant considering brain protection in cardiac surgery.

Methylene blue use in pulmonary hypertension and/ RU DFXWH UHVSLUDWRU\ GLVWUHVV V\QGURPH $5'6

The restriction to ARDS and pulmonary hypertension deserve some comments. Global NO blockade can contribute to an increase in pulmonary vascular resistance, which worsens the pulmonary hypertension that can be associated with sepsis. Trials that used high bolus doses of MB demonstrated an increase in pulmonary pressures, but this effect was absent in trials that used MB infusions. Some researchers have thus suggested that infusions at low doses should be always used for this reason. Simultaneous treatment with inhaled NO might also be considered for this side effect of NO inhibition. There is also evidence that MB attenuates the inhibition of mitochondrial function as well as decreases acute lung injury in sepsis. In addition, Evgenov et al.[30,31] demonstrated that MB reduces the increments in pulmonary capillary pressure, lung lymph ÀRZ SURWHLQ FOHDUDQFH DQG SXOPRQDU\ K\SHUWHQVLRQ DQG HGHma in endotoxemic sheep. Raikhelkar et al.[32] report a case of the use of MB in a patient with acute right ventricular failure and vasoplegic shock after surgical pulmonary embolectomy. The authors discussed, based on the medical literature, that studies have reported MB to increase pulmonary artery pressures and pulmonary vascular resistance. These elevations in pulmonary vascular indices were noted to be clinically and staWLVWLFDOO\ LQVLJQL¿FDQW 2QH PD\ DUJXH WKLV VPDOO LQFUHDVH PD\ exacerbate RV dysfunction in susceptible individuals. This aspect of administration of MB has not been systematically VWXGLHG 7KH DXWKRUV IHHO WKH EHQH¿WV RI DXJPHQWDWLRQ RI 0$3 and coronary perfusion may offset small increases in the right ventricle end diastolic pressure (RVEDP)[32]. Methylene blue neuroprotection and cardiac arrest Cerebral edema, increased blood-brain barrier (BBB) permeability and neurologic injury, are observed early in ischemia induced by cardiac arrest. Upregulation of NO synthase (NOS) is associated with increased production of NO that induces breakdown of the BBB. It has been suggested that pretreatment with pharmacological agents that reduce NO excess or oxidative stress might reduce disruption of BBB permeability caused by ischemia/reperfusion injury. MB, a nontoxic dye and also a scavenger, recently proved to be a potential aid in resuscitation from cardiac arrest by attenuating oxidative, inÀDPPDWRU\ P\RFDUGLDO DQG QHXURORJLF LQMXU\[33-35]. Experimental investigations have proven the cardioprotective and neuroprotective effects of MB in a porcine

CONCLUSION In summary, as already mentioned, there are 2 opposing concepts: (1) The use of MB as rescue therapy to treat vaso-

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plegic syndrome, and (2) the use of MB as an early adjuvant GUXJ ZLQGRZ 0HWK\OHQH EOXH XVH DV D ÂżQDO UHVFXH WKHUDpeutic option is against the above-mentioned concepts. There is the possibility that MB does not act (second window) or acts too late (third window) when circulatory shock is metabolically irreversible, presenting high lactate levels and uncontrollable metabolic acidosis. Regardless of the strong limitations, pointed out by Weiner et al.[18], it would be more sensible to consider MB, not as a late rescue treatment, but as an adjuvant drug to be used early (window 1), not just dismissing its action. Perhaps, an easier concept to understand WKDQ WKH Âł:LQGRZ RI 2SSRUWXQLW\´ GHÂżQLWLRQ LV WKDW 0%ÂśV action to treat vasoplegic syndrome is time-dependent. Many authors are reluctant to recommend early use MB given the unusually limited level of evidence at this time, and the potential adverse effects, encouraging trials that systematically collect data to help address these issues. As emergency situations involving risk of death, circulatory collapse does not permit prospective randomized studies. Although WKHUH DUH QR GHÂżQLWLYH PXOWLFHQWHU VWXGLHV WKH XVH RI 0% WR treat VS, at the present time, is the most rational, safest, and cheapest option. The data from this extended review leaves the impression that the number and quality of publications do not reĂ€HFW WKH IUHTXHQF\ DW ZKLFK 0% LV XVHG LQ FOLQLFDO SUDFWLFH 7KHUHIRUH LW WKH GLIÂżFXOW\ RI FRQGXFWLQJ PXOWLFHQWHU VWXGLHV is implied. The disclosure and possible consecration of this therapy will be passed on as verbal information and depending on the increase of publications, in studies based on evidence. In the literature data and medical practice set, there is still certainty that the soluble guanylate cyclase blockage in distributive shock control remains underestimated.

3. Gomes WJ, Carvalho AC, Palma JH, Teles CA, Branco JN, Silas MG, et al. Vasoplegic syndrome after open heart surgery. J Cardiovasc Surg (Torino). 1998;39(5):619-23. 4. Evora PR, Rodrigues AJ, Vicente WV, Vicente YA, Basseto S, Basile Filho A, Capellini VK. Is the cyclic GMP system underestimated by intensive care and emergency teams? Med Hypotheses. 2007;69(3):564-7. 5. Andrade JCS, Batista Filho ML, Evora PR, Tavares JR, Buffolo E, et al. Utilização do azul de metileno no tratamento da síndrome vasoplÊgica após cirurgia cardíaca. Rev Bras Cir Cardiovasc. 1996;11(2):107-14. 6. Evora PR, Ribeiro PJ, de Andrade JC. Methylene blue administration in SIRS after cardiac operations. Ann Thorac Surg. 1997;63(4):1212-3. 7. Evora PR. Should methylene blue be the drug of choice to treat vasoplegias caused by cardiopulmonary bypass and anaphylactic shock? J Thorac Cardiovasc Surg. 2000;119(3):632-4. 8. Evora PR, Levin RL. Methylene blue as drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2004;127(3):895-6. 9. Leyh RG, Kofidis T, Strßber M, Fischer S, Knobloch K, Wachsmann B, et al. Methylene blue: the drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass? J Thorac Cardiovasc Surg. 2003;125(6):1426-31. 10. Levin RL, Degrange MA, Bilbao J, Maccarone P, Martinez Traba M, Del Mazo CD. Sindrome vasoplegico postoperatorio: reversion con azul de metileno. Rev Argent Cardiol. 2000;68(4):593-5. 11. Levin RL, Degrange MA, Bilbao J. Sindrome vasoplejico en posoperatorio de cirujia cardiaca. Reduccion de la mortalidad mediante el empleo de azul de metileno. Rev Argent Cardiol. 2001;69(5):524-9.

Authors’ roles & responsibilities PRBE LAJ CAF ACM SB AJR ASF WVAV

Main author Final approval of the manuscript Final approval of the manuscript Final approval of the manuscript Final approval of the manuscript Final approval of the manuscript Final approval of the manuscript Final approval of the manuscript

12. Levin RL, Degrange MA, Bruno GF, Del Mazo CD, Taborda DJ, Griotti JJ, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg. 2004;77(2):496-9. 13. Ozal E, Kuralay E, Yildirim V, Kilic S, Bolcal C, KĂźcĂźkarslan N, et al. Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg. 2005;79(5):1615-9.

REFERENCES

14. Evora PR, Ribeiro PJ, Vicente WV, Reis CL, Rodrigues AJ, Menardi AC, et al. Methylene blue for vasoplegic syndrome treatment in KHDUW VXUJHU\ ÂżIWHHQ \HDUV RI TXHVWLRQV DQVZHUV GRXEWV DQG certainties. Rev Bras Cir Cardiovasc. 2009;24(3):279-88.

1. Gomes WJ, Carvalho AC, Palma JH, Gonçalves Júnior I, Buffolo E. Vasoplegic syndrome: a new dilemma. Rev Assoc Med Bras. 1994;40(4):304.

15. Viaro F, Baldo CF, Capellini VK, Celotto AC, Bassetto S, Rodrigues AJ, et al. Plasma nitrate/nitrite (NOx) is not a useful biomarker to predict inherent cardiopulmonary bypass LQĂ€DPPDWRU\ UHVSRQVH - &DUG 6XUJ

2. Gomes WJ, Carvalho AC, Palma JH, Gonçalves I Jr, Buffolo E. Vasoplegic syndrome: a new dilemma. J Thorac Cardiovasc Surg. 1994;107(3):942-3.

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Evora PRB, et al. - Twenty years of vasoplegic syndrome treatment in heart surgery. Methylene blue revised

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16. Lo JC, Darracq MA, Clark RF. A Review of Methylene Blue Treatment for Cardiovascular Collapse. J Emerg Med. 2014;pii: S0736-4679(13)01095-0.

Fidalgo C, Assreuy J. Nitric oxide-dependent reduction in soluble guanylate cyclase functionality accounts for early lipopolysaccharide-induced changes in vascular reactivity. Mol Pharmacol 2006;69(3):983-90.

17. Grubb KJ, Kennedy JL, Bergin JD, Groves DS, Kern JA. The role of methylene blue in serotonin syndrome following cardiac transplantation: A case report and review of the literature. J Thorac Cardiovasc Surg. 2012;144(5):e113-6.

28. Evora PR, JosĂŠ Rodrigues A, Celotto AC. “Methylene blue should EH UHOHJDWHG WR UHVFXH XVH DQG QRW DV ÂżUVW OLQH WKHUDS\´ FDQQRW become a paradigm. J Cardiothorac Vasc Anesth. 2014;28(2):e11-2.

18. Weiner MM, Lin HM, Danforth D et al. Methylene blue is associated with poor outcomes in vasoplegic shock. J Cardiothorac Vasc Anesth. 2013 [Epub ahead of print]

29. Evora PR. Methylene blue does not have to be considered only as rescue therapy for distributive shock. J Med Toxicol. 2013;9(4):426.

19. Evora PR, Rodrigues AJ. Methylene blue revised. J Thorac Cardiovasc Surg. 2006;131(1):250-1; author reply 251.

30. Evgenov OV, Sager G, Bjertnaes LJ. Methylene blue reduces lung ÀXLG ¿OWUDWLRQ GXULQJ WKH HDUO\ SKDVH RI HQGRWR[HPLD LQ DZDNH sheep. Crit Care Med. 2001;29(2):374-9.

20. Grayling M, Deakin CD. Methylene blue during cardiopulmonary bypass to treat refractory hypotension in septic endocarditis. J Thorac Cardiovasc Surg. 2003;125(2):426-7.

31. Evgenov OV, Evgenov NV, Mollnes TE, Bjertnaes LJ. Methylene blue reduces pulmonary oedema and cyclo-oxygenase products in endotoxaemic sheep. Eur Respir J. 2002;20(4):957-64.

21. Kirov MY, Evgenov OV, Bjertnaes LJ. Combination of intravenously infused methylene blue and inhaled nitric oxide ameliorates endotoxin-induced lung injury in awake sheep. Crit Care Med. 2003;31(1):179-86.

32. Raikhelkar JK, Milla F, Darrow B, Scurlock C. Adjuvant therapy with methylene blue in the treatment of right ventricular failure after pulmonary embolectomy. Heart Lung Circ. 2011;20(4):234-6.

22. Cho JS, Song JW, Na S, Moon JH, Kwak YL. Effect of a single bolus of methylene blue prophylaxis on vasopressor and transfusion requirement in infective endocarditis patients undergoing cardiac surgery. Korean J Anesthesiol. 2012;63(2):142-8.

33. Wiklund L, Martijn C, Miclescu A, Semenas E, Rubertsson S, Sharma HS. Central nervous tissue damage after hypoxia and reperfusion in conjunction with cardiac arrest and cardiopulmonary resuscitation: mechanisms of action and possibilities for mitigation. Int Rev Neurobiol. 2012;102:173-87.

23. Taylor K, Holtby H. Methylene blue revisited: management of hypotension in a pediatric patient with bacterial endocarditis. J Thorac Cardiovasc Surg. 2005;130(2):566.

34. Wiklund L, Basu S, Miclescu A, Wiklund P, Ronquist G, Sharma HS. Neuro- and cardioprotective effects of blockade of nitric oxide action by administration of methylene blue. Ann N Y Acad Sci. 2007;1122:231-44.

.RÂżGLV 7 6WUÂ EHU 0 :LOKHOPL 0 $QVVDU 0 6LPRQ $ +DUULQJHU W, Haverich A. Reversal of severe vasoplegia with single-dose methylene blue after heart transplantation. J Thorac Cardiovasc Surg. 2001;122(4):823-4.

35. Miclescu A, Sharma HS, Martijn C, Wiklund L. Methylene blue protects the cortical blood-brain barrier against ischemia/reperfusion-induced disruptions. Crit Care Med. 2010;38(11):2199-206.

25. Evora PR. Methylene blue, serotonergic syndrome, and heart transplant. J Thorac Cardiovasc Surg. 2013;145(3):897.

36. Miclescu A, Basu S, Wiklund L. Cardio-cerebral and metabolic effects of methylene blue in hypertonic sodium lactate during experimental cardiopulmonary resuscitation. Resuscitation. 2007;75(1):88-97.

26. Blacker SN, Whalen FX. Vasoplegic syndrome: does the timing of methylene blue matter? J Anesth Clinic Res. 2013;4:333. 27. Fernandes D, da Silva-Santos JE, Duma D, Villela CG, Barja-

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Yuan SM - Mycobacterial endocarditis: a comprehensive review REVIEW ARTICLE

Braz J Cardiovasc Surg 2015;30(1):93-103

Mycobacterial endocarditis: a comprehensive review Endocardite micobacteriana: uma revisĂŁo abrangente

Shi-Min Yuan1, MMed, PhD

DOI 10.5935/1678-9741.20140113

RBCCV 44205-1619 Resumo Objetivo: Uma anĂĄlise sistemĂĄtica foi feita considerando epidemiologia, quadro clĂ­nico, diagnĂłstico, tratamento e principais resultados da endocardite micobacteriana. MĂŠtodos: )RL UHDOL]DGD XPD SHVTXLVD ELEOLRJUiÂżFD DEUDQgente no MEDLINE, Highwire Press e no Google para publicaçþes sobre endocardite micobacteriana, publicados entre 2000 e 2013. Resultados: As micobactĂŠrias de crescimento rĂĄpido tornam-se os patĂłgenos predominantes, com Mycobacterium chelonae VHQGR D PDLV FRPXP (VVD FRQGLomR VH DOWHURX VLJQLÂżFDtivamente em termos de epidemiologia, desde o inĂ­cio do sĂŠculo DEUDQJHQGR IDL[D HWiULD PDLV DPSOD PDLRU ODWrQFLD SUHYDlecendo infecçþes da valva mitral e melhor prognĂłstico. ConclusĂŁo: Endocardite micobacteriana ĂŠ rara e os patĂłgenos causadores sĂŁo predominantemente as micobactĂŠrias de FUHVFLPHQWR UiSLGR $PLFDFLQD FLSURĂ€R[DFLQD H FODULWURPLFLQD sĂŁo os agentes antimicrobianos mais frequentemente utilizados, mas muitas vezes apresentam respostas pobres. Pacientes com LQIHFo}HV SURIXQGDV SRGHP MXVWLÂżFDU XP SURFHGLPHQWR FLU~Ugico ou retirada de linha. Com a poliquimioterapia periĂłdica JXLDGD SRU WHVWHV GH VHQVLELOLGDGH jV GURJDV H DERUGDJHQV FLU~UJLFDV RV SDFLHQWHV SRGHP REWHU ERQV UHVXOWDGRV WHUDSrXWLFRV

Abstract Objective: A systematic analysis was made in view of the epidemiology, clinical features, diagnosis, treatment and main outcomes of mycobacterial endocarditis. Methods: The data source of the present study was based on a comprehensive literature search in MEDLINE, Highwire Press and Google search engine for publications on mycobacterial endocarditis published between 2000 and 2013. Results: The rapidly growing mycobacteria become the predominant pathogens with Mycobacterium chelonae being the PRVW FRPPRQ 7KLV FRQGLWLRQ KDV FKDQJHG VLJQLÂżFDQWO\ LQ WHUPV of epidemiology since the 21st century, with more broad patient age range, longer latency, prevailed mitral valve infections and better prognosis. Conclusion: Mycobacterial endocarditis is rare and the causative pathogens are predominantly the rapidly growing P\FREDFWHULD $PLNDFLQ FLSURĂ€R[DFLQ DQG FODULWKURP\FLQ DUH the most frequently used targeted antimicrobial agents but often show poor responses. Patients with deep infections may warrant a surgical operation or line withdrawal. With periodic multidrug therapy guided by drug susceptibility testing, and surgical managements, patients may achieve good therapeutic results.

Descritores: Valvas CardĂ­acas. Endocardite. Mycobacterium.

Descriptors: Heart Valves. Endocarditis. Mycobacterium.

1

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

The First Hospital of Putian, Teaching Hospital, Fujian Medical University, Putian, People’s Republic of China. 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 April 24th, 2014 Article accepted on September 30th, 2014

1R ÂżQDQFLDO VXSSRUW

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Yuan SM - Mycobacterial endocarditis: a comprehensive review

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included if the patient had an established diagnosis of mycobacteria endocarditis on current admission and outcome data were reported. Due to the rarity of the condition, all the discovered articles reported only sporadic single or small series; no large population, comparative studies were retrievable. Therefore, data from this systematic review were qualitatively analyzed as suggested in the Quality of Reporting of Meta-Analyses recommendations. 7KH VHDUFK LGHQWLÂżHG UHOHYDQW VWXGLHV IURP WR 2013[7,9-38], including 24 case reports[7,9,10,12,13,15,17-22,24-28,30-33,36-38], 2 case series[14,23], 2 original articles[11,34], 1 medical imaging[16], 1 poster abstract session[29], and 1 “letter to the editorâ€?[35]. After reviewing selected articles, all 31 articles were included and no one was excluded. Data were extracted from WKH WH[W ÂżJXUHV RU WDEOHV DQG LQFOXGHG GHWDLOV RI WKH VWXG\ population, demographics, types of mycobacteria, sites of infections, locations of vegetations, latency, sensitivity, antimicrobial spectrum, management strategies, clearance time, follow-up length and main outcomes (survivals, complications, relapses, reinterventions and mortality). Quantitative data were presented as meanÂąstandard deviation, and intergroup differences were compared by unpaired t-test. Comparisons of frequencies were performed by Fisher’s exact test. P<0.05 was considered statistically VLJQLÂżFDQW

Abbreviations, acronyms & symbols AVR M. MVR

Aortic valve replacement Mycobacterium Mitral valve replacement

INTRODUCTION Cardiac disorders, pregnancy and other surgical maneuvers can be risk factors of bacterial infective endocarditis[1-4]. Increasingly utilization of foreign medical materials, indwelling catheter insertions and intravenous drug uses are recognized risk factors predisposing to bacterial infective endocarditis of the present era[5]. Continuous changes in terms of epidemiology and management strategies of the bacterial infective endocarditis have been elucidated[5]. Staphylococcus aureus has become the most common microorganism of the bacterial infective endocarditis particularly associated with increasing foreign material implant[6], while Streptococcus viridans infections reduced[5]. However, there is no updated elaboration on recent changes of mycobacterial endocarditis. Mycobacterial endocarditis is rare. It showed a sigQLÂżFDQW SUHGLOHFWLRQ RI QRQ WXEHUFXORXV RYHU WXEHUFXORXV mycobacteria in terms of infective endocarditis. Due to more resistant to antimicrobial therapies than other pathogens, mycobacteria are often refractory to antimicrobial treatments and are associated with a very high mortality[7]. Rapid-growth non-tuberculous mycobacteria including Mycobacterium (M.) chelonae, M. abscessus and M. fortuitum accounted for 68% of the isolates[8] and thus being the predominant mycobacteria for the infections. There have been systemic reviews on infective endocarditis caused by M. fortuitum[7,9] in 2002, and by M. abscessus[10] and M. chelonae[11] in recent years. Due to the rarity, regular PDQDJHPHQW VWUDWHJLHV DUH VWLOO VFDQW\ $V IRU WKH GLIÂżFXOW\ RI SDWKRJHQ LGHQWLÂżFDWLRQV SRRU UHVSRQVHV WR DQWLPLFURbial therapy and poor prognosis, this condition remains a challenge with regard to diagnosis and treatment. However, P\FREDFWHULDO HQGRFDUGLWLV KDV QRW EHHQ VXIÂżFLHQWO\ HODERrated. The present study is designed to highlight the clinical pictures of mycobacterial endocarditis based on relevant literature information published since 2000.

