Brazilian Journal of Pulmonology - Volume 39, number 4, July/August - 2013 by Jornal Brasileiro Pneumologia

ISSN 1806-3713

Published once every two months J Bras Pneumol. v.39, number 4, p. 399-528 July/August 2013

PUBLICAÇÃO OFICIAL DA SOCIEDADE BRASILEIRA DE PNEUMOLOGIA E TISIOLOGIA

Jornal Brasileiro de Pneumologia

Highlight

ASTHMA Local adverse effects associated with the use of inhaled corticosteroids in patients with moderate or severe asthma

Transdiaphragmatic intercostal hernia

SURGERY Congenital lobar emphysema: 30-year case series in two university hospitals

COPD Portuguese-language version of the COPD Assessment Test: validation for use in Brazil Reliability of the Brazilian Portuguese version of the fatigue severity scale and its correlation with pulmonary function, dyspnea, and functional capacity in patients with COPD

EXPERIMENTAL Effect of tramadol on lung injury induced by skeletal muscle is chemia-reperfusion: an experimental study Effectiveness of diaphragmatic stimulation with single-channel electrodes in rabbits

July/August 2013 volume 39, number 4

PULMONARY FUNCTION Oxygen desaturation in healthy subjects undergoing the incremental shuttle walk test

Contribution of ﬂow-volume curves to the detection of central airway obstruction Lung function in post-poliomyelitis syndrome: a cross-sectional study

SMOKING Psychological morbidity as a moderator of intention to quit smoking: a study of smokers and former smokers

INTENSIVE CARE Adaptation to different noninvasive ventilation masks in critically ill patients

TUBERCULOSIS Prevalence of nutritional deﬁciency in patients with pulmonary tuberculosis Pulmonary tuberculosis and lung cancer: simultaneous and sequential occurrence

p.399-528

Free Full Text in English www.jornaldepneumologia.com.br

Editorial: COPD Assessment Test José R. Jardim, Laura Zillmer

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Published once every two months

J Bras Pneumol. v.39, number 4, p. 399-494 July/August 2013

Editor-in-Chief Carlos Roberto Ribeiro Carvalho – Universidade de São Paulo, São Paulo, SP

Executive Editors

Associação Brasileira de Editores Científicos

Bruno Guedes Baldi - Universidade de São Paulo, São Paulo, SP Carlos Viana Poyares Jardim - Universidade de São Paulo, São Paulo, SP Pedro Caruso - Universidade de São Paulo, São Paulo, SP Rogério de Souza – Universidade de São Paulo, São Paulo, SP

Associate Editors

Publication Indexed in: Latindex, LILACS, SciELO Brasil, Scopus, Index Copernicus, MEDLINE and ISI Web of Science Available in Portuguese and English from: www.jornaldepneumologia.com.br or www.scielo.br/jbpneu.

Afrânio Lineu Kritski – Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ Álvaro A. Cruz – Universidade Federal da Bahia, Salvador, BA Celso Ricardo Fernandes de Carvalho - Universidade de São Paulo, São Paulo, SP Fábio Biscegli Jatene – Universidade de São Paulo, São Paulo, SP Geraldo Lorenzi-Filho – Universidade de São Paulo, São Paulo, SP Ilma Aparecida Paschoal – Universidade de Campinas, Campinas, SP José Alberto Neder – Universidade Federal de São Paulo, São Paulo, SP Renato Tetelbom Stein – Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS Sérgio Saldanha Menna-Barreto – Universidade Federal do Rio Grande do Sul, Porto Alegre, RS

Editorial Council Alberto Cukier – Universidade de São Paulo, São Paulo, SP Ana C. Krieger – New York School of Medicine, New York, USA Ana Luiza Godoy Fernandes – Universidade Federal de São Paulo, São Paulo, SP Antonio Segorbe Luis – Universidade de Coimbra, Coimbra, Portugal Brent Winston – Department of Critical Care Medicine, University of Calgary, Calgary, Canada Carlos Alberto de Assis Viegas – Universidade de Brasília, Brasília, DF Carlos M. Luna – Hospital de Clinicas, Universidad de Buenos Aires, Buenos Aires, Argentina Carmen Silvia Valente Barbas – Universidade de São Paulo, São Paulo, SP Chris T. Bolliger – University of Stellenbosch, Stellenbosch, South Africa Dany Jasinowodolinski – Universidade Federal de São Paulo, São Paulo, SP Douglas Bradley – University of Toronto, Toronto, ON, Canadá Denis Martinez – Universidade Federal do Rio Grande do Sul, Porto Alegre, RS Edson Marchiori - Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ Emílio Pizzichini – Universidade Federal de Santa Catarina, Florianópolis, SC Frank McCormack – University of Cincinnati School of Medicine, Cincinnati, OH, USA Gustavo Rodrigo – Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevidéu, Uruguay Irma de Godoy – Universidade Estadual Paulista, Botucatu, SP Isabela C. Silva – Vancouver General Hospital, Vancouver, BC, Canadá J. Randall Curtis – University of Washington, Seattle, Wa, USA John J. Godleski – Harvard Medical School, Boston, MA, USA José Antonio Baddini Martinez - Universidade de São Paulo, Ribeirão Preto, SP José Dirceu Ribeiro – Universidade de Campinas, Campinas, SP, Brazil José Miguel Chatkin – Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS José Roberto de Brito Jardim – Universidade Federal de São Paulo, São Paulo, SP José Roberto Lapa e Silva – Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ Kevin Leslie – Mayo Clinic College of Medicine, Rochester, MN, USA Luiz Eduardo Nery – Universidade Federal de São Paulo, São Paulo, SP Marc Miravitlles – Hospital Clinic, Barcelona, España Marcelo Alcântara Holanda – Universidade Federal do Ceará, Fortaleza, CE Marcos Ribeiro – University of Toronto, Toronto, ON, Canadá Marli Maria Knorst – Universidade Federal do Rio Grande do Sul, Porto Alegre, RS Marisa Dolhnikoff – Universidade de São Paulo, São Paulo, SP Mauro Musa Zamboni – Instituto Nacional do Câncer, Rio de Janeiro, RJ Nestor Muller – Vancouver General Hospital, Vancouver, BC, Canadá Noé Zamel – University of Toronto, Toronto, ON, Canadá Paul Noble – Duke University, Durham, NC, USA Paulo Francisco Guerreiro Cardoso – Pavilhão Pereira Filho, Porto Alegre, RS Paulo Pego Fernandes – Universidade de São Paulo, São Paulo, SP Peter J. Barnes – National Heart and Lung Institute, Imperial College, London, UK Renato Sotto-Mayor – Hospital Santa Maria, Lisboa, Portugal Richard W. Light – Vanderbili University, Nashville, TN, USA Rik Gosselink – University Hospitals Leuven, Bélgica Robert Skomro – University of Saskatoon, Saskatoon, Canadá Rubin Tuder – University of Colorado, Denver, CO, USA Sonia Buist – Oregon Health & Science University, Portland, OR, USA Talmadge King Jr. – University of California, San Francisco, CA, USA Thais Helena Abrahão Thomaz Queluz – Universidade Estadual Paulista, Botucatu, SP Vera Luiza Capelozzi – Universidade de São Paulo, São Paulo, SP