RESULTS Demographics The patient setting included 50 patients with mycobacterial endocarditis. There were 29 males and 21 females with a male-to-female ration of 1.38:1. Their ages were 45.9Âą19.8 (range, 0.5-78; median 50) years (n=50). Age distribution of the patients conformed to the normal distribution by probability–probability plot. Clinical features The major symptoms on admission were described in 46 patients including fever in 35 (76.1%)[7,9-29,33,37,38], dyspnea in 10 (21.7%)[10,11,31,32] and chest pain in 1 (2.1%) patient[30] Ȥ2=60.7, P=0.000). The duration of the symptoms was 4.0Âą4.4 (range, 0.17-18; median, 2) months (n=31). The temperature of the febrile patients were 38.9Âą0.8Ô¨ (n=12). Of the febrile patients, fever grade was not indicated in 22[11, 14,18,23,24,26,28,29,33,35,36,38] . In the remaining 13 patients, 5 (38.5%) had a high fever[12,17,19,20,22,29], 5 (38.5%) had a moderate fever[13,15,21,25,34] and 3 (23.1%) had a low-grade fever[9,27,37] Ȥ2=0.9, P=0.630). Of them, 4 were prolonged fever[24,35,36] and 2 were fever of unknown origin[14,16]. The cardiac murmur was mentioned in 15 patients: a cardiac murmur in 12 (80%) (a pansystolic murmur at the apex in 5[14,21,27,30,38], a diastolic murmur in the aortic region

METHODS MEDLINE, Highwire Press and Google search engine were searched for publications in the English language on mycobacterial endocarditis from 2000 to 2013. The terms “mycobacteria�, “heart valve�, “heart valve prosthesis�, “tuberculous�, “non-tuberculous� and “endocarditis� were used for the searches. All the articles, titles and subject headings were screened carefully for potential relevance. Articles were

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in 2[13,18], a systolic murmur in the aortic region[36], a pansystolic murmur at the apex + a diastolic murmur in the aortic region[25], a pansystolic murmur at the apex + a systolic murmur in the aortic region[15], a systolic murmur at the lower left sternal boarder[37] DQG DQ XQVSHFLÂżHG FDUGLDF PXUPXU[32] in 1 patient each) and an absence of a cardiac murmur in 3 (20%) patients[20,22,24] Ȥ2=10.8, P=0.001). Laboratory examinations revealed their hemoglobin was 9.9Âą1.8 (range, 5.9-12.5; median, 10) g/L (n=10)[9,10,12,13,15,18,20, 27,30,36,38] , white blood cell count was 8.9Âą4.4 (range, 3.3-16.8; median, 8.2) Ă—109/L (n=13)[9,10,13,15,20-22,24,27,28,30,33,38], platelet count was 165.6Âą128.7 (range, 67-450; median, 124)Ă—109/L (n=7)[10,13,15,18,20,27,38], C-reaction protein was 6.8Âą4.7 (range, 0.14-11; median, 8) mg/dL (n=4)[10,20,27,28], and CD4 was 240.5 Âą 206.3 (range, 44-587; median 196)/mm3 (n=6) [9,10,13,14,19,37] . CD4 was normal (>500/mm3) in 1 (16.7%) patient, and was abnormal (<500/mm3) in 5 (83.3%) patients Ȥ2=5.3, P=0.021).

Predisposing risk factors Cardiac surgery, foreign material implant, intravenous drug use and miscellaneous risk factors were the underlying etiologies for the development of infective endocarGLWLV Ȥ2=31.9, P=0.000) (Table 1). Of the causative cardiac operations, 23 (85.2%) were heart valve operations and 4 (14.8%) were congenital atrial/ventricular defect SDWFK UHSDLUV Ȥ2=26.7, P=0.000). There were 22 (95.7%) YDOYH UHSODFHPHQWV DQG YDOYH UHSDLU Ȥ2 = 38.4, P=0.000). Eighteen (81.8%) were single valve replacements, and 4 (18.2%) were double valve replacements Ȥ2=17.8, P DQG ZHUH ¿UVW WLPH YDOYH UHSODFHPHQWV DQG ZHUH UHGR RSHUDWLRQV Ȥ2=13.1, P=0.001). A total of 26 valves were replaced including 13 (50%) aortic and 13 (50%) mitral valve replacements; 20 (80%) were biological, and 5 (20%) were mechanical valve SURVWKHVHV Ȥ2 = 18, P=0.000), except the one whose detail of aortic valve prosthesis was not given.

Table 1. Predisposing risk factors. Predisposing risk factors Cardiac operation MVR AVR AVR + coronary artery bypass grafting Composite AVR MVR + AVR Redo-MVR + AVR Redo-AVR Mitral valve ring plasty with aortic valve repair Ventricular septal defect patch repair Atrial septal defect patch closure Foreign material implant Pacemaker Percutaneous coronary intervention $XWRPDWLF LPSODQWDEOH FDUGLRYHUWHU GHÂżEULOODWRU LPSODQW Dialysis, catheter infection, immunosuppressive therapy Hemodialysis Stenting of the abdominal aorta + renal angioplasty IDU IDU alone ,'8 KXPDQ LPPXQRGHÂżFLHQF\ YLUXV LQIHFWLRQ IDU + tricuspid endocarditis (Methicillin-resistant Staphylococcus aureus) Miscellaneity Colostomy and colostomy revision Left foot gangrene Annular subvalvular left ventricular aneurysm (ASLVA) Rheumatic heart disease Radiation therapy + previous infective endocarditis Travel to El Salvador Not stated AVR=aortic valve replacement; IDU=intravenous drug user; MVR=mitral valve replacement

95 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

n (%) 27 (54) 9 (33.3) 5 (18.5) 1 (3.7) 1 (3.7) 1 (3.7) 3 (11.1) 2 (7.4) 1 (3.7) 3 (11.1) 1 (3.7) 11 (22) 4 (36.4) 3 (27.3) 1 (9.1) 1 (9.1) 1 (9.1) 1 (9.1) 5 (10) 2 (40) 2 (40) 1 (20) 7 (14) 1 (14.3) 1 (14.3) 1 (14.3) 1 (14.3) 1 (14.3) 1 (14.3) 1 (14.3)

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The latency from the presence of the predisposing risk factors to symptom onset was 21.9Âą25.9 (range, 0.067-96; median, 12) months (n=31)[7,9,11,12,14-18,20,21,23,26,27,31-33,37]. There were 9 (29.0%) early onsets (latency <8 weeks), 2 (6.5%) intermediate onsets (latency was between 8 weeks and 8 months) and 20 ODWH RQVHWV ODWHQF\ ! PRQWKV Ȥ2=23.9, P=0.000). The latency of the patients with cardiac operations was much shorter than that of the patients with a foreign material imSODQW EXW GLG QRW UHDFK D VWDWLVWLFDO VLJQLÂżFDQFH “ months vs. 34.8Âą39.0 months, P=0.136). It was incompatible with intravenous drug use patients, of which latency was reported in only one patient, and was much shorter than that of the miscellaneity reaching a quasi-statistical difference (16.4Âą20.1 months vs. 44Âą34.6 months, P=0.051) (Figure 1). Bioprosthetic valve endocarditis was associated with a longer ODWHQF\ WKDQ PHFKDQLFDO ZLWKRXW VKRZLQJ D VLJQLÂżFDQW GLIIHUence (17.5Âą22.5 months vs. 10.8Âą7.1 months, P=0.569). Four patients had a delayed diagnosis for 0.81Âą0.24 (range, 0.5-1; median, 0.88) months (n=4)[12,13,20,26].

patients (P=0.067). Native aortic, mitral and tricuspid valves were the most commonly affected sites of mycobacterial endocarditis, representing 29.7%, 26.6% and 10.9%, respectively (Figure 2). No difference was found in the prevalence of infection sites between non-tuberculous and tuberculous mycobacterial endocarditis (Table 2), or in the strain distributions between aortic and mitral valves (Table 3). Vegetations were detected in 44 patients with 43 detected by echocardiography and 1 patient detected by positron emisVLRQ WRPRJUDSK\ ZLWK ) Ă€XRURGHR[\JOXFRVH XSWDNH[16]. Of them, 12 (27.3%) patients did not have a visualized vegetation[7,9,11,14,17,28,31], but one of them with an abscess along the inferior and septal walls, instead[31] and 32 (72.7%) patients had Ȥ2=18.2, P=0.000). The vegetation locations of the remaining 32 patients were mitral valve in 10 (31.3%)[11,20,21,30,36,37] (two of them were in the prosthetic mitral valve)[20,21], aortic valve in 7 (21.9%)[11,13,18,32,33,38] (one was in the prosthetic aortic valve)[33], pacemaker lead in 3 (12.5%)[16,26,27], tricuspid valve in 3 (9.4%)[10,19,35], both mitral valve and right subclavian catheter in 1 (3.1%)[36], both mitral and aortic valves in 2 (6.3%)[12,15], both aortic and tricuspid valves in 2 (6.3%)[22,24], mitral, aortic and tricuspid valves in 1 (3.1%)[25], tricuspid valve and ventricular septal defect patch in 2 (6.3%)[35] and atrial septal patch in 1 (3.1%) patient[23], respectively. The detection time for a positive vegetation was described in 3 patients, which was 5[13], 21[20] and 105 days[15] after admission, respectively. Dimensions of the vegetations were recorded in 16 patients for 17 vegetations. Five vegetations of 5 patients from a single report[11] were recorded as “minimalâ€?, which were excluded from the calculation of the vegetation size. The size of the remaining 12 vegetations of 11 patients was 19.7Âą18.4 (range, 5-70; median, 15.5) mm[10,15,18,20,23-26,30,32,37].

Infection sites The infection sites could be divided into 5 types according the location and number of the mycobacterial infections: single intracardiac infection in 38 (76%), two intracardiac infections in 9 (18%), and triple valve infections, single intracardiac + single extracardiac infections, and double intracardiac + sinJOH H[WUDFDUGLDF LQIHFWLRQV LQ SDWLHQW HDFK Ȥ2=128.5, P=0.000). Including extracardiac infections associated with the endocarditis, totally 64 sites were affected with a mean of 1.28¹0.54 (range, 1-3; median, 1) infection sites per patient. There were 1.24¹0.48 infection sites in the non-tuberculous and 1.75¹0.96 infection sites in the tuberculous endocarditis

Fig. 1 - A comparison of latencies between different risk factors. IDU= intravenous drug use.

Fig. 2 - Distribution of infection sites. ASD=atrial septal defect; AV=aortic valve; MV=mitral valve; RA=right atrium; PV=pulmonary valve; TV=tricuspid valve; VSD=ventricular septal defect

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9DOYH LQVXI¿FLHQF\ ZDV SUHVHQW LQ SDWLHQWV PLWUDO valve regurgitation in 9 (39.1%)[11,30,31,37] (6 were prosthetic mitral valve leaks[11]), aortic valve regurgitation in 5 (21.7%) [11,28,32] (4 were prosthetic aortic valve leaks[11,32]), aortic and mitral valve regurgitation in 5 (21.7%)[11,12,14,38] (2 were prosthetic aortic and mitral valve leaks[11]) and tricuspid valve regurgitation in 4 (17.4%) patients[10,27,35]. There were totally 11 (47.8%) native valve regurgitations and 12 (52.2%) prosWKHWLF YDOYH OHDNV Ȥ2=0.1, P=0.768). Besides, one patient had inferior and septal wall abscess associated with mitral valve regurgitation[31] and one patient had ventricular septal patch dehiscence[35].

M. fortuitum in 7 (31.8%), M. chimaera in 4 (18.2%), M. abscessus in 3 (13.6%), M. chelonae in 2 (9.1%), M. neoaurum in 1 (4.5%), acid-fast bacilli in 2 (9.1%), rapidly growing mycobacteria in 1 (4.5%) and tubercule bacilli in 2 (9.1%), respectively. At least 15 (68.2%) cases were rapid growing mycobacteria infections. Seventeen patients (four of them had additional samples for cultures) had a positive histological staining results by Ziehl-Neelsen and auramine-rhodamine stains[12,17,18,27] with DFLG IDVW RUJDQLVPV VKRZQ RQ ÀXRUHVFHQFH PLFURVFRS\ Ten patients had a molecular analysis of the mycobacteria, where 16s ribosomal deoxyribonucleic acid sequencing was applied in 4 (40%)[14,20,21,23], reverse line blot hybridization in 4 (40%)[29] and a polymerase chain reaction-restriction fragment length polymorphism analysis in 2 (20%) patients [10,33] , respectively. All patients had fresh samples, and one of them had additional cryopreserved samples for investigations. However, analyses on the cryopreserved samples disclosed negative results, while all fresh specimens displayed positive results. In addition, two patients had mycolic acid analysis by biochemical and chromatographic techniques[7,9]. By preliminary blood cultures, histological staining, molecular analyses and chromatographic techniques, the eventuDO P\FREDFWHULDO VWUDLQV ZHUH LGHQWL¿HG LQ DOO EXW RQH SDWLHQW (Figure 3). Distributions of the mycobacteria responding to the four predisposing risk factors showed cardiac operation was associated with more, prevailed rapidly growing mycobacteria (M. chelonae, M. fortuitum and M. chimaera) endocarditis, foreign material implant was associated with M. fortuitum, and intravenous drug use and miscellaneity were prone to be of tuberculous endocarditis (Figure 4, Table 5). According to the antimicrobial spectrum, intravenous amiNDFLQ PJ WZLFH GDLO\ FLSURÀR[DFLQ PJ WZLFH daily and clarithromycin 500 mg twice daily were the most frequently used targeted antimicrobial agents, and imipenem

Pathogens The initial blood culture results were not indicated in 5 patients[29,34]. In the remaining 45 patients, a negative culture prevailed, followed by an acid-fast bacterium (Table 4). Thirty-seven patients had more investigations performed IRU VWUDLQ LGHQWLÂżFDWLRQV )RXUWHHQ SDWLHQWV KDG PRUH VDPples than blood for cultures: 7 (50%) patients had one more sample, 4 (28.6%) patients had 2 more samples, 2 (14.3%) patients had 3 more samples and 1 (7.1%) patient had 4 more samples for cultures, respectively. There were totally 25 additional samples for cultures including 4 (16%) intraoperative excised valves[12,18], or valve prosthesis[7], or prosthetic valve ring[14], 4 (16%) resected vegetations[27,30,35], 3 (12%) sputum[27,28,34], 2 (8%) bronchoalveolar lavage[14,27], 2 (8%) urine[14,27], 2 (8%) bone marrow[14,37], 1 (4%) removed patch[35], removed pacing lead[26], intraoperative specimens (with no details available)[34], pacemaker generator pocket site[26], asSLUDWHG Ă€XLG[26], sternum[7] FHUHEURVSLQDO Ă€XLG[37] and tracheal swab[15] for each, respectively. Lowenstein–Jensen medium was once used for valve, sternum and blood cultures[7]. Three ZHUH QHJDWLYH DQG ZHUH SRVLWLYH Ȥ2=28.8, P 7KH SRVLWLYH FXOWXUHV LGHQWLÂżHG WKH VWUDLQV WR EH

Table 2. A comparison of infection sites between non-tuberculous and tuberculous mycobacterial infective endocarditis Infection site Aortic valve Mitral valve Aortic valve, prosthetic Lead Tricuspid valve Mitral valve, prosthetic Pulmonary valve VSD patch ASD patch Right atrium Right subclavian dialysis catheter Sternum

Non-tuberculous (n = 56) 16 (28.6) 15 (26.8) 5 (8.9) 5 (8.9) 5 (8.9) 2 (3.6) 2 (3.6) 2 (3.6) 1 (1.8) 1 (1.8) 1 (1.8) 1 (1.8)

Tuberculous (n = 8) 3 (37.5) 2 (25) 0 (0) 0 (0) 2 (25) 0 (0) 0 (0) 0 (0) 0 (0) 1 (12.5) 0 (0) 0 (0)

ASD=atrial septal defect; VSD=ventricular septal defect

97 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Ȥ2

P value

0.3 0.0 1.4 1.4 1.9 0.5 0.5 0.5 0.3 2.7 0.3 0.3

0.605 0.915 0.237 0.237 0.173 0.460 0.460 0.460 0.603 0.103 0.603 0.603

Yuan SM - Mycobacterial endocarditis: a comprehensive review

Braz J Cardiovasc Surg 2015;30(1):93-103

Fig. 3 - Eventual mycobacterial strains.

Fig. 4 - Distributions of the mycobacteria responding to the four predisposing risk factors.

Table 3. A comparison of pathogens between aortic and mitral valve endocarditis. Pathogen Chelonae Fortuitum Abscessus Chimaera Peregrinum Rapidly growing mycobacteria Goodii Neoaurum Tuberculous

Aortic valve (n=22) 8 (36.4) 6 (27.3) 3 (13.6) 1 (4.5) 1 (4.5) 1 (4.5) 0 (0) 0 (0) 2 (9.1)

Mitral valve (n=20) 11 (55) 1 (5) 3 (15) 1 (5) 0 (0) 0 (0) 1 (5) 1 (5) 2 (10)

혹2

P value

1.5 3.7 0.0 0.0 1.4 1.4 1.7 1.7 0.0

0.226 0.053 0.900 0.945 0.235 0.235 0.199 0.199 0.920

Table 4. Initial blood culture results. Initial blood culture Negative Acid-fast bacteria Gram-positive bacilli/rod Atypical mycobacterial infection Non-tuberculous mycobacteria Rapidly growing mycobacteria Mycobacterium species Fortuitum Abscessus Neoaurum Chimaera Peregrinum Tuberculous

n (%) 18 (40) 9 (20) 5 (11.1) 1 (2.2) 1 (2.2) 1 (2.2) 1 (2.2) 4 (8.9) 1 (2.2) 1 (2.2) 1 (2.2) 1 (2.2) 1 (2.2)

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References [11,14,25,27,28,30] [7,10,13,22,23,35,36] [15,20,26,31,33] [37] [38] [34] [21] [9,12,17,24] [18] [34] [14] [16] [19]

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Braz J Cardiovasc Surg 2015;30(1):93-103

relapses[9,10]. In the surgical treatment group, all patients received a valve replacement operation, including 2 aortic valve replacements (AVRs), 1 AVR with root replacement, 1 redo-AVR, 1 2nd redo-AVR, 2 AVRs + mitral valve replacements (MVRs), 1 AVR + MVR + tricuspid valvuloplasy, 1 2nd redo-AVR + MVR and 1 redo-MVR. There were 5 event-free survivals[12,17,20,28,33], 3 deaths[12,18,29], 2 complicated (1 preoperative stroke and 1 complication related with his previous ascending aortic replacement)[25,32], 1 relapse[18] and 1 reintervention[32]. In the patients with a FDWKHWHU OHDG GH¿EULOODWRU UHPRYDO WKHUH ZHUH HYHQW IUHH survivals[16,24,26] and 3 deaths[15,27,36]. Time of deaths was described in 11 patients. There were 4 (36.4%) early deaths DQG ODWH GHDWKV Ȥ2=1.6, P=0.201).

(500 mg/6 hours), linezolid, rifampicin and trimethoprim/sulfamethoxazole 160 mg/800 mg (p.o., thrice daily) were more frequently used for non-tuberculous mycobacterial infection; while ethambutol (20 mg/kg/day), isoniazid (10 mg/kg/day), pyrazinamide (25 mg/kg/day) and rifampicin (10 mg/kg/day) were for tuberculous mycobacterial infection. The antimycobacterial course was life in 2 patients[18,35]. In another 19 patie nts[10-13,22-24,26,28,33,34], the treatment course was indicated, which was 2.7¹2.3 (range, 0.83-9; median, 1.67) months. The clearance time interval was 31.8¹58.4 (range, 2-210; median, 12.5) days (n=12)[12,13,15,19-21,23,34,35]. Prognosis Patients were at a follow-up of 48.7¹39.8 (range, 3-116; median, 32) months (n=23)[9,11,17,19-21,23,26,30,32,34]. Totally 27 (50%) patients were event-free survivals[12,16,17,19,20,22-24,26,28,30,33-35], 3 (6.25%) patients relapsed at 0.5, 5 and 10 months, respectively[9,10,18], 4 (6.25%) patients were complicated[21,25,29,32] and one of them required reintervention[32], which constituted the only reintervention of the whole setting, and 17 (34%) patients died[11-15,18,27,29,31,36-38] at 83.9¹85.9 (range, 1-270; median, 64) days (n=11). The death causes were described in 8 patients, which were multiorgan failure in 2[12,15], and candidaemia and hospital-acquired pneumonia[36], persistent mycobacteremia and stroke[29], progressive heart failure[14], respiratory distress[37], splenic rupture[14] and variceal bleeding[31] in 1 patient, each. Two patients did not receive either medical or surgical treatment, but had a good prognosis in each. Of the remaining 48 patients, 32 (66.7%) patients received an antimicrobial therapy alone, 10 (20.8%) patients had a cardiac operation and 6 (12.5%) patients had an intervention for removal of FDWKHWHU OHDG GH¿EULOODWRU Ȥ2=36.8, P=0.000). In the patients with medical treatment, there were 17 event-free survivals[11,19,22,30,34,35], 11 deaths[11,13,14,29,31,37,38], 2 complicated (spleen infarct, renal infarct and cerebral abscess on day 10, and prosthetic valve endocarditis due to coagulase negative staphylococcal species at 1 year in one patient[21]; and periaortic abscess in another[29]) and 2

DISCUSSION In 1959, Runyon[39], according to pigment of colony and rate of growth, divided mycobacteria into 4 types: photochromogen, scotochromogen, nonphotochromogen and rapid grower. The latter one, rapidly growing mycobacterium, was GH¿QHG VR EHFDXVH WKH P\FREDFWHULDO FRORQLHV IRUP DW Û& on solid agar in 5-7 days. Both slowly and rapidly growing mycobacteria are environmental opportunistic mycobacteria that are normal inhabitants of natural waters, drinking water and soils[40]. The most important slowly growing species are M. avium and M. intracellulare, called the M. avium complex; and rapidly growing mycobacteria (M. abscessus, M. chelonae and M. fortuitum), which are opportunistic pathogens[40]. Mycobacterial endocarditis is rare. In a recent report of infective endocarditis incorporating information from 13 tertiary hospitals in Turkey, no myocabacterial endocarditis was reported[41]. Wallace et al.[42] stated that the incidence of mycobacterial endocarditis was 33.3% (4/12) out of M. fortuitum or M. chelonae bacteria and was 3.2% of rapid growth mycobacterial blood infections. Olalla et al.[7] reviewed 19 cases of rapid growth mycobacterial endocarditis and noted that patients’ age was 45 (range, 20-74) years, including 4

Table 5. Pathogens corresponding to predisposing risk factors. Strain Chelonae Fortuitum Chimaera Abscessus Goodii Massiliense Neoaurum Peregrinum Rapidly growing mycobacteria Tuberculosis

Cardiac operation 14 (51.9) 6 (22.2) 2 (7.4) 1 (3.7) 1 (3.7) 1 (3.7) 1 (3.7) 1 (3.7) 0 (0) 0 (0)

Foreign material implant 1 (9.1) 5 (45.5) 0 (0) 3 (27.3) 0 (0) 0 (0) 0 (0) 1 (9.1) 1 (9.1) 0

Injective drug use 0 (0) 2 (33.3) 0 (0) 1 (16.7) 0 (0) 0 (0) 1 (16.7) 0 (0) 0 (0) 2 (33.3)

Miscellaneity

Ȥ2

P value

2 (50) 0 (0) 0 (0) 2 (50) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (50)

40.4 9.3 8.0 2.1 4.0 4.0 2.7 2.7 4.0 8.0

0.000 0.025 0.046 0.558 0.261 0.261 0.446 0.446 0.261 0.046

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native and 15 prosthetic valve endocarditis, with a biological valve prosthesis in 6 and a mechanical valve prosthesis in 9 patients. The degree of fever may not correspond to the severity of the illness[43]. As it was illustrated in the present article, no dominance of fever grade was associated with mycobacterial endocarditis. Strabelli et al.[11] reported that the latent for the febrile onset and development of valve dysfunction was few days and months to years, respectively. In 5 of 13 patients with prosthetic mycobacterial endocarditis, the latent period for the diagnosis of bioprosthetic endocarditis was 1-4 years[11]. Olalla et al.[7] reported a latency of 12 weeks from infection to symptom onset with no difference found between biological and mechanical prosthetic valve endocarditis. The present study revealed a more broad patient age range from infant to 78 years old with a normal age distribution, equality of affected aortic and mitral valves, more native than prosthetic valve and more bioprosthetic than mechanical bioprosthetic endocarditis. Moreover, cardiac operations caused a shorter latency to endocarditis occurrence than foreign material implant and miscellaneous risk factors. Bioprosthetic valve endocarditis was associated with a longer latency than PHFKDQLFDO EXW ODFN RI D VLJQL¿FDQW GLIIHUHQFH .XQLQ HW DO [9] reported a prevailed early onset of mycobacterial endocarditis. Valve dysfunction was noted in 10 (76.9%) patients, while only 3 (23.1%) patients were free of valve dysfuncWLRQ Ȥ2=12.5, P=0.001). The present study demonstrated a predominant late onset and a decreased incidence of valve dysfunction. The most common predisposing risk factors for mycobacterial infections include medical procedures (central venous access, hemodialysis catheter indwelling, various surgical operations including mammoplasty, arthroplasty and cardiothoracic operations)[9], immunocompromised, particuODUO\ SDWLHQWV ZLWK KXPDQ LPPXQRGH¿FLHQF\ YLUXV DFTXLUHG LPPXQRGH¿FLHQF\ V\QGURPH KHPDWRORJLFDO PDOLJQDQFLHV or those treated with immunosuppressive drugs after solid organ transplantation[44]. More recently, the use of tumor necroVLV IDFWRU Ď EORFNHUV KDV EHFRPH DQ DGGLWLRQDO ULVN IDFWRU[45]. Line-related non-tuberculous infections did not have any predominant organisms including M. abscessus, M. chelonae, M. neoaurum, M. fortuitum and M. mucogenicum[34]. Further, possible manufacturer contamination of bioprosthesis by M. chelonea has been recognized[46]. In addition, nosocomial infections were once evidenced from sources like cardioplegic solutions[47], water supply[48], antiseptic solutions[49] and valve prosthesis preservation solutions[50]. Positivity of blood cultures varied according to types of affected valves. It was 75% in mechanical, 20% in biological and 100% in native valves[7]. Removed valve prostheses showed a high positivity of mycobacterial cultures[48]. Upon colonial growth, gram and acid-fast stains should be performed, and then when blood cultures are negative, acid-fast

bacilli stains on histological examination of the removed prosthetic valves[11] and Ziehl-Neelsen stain should be employed, followed by subcultures[40]. Mycobacteria are more resistant to chemical disinfection than other pathogens[11]. Infective endocarditis caused by rapidly growing mycobacteria is always refractory due to extensive drug resistance and substantially delayed diagnosis[36]. The poor response to therapy can be a result of various factors that may lead to drug resistance, including the SUHVHQFH RI ELRÂżOPV W\SH RI DQWLPLFURELDO DJHQW XVHG DQG presence of a novel inducible erm(41) gene[51]. With periodic multidrug therapy guided by drug susceptibility testing, patients may achieve good therapeutic results[51]. Therefore, antimicrobial susceptibility tests of the isolates are of imSRUWDQW FOLQLFDO VLJQLÂżFDQFH[36]. The management of rapidly growing mycobacteria is usually an empiric therapy with two agents and a successive targeted regimen according to drug sensitivity tests[9]. Amikacin was the most reliable agent for the treatment of non-tuberculous mycobacteria and alternaWLYH HIIHFWLYH DJHQWV LQFOXGHG FLSURĂ€R[DFLQ FODULWKURP\FLQ imipenem and linezolid[34]. Non-tuberculous mycobacteria are more sensitive to some antibiotics than other rapidly growing mycobacteria[32]. Clarithromycin was proved to be sensitive WR 0 DEVFHVVXV FKHORQDH 0R[LĂ€R[DFLQ ZDV GLVFRYHUHG WR EH the best to treat M. fortuitum infections, very active against M. chelonae when used alone and more effective against all the strains when combined with clarithromycin and amikacin[52] $ FRPELQHG XVH RI FODULWKURP\FLQ ZLWK PR[LĂ€R[DFLQ RU OLQH]ROLG DW D KLJK FRQFHQWUDWLRQ Č?J PO DOVR GLVSOD\HG activity against M. abscessus[51]. Disseminated infections with atypical mycobacteria often develop in immunocompromised patients with reduced CD4 count and complement levels[37]. A combined antimicrobial therapy with prolonged treatment duration is often the regimen of choice. Amikacin and imipenem have been proved to be effective agents for the disseminated cases[32]. Patients with deep infections of rapidly growing mycobacteria often warrant a surgical intervention including line removal, debridement, or removal of the foreign material[34]. An improved survival was advocated to be associated with surgical interventions[33], whereas some patients with conservative managements failed to survive[13]. In the patient series of Olalla et al.[7] reported in 2002, 15 of 19 cases of M. fortuitum complex (M. fortuitum and M. chelonae) endocarditis were prosthetic valve endocarditis and valve replacement was performed in 8 (42.1%) patients with an overall mortality of 88%. Recently, Strabelli et al.[11] reported 13 patients with M. chelonae endocarditis received a valve replacement and an overall mortality was decreased to 23.1% (3/13) including 1 (7.7%) early and 2 (15.4%) late deaths. Exceptionally, a few patients did not receive any antimicrobial treatment and patients were at long-term event-free survival[11]. These results implied that foreign material implant becomes an apparent

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Yuan SM - Mycobacterial endocarditis: a comprehensive review

Braz J Cardiovasc Surg 2015;30(1):93-103

risk factor for infective endocarditis, and usage of higher dose and combined antimicrobial regimens with reference to the mycobacterial species and surgical treatment can lead to improved outcomes. The rarity of this condition as well as the relevant published materials made this study a limited patient population. Abundant valuable date in the future may replenish the research with more accurate results.

in endocarditis with large vegetations. Rev Bras Cir Cardiovasc. 2009;24(4):570-3. 7. Olalla J, Pombo M, Aguado JM, RodrĂ­guez E, Palenque E, Costa JR, et al. Mycobacterium fortuitum complex endocarditiscase report and literature review. Clin Microbiol Infect. 2002;8(2):125-9. 8. Matos ED, Santana MA, de Santana MC, Mamede P, de Lira Bezerra B, PanĂŁo ED, et al. Nontuberculosis mycobacteria at a multiresistant tuberculosis reference center in Bahia: clinical epidemiological aspects. Braz J Infect Dis. 2004;8(4):296-304.

CONCLUSION Mycobacterial endocarditis is rare but dreadful. The rapidly growing mycobacteria become the predominant pathogens with chelonae being the most common. This condition KDV FKDQJHG VLJQL¿FDQWO\ LQ WHUPV RI HSLGHPLRORJ\ VLQFH WKH 21st century, with more broad patient age range, longer latency, prevailed mitral valve infections and better prognosis. The better prognoses than before might be attributed to the IDVWHU VWUDLQ LGHQWL¿FDWLRQ PROHFXODU WHFKQLTXHV KLJKHU GRVH of antimicrobial agents, periodic multidrug therapy guided by drug susceptibility testing and more requirements of surgical interventions. Authors’ roles & responsibilities SMY

Main Author

.XQLQ 0 6DODPRQ ) :HLQEHUJHU 0 *HQNLQ , 6DJLH $ 7XU .DVSD 5 &RQVHUYDWLYH WUHDWPHQW RI SURVWKHWLF YDOYH HQGRFDUGLWLV due to Mycobacterium fortuitum. Eur J Clin Microbiol Infect Dis. 2002;21(7):539-41. 10. Tsai WC, Hsieh HC, Su HM, Lu PL, Lin TH, Sheu SH, et al. Mycobacterium abscessus endocarditis: a case report and OLWHUDWXUH UHYLHZ .DRKVLXQJ - 0HG 6FL 11. Strabelli TM, Siciliano RF, Castelli JB, Demarchi LM, LeĂŁo SC, Viana-Niero C, et al. Mycobacterium chelonae valve endocarditis resulting from contaminated biological prostheses. J Infect. 2010;60(6):467-73. 12. Collison SP, Trehan N. Native double-valve endocarditis by Mycobacterium fortuitum following percutaneous coronary intervention. J Heart Valve Dis. 2006;15(6):836-8. 13. Spell DW, Szurgot JG, Greer RW, Brown JW 3rd. Native valve endocarditis due to Mycobacterium fortuitum biovar fortuitum: case report and review. Clin Infect Dis. 2000;30(3):605-6. $FKHUPDQQ < 5|VVOH 0 +RIIPDQQ 0 'HJJLP 9 .XVWHU S, Zimmermann DR, et al. Prosthetic valve endocarditis and bloodstream infection due to Mycobacterium chimaera. J Clin Microbiol. 2013;51(6):1769-73.

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7\UDV '+ .DLVHU *& %DUQHU +% /DVNRZVNL /) 0DUU -- Atypical mycobacteria and the xenograft valve. J Thorac Cardiovasc Surg. 1978;75(3):331-7. 47. Wallace RJ Jr, Musser JM, Hull SI, Silcox VA, Steele LC, Forrester GD, et al. Diversity and sources of rapidly growing mycobacteria associated with infections following cardiac surgery. J Infect Dis. 1989;159(4):708-16. .XULWVN\ -1 %XOOHQ 0* %URRPH &9 6LOFR[ 9$ *RRG 5& Wallace RJ Jr. Sternal wound infections and endocarditis due to organisms of the Mycobacterium fortuitum complex. Ann Intern Med. 1983;98(6):938-9. 49. Fraser DW. Bacteria newly recognized as nosocomial pathogens.

Am J Med. 1981;70(2):432-8. /DVNRZVNL /) 0DUU -- 6SHUQRJD -) )UDQN 1- %DUQHU +% .DLVHU G, et al. Fastidious mycobacteria grown from porcine prostheticheart-valve cultures. N Engl J Med. 1977;297(2):101-2. 51. Jarand J, Levin A, Zhang L, Huitt G, Mitchell JD, Daley CL. Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease. Clin Infect Dis. 2011;52(5):565-71. 52. Cremades R, Santos A, RodrĂ­guez JC, GarcĂ­a-PachĂłn E, Ruiz M, Escribano I, et al. Screening for sterilizing activity of antibiotic combinations in an acid model of rapidly growing mycobacteria during the stationary phase of growth. Chemotherapy. 2009;55(2):114-8.

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Neirotti RA - Barriers to development: SPECIAL ARTICLE pushing the boundaries

Braz J Cardiovasc Surg 2015;30(1):104-13

Barriers to development: pushing the boundaries Barreiras ao desenvolvimento: expandindo as fronteiras

Rodolfo A. Neirotti1, MD, PhD, MPA, FECTS “Progress can change people’s consciousness, and when you change people's consciousness, and then their awareness of what is possible changes as well — a virtuous circle.� President Clinton Ultramini-abstract: Why some countries have failed to create democracy, wealth and happiness for their people is one of the great questions of our time. This essay encompasses a description of the multiple barriers to development that may have different characteristics, according to the context and the social structures that maintain these conditions. It would be arrogant to pretend to have all the solutions for these problems.

DOI: 10.5935/1678-9741.20150007

RBCCV 44205-1620

Descriptors: Democracy. Developing Countries.

Descritores: Democracia. PaĂ­ses em Desenvolvimento.

Although this essay focuses on the situation in the emergent countries, “the less privileged parts of the worldâ€? can exist anywhere. To illustrate my point, consider the 42 million people living below the poverty level in the United States of America. Lack of diversity due to social, intellectual, educational, and professional inbreeding, the latter representing cultural stagnation — doing the same thing repeatedly while expecting different results — can easily be responsible for WKH ODFN RI VFLHQWLÂżF SURJUHVV DQG GHYHORSPHQW ,W FRXOG EH \RXU SUREOHP $V (LQVWHLQ UHPLQGV XV Âł7KH VLJQLÂżFDQW problems we face cannot be solved at the same level of thinking we were at when we created themâ€?. The accumulation of mistakes combined with hubris, ignorance, hypocrisy, excess of diplomacy, bureaucracy and rampant corruption at all levels of the society are common 1

ÂżQGLQJV LQ SODFHV ZKHUH GHYHORSPHQW LV HOXVLYH $V D QDWLYH of one of those countries, I experienced it; therefore, it is not without sorrow that I am making these observations. Easy to GHVFULEH KDUG WR Âż[ Because this eclectic article is based on realism — the practice of regarding things in their true nature and dealing with them as they are — rather than employing the primitive defense mechanism of refusing to accept reality, I have no judgment about this piece, nor control over it. Nonetheless, it is possible to transform reality by creatively doing something never completed before. Novelties are often the result of the disruption of reality. As Dean Williams reminds us, “Fundamentally, the adaptive work of a creative challenge is group effort, and not to produce an individual psychological state of creativity‌ Anyone who has tried to exercise leadership in the face Correspondence adress: 1199 Beacon St, Unit 2. Brookline MA 02446 USA Email: RA_Neirotti@ksg06.harvard.edu

Honorary Member of the Brazilian Society of Cardiovascular Surgery.