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The Brazilian Journal of Pulmonology (ISSN 1806-3713) is published once every two months by the Brazilian Thoracic Society (BTS). The statements and opinions contained in the editorials and articles in this Journal are solely those of the authors thereof and not of the Journal’s Editor-in-Chief, peer reviewers, the BTS, its officers, regents, members, or employees. Permission is granted to reproduce any figure, table, or other material published in the Journal provided that the source for any of these is credited. BTS Board of Directors (2013-2014 biennium): President: Jairo Araujo Sponholz (PR) Secretary-General: Raquel Melo Nunes Carvalho Feitosa (DF) Director, Professional Advocacy: Mário Sérgio Nunes (DF) CFO: John Daniel Rego Bringel (DF) Scientific Director: Emilio Pizzichini (SC) Director, Education and Professional Practice: Alberto Cukier (SP) Director, Communications: Marcelo Alcantara Netherlands (EC) President, BTS Congress 2014: José Miguel Chatkin (RS) President Elect (2015/2016 biennium): Renato Maciel (MG) Chairman of the Board: Roberto Stirbulov (SP) AUDIT COMMITTEE: Active Members: Carlos Alberto Gomes dos Santos (ES), Clovis Botelho (MT), Maia Saul Davila Melo (SE) Alternates: Maurice Meireles Goes (MG), Angelo Ferreira da Silva (SC), Valeria Maria Augusto (MG) COORDINATORS, BTS DEPARTMENTS: Programmatic Initiatives - Alcindo Cerci Neto (PR) Thoracic Surgery - Darcy Ribeiro Pinto Filho (RS) Sleep-disordered Breathing - Gleison Marinho Guimaraes (RJ) Respiratory Endoscopy - Viviane Rossi (SP) Pulmonary Function - John Mark Salge (SP) Imaging - Alexandre Dias Mançano Lung Diseases - Rimarcs Gomes Ferreira (SP) Clinical Research - Oliver Augusto Nascimento (SP) Pediatric Pulmonology - Paulo Cesar Kussek (PR) Residency - Alberto Cukier (SP) COORDINATORS, BTS SCIENTIFIC COMMITTEES: Asthma - Marcia Margareth Menezes Pizzichini (SC) Lung Cancer - Ilka Santoro Lopes (SP) Pulmonary Circulation - Daniel Waetge (RJ) Advanced Lung Disease - Valeria Maria Augusto (MG) Interstitial Diseases - Mariana Silva Lima (SP) Environmental and Occupational Respiratory Diseases - Albuquerque Hermano Castro (RJ) COPD - Fernando Luiz Cavalcanti Lundgren (EP) Epidemiology - Ricado Corrêa de Amorim (MG) Cystic Fibrosis - Marcelo Bicalho of Fuccio (MG) Respiratory Infections and Mycoses - Mara Rubia Fernandes de Figueiredo (EC) Pleura - Bernard H. Maranhão (RJ) International Relations - Musa Mauro Zamboni (RJ) Smoking - Luiz Carlos Corrêa da Silva (RS) Intensive Care - Augusto Farias Manoel de Carvalho (BA) Tuberculosis - Eliana Matos Dias (BA) ADMINISTRATIVE SECRETARIAT OF THE BRAZILIAN JOURNAL OF PULMONOLOGY Address: SCS Quadra 01, Bloco K, Asa Sul, salas 203/204. Edifício Denasa, CEP 70398-900, Brasília, DF, Brazil. Tel. +55 61 3245-1030/+55 0800 616218. Assistant Managing Editor: Luana Maria Bernardes Campos. E-mail: jpneumo@jornaldepneumologia.com.br Circulation: 1,100 copies Distribution: Free to members of the BTS and libraries Printed on acid-free paper SUPPORT: APOIO:

Published once every two months

J Bras Pneumol. v.39, number 4, p. 399-494 July/August 2013

EDITORIAL 399 - COPD Assessment Test: rapid and easily applied test that promotes patient self-management

COPD Assessment Test: teste rápido e de fácil utilização que promove o automanejo José Roberto Jardim, Laura Zillmer

ARTIGOS ORIGINAIS / ORIGINAL ARTICLES 402 - Portuguese-language version of the COPD Assessment Test: validation for use in Brazil

Validação do Teste de Avaliação da DPOC em português para uso no Brasil

Guilherme Pinheiro Ferreira da Silva, Maria Tereza Aguiar Pessoa Morano, Cyntia Maria Sampaio Viana, Clarissa Bentes de Araujo Magalhães, Eanes Delgado Barros Pereira 409 - Local adverse effects associated with the use of inhaled corticosteroids in patients with moderate or severe asthma

Eventos adversos locais associados ao uso de corticosteroides inalatórios em pacientes com asma moderada ou grave

Charleston Ribeiro Pinto, Natalie Rios Almeida, Thamy Santana Marques, Laira Lorena Lima Yamamura, Lindemberg Assunção Costa, Adelmir Souza-Machado 418 - Congenital lobar emphysema: 30-year case series in two university hospitals

Enfisema lobar congênito: série de casos de 30 anos em dois hospitais universitários Daniele Cristina Cataneo, Olavo Ribeiro Rodrigues, Erica Nishida Hasimoto, Aurelino Fernandes Schmidt Jr, Antonio José Maria Cataneo

427 - Reliability of the Brazilian Portuguese version of the fatigue severity scale and its correlation with pulmonary function, dyspnea, and functional capacity in patients with COPD

Reprodutibilidade da versão brasileira da escala de gravidade da fadiga e sua correlação com função pulmonar, dispneia e capacidade funcional em pacientes com DPOC Silvia Valderramas, Aquiles Assunção Camelier, Sinara Alves da Silva, Renata Mallmann, Hanna Karine de Paulo, Fernanda Warken Rosa

434 - Effect of tramadol on lung injury induced by skeletal muscle ischemia-reperfusion: an experimental study

Efeito do tramadol na lesão pulmonar induzida por isquemia-reperfusão de músculo esquelético: um estudo experimental Mohammad Ashrafzadeh Takhtfooladi, Amirali Jahanshahi, Amir Sotoudeh, Gholamreza Jahanshahi, Hamed Ashrafzadeh Takhtfooladi, Kimia Aslani

440 - Oxygen desaturation in healthy subjects undergoing the incremental shuttle walk test

Dessaturação em indivíduos saudáveis submetidos ao incremental shuttle walk test

Daniel Machado Seixas, Daniela Miti Tsukumo Seixas, Monica Corso Pereira, Marcos Mello Moreira, Ilma Aparecida Paschoal 447 - Contribution of flow-volume curves to the detection of central airway obstruction

Contribuição da curva de fluxo-volume na detecção de obstrução da via aérea central

Liliana Bárbara Perestrelo de Andrade e Raposo, António Bugalho, Maria João Marques Gomes 455 - Lung function in post-poliomyelitis syndrome: a cross-sectional study

Função pulmonar em pessoas com síndrome pós-poliomielite: um estudo transversal

Claudio Andre Barbosa de Lira, Fábio Carderelli Minozzo, Bolivar Saldanha Sousa, Rodrigo Luiz Vancini, Marília dos Santos Andrade, Abrahão Augusto Juviniano Quadros, Acary Souza Bulle Oliveira, Antonio Carlos da Silva 461 - Psychological morbidity as a moderator of intention to quit smoking: a study of smokers and former smokers

Morbidade psicológica como moderador da intenção para deixar de fumar: um estudo com fumantes e ex-fumantes Maria Fernanda Besteiro Afonso, Maria Graça Pereira Alves

Published once every two months

J Bras Pneumol. v.39, number 4, p. 399-494 July/August 2013

469 - Adaptation to different noninvasive ventilation masks in critically ill patients

Adaptação a diferentes interfaces de ventilação mecânica não invasiva em pacientes críticos

Renata Matos da Silva, Karina Tavares Timenetski, Renata Cristina Miranda Neves, Liane Hirano Shigemichi, Sandra Sayuri Kanda, Carla Maekawa, Eliezer Silva, Raquel Afonso Caserta Eid 476 - Prevalence of nutritional deficiency in patients with pulmonary tuberculosis

Prevalência de deficiência nutricional em pacientes com tuberculose pulmonar

Silvana Gomes Nunes Piva, Maria da Conceição Nascimento Costa, Florisneide Rodrigues Barreto, Susan Martins Pereira 484 - Pulmonary tuberculosis and lung cancer: simultaneous and sequential occurrence

Tuberculose pulmonar e câncer de pulmão: ocorrência simultânea ou sequencial

Denise Rossato Silva, Dirceu Felipe Valentini Junior, Alice Mânica Müller, Carlos Podalirio Borges de Almeida, Paulo de Tarso Roth Dalcin

COMUNICAÇÃO BREVE / BRIEF COMUNICATION 490 - Effectiveness of diaphragmatic stimulation with single-channel electrodes in rabbits

Efetividade da estimulação diafragmática com eletrodos monocanais em coelhos

Rodrigo Guellner Ghedini, Julio de Oliveira Espinel, Elaine Aparecida Felix, Artur de Oliveira Paludo, Rodrigo Mariano, Arthur Rodrigo Ronconi Holand, Cristiano Feijó Andrade

ARTIGO DE REVISÃO / REVIEW ARTICLE 495 - Pseudomonas aeruginosa infection in patients with cystic fibrosis: scientific evidence regarding clinical impact, diagnosis, and treatment

Infecção por Pseudomonas aeruginosa em pacientes com fibrose cística: evidências científicas sobre o impacto clínico, diagnóstico e tratamento Luiz Vicente Ribeiro Ferreira da Silva Filho, Flavia de Aguiar Ferreira, Francisco José Caldeira Reis, Murilo Carlos Amorim de Britto, Carlos Emilio Levy, Otavio Clark, José Dirceu Ribeiro

RELATO DE CASO / CASE REPORT 513 - Transdiaphragmatic intercostal hernia: imaging aspects in three cases

Hérnia intercostal transdiafragmática: aspectos de imagem em três casos

Ana Carolina Sandoval Macedo, Fernando Uliana Kay, Ricardo Mingarini Terra, José Ribas Milanez de Campos, André Galante Alencar Aranha, Marcelo Buarque de Gusmão Funari

CARTAS AO EDITOR / LETTER TO THE EDITOR 518 - Not all that wheezes is asthma!

Nem tudo que sibila é asma!

José Antônio Baddini Martinez 521 - Visual scale for the quantification of hyperhidrosis

Escala visual para a quantificação da hiper-hidrose Roberto de Menezes Lyra

523 - Pulmonary histoplasmosis presenting with a halo sign on CT in an immunocompetent patient

Histoplasmose pulmonar presente com sinal do halo em TC em um paciente imunocompetente Graziella Hanna Pereira, Liliane Yuri Almeida, Rosa Shizuda Okubo, Edson Marchiori

525 - Stress cardiomyopathy following acute ischemic stroke during flexible bronchoscopy: a rare sequence of complications

Cardiomiopatia induzida por stress após acidente vascular cerebral isquêmico agudo durante broncoscopia flexível: uma rara sequência de complicações

Sonja Badovinac, Marta Korsic, Branka Cucevic, Valentina Slivnjak, Andrea Vukic Dugac, Marko Jakopovic

Editorial COPD Assessment Test: rapid and easily applied test that promotes patient self-management COPD Assessment Test: teste rápido e de fácil utilização que promove o automanejo

José Roberto Jardim, Laura Zillmer In 2001, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) released a consensus report that ushered in a new era in the diagnosis, management, and prevention of COPD. The somewhat long document was aimed at general practitioners. However, because it was developed by leading experts in pulmonology in various parts of the world, it was adopted as COPD guidelines virtually worldwide. One of the chapters that drew the most attention at the time and that virtually universalized the diagnosis of COPD was the chapter on which the adoption of a FEV1/FVC ratio < 0.70 is described.(1) At the time, there were two opposing views. One was that the FEV1/FVC ratio was appropriate for the diagnosis of COPD, and the other was that the use of the FEV1/FVC ratio might lead to false-positive diagnoses in elderly individuals. In addition, spirometry was reported to serve as a method for assessing the severity of COPD exclusively on the basis of FEV1 in percentage of predicted. A chart was developed in order to guide treatment decisions based on disease severity. However, studies published over the years (and the consequent increase in knowledge of COPD) showed that FEV1 alone was not a good marker of COPD severity. The study that best demonstrated that was a study conducted by Celli et al. and published in 2004; the study showed that a multisystem evaluation approach, including body weight, FEV1, degree of dyspnea, and exercise capacity, was better at predicting the probability of survival of COPD patients than was the assessment of FEV1 alone.(2) The resulting index, which was designated BODE, was shown to correlate with exacerbations, hospitalizations, quality of life, and various other parameters. After the publication of the study in which the BODE index was devised, other indices have been devised, emphasizing other measures, notably exacerbations. In 2011, the GOLD published its quinquennial review. In response to the concerns of the scientific community, the GOLD revolutionized the classification of COPD, which now included,

in addition to lung function (as assessed by FEV1), the number of exacerbations, the symptom of dyspnea, and the quality of life in COPD patients, as assessed by the COPD Assessment Test (CAT). The combination of those parameters led the GOLD to classify COPD patients into quadrants (A, B, C, and D).(1) More recently, hospitalization and another questionnaire, the COPD Clinical Questionnaire (CCQ), were included in the classification.(1) The CAT was developed as a simple, patient-completed questionnaire that is rapidly administered and that can provide information on a variety of areas. The first author of the CAT is Paul Jones, recognized for his expertise in developing respiratory disease questionnaires, the most well-known being the Saint George’s Respiratory Questionnaire (SGRQ), which was translated to Brazilian Portuguese and culturally adapted for use Brazil in 2000.(3) However, the SGRQ and other specific or generic questionnaires commonly used in research are not used in the everyday clinical care of patients with COPD, because those questionnaires are long and complex. The CAT was designed to be a simple health status measure for use in daily practice, being designed to aid in patient-clinician communication and in optimizing treatment. The essential requirements established by the authors were that the CAT should provide a valid and reliable measure of health status, be rapid and easy to use (having 5-7 questions), and be applicable worldwide. In an initial study, the authors sought to understand the experiences of COPD patients regarding the disease. The authors assessed the variability of those experiences, seeking to understand the language used by patients to describe them. At the same time, the authors sought to explore the patient characteristics used by physicians to determine whether their patients are being optimally managed, as well as seeking to determine the methods used by physicians to evaluate those characteristics. To that end, three focus groups of 58 patients were formed, 21 J Bras Pneumol. 2013;39(4):399-401