Article received on December 17th, 2014 Article accepted on January 14th, 2015

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of a creative challenge soon realizes that creativity depends on the interaction among multiple people with different skills, perspectives, personalities, and attitudes. One individual may have a novel idea but not the ability to make it attractive or inspirational to othersâ€?[1]. 7KH ÂżJKW IRU WKH IXWXUH QRZ UHTXLUHV D GLIIHUHQW PLQG VHW one that includes a future that is struggling to be born, as former President Clinton put it: “Many of the world’s greatest challenges today are modern expressions of our oldest demons. The future never had enough voters — those interested in present gain usually win outâ€?. Our profession is immersed in the society and professionals are often absorbed in their daily activities without realizing that HYHQWV EH\RQG DQG DURXQG WKHP KDYH D VLJQLÂżFDQW LPSDFW LQ their lives and work. An intellectual revolution in performance, looking for ways to assess and apply the right changes to enFRXUDJH RQJRLQJ JURZWK LQ GHYHORSLQJ FRXQWULHV LV UHTXLUHG Governments, the private sector and foundations working together in innovative ways can lead to greater advancements than any of those groups could do on their own[2]. Assault on the Senses: First, listen! Then Boo! Although in their own way, some may hear it and become a factor of change altering the course of the events. Sometimes it is necessary to push audiences to the very limits of what they could understand or accept — and far beyond even if it sounds dissonant and that little immediate tradition lies behind it, as happened in Paris, in May 1913, during the premier of Stravinsky’s “The Rite of Springâ€? ballet. Though it is now one of Stravinsky’s most famous works, the inharmonic QRWHV RI WKH DYDQW JDUGH PXVLF RI KLV FUHDWLRQ ZDV ÂżUVW PHW with harsh criticism, negative reviews, and yes - a riot[3]. There is no easy time to say hard things. When to speak or not speak about pressing issues? Michael Bloomberg, former mayor of New York City, said in his 2014 Harvard University Commencement discourse “Do not feel reticent to speak what is right. Do not EH FRPSOLFLW 'R QRW IROORZ WKH FURZG 6SHDN XS DQG ÂżJKW back.â€? Supporting the free debate of opposing views is “a sacred trustâ€? of universities and the basis of a democratic society. At the same event, Drew Faust, President of Harvard University, emphasized that universities owe the future answers to QHZ TXHVWLRQV WKDW VWLPXODWH LQTXLU\ DQG GHEDWH DQG WKH DELOLW\ WR XQGHUVWDQG DQVZHUV WR TXHVWLRQV² DERXW WUXWK MXVWLFH JRRGQHVV and our origin — and develop meaning from them. In Atlas Shrugged, in which Ayn Rand expresses the advocacy of reason, individualism, capitalism, and the failures of governmental coercion, she aptly described ZKDW ZH ÂżQG LQ PDQ\ GHYHORSLQJ FRXQWULHV ÂłWhen you notice that to produce, you need to obtain authorization of those who produce nothing. When you see that the money Ă€RZV WR WKRVH ZKR WUDIÂżF QRW LQ JRRGV EXW IDYRUV When you see that men get richer by graft and by pull rather than by work and your laws do not protect you against them, but

protect them against you. When you see that corruption is UHZDUGHG DQG KRQHVW\ EHFRPHV D VHOI VDFULÂżFH WKHQ \RX ZLOO be able to claim without fear to be wrong, that your society is doomedâ€?[4]. The drama unfolds between predator and vicWLP $OWRJHWKHU LW LV WKH VDQFWLRQ RI WKH YLFWLPV GHÂżQHG E\ Leonard Peikoff as “the willingness of the good to suffer at the KDQGV RI WKH HYLO WR DFFHSW WKH UROH RI VDFULÂżFLDO YLFWLP IRU WKH ‘sin’ of creating valuesâ€?[5]. The driving forces of societies are Politics, Economics, and Culture Politics: Governments can play great roles in their countries, regions, and cities facilitating or leading the resolution of festering problems and opening new pathways for progress. Good citizens generate good politicians that are eventually responsible for good governance — the ability of a society’s leaders to think long term, address their problems with the optimal legislation and attract capable and honest people into government. Collaborative political leaders would look very GLIIHUHQW IURP WKH RQHV ZH DUH XVHG WR ,Q WKH ÂżUVW SODFH WKH\ would do what they could to create a culture of cooperation, not competition. An educated population should know how to elect honest and competent politicians. What is a True Democracy? Depending on the kind of political philosophy people are used to embracing, a true democracy is a society in which the citizens are not only electors, but also permanent actors in public affairs. When their participation is limited to elections, they lose their sovereignty soon after the vote. A true democracy is sustainable when people are committed to develop themselves intellectually, to expand WKHLU VFLHQWLÂżF NQRZOHGJH KLVWRU\ DQG PDNLQJ UHOLJLRXV EHliefs and erroneous beliefs a personal affair[6]. Faith must never EH WKH ÂżQDO ZRUG ZKHQ LW FRPHV WR ZULWLQJ WKH ODZ Ambiguous Democracy. Democracy vs. populism: Some believe that it is possible to achieve collective wisdom born out of individual ignorance. For others, democracy is self-correcting. Winston Churchill once said, “Democracy is a terrible thing — until you look at all the alternatives.â€? +RZHYHU LW LV HURGLQJ EHFDXVH FRUSRUDWLRQV DQG ÂżQDQFH FDSLWDOLVP DUH JURZLQJ IDVWHU WKDQ GHPRFUDF\ DQG LQĂ€XHQFLQJ it for their own ends. People spend their time “getting into politicsâ€? and too little time on why they want to be in politics, failing to ask: • First, “What do I believe in and why do I believe it?â€? • Second, “What do I want to do about giving effect to those beliefs, what policies would I want to change and what would I want to replace them with?â€? • Third, “What can I do now to bring about those changes?â€?[7] How could politicians that live in fear of mobilizing the “wrongâ€? voters ever vote to change the system that keeps them comfortably in power and provides lucrative post-politics careers? In addition, politicians have no interest in projects

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promoted by their predecessors — a potential explanation IRU WKH SROLWLFDO ODQGVFDSH OLWWHUHG ZLWK PLQHÂżHOGV WR VWRS action from happening. Their intentions sound good but then the actions are like a snail, with wonderful speeches not followed by coherent actions, using democracy for decoration rather than direction. The result is a loss of leadership and momentum, affecting the implementation of policies that assure sustainable growth for those living ten years from now. When blaming the politicians and showing your disrespect for the government, please remember that they are not aliens; they are elected members of your society with the same idiosyncrasy and values. Economics: Man wishes are growing continuously. Maslow’s Sets of Needs: As soon as needs on a lower OHYHO RI WKH S\UDPLG DUH IXOÂżOOHG WKRVH RQ WKH QH[W OHYHO ZLOO emerge and demand satisfaction. 1. Physiological needs. The basic needs cannot be postponed for long. These are food, shelter, clothing, rest, air, water, sleep, etc. 2. Safety needs. The desire to be safe is connected with the psychological fear of loss of jobs, property, natural calamities or hazards. 3. Social needs. Our needs for love, friendship, and to stay in a group. 4. Esteem needs. Our needs for social recognition, status and respect. 5. Self-actualization 7KLV LV DERXW IXOÂżOPHQW DQG WKH RSportunity for personal growth, to become what one is capable of becoming[8]. Persistent Development Failure: The causes are multiple DQG WKH FRQVHTXHQFHV KDYH DQ HQRUPRXV QHJDWLYH LPSDFW RQ SHRSOH DQG VRFLHW\ /LVWLQJ WKH SUREOHPV PD\ EH HDV\ ÂżQGLQJ solutions is not, creating a capability trap that is responsible for the persistent development failure. Fundamental changes in the world’s architecture and economy are needed. 'HYHORSPHQW LV MHRSDUGL]HG E\ XQLTXH OHYHOV RI GDLO\ LQterruptions that erode people’s ability to identify their purpose, to focus their attention on it, eventually disrupting their efforts to achieve excellence[9]. In this complex environment, repeating history and failing to form a direct path to destinaWLRQ LV D FRPPRQ ÂżQGLQJ ² FLUFXODU SURJUHVV ² LQVWHDG RI D straight pathway to it — linear progress[10]. Restricted Resources: Leadership, patience, perseverance, dedication, the capacity to adapt, and the creativity that will come with having to work under adverse circumstances, can result in temporary achievements but do not necessarily ensure sustainability in a social order with limited wealth. Things happen thanks to the hard work and creative adaptation of individuals who are able to stretch the bounds of their DELOLWLHV LQ VSLWH RI WKH UHVWULFWHG PHDQV ,QDGHTXDWH IXQGV are a constant problem forcing them to focus on short-term creativity and innovation about tomorrow’s needs. A great

deal of energy, in the form of leadership and negotiations, LV UHTXLUHG WR LQVXUH WKDW SHRSOH VXUSDVV WKHPVHOYHV DQG continue to work hard for a low pay continuously challenging themselves and those around them[11]. Altogether, contributing factors for emotional exhaustion, high level of depersonalization and a low level of personal accomplishment. Culture: Social ills in developing countries are blamable for the deterioration of the civil society. Lower rankings on such measures as the Index of Economic Freedom and Transparency International government corruption index, plus a fragile judiciary with limited independence, and a cloudy legislative process, are manifestations of unaddressed institutional weakness[12]. Interestingly, the world’s maps depicting corruption, health expenditures per capita, the burden of congenital heart disease and the absence of economic freedom clearly point to these countries. Importance of Institutional Quality: /RZ TXDOLW\ LQVWLtutions create “contaminatedâ€? incentives. Institutions are the VLWH RI PDQ\ RI RXU GLIÂżFXOW PRUDO SUREOHPV DQG WKH VRXUFH IRU PDQ\ RI WKH VROXWLRQV ,QVWLWXWLRQDO TXDOLW\ UHTXLUHV TXDOLW\ SHRSOH 7KH\ DUH WKH NH\ WR PDNLQJ TXDOLW\ SURGXFWV DQG PDNLQJ WKH best use of the ordinary distribution of human talent. Countries with a long history of incentivizing the development of strong political institutions (constitutions, regulatory authority, legal systems, and distribution of power) are more likely to succeed. In contrast, those that fail to develop have weak institutions where the government violates property rights and concentrates wealth and power in a class of elites at the cost of the majority— IUHTXHQWO\ DQ XQGHVLUDEOH VLGH HIIHFW RI SRSXOLVP[13]. Society, a complex system. Understanding Complexity: A system is a group of mutually supporting elements that are working together with a common objective. They are made up of individuals, activities, connections, and pathways. Ideally, in complex systems, all members contribute WR WKH TXDOLW\ RI RXWFRPHV WKURXJK DQ LQWHJUDWHG PDQQHU LQ which communication, organization, interdependence and reciprocal supervision are crucial. Still, like in an orchestra, a conductor is vital. The observations below describe the complexity and WKH GLIÂżFXOW\ LQ ÂżQGLQJ D ZD\ RXW Crime-Security expenditures are a drain on the economy: “Criminal activity acts like a tax on the entire economy: it discourages domestic and foreign direct investments; it reduces ÂżUPVÂś FRPSHWLWLYHQHVV DQG UHDOORFDWHV UHVRXUFHV FUHDWLQJ XQFHUWDLQW\ DQG LQHIÂżFLHQF\´[14]. “Crime not only leads to material and immaterial costs for those who have become victimized, but crime also forces local and national authorities to spend

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billions on the prevention of crime and the detection, prosecution and punishment of criminalsâ€?. Unfortunately, some governments prioritize economic reforms, and play down law and order, as the way to modernize WKHLU FRXQWULHV ZLWKRXW DGPLWWLQJ WKDW ERWK DUH HTXDOO\ LPSRUWDQW Suboptimal education. Education of the underclass is a challenge with many unanswered questions: “When will we start to talk about practical ways of confronting the fact that many so-called at-risk children are in family situations that place them at a disadvantage at birth? What are both constitutionally acceptable and morally acceptable and practicable solutions to addressing this issue? How can we support families (single mothers) who lack the knowledge, motivation, and FDSDELOLW\ IRU SUHSDULQJ WKHLU FKLOGUHQ WR EHQHÂżW IURP HGXFDWLRQ" 7KHVH DUH WRXJK TXHVWLRQV WKDW DUH QRW EHLQJ DGGUHVVHG Without doing so, “education, education, and educationâ€? is a mere sayingâ€?[15]. “Unfortunately, the parents of these children are barely surviving and do not have the money and time to prepare them to learn in school. So where are the funds coming from? Our capitalist culture does not agree to provide these children with more services. We watch them fall behind because of their parents’ lack the knowledge, motivation, and capability IRU SUHSDULQJ WKHLU FKLOGUHQ WR EHQHÂżW IURP HGXFDWLRQ´[16]. There is a gap between what educational systems provide and what employers need. Universities should modernize their curriculum according to individual learning needs rather than WKH RQH VL]H ÂżWV DOO DSSURDFK DGRSWLQJ HGXFDWLRQDO PRGHOV that allow adaptation of resources to address local priorities. In today’s economy, we need people who can take knowledge, apply it to new things and create new possibilities. Education is not a luxury; it is a necessity in this new century. Lessons of the Finnish education system: Purpose: to create a system that people are happy with — 90% in Finland vs. 29% in the USA when most of the ideas come from the USA! Successful State: among the best in most of World Economic Forum indexes. Six percent of GDP invested in education. Equal Society: /RZ LQFRPH LQHTXDOLW\ FKLOG SRYHUW\ UDWH DQG ORZ *LQL FRHIÂżFLHQW GHPRQVWUDWLQJ WKDW ZKHQ \RX close the gap the bar will rise. Cooperative Society: Teaching is a team effort. Schools ready for all children. Great schools for each child. Winners do not compete they collaborate. Autonomy of the schools: over curricula and assessment WR LPSURYH TXDOLW\ DQG WR ÂżQG \RXU WDOHQW 6WURQJ FRUUHODWLRQ between student’s achievement and family background[17]. Knowledge gap: Latin America, with a low number of patents has not excelled at doing new things or at doing the

same things in a new and better way — disruptive innovaWLRQV ,W KDV EHHQ VORZ WR DFTXLUH DGRSW DQG DGDSW WHFKQRORgies that exist in other places. Yet there is no lack of talented and passionate people in this part of the world, nor of problems to solve. The bottleneck is in the support to let their innovative WDOHQWV Ă€RXULVK 7DOHQW DQG LQWHOOLJHQFH PD\ EH VSUHDG HYHQO\ across the planet, but opportunities are not. Regrettably, most RI WKH UHTXLUHPHQWV IRU LQQRYDWLRQ LQFOXGLQJ UHIRUPV LQ WHUtiary education are often not present in poor countries and in emerging economies. Inequality and Poverty. Social Considerations: GrowLQJ LQFRPH LQHTXDOLW\ DIIHFWLQJ LQWHUJHQHUDWLRQDO PRELOLW\ ² even among advanced economies — is one of the biggest social, economic and political challenges of our time. “Should the improvement in the circumstances of the lower ranks of the people — Great Divide — be regarded as an advantage RU DV DQ LQFRQYHQLHQFH WR VRFLHW\" 7KH DQVZHU VHHPV DW ÂżUVW abundantly plain. What improves the situation of the greater part can never be regarded as problematic to the whole. No VRFLHW\ FDQ VXUHO\ EH Ă€RXULVKLQJ DQG KDSS\ LI WKH JUHDWHU SDUW of the numbers are poor and miserableâ€? [18]. Scarcity has many faces, changing from place to place and across time. Scarcity creates a similar psychology for everyone struggling to manage with less than they need. Just as busy peoSOH IDLO WR PDQDJH WKHLU WLPH HIÂżFLHQWO\ IRU WKH VDPH UHDVRQV the poor fail to manage their money. Up to now, efforts to GHYHORS D XQLÂżHG ÂżHOG WKHRU\ WR VROYH WKH SUREOHP KDYH LQHYitably fallen short[19]. - Poverty is hunger, is lack of shelter, and is being sick and not being able to see a doctor. - Poverty is not having access to school and not knowing how to read. - Poverty is not having a job, is fear for the future, and is living one day at a time. - Poverty is losing a child to illness brought about by unclean water. - Poverty is powerlessness, lack of representation and freedom. - “Poverty is the most lethal weapon of mass destructionâ€?[20]. “Nearly 164 million people live in poverty in Latin America (27.9% of the population), 68 million of whom are considered destitute. Since 2002, poverty in Latin America has fallen by 15% and destitution has dropped by 8%, but ÂżJXUHV IURP D UHFHQW VWXG\ E\ WKH (FRQRPLF &RPPLVVLRQ for Latin America and the Caribbean (ELAC) show that the rate of decrease is slowing. While poverty and destitution in this region decreased in 2012 in comparison with 2011, it remained unchanged in 2013. Countries in this region should push for more rapid structural changes in their economies to SURPRWH VXVWDLQHG JURZWK ZLWK JUHDWHU HTXDOLW\´[21]. Nonetheless, the middle class has grown in those countries with faster economic growth — in which center-left

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governments have adopted redistributive policies, spending the fruits of the now ending commodities boom on social programs, young people are more educated, empowered, and demanding better public services[22]. ,Q DGGLWLRQ WR WKH HFRQRPLF LQHTXDOLW\ WKHUH LV RIWHQ LQHTXDOLW\ EHIRUH WKH ODZ ² RQH ODZ IRU WKH SRRU DQG GLVDGYDQtaged and another for the rich and famous that can afford to hire the best lawyers and mount the best defense possible. When was the last time that a wealthy man was executed? A two-tiered criminal justice system discriminating based on socioeconomic VWDWXV UDFH DQG JHRJUDSK\ LV PRUDOO\ XQDFFHSWDEOH ,QĂ€XHQFH brings privilege, and privilege can plainly mean getting away with wrongdoing. A further burden of poverty is inadequate health care: In emerging economies, low per capita expenditures and the LQDGHTXDWH DOORFDWLRQ RI IXQGV H[SODLQ WKH GLIIHUHQFHV LQ VXFcess in the rich countries. Sixty percent of cancer cases and 70% of deaths from cancer happen in Africa, Asia, Central America and South America[23]. Unemployment: Although two thirds of the recent global economic growth happened in the developing world, a vast number of the young grew restless because of unemployment. Furthermore, the development of the infrastructure and professional skills has not kept pace with the surging demand for skilled workers despite the expanding economy[24]. Thanks to the electronic media, people are increasingly aware that these wrongs cannot be easily or rapidly put right and that those opportunities are more attractive in developed countries. Corruption: What is happening in many countries today is not just a pathology, but a predictable pathology that arises whenever a society has no checks on behavior, no acceptance of any rule of law, and no respect for rules of procedure[25]. Does corruption arises from individuals’ diminished personal integrity and misconduct or from institutional arrangements? Institutional corruption is the result of a guidance ZLWKLQ DQ HFRQRP\ RI LQĂ€XHQFH WKDW LOOHJLWLPDWHO\ ZHDNHQV institutional effectiveness especially by weakening the public trust — “Crisis of Credibilityâ€?[26]. Interestingly, Aristotle in “Nicomachean Ethicsâ€?, a compilation of lecture notes, emphasizes the role of an active condition in the moral search for ethical virtue, a state that consists in choosing “the just oneâ€? between the two ends. The no and the yes are always in our power. Both, virtue and corruption are in our control. It is in our power to do something, as it is not to doing it[27]. In “Theory of Moral Sentimentsâ€?, Adam Smith introGXFHG D GLIIHUHQW H[SODQDWLRQ DERXW WKH DFTXLVLWLRQ RI PRUDO values, suggesting that it is a process starting early in life and based on the approval or disapproval of what happens around us.

Are these concepts compatible in an era in which social, SROLWLFDO DQG ÂżQDQFLDO V\VWHPV DUH FRUUXSWHG HOHFWLRQV DQG democracy manipulated by corporate interests, religious groups taking over governments, or charlatans dominating DQG FRQWUROOLQJ ÂżQDQFLDO V\VWHPV DQG WKHUHE\ LQĂ€XHQFLQJ the legislative and judicial integrity? Corruption is not just a TXHVWLRQ RI HWKLFV EXW DOVR RQH RI HFRQRPLFV $V FRPSDQLHV in rich nations push into poorer regions, illicit gains connected with politics or business go global. The World Bank estimates that $1 trillion in bribes is paid DQQXDOO\ WR RIÂżFLDOV $Q HVWLPDWHG WULOOLRQ D \HDU LV EHLQJ taken out of poor countries and 3.6 million lives are lost because of corruption. In Africa alone, $148 billion is siphoned off annually. Not surprisingly, protective of their interests, corporaWLRQV SUHIHU VHWWOHPHQWV WR WKH FDWDVWURSKLF ÂżQDQFLDO SHQDOWLHV and the bad publicity if they lose in court. In the end, some of the people that are charged are extremely rich and powerful, and can afford great attorneys[28]. Corruption is a societal pathology closely related to blind spots and perception of legality: “Why do we often fail to do what is right? When confronted with an ethical dilemma, most of us like to think we would stand up for our principles, but we may not be as ethical as we think we are, due to blind spots. We often overestimate our ability to do what is right and act unethically without meaning to. There is no good reason to believe that we would behave any differently from the agent, the auditor, the buyer, or the seller when ZH KDYH FRQĂ€LFWLQJ PRWLYDWLRQV DQG LQWHUHVWV 7R DYRLG VXFK XQLQWHQGHG XQHWKLFDO EHKDYLRUV WKH ÂżUVW VWHS LV WR UHFRJQL]H our own fallibility.â€?[29]. Not surprisingly, ethical fading — the removal of ethics from the decision making process — can negatively affect our judgment by shifting our ethical values. “We can become more ethical by bridging the gap between who we are and who we want to be.â€?[30]. Lack of integrity is the main obstacle. “Without integrity, there is no trust. Without trust, there is no leadership, with everyone for himself. Without integrity, there is corruption, no respect for rule of law, and no true democracy. Unfortunately, once corruption becomes ingrained and an integral part of the society, it takes a miracle to change itâ€?[31]. Tax evasion. Merits of taxes: ‡³1R RQH VL]H ÂżWV DOO´ $Q HIIHFWLYH VWUDWHJ\ WR UHGXFH WD[ HYDVLRQ DQG DYRLGDQFH WKDW QHHGV WR EH WDLORUHG WR WKH VSHFLÂżF country’s environment. •A strategy should involve both measures at the national as well as the international level. Actions at the international OHYHO FDQ RQO\ EH LPSOHPHQWHG VXFFHVVIXOO\ LI VSHFLÂżF SUHUHTXLVLWHV RQ WKH QDWLRQDO OHYHO DUH JXDUDQWHHG ‡(TXDOO\ PHDVXUHV XQGHUWDNHQ DW WKH LQWHUQDWLRQDO OHYHO KDYH WR EH DFFRPSDQLHG E\ DGHTXDWH VWUDWHJLHV DW WKH QDWLRQDO OHYHO

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health security a priority in individual countries. Alarmed by Ebola, the public is not reassured by what specialists say, and anxiety has soared about the potential for contagion. Lessons from this epidemic can be helpful for future outbreaks.