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Jardim JR, Zillmer L

questions being initially developed in order to address breathlessness, wheezing, cough, sleep, energy/fatigue, social functioning, and anxiety.(4) Those questions were tested in 1,503 COPD patients in six countries. In order to reduce the number of items, the authors used the Rasch model, which tests how items fit a one-dimensional model through an iterative process and a statistical guide for removing the items. At the end of seven rounds, the authors concluded that it would be impossible to limit the CAT to 5 questions, as initially intended. The final version of the CAT comprises 8 questions addressing the following: cough; phlegm; chest tightness; breathlessness going up a hill/stairs; activity limitation at home; confidence in leaving the house; sleep; and energy. The CAT was tested and showed good internal consistency (Cronbachâ&#x20AC;&#x2122;s alpha coefficient = 0.88) and good reproducibility (intraclass correlation coefficient = 0.80). However, the correlations of the CAT with gender and age were weak or nonexistent. Nevertheless, the CAT correlated well with the CCQ (0.83) and the SGRQ (0.87), having correlated moderately with exacerbation (r = 0.60). To date, there have been 25 published studies investigating COPD patients and using the CAT as a dependent variable. In a study published in this issue of the Brazilian Journal of Pulmonology, Silva et al. validate a Brazilian Portuguese-language version of the CAT for use in Brazil.(5) The version was available on a website(6) containing different language versions of the CAT. However, it had yet to be validated for use in Brazil, and its reproducibility had yet to be determined. A series of steps are required in order to use a questionnaire in a language other than that in which it was originally written. The first step is the translation and cross-cultural adaptation of the questionnaire by using appropriate words and methods. A questionnaire originally addressing fatigue when shoveling snow evidently cannot be administered to patients living in a tropical country. The substitution of a given activity in the original questionnaire for another in the translated version should always be carried out with the participation of the first author of the original questionnaire, because the first author is the person who knows the degree of difficulty that he/she had in mind when developing the question. That is why the first author of the original questionnaire should be one of the authors of J Bras Pneumol. 2013;39(4):399-401

the study validating a translated version of the original. The first author of the CAT, Dr. Paul Jones, did not participate in the study published in this issue of the Brazilian Journal of Pulmonology, because the questionnaire had previously been translated and was posted on the website of the company holding the copyright. However, he did participate in the initial translation. After the final version of the translated questionnaire is arrived at, the questionnaire is back-translated into the original language by a person who is proficient in both languages and has had no previous contact with the questionnaire. The backtranslated version (i.e., in the original language) is sent to the original author for comparison with the original version, the original author subsequently giving his/her opinion on it. The intraobserver and interobserver reliability of the CAT (as assessed by the intraclass correlation coefficient) was found to be excellent. This means that the same individual or different individuals will obtain the same results when administering the questionnaire to the same patient. This shows that the questions in the CAT are objective and are not influenced by whoever administers the questionnaire. To validate a questionnaire is to prove that it provides the same information as does a physiological test or a more complex questionnaire that has previously been validated for its intended purpose. The Brazilian Portugueselanguage version of the CAT correlated weakly with the six-minute walk test. This was expected because it has been shown that quality of life does not correlate with exercise capacity. In addition, the CAT has only one question directly related to exercise capacity. It is of note that, although the original CAT correlated well with the SGRQ (r = 0.80), the translated version correlated moderately with the SGRQ. It is difficult to understand this difference. However, questionnaires are developed for a given population, habitually that of the country of origin of the authors. Although translated versions of a given questionnaire are cross-culturally adapted for use, it is possible that the translated questions do not fully reflect the situation in the country where the translated version will be used. The CAT was developed on the basis of focus groups in three different countries, none of which are developing countries. Nevertheless, the fact that the study did not show a high correlation between the questionnaire and the parameters evaluated does not invalidate the

COPD Assessment Test: rapid and easily applied test that promotes patient self-management

use of the test, because it had previously been validated. Strictly speaking, there is no need to validate a questionnaire in the country where it was translated. The study by Silva et al.(5) opens the possibility of using the CAT in studies conducted in Brazil, with the confidence that the answers to the questions will reflect the quality of life of COPD patients in the country. The CAT will allow us to classify COPD patients in Brazil more accurately, so that they can be compared with those in other countries.

José Roberto Jardim Tenured Professor of Pulmonology, Federal University of São Paulo Paulista School of Medicine, São Paulo, Brazil Laura Zillmer Researcher, Pulmonary Rehabilitation Center, Federal University of São Paulo Paulista School of Medicine, São Paulo, Brazil

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References 1. Global Initiative for Chronic Obstructive Lung Disease GOLD [homepage on the Internet]. GOLD; c2001-2013 [cited 2013 Jul 29]. Available from: www.goldcopd.org 2. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(10):1005-12. http://dx.doi.org/10.1056/ NEJMoa021322 PMid:14999112 3. Sousa TC, Jardim JR, Jones P. Validation of the Saint George’s Respiratory Questionnaire in patients with chronic obstructive pulmonary disease in Brazil. J Pneumol. 2000;26(3):119-25. http://dx.doi.org/10.1590/ S0102-35862000000300004 4. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009;34(3):64854. http://dx.doi.org/10.1183/09031936.00102509 PMid:19720809 5. Silva GP, Morano MT, Viana CM, Magalhães CB, Pereira ED. Validação do Teste de Avaliação da DPOC em português para uso no Brasil. J Bras Pneumol. 2013;39(4):xxx-xxx. 6. CAT – COPD Assessment Test [homepage on the Internet]. Middlesex: GlaxoSmithKline Services Unlimited; c2009 [updated 2013 Feb 9; cited 2013 Jul 29]. Available from: www.catestonline.org

J Bras Pneumol. 2013;39(4):399-401

Original Article Portuguese-language version of the COPD Assessment Test: validation for use in Brazil* Validação do Teste de Avaliação da DPOC em português para uso no Brasil

Guilherme Pinheiro Ferreira da Silva, Maria Tereza Aguiar Pessoa Morano, Cyntia Maria Sampaio Viana, Clarissa Bentes de Araujo Magalhães, Eanes Delgado Barros Pereira

Abstract Objective: To validate a Portuguese-language version of the COPD assessment test (CAT) for use in Brazil and to assess the reproducibility of this version. Methods: This was multicenter study involving patients with stable COPD at two teaching hospitals in the city of Fortaleza, Brazil. Two independent observers (twice in one day) administered the Portuguese-language version of the CAT to 50 patients with COPD. One of those observers again administered the scale to the same patients one week later. At baseline, the patients were submitted to pulmonary function testing and the six-minute walk test (6MWT), as well as completing the previously validated Portuguese-language versions of the Saint George’s Respiratory Questionnaire (SGRQ), modified Medical Research Council (MMRC) dyspnea scale, and hospital anxiety and depression scale (HADS). Results: Inter-rater and intrarater reliability was excellent (intraclass correlation coefficient [ICC] = 0.96; 95% CI: 0.93-0.97; p < 0.001; and ICC = 0.98; 95% CI: 0.96-0.98; p < 0.001, respectively). Bland & Altman plots showed good test-retest reliability. The CAT total score correlated significantly with spirometry results, 6MWT distance, SGRQ scores, MMRC dyspnea scale scores, and HADS-depression scores. Conclusions: The Portuguese-language version of the CAT is a valid, reproducible, and reliable instrument for evaluating patients with COPD in Brazil. Keywords: Pulmonary disease, chronic obstructive; Questionnaires; Validation studies; Quality of life; Reproducibility of results.

Resumo Objetivo: Realizar a validação e verificar a reprodutibilidade da versão em português do Brasil do COPD Assessment Test (CAT). Métodos: Estudo multicêntrico, no qual foram selecionados pacientes com DPOC estável em dois hospitais de ensino na cidade de Fortaleza, CE. A versão do CAT foi aplicada duas vezes a 50 pacientes com DPOC por dois observadores independentes no mesmo dia. Após uma semana, esse mesmo questionário foi aplicado novamente aos mesmos pacientes por um dos observadores. No primeiro dia, os pacientes foram submetidos à prova de função pulmonar e ao teste de caminhada de seis minutos (TC6) e responderam as versões validadas de Saint George’s Respiratory Questionnaire (SGRQ), escala de dispneia Modified Medical Research Council (MMRC) e hospital anxiety and depression scale (HADS). Resultados: As reprodutibilidades interobservador e intraobservador foram excelentes (coeficiente de correlação intraclasse [CCI] = 0,96; IC95%: 0,93-0,97; p < 0,001; e CCI = 0,98; IC95%: 0,96-0,98; p < 0,001, respectivamente). As disposições gráficas de Bland & Altman demonstraram boa confiabilidade teste-reteste. Houve correlações significativas do escore total do CAT com os resultados de espirometria, TC6, SGRQ, escala de dispneia MMRC e HADS-depressão. Conclusões: A versão brasileira do CAT é um instrumento válido, reprodutível e confiável para a avaliação dos pacientes com DPOC na população brasileira. Descritores: Doença pulmonar obstrutiva crônica; Questionários; Estudos de validação; Qualidade de vida; Reprodutibilidade dos testes.

*Study carried out at the Federal University of Ceará and at the Dr. Carlos Alberto Studart Gomes Messejana Hospital, Fortaleza, Brazil. Correspondence to: Eanes Delgado Barros Pereira, Rua Barbara de Alencar, 1401, CEP 60140-000, Fortaleza, CE, Brasil. Tel. 55 85 494-9000. E-mail: eanes@fortalnet.com.br Financial support: This study received financial support from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education). Submitted: 22 January 2013. Accepted, after review: 7 May 2013.

J Bras Pneumol. 2013;39(4):402-408

Portuguese-language version of the COPD Assessment Test: validation for use in Brazil

Introduction Classically, COPD is defined as chronic progressive airflow limitation that is partially reversible and causes significant extrapulmonary effects, culminating in a reduction in the functional capacity, social interaction, and well-being of the patients, negatively affecting their health-related quality of life (HRQoL).(1,2) The literature indicates that the chronic symptoms of COPD associated with the systemic manifestations of the disease are the major factors responsible for the worsening of HRQoL. Although the airflow obstruction is partially reversible, the disease control interventions are primarily aimed at improving the HRQoL of patients, which thereby becomes an important measure to be assessed. (3,4) The administration of questionnaires to assess the HRQoL of patients with COPD has been widely discussed in the literature. The results inferred by the use of these instruments generate reliable, valid, and reproducible evidence.(5) Disease-specific questionnaires designed to assess COPD impact are widely used in clinical studies. However, these questionnaires are still considered complex and extensive, requiring a substantial amount of time to completion. Chief among them are the Saint George’s Respiratory Questionnaire (SGRQ), (6) the Chronic Respiratory Questionnaire (CRQ),(7) the Breathing Problems Questionnaire, (8) and the Airways Questionnaire 20 (AQ20), (9) all of which have been validated for use in Brazil. Recently, a group of researchers in the United Kingdom developed and validated the COPD Assessment Test (CAT), which is a short, simple instrument for quantifying COPD impact during routine clinical practice, in addition to aiding health status assessment and facilitating communication between patients and health professionals.(10) However, this questionnaire has not been validated for use in Brazil. Therefore, the objective of the present study was to validate a Portuguese-language version of the CAT for use in Brazil and to assess the reproducibility of this version.

Methods This was a cross-sectional study, conducted between January and November of 2012, involving patients treated at the Pulmonology

403

Outpatient Clinic of the Federal University of Ceará Walter Cantídio University Hospital and patients eligible for pulmonary rehabilitation at the Dr. Carlos Alberto Studart Gomes Messejana Hospital, both of which are located in the city of Fortaleza, Brazil. The present study was conducted in accordance with Brazilian National Health Council Resolution 196/96, which sets out the ethical principles for human research, and was approved by the ethics committees of the two hospitals (Ruling no. 108.10/11 and Ruling no. 880/12, respectively). All patients gave written informed consent prior to their inclusion in the study. The inclusion criteria were as follows: having been clinically diagnosed with COPD with moderate to severe airflow obstruction and having an FEV1/ FVC ratio < 0.7 (as measured by spirometry), in accordance with the recommendations of the Global Initiative for Chronic Obstructive Lung Disease(1); being between 40 and 80 years of age; being clinically stable (no hospitalizations or infections in the three months prior to the study); and being a smoker or former smoker with a smoking history greater than 10 pack-years. The exclusion criteria were as follows: experiencing an exacerbation of COPD requiring therapeutic intervention; and having other nonpulmonary diseases that are considered disabling, severe, or difficult-to-control. The CAT consists of eight items, designated cough, phlegm, chest tightness, breathlessness, activity limitations at home, confidence leaving home, sleep, and energy. For each item, the patient chooses only one response option, which is scored from zero to five (Appendix 1). At the end of the test, all response scores are summed, and then the clinical impact of COPD is determined on the basis of the stratification scoring of the study that developed and validated the CAT.(10) The results vary according to the range within which the scores obtained lie, being classified by clinical impact as follows: 6-10 points, mild; 11-20, moderate; 21-30, severe; and 31-40, extremely severe. In order to test the inter-rater reliability of the CAT, the patients were administered the questionnaire twice by two observers, 30 minutes apart, during the first visit (V1). The second visit (V2) occurred 7 days after the first one, and the CAT was again administered to the same patients J Bras Pneumol. 2013;39(4):402-408