Main Factors facilitating tax evasion and avoidance: -Low willingness to pay taxes by taxpayers usually results from the tax rates and perception that they are unfair, or from the lack of transparency and accountability in the use of public funds, or the lack of service in return, or of the rule of law, as well as poor tax morale, and high compliance costs. -Low ability to enforce tax law and tax collection due to low probability of detection, low penalties, high level of corruption, large informal sector, and incompetence of the tax administration[32].

The absence of a social contract: an actual or hypothetical agreement among the members of an organized VRFLHW\ RU EHWZHHQ D FRPPXQLW\ DQG LWV UXOHUV WKDW GHÂżQHV and limits the rights and duties of each. The people agree to obey the ruler in all matters in return for a guarantee of peace and security. In surrendering their individual freeGRP WKH\ DFTXLUH OLPLWHG DJUHHG XSRQ SROLWLFDO OLEHUW\ DQG FLYLO ULJKWV D FRYHQDQW IRU PXWXDO EHQHÂżW EHWZHHQ DQ individual or group and the government or community as a whole. Regrettably, people often act slavishly by voting every few years and then passively accept what their representatives say[36].

Lack of independent and reliable justice. Checks and balances: In many developing countries, because of the lack of separation of powers, it is never easy and often impossible to legislate against the will of the executive branch. Government systems that employ a separation of powers need a way to balance each of the branches to induce them to cooperate and to prevent one branch from becoming supreme. Typically, the latter is avoided through “checks and balances� — a system-based regulation that allows one branch to limit another, helping to ensure that no one branch becomes too powerful. Although it will not be an easy win, it is also necessary to balance the power of big money with the power of big ideas. http://en.wikipedia.org/wiki/Separation_of_powers Unfortunately, regimes that violate these principles could survive a long time despite an economic crisis if the level of control over all government institutions, the press, education, and the business environment, is strong. Many perceive the job of the police and the courts as implementing political control, rather than investigating thugs.

Lack of solidarity and social responsibility. Participation: It is important that people take an active role in the social, political, and economic aspects of the society in order to defend the interests of those suffering. The time has come, to decide whether they will continue to be a part of the problem, or whether they will be part of the solution. Modest philanthropic efforts: Philanthropy is sub-optimal despite not everyone’s being poor in the poor countries due to culture and/or interpretation, religion, lack of trust, and lack of tax incentives, as well as tax evasion. Philanthropy is not the solution for poverty. A combination of economic growth, higher human capital, social inclusion, and political will can help.

Lack of long-term planning and a consistent model: Has the traditional approach of the Big World Planners found the solution to enrich the poor, to feed the hungry, and to save the dying? The answer is No, due to ineffective efforts, despite spending more than $ 2 trillion[33]. Outdated infrastructure. The recent Ebola epidemics is a clear example of the dismal infrastructure in the affected countries and the weaknesses of their health systems. The risks for volunteers is high. According to the WHO, a significant number of healthcare workers have been infected since the outbreak began and many of them have died[34]. “If there was a health care infrastructure able of rapidly identifying DQG LVRODWLQJ FDVHV DQG SURYLGLQJ DGHTXDWH PHGLFDO FDUH DQG doing the proper contact tracing then this epidemic might have been put under control a long time ago�[35]. As Paul Farmer, co-founder of Partners in Health put it, “Outbreaks are inevitable. Epidemics are optional.� $ &RDOLWLRQ RI ,QDFWLRQ 7KH LQDGHTXDWH DQG ODWH UHVSRQVH to the current epidemic stresses how little focus has been on the need of a strong global health set-up and making global

All of the above indicate that social and human capital DV GHÂżQHG EHORZ DUH ORZ LQ GHYHORSLQJ FRXQWULHV Social Capital and Social Bonds: The levels of trust, tolerance, cooperation and reciprocity among individuals in a particular social environment is the base for teamwork. The success of a society depends on the strength of its communities rather than on peer pressure. Bad things happen when good people do nothing. Human Capital: This is the knowledge, skills, and experWLVH WKDW LQGLYLGXDOV DFTXLUH WKURXJK HGXFDWLRQ DQG WUDLQLQJ XVHG WR SURGXFH WKLQJV VHUYLFHV RU LGHDV 7KH JUHDWHU TXDQWLW\ DQG TXDOLW\ RI VNLOOHG ZRUNHUV LQ ULFK FRXQWULHV VXJJHVW that human capital is a central vessel for social and economic GHYHORSPHQW 7KH TXDQWLW\ DQG TXDOLW\ RI FRPSHWHQW ZRUNHUV has a direct effect on the economic improvement of a society. The power is in the hands of each citizen[37]. Collaborative Rationality: Both social and human capital are complementary for getting better together, which is a different way of knowing, generating, making and justifying decisions based on diversity, interdependence, and authentic

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dialogue. The agents, facing a common problem, think logically and interact exchanging information in an open system, WR LGHQWLI\ D FRPPRQ VROXWLRQ IRU WKH EHQHÂżW RI DOO DYRLGLQJ the limitations of acting unilaterally. The culture of the group overcomes the culture of the superstar[38]. Raising the bar. Upward Comparison. Since we tend to overestimate where we stand in contrast to others, comparing our self to others is not bad if we avoid a twisting strategy to ÂżW GDWD ² 3VHXGR 0DWKHPDWLFV[39]. Upward comparison, as economists and psychologists call it, can diminish our success — we are not the best anymore — but also encourage us to learn. Although looking around us can be punishing, it is better to watch good players, and improve our performance, than bad ones and feel superior[40].

Notwithstanding the extensive use of foreign advisors in emergent countries, there has been little examination of their roles. Outside consultants should not become insiders. One of the things necessary for them is to remain outsiders. Foreign technical advisers work by a different set of rules than nationals within the hierarchy. How do their roles differ from those of the KRVW FRXQWU\" +RZ GR RXWVLGHUV DFTXLUH LQĂ€XHQFH" 7R ZKRP DUH WKH\ DFFRXQWDEOH" 7KHVH UHPDLQ LPSRUWDQW TXHVWLRQV VLQFH WKH DGYLVRUV H[HUFLVH YDVW LQĂ€XHQFH ZLWK OLPLWHG DFFRXQWDELOLty and without organizational authority. Foreigners have the responsibility to consider the feasibility and broader context of their recommendations for moving people from dependency to VHOI VXIÂżFLHQF\[44]. Useful Rules for Wise Advisors. Listening is an act of love: -“Encourage your advisee to tell their stories in order to understand the problems faced by locals. First listen and let them tell you why they need your help, and then ask what help they feel they need.â€? -“Do not talk too soon. Avoid proving your value by offering advice before you know the problem fully.â€? -“Avoid early judgment. If the advisee senses that you are judgmental, he/she will probably become defensive and guarded. An open-minded understanding helps to gain trust and cooperationâ€?[45].

Why some nations are rich and others are poor and volatile. Order vs. Disorder Regardless of the effort and brainpower that go into designing complex systems and their “system of workâ€?, it is impossible to do it perfectly and to predict the behavior of individuals under the conditions in which they must perform[41]. Order. Developed countries set themselves apart in how they deal with the unpredictable problems of complex systems. They manage to stay ahead because of their endurance, responsiveness, and their velocity in self-correction by bringing their modules together and making them better than the sum of their parts. Altogether bring about more capabilities, and the more capabilities they have the more likely they are to grow economically[42]. Disorder. Conversely, in emerging countries their parts come together through hard work, goodwill, and improvisaWLRQ ² D SDWFKZRUN DSSURDFK WR Âż[LQJ SUREOHPV 7KHLU FRPponents are managed as if they operated independently when in fact they are interdependent[41].

The Power of Noticing: What Effective Leaders See. What are the critical threats and challenges that we are ignoring or denying? Why the leaders of some organizations fail to identify key problems and act before things turn catastrophic? Cognitive dissonance: a pandemic phenomenon, whereby people do not want to see or cannot see because the group is not designed to see, and there are other people who are keeping us from seeing — motivated blindness, projecting an Âł(YHU\WKLQJ LV MXVW ÂżQH´ DWWLWXGH

Are foreign advisors useful? Yes, when they are aware of the local context. International executives need “contextual intelligence� — the ability to recognize the limits of their knowledge and adapt it to different environments [43]. The link between leadership and culture is complex. It is not always easy to appreciate or understand that what people do, mean, and say, varies from one culture to the next. Understanding another part of the world better is an avenue for transcultural understanding. Without this understanding, it is impossible to lead in another culture. A style that would be effective in one culture might be dysfunctional in another. This is the case in the national culture as well as in the corporate culture. Furthermore, diplomacy is often necessary to pass the borders of ignorance, culture, and geography. “Despite what we would like to believe, management practices — even the most effective ones — do not travel across borders�[43].

Adapting Development Models: Experiences from other global efforts may reveal the obstacles while providing valuable strategies for success[46]. However, as Lant Pritchett has noted, "models with proven effectiveness in other settings often fail to take hold in developing countries even despite having governments and international support. The name for the practice behind the problem is isomorphic mimicry. This KDSSHQV ZKHQ FRQVXOWDQWV DQG SXEOLF RIÂżFLDOV GURS D UHSOLFD RI a proven model into an obsolete system. Unless resident agents work to give it a life of its own, it remains a replicaâ€?[47]. Recipient Responsibility. Impact of mindset: In the words of Robert G. Gard, “What cannot be taught, however, LV PRWLYDWLRQ RU LQFHQWLYH ² PRUDOH RU FRQÂżGHQFH LQ DQG commitment to, the nation’s institutions and leadership. This intangible element, essential to success, depends on the

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legitimacy of domestic governance. The legitimacy of the parent institutions is as necessary to success as well-trained personnelâ€?[48]. People’s self-theories about intelligence have DQ LQWHQVH LQĂ€XHQFH RQ WKHLU PRWLYDWLRQ WR OHDUQ DQG VXEVHTXHQWO\ RQ LQVWLWXWLRQV 7KRVH ZKR KROG D ³¿[HG´ WKHRU\ DUH mainly concerned with how smart they are — they prefer tasks they can already do well and avoid ones on which they may make mistakes and not look smart. In contrast, people who believe in an “expandableâ€? or “growthâ€? theory of intelligence want to challenge themselves to increase their DELOLWLHV HYHQ LI WKH\ IDLO DW ÂżUVW[49].

changes by deciding which parts of their business model to preserve and which to dump. Real Leadership: Instead of looking for saviors, we should EH FDOOLQJ IRU D OHDGHU WKDW ZLOO FKDOOHQJH XV WR IDFH GLIÂżFXOWLHV IRU ZKLFK WKHUH DUH QR VLPSOH VROXWLRQV UHTXLULQJ XV WR OHDUQ new ways. Making progress on these problems demands not someone who provides answers from on high but changes in our attitudes, behavior, and values[1]. Successful leaders have the guts to marginalize radicals and nihilists who refuse to play by the rules of the institution. Maladaptive practices exist everywhere and they eventually become adaptive challenges that do not subside with the application of technical skills provided by the professional. The IUHTXHQF\ DQG SHUVLVWHQFH RI PDODGDSWLYH SUDFWLFHV LV UHODWHG to the resistance of people to change and human nature’s tendency to apply the “minimal riskâ€? and “least effortâ€? strategies that result in incomplete adaptive work, allowing subsistence but no optimal result[1]. The principle-policy-implementation gap plays an additional roll. Flexible adaptive leadership allows leaders to adjust, react and operate according to the needs of different contexts. The capacity to adapt enables both individual and business needs to be met through making changes to the time (when), location (where), and manner (how) in which people work[53].

Resistance to change. Ask what you can do and imagine what we can do together: Instinctively, people know that something is wrong but talk about change is often located in the near future, rarely in the present. Almost everybody accepts the idea of an out-of-date society or system trying to become a normal and modern developed country. The ability to see room for improvement, however, is not of much use unless one also has a strong desire to improve. Agreement on a problem does not produce agreement on a solution. An early desire to look different can be abandoned when key supporters realize this means real changes and is against their interest — which produces a policy-implementation gap. Unfortunately, people appear to have the right to complain but do not believe that it is WKHLU GXW\ WR GR VRPHWKLQJ DERXW LW Âż[ ZKDW LV EURNHQ DQG to make the world a better place. Reinforcing a dysfuncWLRQDO V\VWHP VWUDQJOHV LQQRYDWLRQ DQG VWLĂ€HV WKH SURJUHVV of organic adaptation. Fundamental transformation of human nature is utopian, but partial transformations of human behavior occur all the time. Progress can change people’s awareness of what is possible. Without failure, there is no innovation. Do not be afraid to explore what you could be! Change is in each of us[50]. “If we who have the talent and knowledge don’t look after the problems ourselves, then others who are less talented and more ignorant of those problems will certainly do it for usâ€?[51].

Technology vs. Humans. Will technology assist individuals or limit them? $GYDQFHV LQ DUWLÂżFLDO LQWHOOLJHQFH ZLOO PHDQ WKDW FRPSXWHUV rather than people will make more judgments and computers may not be able to explain their reasoning. All of us should ask ourselves what we could do now to improve the chances of JDLQLQJ WKH EHQHÂżWV DQG DYRLGLQJ WKH ULVNV ,Q WKH QHDU IXWXUH DFFHVV WR LQIRUPDWLRQ DQG QHZ WHFKQRORJ\ PD\ PDNH SURÂżWV DQG SULYDF\ REVROHWH DQG IRUFH XV WR UHGHÂżQH WKH ERXQGDULHV between humanity and machines. These are advancing fast, and bring with them great hopes, but also great fears. Technology is neutral but people are not!

Business Model Innovation: a different way of generating change. A less radical and less expensive alternative is creating value through business model innovation — how companies do business; this can decrease resistance and simplify execution. It can be done by business model improvements, which can occur in a number of ways by adding and integrating novel activities and/or linking activities in a new way, changing one or more parties that perform any of the activities. “Who performs what? The “whatsâ€? DUH QRQVSHFLÂżF the “howsâ€? DUH VSHFLÂżF WR \RX DQG WKH RUJDQL]DWLRQ \RX DUH working with: going from what to how has to be understood through practiceâ€?[52].What they do will be less important proYLGLQJ WKDW TXDQWLWDWLYH HYDOXDWLRQ RI LWV LPSDFW IROORZV WKH change. Countries and organizations can survive dramatic

Hopes: •Internet: communications, information, networking. “Exported knowledge fuels development. Tacit knowledge is VSUHDG WKURXJK KXPDQ LQWHUDFWLRQV ZKLFK XVXDOO\ UHTXLUHV proximity. Bridges between people in different countries have increased, as global communications develop. This local diffusion of knowledge can help explain the well-known fact that rich and poor countries tend to be geographically clusteredâ€?[54]. Cluster: a geographically proximate group of interconnected companies and associated institutions in a SDUWLFXODU ÂżHOG OLQNHG E\ FRPPRQDOLWLHV DQG FRPSOHPHQtarities[55]. • Education: free online education, classes, courses and degrees.

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• Innovation: robotics, automation, energy, additive manufacturing and 3D bioprinting in which tissues containing blood vessels and multiple cell types can now be assembled in architectures approaching the complexity of human tissues. • Sciences: improving connectivity and removing barriers to cooperation, exchange of knowledge and interdisciplinary alliances. • Health Care Quality

ACKNOWLEGMENT The author is grateful to Professor Gilbert R. Davis, PhD, Emeritus, Grand Valley University, Grand Rapids, MI, for his valuable suggestions and help in preparing the different parts of this manuscript.

Fears to the downsides of advancing technology: The only way to beat an existing technology is to bring in a disruptive and creative new technology that is a strong alternative. Just bad-mouthing it and stressing its handicaps do not go very far. • Overuse/misuse • Health Care Cost. “In every other sector of the economy, technology makes life cheaper, easier and better. In medicine, new treatments and devices usually do the last thing in that WULR VRPHWLPH WKH VHFRQG EXW UDUHO\ LI HYHU WKH ÂżUVW´[56]. • Unemployment (youth): a time bomb! ‡ ,QHTXDOLW\ • Cybercrime. National security. Many countries have nuclear materials in installations that are not safe. Sophisticated technology is not yet in the hands of terrorist organizations, but it might be one day in the future. • Addiction, dependence, and distraction: today, all facets of the information age lead to overwhelmingly negative interUXSWLRQV ,Q WKH HQG D SHUVRQ UHTXLUHV D PHWKRG +H PXVW EH able to distinguish between creative and destructive distractions by the sort of taste they have, whether they feel depleting or IXOÂżOOLQJ 0RUHRYHU WKLV FDQ ZRUN RQO\ LI KH LV LQ JRRG FRPPXnication with himself — an artist of his own life. • Quality of life, stress? A Word of Caution: “Often people get what they could get, but getting the wrong thing is not necessarily the right thing to do. In medicine, for example, there is always a risk of being VDWLVÂżHG ZLWK GHOLYHULQJ VXE VWDQGDUG FDUH LQ UHVRXUFH OLPLWHG settings, assuming that offering some care is better than no care, or that reaching a larger number of people with sub-optimal care is preferable to reaching fewer people with more sophisticated and therefore more expensive careâ€? [57]. Quo Vadis? In developing countries, government ofÂżFLDOV DQG WKHLU SRSXODWLRQ KDYH WR GHFLGH ZKHUH WKH\ DUH heading: - “For the sailor who does not know where it goes, there is never a favorable wind“ -´3DUD R PDULQKHLUR TXH QmR VDEH SDUD RQGH YDL QXQFD Ki XP YHQWR IDYRUiYHO´ Âł3DUD HO QDYHJDQWH TXH QR VDEH DGyQGH YD QXQFD KD\ vientos favorablesâ€? Lucio Seneca (4 BC - 65 AD)

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118 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Kubrusly LF, et al. - Comparison of polyurethane with cyanoacrylate in EXPERIMENTAL WORK hemostasis of vascular injury in guinea pigs

Braz J Cardiovasc Surg 2015;30(1):119-26

Comparison of polyurethane with cyanoacrylate in hemostasis of vascular injury in guinea pigs Comparação do poliuretano com cianoacrilato na hemostasia de injúria vascular em cobaias

Luiz Fernando Kubrusly1, PhD; Marina Simþes Formighieri2,3; JosÊ Vitor Martins Lago2,3; Yorgos Luiz Santos de Salles Graça2,3, MD; Ana Cristina Lira Sobral2, MD; Marianna Martins Lago4, MD

DOI 10.5935/1678-9741.20140125

RBCCV 44205-1622

Abstract Objective: To evaluate the behavior of castor oil-derived polyurethane as a hemostatic agent and tissue response after abdominal aortic injury and to compare it with 2-octyl-cyanoacrylate. Methods: Twenty-four Guinea Pigs were randomly divided into three groups of eight animals (I, II, and III). The infrarenal abdominal aorta was dissected, clamped proximally and distally to the vascular puncture site. In group I (control), hemostasis was achieved with digital pressure; in group II (polyurethane) castor oil-derived polyurethane was applied, and in group III (cyanoacrylate), 2-octyl-cyanoacrylate was used. Group II was subdivided into IIA and IIB according to the time of preparation of the hemostatic agent. Results: Mean blood loss in groups IIA, IIB and III was 0.002 grams (g), 0.008 g, and 0.170 g, with standard deviation of 0.005 g, 0.005 g, and 0.424 g, respectively (P=0.069). The drying time for cyanoacrylate averaged 81.5 seconds (s) (standard deviation: 51.5 seconds) and 126.1 s (standard deviation: 23.0 s) for polyurethane B (P=0.046). However, there was a trend (P=0.069) for cyanoacrylate to dry more slowly than polyurethane A (mean: 40.5 s; SD: 8.6 s). Furthermore, polyurethane A had a shorter drying time than polyurethane B (P=0.003), mean IIA of 40.5 s (standard deviation: 8.6 s). In group III, 100% RI WKH DQLPDOV KDG PLOG VHYHUH ÂżEURVLV ZKLOH LQ JURXS ,, RQO\ VKRZHG WKLV GHJUHH RI ÂżEURVLV P=0.001).