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Silva GPF, Morano MTAP, Viana CMS, Magalhães CBA, Pereira EDB

by only one of the observers in order to test the intra-rater reliability. Also at baseline, the patients underwent the six-minute walk test (6MWT) and spirometry, as well as being administered the previously validated Portuguese-language versions of the SGRQ,(6) hospital anxiety and depression scale (HADS), and modified Medical Research Council (MMRC) dyspnea scale. Spirometry was performed with a Respiradyne II Plus spirometer (Sherwood Medical, St. Louis, MO, USA), in accordance with Brazilian guidelines,(11) using the reference values for the Brazilian population established by Pereira et al.(12) The 6MWT was performed in accordance with guidelines established by the American Thoracic Society,(13) with the patient being encouraged to walk as far as possible, in six minutes, on a 30-m level corridor. At the end of the test, the examiner recorded the distance covered. The HADS consists of 14 items, of which 7 focus on the assessment of anxiety (HADS-A) and 7 focus on the assessment of depression (HADS-D). Each item can be scored from zero to three, the maximum score on each subscale being 21 points. We adopted the cut-off points recommended for both subscales: 0-8 points, absence of anxiety and/or depression; and ≥ 9 points, presence of anxiety and/or depression.(14) Dyspnea was assessed with the MMRC dyspnea scale. (11) Data were statistically analyzed with the Statistical Package for the Social Sciences, version 17.0 (SPSS Inc., Chicago, IL, USA) and GraphPad Prism, version 6.0 (GraphPad Software Inc., San Diego, CA, USA). For the analysis of the reliability of the administration of the CAT (V1 vs. V2), we used the intraclass correlation coefficient (ICC). The Wilcoxon test was used to compare the scores obtained from the administration of the CAT by the observer in V1 and V2. In order to assess the agreement between V1 and V2, we used Bland & Altman plots. The instruments were tested for internal consistency by Cronbach’s alpha coefficient. In order to validate the CAT, we assessed the correlations (Spearman’s correlation test) of its scores with those obtained on the SGRQ (gold standard questionnaire), HADS, and MMRC dyspnea scale, as well as with 6MWD and spirometry values. The level of significance was set at 5%. J Bras Pneumol. 2013;39(4):402-408

Results The study sample comprised 50 patients with COPD, 26 of whom were female (52%). The mean age of the patients was 62.2 ± 8.4 years, whereas the mean height and weight were 1.58 ± 0.08 cm and 65.8 ± 15.9 kg, respectively. There were no significant differences between the total scores obtained from the administration of the CAT by the same observer in V1 and V2 (20.7 ± 9.8 vs. 20.1 ± 9.4; p = 0.8). The ICC for intra-rater reliability (V1 vs. V2) was 0.96 (95% CI: 0.93-0.97). Table 1 - Characteristics of the sample of 50 COPD patients studied.a Variable Result Age, years

62.4 ± 8.4

Genderb Male

24 (48)

Female

26 (52)

Level of education

Illiterate

34 (68)

> 9 years of schooling

6 (12)

9 years of schooling

3 (6)

High school (incomplete)

4 (8)

High school (complete)

2 (4)

College (complete)

1 (2)

Height, cm

1.58 ± 0.08

Weight, kg

65.8 ± 15.9

BMI, kg/cm2

26.0 ± 4.9

Post-BD FEV1, L

1.05 ± 0.41

Post-BD FEV1, % of predicted

44.0 ± 13.8

Post-BD FVC, L

2.19 ± 0.78

Post-BD FVC, % of predicted Post-BD FEV1/FVC

72.3 ± 18 0.48 ± 0.10

MMRC dyspnea scale score

1.8 ± 1.0

6MWD, m

344 ± 97

BMI: body mass index; BD: bronchodilator; MMRC: modified Medical Research Council; and 6MWD: six-minute walk distance. aValues expressed as mean ± SD, except where otherwise indicated. bValues expressed as n (%).

Table 2 - Correlations (Spearman’s correlation test) of the COPD Assessment Test scores with the Saint George’s Respiratory Questionnaire scores, spirometry values, six-minute walk distance, modified Medical Research Council dyspnea scale scores, and hospital anxiety and depression scale scores. Variable r p SGRQ Symptoms Activity

0.60 0.59

< 0.001 < 0.001

Impact

0.51

< 0.001

Total

0.64

< 0.001

FEV1, L

−0.38

0.006

FEV1, % of predicted

−0.25

0.07

FVC, L

−0.39

0.005

FVC, % of predicted

−0.30

0.03

FEV1/FVC

0.01

0.9

6MWD

−0.37

0.008

MMRC dyspnea scale score HADS-A score

0.48

< 0.001

0.03

0.7

HADS-D score

0.39

0.001

SGRQ: Saint George’s Respiratory Questionnaire; 6MWD: six-minute walk distance; MMRC: modified Medical Research Council; HADS-A: hospital anxiety and depression scaleanxiety subscale; and HADS-D: hospital anxiety and depression scale-depression subscale.

There were also no significant differences in the scores between the two observers of the study (20.7 ± 8.5 vs. 21.2 ± 9.0; p = 0.4). The ICC for inter-rater reliability was 0.98 (95% CI: 0.96-0.98). The Cronbach’s alpha coefficient for the CAT was 0.98 (p < 0.001). Bland & Altman plots showed good testretest reliability and good inter-rater reliability (Figure 1). There were significant correlations between the CAT score and the SGRQ total and domain scores (0.51 < r < 0.64). The CAT score correlated better with the MMRC dyspnea scale score than with the HADS-D score (r = 0.48 vs. r = 0.39; p < 0.05 for both). The CAT scores correlated negatively with 6MWD (r = −0.37) and with some pulmonary function measurements, such as FEV 1 in L (r = −0.38);

Individual differences in the CAT values obtained Individual differences in the CAT values obtained by observers 1 and 2 in visit 1 by observer 1 in visits 1 and 2

Portuguese-language version of the COPD Assessment Test: validation for use in Brazil

405

15 10

5 0

Mean

-5 -10

Individual mean CAT values obtained by observer 1 in visits 1 and 2

B 10 5

-5

Mean

-10 Individual mean CAT values obtained by observers 1 and 2 in visit 1

Figure 1 - Bland & Altman plots. In A, intra-rater analysis: mean = 0.64; upper limit (UL) = 5.69 and lower limit (LL) = −4.41. In B, inter-rater analysis: mean = −0.26; UL = 4.80 and LL = −5.32.

FVC in L (r = −0.39); and FVC as % of the predicted value (r = −0.30; Table 2). The mean administration time was 104.00 ± 0.69 seconds.

Discussion The present study showed that the Portugueselanguage version of the CAT had excellent reliability when administered by different observers and when administered by the same observer at two distinct time points. Bland & Altman plots showed that the CAT has good test-retest reliability, as well as a high Cronbach’s alpha coefficient and a good correlation with the SGRQ (total and domain scores). The process of development and preparation of the CAT arose from the need for new instruments for evaluating COPD impact on HRQoL and clinical practice in a simple, fast, and effective way.(10) J Bras Pneumol. 2013;39(4):402-408

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Various studies conducted in countries such as Spain,(15) China,(16) South Korea,(17) and Saudi Arabia(18,19) have validated versions of the CAT in their language and reported the instrument to have good reproducibility. We found no studies validating a Portuguese-language version of the CAT for use in Brazil or assessing the reproducibility of the CAT. During test-retest, the ICC was found to be 0.98. Jones et al.(10) found high ICC values and high Cronbach’s alpha coefficients when they performed the first validation of the CAT in a multicenter study. The Cronbach’s alpha coefficient of 0.98 found in the present study shows that the questionnaire has excellent internal consistency. The questionnaires used for the validation of the CAT were the SGRQ, MMRC dyspnea scale, and HADS. These instruments were used because they are related to some specific items of the CAT, such as those concerning respiratory symptoms and limitations in activities of daily living (which are also addressed in the SGRQ and MMRC dyspnea scale) and those concerning self-confidence and energy (which are also addressed in the HADS and SGRQ). In general, there were high and significant correlations between the CAT scores and the SGRQ total and domain scores. Previous studies have demonstrated that the CAT can measure the impact of COPD on the lives of patients, showing correlations with standard questionnaires other than the SGRQ, such as the CRQ and the Clinical COPD Questionnaire. (20-24) Regarding the pulmonary function variables, the present study showed that there was a weak but significant correlation of the CAT scores with some spirometry values and 6MWD. This might represent a discrepancy between patient experiences and perspectives and the degree of respiratory dysfunction. Other studies have also shown weak correlations between the CAT scores and pulmonary function values, especially FEV 1. (17,20,21,25) Regarding the sensation of dyspnea, the CAT scores correlated significantly with MMRC dyspnea scale scores and SGRQ symptom scores, showing that the CAT can detect the patient’s respiratory complaints. There was no significant correlation between the CAT scores and the anxiety scores. However, for the depression scores, the correlation was J Bras Pneumol. 2013;39(4):402-408

found to be weak. This might have occurred because, among the CAT questions, only the items concerning energy and confidence leaving home address issues that are more directly related to the psychological component of the patient. The administration time of the CAT in the present study was, on average, 104 s; this occurred because of the simplicity of the questions and response options. While administering the CAT to patients with COPD, Ringbaek et al.(26) found that it required a shorter administration time than did the SGRQ and CRQ (107 s, 134 s, and 578 s, respectively). There was no back-translation analysis of the CAT, since there is already a Portuguese-language version, written in congruent, easy-to-understand language, ready for use. None of the items in the present version sounded odd in Brazilian Portuguese or seemed to be alien to the Brazilian culture and society, and therefore there was no need for any significant adaptations. Since the present study was cross-sectional in design, it was not possible to evaluate the responsiveness of the Portuguese-language version of the CAT to interventions, such as pulmonary rehabilitation. This can be considered a limitation of the study; however, other studies have used the same approach.(15,21,23,26) Following this line of thought and knowing that the Portugueselanguage version of the CAT proved to be valid and reproducible, we believe that, in future studies, it will prove to be responsive. In conclusion, the Portuguese-language version of the CAT is a valid, reproducible, and reliable instrument for assessing the impact of COPD on the lives of patients in Brazil.

References 1. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532-55. http://dx.doi. org/10.1164/rccm.200703-456SO PMid:17507545 2. Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res. 2010;11:122. PMid:20831787 PMCid:2944278 3. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J. 2009;33(5):116585. http://dx.doi.org/10.1183/09031936.00128008 PMid:19407051 4. Ng TP, Niti M, Tan WC, Cao Z, Ong KC, Eng P. Depressive symptoms and chronic obstructive pulmonary disease: effect on mortality, hospital readmission, symptom

Portuguese-language version of the COPD Assessment Test: validation for use in Brazil

burden, functional status, and quality of life. Arch Intern Med. 2007;167(1):60-7. http://dx.doi.org/10.1001/ archinte.167.1.60 PMid:17210879 5. Ferreira CA, Cukier A. Evaluating COPD from the perspective of the patient. J Bras Pneumol. 2006;32(2):vii-viii. PMid:17273576 6. Sousa TC, Jardim JR, Jones P. Validação do Questionário do Hospital Saint George na Doença Respiratória (SGRQ) em pacientes portadores de doença pulmonar obstrutiva crônica no Brasil. J Pneumol. 2000; 26(3):119-28. http:// dx.doi.org/10.1590/S0102-35862000000300004 7. Moreira GL, Pitta F, Ramos D, Nascimento CS, Barzon D, Kovelis D, et al. Portuguese-language version of the Chronic Respiratory Questionnaire: a validity and reproducibility study. J Bras Pneumol. 2009;35(8):737-44. http://dx.doi. org/10.1590/S1806-37132009000800004 PMid:19750325 8. Silva PN, Jardim JR, Costa e Souza GM, Hyland ME, Nascimento OA. Cultural adaptation and reproducibility of the Breathing Problems Questionnaire for use in patients with COPD in Brazil. J Bras Pneumol. 2012;38(3):339-45. Erratum in: J Bras Pneumol. 2012;38(4):538. http://dx.doi. org/10.1590/S1806-37132012000300009 PMid:22782604 9. Camelier A, Rosa F, Jones P, Jardim JR. Validação do questionário de vias aéreas 20 (“Airways questionnaire 20” – AQ20) em pacientes portadores de doença pulmonar obstrutiva crônica (DPOC) no Brasil. J Pneumol. 2003;29(1):28-35. 10. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009;34(3):648-54. http:// dx.doi.org/10.1183/09031936.00102509 PMid:19720809 11. Sociedade Brasileira de Pneumologia e Tisiologia. II Consenso Brasileiro de Doença Pulmonar Obstrutiva Crônica (DPOC) - 2004. J Bras Pneumol. 2004;30(5):1-42. 12. Pereira CA, Barreto SP, Simoes JG, Pereira FW, Gerstler JG, Nakatami J. Valores de referência para a espirometria em uma amostra da população brasileira adulta. J Pneumol. 1992;18(1):10-22. 13. Brooks D, Solway S, Gibbons WJ. ATS statement on six-minute walk test. Am J Respir Crit Care Med. 2003;167(9):1287. http://dx.doi.org/10.1164/ajrccm.167.9.950 PMid:12714344 14. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-70. http:// dx.doi.org/10.1111/j.1600-0447.1983.tb09716.x 15. Agustí A, Soler JJ, Molina J, Mu-oz MJ, García-Losa M, Roset M, et al. Is the CAT questionnaire sensitive to changes in health status in patients with severe COPD exacerbations? COPD. 2012;9(5):492-8. http://dx.doi.org/10.3109/15412 555.2012.692409 PMid:22958111 16. Wiklund I, Berry P, Lu KX, Fang J, Fu C. The Chinese translation of COPD Assessment Test™ (CAT) provides a valid and reliable measurement of COPD health status in Chinese COPD patients. Am J Respir Crit Care Med 181;2010:A3575. 17. Lee S, Lee JS, Song JW, Choi CM, Shim TS, Kim TB, et al. Validation of the Korean version of Chronic Obstructive Pulmonary Disease Assessment Test (CAT) and Dyspnea-12