Conclusion: Polyurethane derived from castor oil showed similar hemostatic behavior to octyl-2-cyanoacrylate. There was less perivascular tissue response with polyurethane when compared with cyanoacrylate.

1

Correspondence address: Luiz Fernando Kubrusly Instituto de Pesquisa Denton Cooley Rua Alferes Ă‚ngelo Sampaio, 1896 - Bairro Batel, Curitiba, PR, Brazil Zip code: 80420-160 E-mail: kubrusly@incorcuritiba.com.br

Serviço de Cirurgia Cardiovascular do Instituto do Coração de Curitiba Hospital Vita, Curitiba, PR, Brazil. 2 Faculdade EvangÊlica do Paranå, Curitiba, PR, Brazil. 3 Instituto de Pesquisa Denton Cooley, Curitiba, PR, Brazil. 4 Instituto de Infectologia Emílio Ribas, São Paulo, SP Brazil.

Descriptors: Polyurethanes. Cyanoacrylates. Guinea Pigs. Hemostasis. Castor Oil.

Resumo Objetivo: Avaliar o comportamento hemoståtico e a reação tecidual do poliuretano, derivado da mamona, após injúria da aorta abdominal de cobaias e comparå-lo com o 2-octil-cianoacrilato. MÊtodos: Vinte e quatro cobaias foram divididas aleatoriamente em três grupos de oito animais (I, II e III). A aorta abdominal infrarrenal foi dissecada, pinçada proximal e distalmente ao local que se procedeu à punção vascular. No grupo I (controle), a hemostasia foi feita com digitopressão; no grupo II (poliuretano), aplicou-se o selante vegetal e, no grupo III (cianoacrilato), aplicou-se o 2-octil-cianoacrilato. O grupo II foi subdividido em IIA e IIB, conforme o tempo de preparo do poliuretano. Resultados: A mÊdia de perda sanguínea nos grupos IIA, IIB e III foi 0,002 g, 0,008 g e 0,170 g, com desvios padrþes de 0,005 g,

Work carried out at Instituto de Pesquisa Denton Cooley, Curitiba, PR, Brazil Article received on July 12nd, 2014 Article accepted on December 22nd, 2014

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119 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Kubrusly LF, et al. - Comparison of polyurethane with cyanoacrylate in hemostasis of vascular injury in guinea pigs

Braz J Cardiovasc Surg 2015;30(1):119-26

0,005 g e 0,424 g, respectivamente (P=0,069). O tempo de secagem do selante cianoacrilato foi em mĂŠdia 81,5 segundos (s) (desvio padrĂŁo: 51,5 s), enquanto o poliuretano B levou 126,1 segundos (desvio padrĂŁo: 23,0 s) (P=0,046). Entretanto, houve tendĂŞncia (P=0,069) do cianoacrilato apresentar um tempo maior de secagem que o poliuretano A. AlĂŠm disso, o poliuretano A teve um tempo de secagem menor que o poliuretano B (P=0,003), com mĂŠdia para o IIA de 40,5 segundos (desvio padrĂŁo: 8,6 s). No grupo III, 100%

GRV DQLPDLV WLYHUDP ÂżEURVH PRGHUDGD DFHQWXDGD HQTXDQWR QR grupo II apenas 12,5% (P=0,001). ConclusĂŁo: O poliuretano derivado da mamona apresentou comportamento hemostĂĄtico semelhante ao 2-octil-cianoacrilato. A cola vegetal demonstrou menor reação tecidual perivascular. Descritores: Poliuretanos. Cianoacrilatos. Cobaias. Hemostasia. Ă“leo de RĂ­cino.

INTRODUCTION Hemostatic control of small vessels sutures is a crucial point in cardiovascular surgeries and demands great experience of the surgeon[1]. Nevertheless, bleeding through the suture line is a major cause of mortality. In other areas such as surgical trauma, solid organs such as liver and spleen may DOVR KDYH EOHHGLQJ RU PD\ GLI¿FXOW WR FRQWURO GXH WR IULDELOLW\ and high vascularization[2]. One major concern is the length of clamping time during vascular injury repair, considering the ischemic damage observed in terminal organs—the longer the ischemia, the more severe the organ injury. Therefore, it is crucial to minimize the duration of ischemia in any type of vascular injury[3]. In the search for a simpler and faster technique, alternative methods of anastomosis have been studied, such as the use of mechanical connecting devices. However, those devices are impractical in some contexts, for instance, when there is a discrepancy in the caliber of the vessels to be joined by anastomosis. Another alternative are vascular sealants such DV F\DQRDFU\ODWH DQG ¿EULQ JOXH D V\QWKHWLF DQG D QDWXUDO (biological) adhesive, respectively[1]. The mechanism of action of cyanoacrylate is polymerization on contact with proteins that function as catalysts, leaving a crust on the lesion surface. Among the cyanoacrylate characteristics worth emphasizing are its bactericidal and bacteriostatic power, minimal tissue toxicity, and blue color, which allows easy visualization of the adhesive in the operDWLYH ¿HOG[4]. On the other hand, cyanoacrylate causes some DGYHUVH HIIHFWV VXFK DV LQWHQVH LQÀDPPDWLRQ ZLWK GLVVHFWLRQ RI WKH HODVWLF ODPLQD FDOFL¿FDWLRQ RI WKH PHGLD DQG WKLQQLQJ and deformation of the vessel wall. Furthermore, there are accounts of pseudoaneurysm formation and it has been reported that leakage of the glue into the vessel lumen invariably leads to thrombosis[1].

Ideally, a hemostatic agent should be easy to use and conserve, be amiable to sterilization, act only at the site of application, bond quickly to tissue, not release excess heat, be stable at body temperature, maintain adhesiveness even in FRQWDFW ZLWK PRLVW VXUIDFHV RQO\ GHJUDGH DW WKH ÂżQDO VWDJH of wound healing, be safe for both patient and surgeon, and not have toxicity or carcinogenic action. Unfortunately, an adhesive like this is not yet available[5,6]. It has been demonstrated that vascular sealants, adjuncts to vascular suture, play a major role in reducing operative time, enhancing hemostasis, and reducing the need for addiWLRQDO VWLWFKHV 7LPH KRQRUHG VHDODQWV VXFK DV ÂżEULQ JOXH DQG cyanoacrylate have shown disadvantages in some respects, VXFK DV WKH KLJK FRVW DQG LQWHQVH LQĂ€DPPDWRU\ UHVSRQVH UHspectively[1,3,7]. The aim of the present study was to determine the hemostatic behavior and induced tissue response of bio-based polyurethane derived from castor oil in comparison to 2-octyl-cyanoacrylate following aortic artery injury in guinea pigs. METHODS This experimental randomized interventional study was conducted by the Denton Cooley Institute at the histology and cell biology laboratories, the animal colony, and the clinical and surgical experimentation laboratory of the Faculdade EvangĂŠlica do ParanĂĄ (FEPAR). Ethical Statement The Animal Research Ethics Committee (ComitĂŞ de ÉtiFD HP 8VR GH $QLPDLV௅&(8$ DSSURYHG WKH SUHVHQW VWXG\ under Formal Opinion No. 5517/2012. The study was conducted in compliance with the ethical principles in animal experimentation adopted by the Brazilian College of Animal Experimentation (ColĂŠgio Brasileiro de Experimentação $QLPDO௅&2%($ DQG WKH UHJXODWLRQV ODLG RXW LQ WKH Âł*XLGH

120 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Kubrusly LF, et al. - Comparison of polyurethane with cyanoacrylate in hemostasis of vascular injury in guinea pigs

Braz J Cardiovasc Surg 2015;30(1):119-26

for the Care and Use of Laboratory Animalsâ€? (Institute of Laboratory Animal Resources, National Academy of Sciences, Washington, D.C., 1996). Moreover, there is no FRQĂ€LFW RI LQWHUHVW Sample Design The study sample was composed of 24 male guinea pigs (Cavia porcellus), Rodentia, Mammalia, Caviidae, aged 4 PRQWKV DQG ZHLJKLQJ EHWZHHQ ௅ J PHDQ g), obtained from the Instituto de Tecnologia do ParanĂĄ (TECPAR). The animals were housed at the FEPAR animal colony in a controlled environment—a room with a low noise level, 12-h light/dark cycles, and mean temperature of 21°C, varying from 19°C to 24°C. The guinea pigs stayed in the animal colony for 30 days prior to the experiment for acclimation and observation. They were kept in cages and received Nuvital chow and water ad libitum[8]. The animals were randomly allocated into three groups of eight animals each[9]: group I (control), group II (polyurethane), and group III (cyanoacrylate). Group II was subdivided on the basis of the adhesive/catalyst mixture time: 6.5 min for subgroup IIA and 3.5 min for IIB. This difference derived from the homogenization time of polyurethane. Material The guinea pigs were purchased from the Institute of Technology of ParanĂĄ (TECPAR), while the vascular sealants, polyurethane (VetasuperÂŽ) and 2-octyl-cyanoacrylate (DermabondÂŽ), from processed products. Surgery Description After a 6-hour fast for chow and a 4-hour fast for water, the guinea pigs were anesthetized according to the Barzago protocol with ketamine (87 mg/kg) and xylazine (13 mg/kg), intraperitoneally[10]. Abdominal hair was shaved using an electric razor, after which the animals were weighed and tied to the operating board in the supine position. Subsequently, SURSK\ODFWLF HQURĂ€R[DFLQ PJ NJ ZDV DGPLQLVWHUHG LQtramuscularly. The guinea pigs were wrapped in plastic to prevent hypothermia. Extensive antisepsis with PVPI was done, followed by local anesthesia of the abdominal wall with 2% lidocaine diluted in normal saline (1:4)[11]. We performed median laparotomy with an incision of about 5 cm. The bladder was emptied by puncture with a 13 mm x 0.45 mm needle. The small bowel loops and the descending colon were pushed aside to the right. The ureters were pushed aside and the retroperitoneum was opened. The aorta was dissected from the infrarenal region about 5 mm from the iliac arteries using a small curved hemostat to ensure minimal direct manipulation to minimize vascular injury. Papaverine was applied all around the dissected aorta to prevent vasospasm[12]. The aorta was isolated from the vena cava and

clamped using two DeBakey bulldog clamps, proximally and distally to the site being manipulated. We punctured the infrarenal abdominal aorta using a 0.70 mm x 25 mm needle[3]. From this point onward, hemostasis was performed differently for each group. In group I, after puncture of the aorta, the clamps were released and hemostasis was achieved through GLJLWDO FRPSUHVVLRQ ZLWK JDX]H $IWHU LW ¿QLVKHG EOHHGLQJ FRPSUHVVLRQ ZDV VWRSSHG UHVWRULQJ EORRG ÀRZ In group II, hemostasis was achieved using the bio-based polyurethane sealant in conjunction with a catalyst (at a ratio of 2:1). The mixture was prepared on a sterile slide with varying preparation times as mentioned above. For both subgroups, the sealant was applied at the puncture site using the bare end of a sterile swab stick (Figure 1). To assess the drying time of the adhesive, the proximal clamp was partially released approximately every 15 seconds and blood loss was estimated. After the polyurethane drying process was completed, the DeBakey bulldog clamps were released and arteULDO EORRG ÀRZ ZDV UHVWRUHG For group III, the process began when the capsule containing the 2-octyl-cyanoacrylate adhesive was broken and the product was exposed to air humidity. The adhesive was then placed on a VWHULOH VOLGH ,Q WKLV JURXS WKHUH ZDV QR VSHFL¿F SUHSDUDWLRQ WLPH since the synthetic adhesive was ready for use in only a few seconds. The technique to apply the cyanoacrylate to the injury site and to assess drying time was identical to that of group II.

Fig. 1 - Proximal and distal clamping of the aorta with Bulldog De Bakey and hemostasis with polyurethane.

To estimate blood loss after the aortic puncture in groups II and III, gauze sponges were weighed on a high-precision scale immediately before they were used and again immediately after. Hemostasis was achieved with sealants; for that reason, the gauze sponges were only used to allow an estimate of blood loss after the puncture and in case of hemostasis failure.

121 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Kubrusly LF, et al. - Comparison of polyurethane with cyanoacrylate in hemostasis of vascular injury in guinea pigs

Braz J Cardiovasc Surg 2015;30(1):119-26

Subsequently, the bowel loops were repositioned without retroperitoneal closure. The abdominal wall was closed in two planes (muscle and skin) with a continuous mononylon 3.0 suture[13]. During the experiment, the following were evaluated: weight of the animal, time of application (puncture of the aorta until the application of sealant), drying time (applying the glue until the opening of the clamps) and blood loss. Except for the weight of the animal, the other variables were analyzed only in groups II and III.

RESULTS

Postoperative period Postanesthesia recovery took place in a glass box with incandescent light heating, under constant observation of the investigators. After recovery, the animals were returned to their cages. They were given pain medication (5 mg/kg WUDPDGRO K\GURFKORULGH LQWUDPXVFXODUO\ GXULQJ WKH ¿UVW postoperative (PO) days[14]. On PO day 14, the guinea pigs were humanely killed in a CO2 chamber. Following a second median laparotomy, the aorta was surgically removed en bloc from the infrarenal region to about 5 mm from the iliac arteries for histological studies. Histological Study 7KH VXUJLFDO VSHFLPHQV SURSHUO\ LGHQWL¿HG ZHUH LPmersed in 10% formaldehyde for 72 hours at room temperature. The material was routinely processed for slide preparation at the FEPAR histotechnique laboratory. Twelve cuts were made throughout each piece. The microscope for the histological study was a Nikon Eclipse 200 model. The specimens were analyzed qualitatively DQG TXDQWLWDWLYHO\ DW [ DQG [ PDJQL¿FDWLRQ UHVSHFWLYHO\ Fibrous tissue formation was analyzed qualitatively on glass slides using the Masson’s trichrome staining technique. Fibrosis was rated as absent/mild or moderate/severe. In the quantitative analysis with hematoxylin-eosin stainLQJ WKH FHOO W\SHV ZHUH FRXQWHG LQ ¿HOGV XQGHU WKH PLFURscope. The following types were counted: histiocytes, neutrophils, giant cells, and lymphocytes[11]. Statistical Analysis The results of the quantitative variables were expressed as means, minimum values, maximum values, and standard deviations. The qualitative variables were represented as frequencies and percentages. The nonparametric Mann-Whitney test was used in pairwise comparisons for quantitative variables; comparisons involving more than two groups were made using the nonparametric Kruskal-Wallis test. For the qualitative variables, the groups were compared using Fisher’s exact test. Values of P LQGLFDWHG VWDWLVWLFDO VLJQL¿cance. The data were analyzed with the aid of the Statistica software, version 8.0.

There were no anesthetic complications. Two animals died postoperatively: 1 in group I on PO day 1 (embolism) and 1 in group III on PO day 2 (evisceration). Given that the deaths occurred in the PO period, we analyzed the intraoperative variables; however, it was not possible to analyze the histological variables, since those animals did not survive through PO day 14. Group I was only assessed in relation to the weight of the animal and histological variables. The subdivision of group II was only considered for the intraoperative variables, since this group was judged to be homogeneous for the purposes of the histological study, which assessed the tissue response to the same material across groups. Comparison between groups I, IIA, IIB, and III for intraoperative variables Application time (seconds): Group IIA (4 animals, mean 55.2, minimum 34.4, maximum 63.9, SD 13.9). Group IIB (4 animals, mean 45.0, minimum 26.6, maximum 69.9, SD 20.7). Group III: (8 animals, mean 53.7, minimum 25.7, PD[LPXP 6' 7KHUH ZDV QR VWDWLVWLFDO VLJQLÂżcance (P>0.05) among the three groups. Drying time (seconds): Group IIA (4 animals, mean 40.5, minimum 28.2, maximum 48.4, standard deviation 8.6), Group IIB (4 animals; 126.1 average, minimum 102.8, maximum 156.6, SD 23.0). Group III (8 animals, mean 81.5, minimum 33.5, maximum 192.8, SD 51.5). Drying times were statistically different (P=0.023) among the three experimental groups. In the pairwise comparisons, we observed a trend for a longer drying time in group III relative to group IIA (P=0.069). Group III had a shorter drying time than subgroup IIB (P=0.046); group IIA had a shorter drying time than subgroup IIB (P=0.003). Blood Loss (grams): Group IIA (4 animals, mean 0.002, minimum 0.000, maximum 0.010, standard deviation 0.005); Group IIB (4 animals, mean 0.008, minimum 0.000, maximum 0.010, standard deviation 0.005); Group III: (8 animals, mean 0.170, minimum 0.000, maximum 1.22, standard deviDWLRQ 7KHUH ZDV QR VWDWLVWLFDO VLJQLÂżFDQFH EHWZHHQ the three groups (P>0.05). Descriptive statistics regarding the comparison between groups I, IIA, IIB, and III are shown in Table 1. Comparison between groups I, II, and III regarding WKH KLVWRORJLFDO TXDOLWDWLYH YDULDEOH ÂżEURVLV

Fibrosis was categorized as either absent/mild or moderate/severe on the slides (Table 2). Fibrosis: Group I: absent/mild: 4 (57.14%); moderate/ severe: 3 (42.86%). Group II: absent/mild: 7 (87.50%); moderate/severe: 1 (12.50%). Group III: absent/mild: 0 (0.00%); moderate/severe: 7 (100%).

122 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Kubrusly LF, et al. - Comparison of polyurethane with cyanoacrylate in hemostasis of vascular injury in guinea pigs

Braz J Cardiovasc Surg 2015;30(1):119-26

Table 1. Comparison of groups IIA (polyurethane A), IIB (polyurethane B), and III (cyanoacrylate) regarding the intraoperative variables. Variable Application Time (seconds) Drying Time (seconds) Blood Loss (grams)

Group Cyanoacrylate Polyurethane A Polyurethane B Cyanoacrylate Polyurethane A Polyurethane B Cyanoacrylate Polyurethane A Polyurethane B

N 8 4 4 8 4 4 8 4 4

Mean 53.7 55.2 45.0 81.5 40.5 126.1 0.170 0.002 0.008

Maximum 89.0 63.9 69.9 192.8 48.4 156.6 1.220 0.010 0.010

Minimum 25.7 34.4 26.6 33.50 28.2 102.8 0.0000 0.000 0.000

SD 24.4 13.9 20.7 51.5 8.6 23.0 0.424 0.005 0.005

P-value*

0.810

0.023

0.069

*Nonparametric Kruskal-Wallis test, P<0.05

7DEOH 3HUFHQWDJH RI ÂżEURVLV LQ JURXSV , ,, DQG ,,, Fibrosis Absent/Mild Moderate/Severe Total

Group Polyurethane 7 87.50% 1 12.50% 8

Control 4 57.14% 3 42.86% 7

Cyanoacrylate 0 0.00% 7 100.00% 7

Fig. 2 - Fibrosis absent/mild in polyurethane group (left) and moderate/severe in the cyanoacrylate group (right) stained with Masson’s trichrome.

We used pairwise group comparisons to test the null hypothesis that the likelihood of a moderate/severe rating was the same for the two groups compared vs. the alternative hypothesis that the likelihood was different. Group II had VWDWLVWLFDOO\ OHVV ÂżEURVLV WKDQ JURXS ,,, P=0.001), as shown LQ )LJXUH 7KHUH ZDV D WUHQG WRZDUG LQFUHDVHG ÂżEURVLV LQ group III relative to group I (P 1R VWDWLVWLFDO VLJQLÂżcance was found between groups I and II.

Comparison between groups I, II, and III regarding the histological quantitative variables For each of these variables, we tested the null hypothesis that the results were equivalent across groups vs. the alternative hypothesis that at least 1 of the groups had different results from the others. The descriptive statistics for the groups and the P-values of the statistical tests are shown in Table 3.

123 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Kubrusly LF, et al. - Comparison of polyurethane with cyanoacrylate in hemostasis of vascular injury in guinea pigs

Braz J Cardiovasc Surg 2015;30(1):119-26

Table 3. Comparison of groups I, II, and III in relation to the histological quantitative variables. Anatomo-pathological Variables* Histiocytes

Neutrophils

Lymphocytes

Giant cells

Group Cyanoacrylate Polyurethane Control Cyanoacrylate Polyurethane Control Cyanoacrylate Polyurethane Control Cyanoacrylate Polyurethane Control

N 7 8 7 7 8 7 7 8 7 7 8 7

Mean 47.0 26.1 28.4 17.1 15.1 4.3 58.3 32.3 26.0 2.7 1.5 2.9

Median 25 12 12 8 4.5 5 22 10.5 10 3 0 0

Minimum 18 0 0 4 0 0 12 7 5 0 0 0

Maximum 112 135 120 54 54 8 220 120 82 6 4 12

SD 40.6 44.4 42.6 18.1 21.4 3.4 74.9 42.4 28.8 2.3 2.1 5.0

P-valueâ€

0.094

0.254

0.267

0.578

&RXQWLQJ WKH QXPEHU RI UHVSHFWLYH FHOOV LQ ¿YH PLFURVFRSLF ¿HOGV DW [ †Nonparametric Kruskal-Wallis test, P<0.05

1R VWDWLVWLFDOO\ VLJQLÂżFDQW GLIIHUHQFHV ZHUH IRXQG LQ WKH quantitative analysis of the cell types. DISCUSSION We chose to work with guinea pigs (Cavia porcellus) because of the small body size of the animal, the ease of handling, and the experience of the research group with this specie. The choice for 2-octyl-cyanoacrylate was due to our knowledge of several promising studies in cardiovascular surgery such as those of Hall et al.[15], Aziz et al.[16], and Buijsrogge et al.[17]. In addition, this adhesive type is easily accessible—both comPHUFLDOO\ DQG ÂżQDQFLDOO\²FRPSDUHG WR RWKHU F\DQRDFU\ODWHV IRU H[WHUQDO LQWHUQDO XVH Q EXW\O F\DQRDFU\ODWH RU ÂżEULQ JOXH In the case of polyurethane, its biocompatibility and PHFKDQLFDO SURSHUWLHV HJ Ă€H[LELOLW\ DQG DGKHVLYHQHVV DUH advantageous; hence, this adhesive is an alternative to the available sealants[11,18]. The currently used polyurethane formulation costs approximately R$ 25.00 (Brazilian Reals) per liter, which would make its use feasible on a large scale. However, for polyurethane to be commercially available as a medical grade product, sterilization processes would be required—and this would raise costs. The ideal choice for the present experiment regarding hemostasis would be the microvascular suture technique with an adjunctive sealant, as used by Reicher et al.[13], Cho[1], and Ersoy et al.[3]. However, this procedure demands a long learning curve to reduce the risk of anastomotic stenosis, morbidity, and mortality. Therefore, we chose a relatively more simple technique: the aortic puncture, similarly to that described by Ferretti et al.[9]. The intention of the control group was to prove that the GLDPHWHU RI WKH RULÂżFH FDXVHG LQ WKH DRUWD ZDV VXIÂżFLHQWO\ large not to stop bleeding spontaneously, requiring a hemostatic method. As the hemostatic technique was different IURP WKH RWKHU WZR JURXSV FRQWURO KDG SDUWLDO EORRG Ă€RZ we did not calculate the surgical time or blood loss.

Therefore, the aim of the intraoperative variables was to FRPSDUH RQO\ ,,$ ,,% ZLWK ,,, WKDW LV WR DQDO\]H WKH HIÂżFLHQcy of a sealant known as cyanoacrylate with different preparations of polyurethane. The drying time was more effective in the cyanoacrylate group (III) compared with the polyurethane B subgroup (IIB), that is, its shorter drying time propitiated quicker hemostasis. However, when group III was compared with subgroup IIA, we noted a trend for polyurethane to be more effective than cyanoacrylate. Considering that the length of time for polyurethane preparation (mixture of adhesive and catalyst) LQĂ€XHQFHV GU\LQJ WLPH ZH PLJKW KDYH IRXQG D VWDWLVWLFDOO\ VLJQLÂżFDQW GLIIHUHQFH EHWZHHQ WKH KHPRVWDWLF HIÂżFDF\ RI polyurethane vs. cyanoacrylate if the preparation time of the bio-based adhesive were longer than 6.5 minutes. The reason for this is that polyurethane acquires greater adhesiveness with the passing of time after the mixture. One major advantage of cyanoacrylate is the fact that it is a one-part drying adhesive; thus, it does not require a catalyst, which shortens operative time. One possibility to bring polyurethane closer to this favorable characteristic would be to formulate a novel catalyst or to improve timing in the operating room so that one member of the surgical team would initiate the adhesive mixture only a few minutes before use. The downside of 2-octyl-cyanoacrylate is its short working life (ie, fast preparation). The cyanoacrylate adhesive quickly VROLGLÂżHV DIWHU H[SRVHG WR DLU KXPLGLW\ ZKLFK SUHFOXGHV PDnipulation if an error leads to a delay in the application of the adhesive. This aspect could entail greater loss of cyanoacrylate in unskilled hands and further raise the costs of the procedure. In some animals, it was observed by researchers that there was a relatively greater blood loss in group III than in groups ,,$ DQG ,,% EXW ZLWKRXW VWDWLVWLFDO VLJQLÂżFDQFH 2QH SRVVLble explanation is that cyanoacrylate forms a crust, as noted by Bettes[19] and Fontes et al.[4], and in the event of the crust coming off, massive bleeding would ensue. By contrast, poly-

124 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Kubrusly LF, et al. - Comparison of polyurethane with cyanoacrylate in hemostasis of vascular injury in guinea pigs

Braz J Cardiovasc Surg 2015;30(1):119-26

urethane, which has elastomeric properties, showed minimally progressive bleeding, thus enabling prompt control of the bleeding. Radosevish et al.[20], in a review study, stated that cyanoacryODWH FRXOG OHDG WR H[WHQVLYH ¿EURVLV +HUUHUD HW DO [21] investigated the topical application of cyanoacrylate surrounding previously healthy common carotid arteries in rats—a technique used to strengthen aneurysm walls. Those authors observed intense inÀDPPDWLRQ ZLWK PDUNHG SUHVHQFH RI ¿EUREODVWV RYHU WKH ¿UVW 32 GD\V DQG PRGHUDWH SUHVHQFH RI ¿EUREODVWV DW DQG 32 days. The adventitia was found to be thickened due to increased ¿EURWLF FRQQHFWLYH WLVVXH ,Q DGGLWLRQ WKRVH DXWKRUV IRXQG VPRRWK PXVFOH FHOO QHFURVLV DQG UXSWXUH RI HODVWLF ¿EHUV LQ WKH media. Gßrhan Ulusoy et al.[22] constructed anastomoses with both suture and cyanoacrylate in the femoral artery of rats and, DIWHU GD\V REVHUYHG SHULOXPLQDO ¿EUREODVWV DQG IRUHLJQ ERG\ JLDQW FHOOV 7KHVH ZRUNV FRUURERUDWH RXU ¿QGLQJV RI HQKDQFHG ¿EURVLV DW 32 GD\V LQ WKH RFW\O F\DQRDFU\ODWH JURXS Maria et al.[23] reported that the proximal portions of bone grafts of castor-derived polyurethane were covered by ¿EURWLF WLVVXH ZLWK WKH GHJUHH RI ¿EURVLV YDU\LQJ EHWZHHQ mild, moderate, and severe. Testing the biocompatibility of implants containing polyurethane, Lu et al.[24] DI¿UPHG WKDW WKRVH SURVWKHVHV ZHUH RQO\ SDUWLDOO\ VXUURXQGHG E\ ¿EURWLF tissue. In vascular surgery, Hu et al.[25] demonstrated that, unOLNH SRO\WHWUDÀXRUHWK\OHQH ZKLFK LQGXFHV PDUNHG ¿EURVLV SRO\XUHWKDQH JUDIWV FDXVHG ¿EURVLV WR D VPDOO GHJUHH ,Q RXU experiment, polyurethane used as a vascular sealant induced VLJQL¿FDQWO\ OHVV ¿EURVLV WKDQ RFW\O F\DQRDFU\ODWH ZLWK D SUHGRPLQDQFH RI DEVHQW RU PLOG ¿EURVLV CONCLUSION

-90/

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ACLS MML

2. Freire DF, Taha MO, Soares JH, Simþes MJ, Fagundes AL, Fagundes DJ. The laparoscopy splenic injury repair: the use RI ¿EULQ JOXH LQ D KHSDULQL]HG SRUFLQH PRGHO $FWD &LU %UDV 2011;26(3):235-41. (UVR\ 2) .D\DRáOX +$ &HOLN $ 2]NDQ 1 /RUWODU 1 2PHURáOX S. Comparison of cyanoacrylate-assisted arteriotomy closure with conventional closure technique. Ulus Travma Acil Cerrahi Derg. 2009;15(6):535-40. 4. Fontes CER, Taha MO, Fagundes DJ, Ferreira MV, Padro Filho 25 0DUGHJDQ 0- (VWXGR FRPSDUDWLYR GR XVR GH FROD GH ¿EULQD e cianoacrilato em ferimento de fígado de rato. Acta Cir Bras. 2004;19(1):37-42. 5. Soares Júnior C. Uso de 2-octil cianoacrilato em anastomose colônica: estudo experimental em ratos wistar [Tese de doutorado]. Belo Horizonte: Universidade Federal de Minas Gerais; 2008. 92p. 6. Silva LS, Figueira Neto JB, Santos AL. Utilização de adesivos teciduais em cirurgias. Biosci J. 2007;23(4):108-19. 7. Rocha EAV, Souza C. Avaliação hemodinâmica de anastomoses DUWHULDLV UHIRUoDGDV FRP VHODQWH GH ¿EULQD HVWXGR H[SHULPHQWDO em suínos. Rev Bras Cir Cardiovasc. 2007;22(1):81-6.

)HUUHWWL / 4LX ; 9LOODOWD - /LQ * (IÂżFDF\ RI %ORRG6723 iX, surgicel, and gelfoam in rat models of active bleeding from partial nephrectomy and aortic needle injury. Urology. 2012;80(5):1161.e1-6.

Authors’ roles & responsibilities

06)

&KR $% $SOLFDomR GD FROD GH ÂżEULQD HP PLFURDQDVWRPRVHV vasculares: anĂĄlise comparativa com a tĂŠcnica de sutura convencional utilizando um modelo experimental de retalho microcirĂşrgico [Tese de doutorado]. SĂŁo Paulo: Faculdade de Medicina de SĂŁo Paulo, 2008. 96p.

8. Fontes CER, Taha MO, Fagundes DJ, Prado Filho O, Ferreira MV, Mardegan MJ. Estudo do reparo do ferimento de colon com o lado seroso da parede de jejuno, utilizando cianoacrilato e cola GH ÂżEULQD 5HY &RO %UDV &LU

Castor oil-derived polyurethane exhibited a similar hemostatic behavior to that of 2-octyl-cyanoacrylate and showed less intense perivascular tissue response compared to 2-octyl-cyanoacrylate.

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Letters to the Editor

Braz J Cardiovasc Surg 2015;30(1):127-8

Letters to the Editor DOI: 10.5935/1678-9741.20150013

RBCCV 44205-1623

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DOI: 10.5935/1678-9741.20150002

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127 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Letters to the Editor

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128 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Braz J Cardiovasc Surg 2015;30(1):129

REVIEWERS

Reviewers BJCVS 30.1 The Brazilian Journal of Cardiovascular Surgery (BJCVS) is grateful for the useful work of the dedicated reviewers, OLVWHG EHORZ ZKLFK FROODERUDWH LQ WKLV LVVXH 7KH\ DUH HVVHQWLDO WR PDLQWDLQ WKH KLJK VFLHQWLÂżF OHYHO RI RXU MRXUQDO

Domingo Braile Editor-in-Chief BJCVS/RBCCV

Anderson BenĂ­cio

Moise Dalva

Bruno Botelho Pinheiro Bruno da Costa Rocha

Neuseli Marino Lamari

'MDLU %ULQGHLUR )LOKR

2PDU $VGU~EDO 9LOFD 0HMtD Otoni Moreira Gomes

Elaine Soraya Barbosa de Oliveira Severino

Paulo Roberto Barbosa Evora

Juliana Bassalobre Carvalho Borges

Reinaldo Bestetti Ricardo Adala Benfatti Roberto Gomes de Carvalho Rubens Toffano de Barros

/LQGHPEHUJ GD 0RWD 6LOYHLUD )LOKR Luiz CĂŠsar Guarita Souza Manuel de Jesus Antunes Marcelo Arruda Nakazone Mauricio de Nassau Machado Mauro Paes Leme de SĂĄ Michel Pereira Cadore 0RDFLU )HUQDQGHV GH *RGR\

Tomas Salerno 9LFWRU 5RGULJXHV 5LEHLUR )HUUHLUD Walter JosĂŠ Gomes

129 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Braz J Cardiovasc Surg 2015;30(1):130

ERRATUM

Erratum In the print version of the 29.4 edition of the Brazilian Journal of Cardiovascular Surgery /Revista Brasileira de Cirurgia Cardiovascular, due to a failure in internal control, the article “Distribution of saphenous vein valves and its pratical importance” was published in duplicate, while the “Aortic Center: specialized care Improves outcomes and Decreases mortality “was not published. In the on-line version, the two articles were made available correctly.

130 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Information for Authors

Braz J Cardiovasc Surg 2015;30(1):131-5

INFORMATION FOR AUTHORS BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY/ Revista Brasileira de Cirurgia Cardiovascular Editor Prof. Dr. Domingo M. Braile Av. Juscelino Kubitschek de Oliveira, 1.505 – Jardim Tarraf I 15091-450 – São JosÊ do Rio Preto – SP - Brasil E-mail: revista@sbccv.org.br

The Brazilian Journal of Cardiovascular Surgery %-&96 LV WKH RIÂżFLDO MRXUQDO RI WKH %UD]LOLDQ 6RFLHW\ RI Cardiovascular Surgery (BSCVS). It is a quarterly publication, with regular circulation since 1986. BJCVS is indexed LQ WKH 7KRPVRQ 6FLHQWLÂżF ,6, 0HGOLQH 3XE0HG 6&2386 SciELO, LILACS, Scirus and SCImago database. %-&96 DLPV WR UHFRUG WKH VFLHQWLÂżF SURGXFWLRQ LQ FDUdiovascular surgery, encouraging the study, improving and updating the professional specialty. Studies submitted for publication in BJCVS must deal with themes related to cardiovascular surgery and related ÂżHOGV 7KH MRXUQDO SXEOLVKHV WKH IROORZLQJ W\SHV RI DUWLFOHV original article, editorial, review article, special article, case report, how to do it, short communications, preliminary notes, clinical-surgical correlation, experimental study, multimedia and letter to editor. $FFHSWDQFH ZLOO EH EDVHG RQ RULJLQDOLW\ VLJQLÂżFDQFH DQG VFLHQWLÂżF FRQWULEXWLRQ $UWLFOHV ZLWK PHUHO\ SURSDJDQGD RU commercial purposes will not be accepted. The authors are responsible for the content and information contained in their manuscripts. BJCVS vehemently rejects plagiarism and self-plagiarism. On submission of manuscripts, the authors sign a statement declaring they are aware of the consequences of violation. 7KH MRXUQDO ZLOO EH SXEOLVKHG LQ IXOO RQ WKH MRXUQDOÂśV ZHEVLWH ZZZ UEFFY RUJ EU ZZZ EMFYV RUJ DQG 6FL(/2 ZZZ VFLHOR EU UEEFY ZLWK VSHFLÂżF OLQNV LQ WKH %-&96 VLWH ZZZ sbccv. org.br) and CTSnet (www.ctsnet.org). EDITORIAL POLICY Standard BJCVS adopts the Standards of Vancouver - Uniform Requirements for Manuscripts Submitted to Biomedical Journals, organized by the International Committee of Medical -RXUQDO (GLWRUV DYDLODEOH DW ZZZ LFPMH RUJ Submission and Publication Policy Only manuscripts whose data is not being assessed by RWKHU MRXUQDOV DQG RU KDYH QRW EHHQ SUHYLRXVO\ SXEOLVKHG ZLOO be considered for review. Manuscripts accepted may only be reproduced in whole or in part, without the express consent of the editor of BJCVS.

Electronic Submission Manuscripts should be compulsorily submitted electronically on site http://www.rbccv.org.br/sgp/. When entering this link, the system will ask for the username and password if the user have already registered. Otherwise, click on “I want to registerâ€? and register. Or, if the user have forgotten his password, the mechanism to remember the password can be used, which will generate an email containing such password. The submission system is self-explanatory and includes eight steps: Step 1: &ODVVLÂżFDWLRQ RI WKH DUWLFOH Step 2: Adding title and keywords Step 3: Registering for authors Step 4: Inclusion of summary and Abstract Step 5: Inclusion of the manuscript itself with references Step 6: Sending images Step 7: *HQHUDWLRQ RI FRS\ULJKW GHFODUDWLRQV FRQĂ€LFW of interest and copy of the Opinion of the Research Ethics Committee of the Institution 8th Step: $XWKRUÂśV DSSURYDO ÂżQDOL]DWLRQ RI VXEPLVVLRQ 7KH WH[WV PXVW EH HGLWHG LQ ZRUG IRUPDW DQG ÂżJXUHV DQG WDEOHV VKRXOG EH LQ VHSDUDWH ÂżOHV Keep your records updated because communication with authors is exclusively by e-mail. :KHQ ÂżQLVKLQJ WKH VXEPLVVLRQ RI WKH VWXG\ LW ZLOO JHQHUate an e-mail stating that the submission was made correctly, another email will be generated after checking if it is within the standards. If the article is “Out of Standardâ€?, the author will be noWLÂżHG E\ HPDLO DQG FDQ Âż[ LW LQWR WKH 6*3 %-&96 LQ ZZZ EMFYV RUJ VJS Authors may follow the course of their study at any time E\ 6*3 %-&96 WKURXJK WKH Ă€RZ FRGH DXWRPDWLFDOO\ JHQHUated by GSP, or even by the title of his study. Peer review $OO VFLHQWLÂżF FRQWULEXWLRQV DUH UHYLHZHG E\ WKH (GLWRU Associate Editors, Editorial Board Members and/or Guests Reviewers. The reviewers answer a questionnaire in which they rated the manuscript, their rigorous examination on all LWHPV WKDW FRPSRVH D VFLHQWLÂżF VWXG\ E\ DVVLJQLQJ D VFRUH IRU each of the questionnaire items. At the end, general comments about the study and suggestion if it should be published, cor-

131 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Information for Authors

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UHFWHG DFFRUGLQJ WR WKH UHFRPPHQGDWLRQV RU GHÂżQLWLYHO\ UHMHFWHG DUH PDGH :LWK WKHVH GDWD WKH (GLWRU ZLOO PDNH D GHcision. In case of discrepancies between the reviewers, a new RSLQLRQ FDQ EH UHTXHVWHG LQ RUGHU WR SURYLGH D EHVW MXGJPHQW :KHQ PRGLÂżFDWLRQV DUH VXJJHVWHG WKH\ ZLOO EH IRUZDUGed to the author and then the reviewers to verify that these requirements have been met. The authors have 30 days to make the changes requested by reviewers and resubmit the article. In response to the comments/suggestions of the reviewers, authors should highlight the changes made in the text. The non-observance of this period will involve the removal of the article from the review process. 2QFH WKH DUWLFOH LV DSSURYHG DXWKRUV ZLOO EH QRWLÂżHG E\ e-mail registered on the site and shall forward an abstract of up to 60 words in Portuguese and English, of the article. They are inserted into the electronic mailing and sent to all members when the BJCVS is available online. Once accepted for publication, a proof of the edited article (PDF format) will be sent to the corresponding author for DVVHVVPHQW DQG ÂżQDO DSSURYDO Language Articles should be written in English, using easily and accurately language and avoiding informality of colloquial language. For those studies whose standard the English language is deemed inappropriate by the Editorial Board, the MRXUQDO ZLOO SURYLGH FRUUHFWLRQ DQG FRVWV VKRXOG EH DVVXPHG by the authors. 5HVHDUFK RQ KXPDQ VXEMHFWV PXVW EH VXEPLWWHG WR WKH (WKLFV &RPPLWWHH RI WKH LQVWLWXWLRQ IXOÂżOOLQJ WKH 'HFODUDtion of Helsinki 1975, revised in 2008 (World Medical Association, available at: http://www.wma.net/en/30publications/10policies/b3/ 17c.pdf) and Resolution 196/96 of the National Health Council (available at: http://conselho.saude. gov.br/resolucoes/reso_96.htm). In experimental study involving animals the guidelines established in the Guide for Care and Use of Laboratory Animals should be respected (Institute of Laboratory Animal Resources, National Academy of Sciences, Washington, DC, United States), 1996, and Ethical Principles Animal Experimentation (Brazilian College of Animal Experimentation COBEA, available at: www.cobea.org.br), 1991. Randomized studies should follow the CONSORT guidelines (available at: www.consort-statement.org/consort-statement). BJCVS supports policies for the registration of clinical trials of the World Health Organization (WHO) and the International Committee of Medical Journal Editors (ICMJE), recognizing the importance of these initiatives for the registration and international open access dissemination of information on clinical trials. Thus, only be accepted for publication, the clinical research articles that have received an LGHQWLÂżFDWLRQ QXPEHU LQ RQH RI WKH &OLQLFDO 7ULDO 5HJLVWHUV validated by the criteria established by WHO and ICMJE,

whose addresses are available at the ICMJE website (http:// ZZZ LFPMH RUJ 7KH QXPEHU VKRXOG EH UHFRUGHG DW WKH HQG of the abstract. The statement of approval of the study by the Ethics and/ RU 6FLHQWLÂżF ,QVWLWXWLRQDO &RPPLWWHH PXVW EH VHQW DW WKH WLPH of submission of the manuscript. &RS\ULJKW 7UDQVIHU DQG 'HFODUDWLRQ RI &RQĂ€LFW RI ,QWHUHVW The authors should submit manuscripts at the time of submission, the copyright declaration signed by all authors. All published manuscripts become the permanent property of the Brazilian Journal of Cardiovascular Surgery and can not be published without the written consent of the editor. /LNHZLVH IRU FRQÂżUPDWLRQ RI WKH VXEPLVVLRQ RI WKH PDQXVFULSW D VWDWHPHQW RI FRQĂ€LFW RI LQWHUHVW VLJQHG E\ DOO DXthors should be sent. Both documents, statement of copyright transfer and decODUDWLRQ RI FRQĂ€LFWV RI LQWHUHVW DUH VWDQGDUGL]HG DQG JHQHUDWed by the SGP at the time of submission of the manuscript. Authoring Criteria & Individual Contribution to Research We suggest the author to adopt the criteria for authorship of the articles according to the recommendations of the International Committee of Medical Journal Editors. Thus, only those people who contributed directly to the intellectual content of the study should be listed as authors. Authors should meet all the following criteria in order to be able to take public responsibility for the content of the study: 1. have conceived and planned the activities that led to the study or interpreted the data it presents, or both; 2. have written the study or revised successive versions and took part in the review process; KDYH DSSURYHG WKH ÂżQDO YHUVLRQ People who do not meet the above requirements and who had purely technical or of general support participation, should be mentioned in the acknowledgments section. On submission, the kind of contribution of each author when performing the study and manuscript preparation in the following areas should be made explicit: 1. Study Design 2. Collection, analysis and interpretation of data 3. Drafting of the manuscript Abbreviations and Terminology The use of abbreviations should be minimal. When extensive expressions need to be repeated, it is recommended that WKHLU LQLWLDO FDSLWDO OHWWHUV UHSODFH WKHP DIWHU WKH ÂżUVW PHQtion. It should be followed by the letters in parentheses. All DEEUHYLDWLRQV LQ WDEOHV DQG ÂżJXUHV VKRXOG EH GHÂżQHG LQ WKH respective legends. The use of abbreviations in the Summary and Abstract Should be avoided.

132 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

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Braz J Cardiovasc Surg 2015;30(1):131-5

Only the generic name of the drug used should be cited in the study, and we discourage the use of trade names. %-&96 DGRSWV 8QLYHUVDO 2IÂżFLDO $QDWRPLFDO 7HUPLQROogy, approved by the International Federation of Anatomists Associations (FIAA). PREPARATION OF MANUSCRIPT Manuscript Sections Title and Authors. The study title, in Portuguese and English, should be concise and informative. The full names of authors, tiWOHV DQG WKHLU LQVWLWXWLRQDO DIÂżOLDWLRQ VKRXOG EH SURYLGHG Summary and Abstract. The abstract should be structured LQ IRXU VHFWLRQV 2EMHFWLYH 0HWKRGV 5HVXOWV DQG &RQFOXsion. The Abstract (literal version, in English, of Abstract in Portuguese) should follow the same structure of the summary LQWR IRXU VHFWLRQV 2EMHFWLYH 0HWKRGV 5HVXOWV DQG &RQFOXsion. Abbreviations should be avoided. The maximum number of words should follow the recommendations in the table. In the Articles Case Reports and How-I-Do, the abstract should not be structured (informative or free). The Clinical and Surgical Correlations and sections Multimedia exempt summary and abstract. 'HVFULSWRUV )URP WKUHH WR ÂżYH GHVFULSWRUV NH\ZRUGV should also be included as well as their translation. The descriptors can be found at the website http://decs.bvs.br/, which contains terms in Portuguese, Spanish and English or www.nlm.nih.gov/mesh for terms in English only, or in the respective links available at the submission system of WKH MRXUQDO Body of the manuscript. Original Articles and Experimental Study should be divided into the following sections: Introduction, Methods, Results, Discussion, Conclusion and Acknowledgements (optional). The Case Reports should be structured in sections: Introduction, Case Report and Discussion, and Clinical-surgical Correlations in Clinical Data, Electrocardiography, Radiogram, Echocardiogram, Diagnosis and Operation. The section Multimedia should have the following sections: Patient Characterization and Description of the Technique. The Review Articles and Special Articles can be structured into sections according WKH DXWKRUÂśV FULWHULD Letters to the Editor, in principle, should comment, discuss or criticize articles published in BJCVS, but it can also be about other topics of general interest. It is recommended a maximum size of 1000 words, including references - that VKRXOG QRW H[FHHG ÂżYH DQG WKH\ PD\ RU PD\ QRW LQFOXGH WLWOH Whenever possible and appropriate, a response from the authors of the article in question will be published with the letter.

by the International Committee of Medical Journal Editors ,&0-( DYDLODEOH DW KWWS ZZZ LFPMH RUJ 5HIHUHQFHV VKRXOG EH LGHQWLÂżHG LQ WKH WH[W ZLWK $UDELF numerals in square brackets, following the order of citation in the text, overwritten. The accuracy of references is the responsibility of the author. If more than two references ZHUH FLWHG LQ VHTXHQFH RQO\ WKH ÂżUVW DQG ODVW PXVW EH W\SHG separated by a dash (Example: [6-9]). In case of alternate citation, all references should be typed, separated by commas (Example: [6,7,9]). Publications with up to six authors, all authors should be FLWHG SXEOLFDWLRQV ZLWK PRUH WKDQ VL[ DXWKRUV WKH ÂżUVW IROlowed by the Latin phrase “et al.â€? should be cited. 7LWOHV RI MRXUQDOV VKRXOG EH DEEUHYLDWHG DFFRUGLQJ WR WKH List of Journals Indexed for MEDLINE (available at: http:// ZZZ QOP JRY WVG VHULDOV OML KWPO References Models Journal Article Issa M, Avezum A, Dantas DC, Almeida AFS, Souza LCB, Sousa AGMR. Fatores de risco prĂŠ, intra e pĂłs-operatĂłrios para mortalidade hospitalar em pacientes submetidos Ă cirurgia de aorta. Rev Bras Cir Cardiovasc. 2013;28(1):10-21. Organization as Author Diabetes Prevention Program Research Group. Hypertension, insulin, and proinsulin in participants with impaired glucose tolerance. Hypertension. 2002;40(5):679-86. No indication of authorship 21st century heart solution may have a sting in the tail. BMJ. 2002;325(7357):184. Article electronically published before the print version (“ahead of printâ€?) Atluri P, Goldstone AB, Fairman AS, Macarthur JW, Shudo Y, Cohen JE, et al. Predicting right ventricular failure in WKH PRGHUQ FRQWLQXRXV Ă€RZ OHIW YHQWULFXODU DVVLVW GHYLFH HUD Ann Thorac Surg. 2013 Jun 21. [Epub ahead of print] Online Journal Article Machado MN, Nakazone MA, Murad-Junior JA, Maia LN. Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center. Rev Bras Cir Cardiovasc [online]. 2013[cited 2013 Jun 25];28(1):29-35. Available from: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0102-76382013000100006&lng=en&nrm=iso> Book Chapter Chai PJ. Intraoperative myocardial protection. In: Mavroudis C, Backer C, eds. Pediatric cardiac surgery. 4th ed. Chichester: Wiley-Blackwell; 2013. p.214-24. Book Cohn LH. Cardiac surgery in the adult. 4th ed. New York: McGraw-Hill;2012. p.1472.

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alphabetically at the bottom, with their forms in full. LikeZLVH WKH DEEUHYLDWLRQV HPSOR\HG LQ WKH ÂżJXUHV VKRXOG EH explained in the legends. 7KH ÂżJXUHV ZLOO EH SXEOLVKHG LQ FRORU RQO\ LI WKH DXWKRU agrees to bear the cost of printing color pages. We will only accept images in TIFF or JPEG format with a minimum resolution according to the type of image, both for black and white and for color images. BJCVS prompts the authors to archive their possession the original images, as if the images submitted online present any impediment to print, we will contact the author to send us these originals.

Thesis Dalva M. Estudo do remodelamento ventricular e dos anÊis valvares na cardiomiopatia dilatada: avaliação anåtomo-patológica [Tese de doutorado]. São Paulo: Universidade de São Paulo, 2011. 101p. Legislation Conselho Nacional de Saúde. Resolução n. 196, de 10 de outubro de 1996. Dispþe sobre diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. BioÊtica. 1996;4(2 Supl):15-25. Other examples of references can be found at: http://www.nlm.nih.gov/bsd/uniform_requirements.html Tables and Figures Tables and Figures should be numbered according to the order of appearance in the text, with a title and be in separate ¿OHV 7DEOHV VKRXOG QRW FRQWDLQ UHGXQGDQW GDWD DOUHDG\ FLWHG in the text. They should be open on the sides and a totally white background. The abbreviations used in the tables should be listed

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Table example: Cardiovascular Risk Factors in Study Group Cardiovascular Risk Factors Hypertension (>140 mm Hg systolic and >90 mm Hg diastolic) Insulin-dependent diabetes mellitus Hypercholesterolemy ( 240 mg/dL) Hypertriglyceridemy ( 250 mg/dL) Cigarette smoking ( 10 cigarettes/d) Previous contraceptive therapy Previous myocardial infarction Family history of cardiovascular disease

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Number of Patients 11 6 12 6 12 2 11 12

Percentage of Patients 55 30 60 30 60 10 55 60

Checklist before sending the manuscript - Submission letter indicating category of manuscript - Declaration from authors and co-authors saying that they agree with the content of manuscript - Research approved by the Institution Ethics Comitee - Manuscript made out in Word 2007 text processor or superior (format A4); type 12; space 1,5; font Times News Roman; paged

Histogram showing effects of transdermal 17Ă&#x;-estradiol on left internal mammary artery (LIMA) graft cross-sectional area. It increased by 30% (3.45 Âą 1. 2 mm2 versus 4.24 Âą 1 mm2; p = 0.039).

- Manuscript within limits adopted by Brazilian Journal of Cardiovascular Surgery for its category

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Braz J Cardiovasc Surg 2015;30(1):131-5

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135 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Meetings Calendar

Braz J Cardiovasc Surg 2015;30(1):136-8

MEETINGS CALENDAR - 2015

March

Informations: Peenutchanee Chartiburus Phone: +66 81 9153651 Fax: +66 2 3548149 E-mail: peenuchee@hotmail.com Site: http://www.rsbonline.org

1 to 6 - Interventional Cardiology 2015: 30th Annual International Symposium Snowmass Village, USA Informations: Promedica International CME Phone: 760-720-2263 E-mail: rlaw@promedicacme.com Site: http://www.promedicacme.com/meeting/InterventionalCardiology-2015-30th-Annual-106.html

25 to 27 - ACTA/SCTS Joint Annual Meeting & Cardiothoracic Forum Manchester, UK Informations: Isabelle Ferner Phone: +44 (0) 20 7869 6893 Fax: +44 (0) 20 7869 6890 E-mail: sctsadmin@scts.org Site: www.scts.org

1 to 4 - APACVS 34th Winter Educational Meeting Las Vegas, USA Informations: Lisa Weber Phone: 978-927-8330 Site: http://apacvs.org/conferences/Winter-Educational/

26 and 27 - 12th Annual Advanced Pectus Course Norfolk, USA Informations: Children’s Hospital of The King’s Daughters Phone: (757) 668-9646 E-mail: pectus@chkd.org Site: www.chkd.org/nussconference

5 to 7 - The Houston Aortic Symposium: Frontiers in Cardiovascular Disease, the Eighth in the Series Houston, USA Informations: Promedica International CME Phone: 760-720-2263 Fax: 760-720-6263 E-mail: rlaw@promedicacme.com

26 and 27 - 3rd Asian Single Port VATS Symposium & Live Surgery Hong Kong, China Informations: Secretariat Phone: 852 - 2632 2629 Fax: 852 - 2637 7974 E-mail: s-portvats2015@surgery.cuhk.edu.hk Site: http://www.surgery.cuhk.edu.hk/vats2015/

8 to 15 - 33rd Cardiovascular Surgical Symposium Arlberg, Austria Informations: Karl Landsteiner, Institute of Cardiovascular Surgical Research E-mail: congress@surgery-zurs.at

26 and 27 - Aortic Valve Repair: A Step by Step Approach Paris, France Informations: Emmanuel Lansac and Sabine Ruck E-mail: s.ruck@kelcon.de Site: http://www.caviaar.com/

12 to 15 - General Thoracic Surgical Club 28th Annual Meeting Naples, USA Informations: Bonnie Lemmerman Phone: 507-696-4665 E-mail: gtscmail@gmail.com Site: www.gtsc.org

26 to 28 – 42th Congress of the Brazilian Society of Cardiovascular Surgery Curitiba, Brazil Informations: Ab Eventos Phone: +55 51 3061-2959 E-mail: recepcao@abev.com.br Site: http://sbccv.org.br/42Congresso/

19 to 21 - Introduction to Aortic Surgery Windsor, UK Informations: EACTS Phone: +44 (0)1753 832166 Fax: +44 (0)1753 620407 E-mail: info@eacts.co.uk Site: http://www.eacts.org/academy/2015-programme/

26 to 29 - 64th International Congress of the European Society for Cardiovascular and Endovascular Surgery Istambul, Turkey Informations: Bengu Tokatlioglu Phone: +90 212 292 88 08 Fax: +90 212 292 88 07 E-mail: info@escvs2015.org Site: http://escvs2015.org/

20 to 22 - 2nd Annual Chest Medicine Conference: State-of-the-Art Therapies in Thoracic Oncology/Hands-On Training & Simulation New York, USA Informations:Mary B. Strong, MA Phone: 516-465-3263 Fax: 516-465-8204 E-mail: mstrong@nshs.edu Site: www.northshorelij.edu/cme

28 and 29 - First Southeast Asian Workshop on Totally Endoscopic Cardiac Surgery Using Einstein 3D Vision Coimbatore, India Informations: Dr. Prashant Vaijyanath Phone: +917708455111

WR $VLD 3DFL¿F 0DVWHUFODVV LQ &RURQDU\ 5HYDVFXODUL]DWLRQ Phuket, Thailand

136 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Meetings Calendar

Braz J Cardiovasc Surg 2015;30(1):136-8

Fax: +917708455111 E-mail: vaijyanath3@gmail.com Site: www.kmchhospitals.com

15 to 18 - Australasian Thoracic Aortic Symposium 2015 Melbourne, Australia Informations:Taylored Images E-mail: 2015atas@tayloredimages.com.au Site: http://www.tayloredimages.com.au/atas2015/index.html

April

17 - Essential Surgical Skills for Cardiologists Informations: RCS Education Phone: 020 7869 6300 Site: https://www.rcseng.ac.uk/courses/course-search/essentialsurgical-skills-for-cardiologists

13 and 14 - 62nd Annual Conference of the Israel Heart Society in Association With the Israel Society of Cardiothoracic Surgery Telaviv, Israel Informations: (Paragon Israel) Dan Knassim Phone: 972-2-9591034 E-mail: secretariat@israelheart.com Site: http://2015.en.israelheart.com

23 to 24 - AATS Mitral Conclave 2015 New York, USA Informations: American Association for Thoracic Surgery E-mail: mitral@aats.org Site: http://aats.org/mitral/

13 to 17 - Thoracic Surgery: Part I Windsor, UK Informations: EACTS Phone: +44 (0)1753 832166 E-mail: info@eacts.co.uk Site: http://www.eacts.org/academy/2015-programme

25 to 29 - AATS 95th Annual Meeting Seattle, USA Informations: American Association for Thoracic Surgery E-mail: mitral@aats.org Site: http://aats.org/mitral/

15 to 18 - European Lung Cancer Conference Genebra, Switzerland E-mail: www.esmo.org

137 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

Meetings Calendar

Braz J Cardiovasc Surg 2015;30(1):136-8

138 Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

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