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Questionnaire. Tuberc Respir Dis. 2010;69(3):171-6. http:// dx.doi.org/10.4046/trd.2010.69.3.171 18. Al-Moamary MS, Al-Hajjaj MS, Tamim HM, Al-Ghobain MO, Al-Qahtani HA, Al-Kassimi FA. The reliability of an Arabic translation of the chronic obstructive pulmonary disease assessment test. Saudi Med J. 2011;32(10):102833. PMid:22008922 19. Al Moamary MS, Tamim HM, Al-Mutairi SS, Al-Khouzaie TH, Mahboub BH, Al-Jawder SE, et al. Quality of life of patients with chronic obstructive pulmonary disease in the Gulf Cooperation Council countries. Saudi Med J. 2012;33(10):1111-7. PMid:23047217 20. Jones PW, Price D, van der Molen T. Role of clinical questionnaires in optimizing everyday care of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2011;6:289-96. http://dx.doi.org/10.2147/ COPD.S18181 PMid:21697993 PMCid:3119104 21. Tsiligianni IG, van der Molen T, Moraitaki D, Lopez I, Kocks JW, Karagiannis K, et al. Assessing health status in COPD. A head-to-head comparison between the COPD assessment test (CAT) and the clinical COPD questionnaire (CCQ). BMC Pulm Med. 2012;12:20. http:// dx.doi.org/10.1186/1471-2466-12-20 PMid:22607459 PMCid:3431277 22. Weldam SW, Schuurmans MJ, Liu R, Lammers JW. Evaluation of Quality of Life instruments for use in COPD care and research: a systematic review. Int J Nurs Stud. 2013;50(5):688-707. http://dx.doi.org/10.1016/j. ijnurstu.2012.07.017 PMid:22921317 23. Dodd JW, Marns PL, Clark AL, Ingram KA, Fowler RP, Canavan JL, et al. The COPD Assessment Test (CAT): shortand medium-term response to pulmonary rehabilitation. COPD. 2012;9(4):390-4. PMid:22497561 24. Mackay AJ, Donaldson GC, Patel AR, Jones PW, Hurst JR, Wedzicha JA. Usefulness of the Chronic Obstructive Pulmonary Disease Assessment Test to evaluate severity of COPD exacerbations. Am J Respir Crit Care Med. 2012;185(11):1218-24. http://dx.doi.org/10.1164/ rccm.201110-1843OC PMid:22281834 25. Ghobadi H, Ahari SS, Kameli A, Lari SM. The relationship between COPD Assessment Test (CAT) scores and severity of airflow obstruction in stable COPD patients. Tanaffos. 2012;11(2):22-6 26. Ringbaek T, Martinez G, Lange P. A comparison of the assessment of quality of life with CAT, CCQ, and SGRQ in COPD patients participating in pulmonary rehabilitation. COPD. 2012;9(1):12-5. http://dx.doi.org/10.3109/154 12555.2011.630248 PMid:22292593

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About the authors Guilherme Pinheiro Ferreira da Silva

Physical Therapist. Hospital Distrital Gonzaga Mota – José Walter, Fortaleza City Hall, Fortaleza, Brazil.

Maria Tereza Aguiar Pessoa Morano

Head. Department of Pulmonary Rehabilitation, Dr. Carlos Alberto Studart Gomes Messejana Hospital, Fortaleza, Brazil.

Cyntia Maria Sampaio Viana

Pulmonologist. Department of Pulmonary Rehabilitation, Dr. Carlos Alberto Studart Gomes Messejana Hospital, Fortaleza, Brazil.

Clarissa Bentes de Araujo Magalhães

Resident in Physical Therapy/Intensive Care. Federal University of Ceará, Fortaleza, Brazil.

Eanes Delgado Barros Pereira

Associate Professor. Department of Clinical Medicine and Master’s Program in Medical Sciences, Federal University of Ceará, Brazil.

Appendix 1 - Portuguese-language version of the COPD Assessment Test. TM

O seu nome:

CAT

Data de hoje:

COPD Assessment Test

Como está a sua DPOC (Doença Pulmonar Obstrutiva Crônica)? Faça o Teste de Avaliação da DPOC (COPD Assessment Test™–CAT) Esse questionário irá ajudá-o e ao seu profissional da saúde a medir o impacto que a DPOC (Doença Pulmonar Obstrutiva Crônica) causa no seu bem estar e o no seu dia a dia.As suas respostas e a pontuação do teste podem ser utilizadas por você e pelo seu profissional da saúde para ajudar a melhorar o controle da sua DPOC e a obter o máximo benefício do tratamento. Para cada um dos itens a seguir, assinale com um (X) o quadrado que melhor o descrever presentemente. Certifique-se de selecionar apenas uma resposta para cada pergunta.

Por exemplo: Estou muito feliz

Estou muito triste PONTUAÇÃO

Nunca tenho tosse

Tenho tosse o tempo todo

Não tenho nenhum catarro (secreção) no peito

O meu peito está cheio de catarro (secreção)

Não sinto nenhuma pressão no peito

Sinto uma grande pressão no peito

Não sinto falta de ar quando subo luma ladeira ou um andar de escada

Sinto bastante falta de ar quando subo uma ladeira ou um andar de escada

Não sinto nenhuma limitação nas minhas atividades em casa

Sinto-me muito limitado nas minhas atividades em casa

Sinto-me confiante para sair de casa, apesar da minha doença pulmonar

Não me sinto nada confiante para sair de casa, por causa da minha doença pulmonar

Durmo profundamente

Não durmo profundamente devido à minha doença pulmonar

Tenho muita energia (disposição)

Não tenho nenhuma energia (disposição)

J Bras Pneumol. 2013;39(4):402-408

PONTUAÇÃO TOTAL

Original Article Local adverse effects associated with the use of inhaled corticosteroids in patients with moderate or severe asthma* Eventos adversos locais associados ao uso de corticosteroides inalatórios em pacientes com asma moderada ou grave*

Charleston Ribeiro Pinto, Natalie Rios Almeida, Thamy Santana Marques, Laira Lorena Lima Yamamura, Lindemberg Assunção Costa, Adelmir Souza-Machado

Abstract Objective: To describe and characterize local adverse effects (in the oral cavity, pharynx, and larynx) associated with the use of inhaled corticosteroids (ICSs) in patients with moderate or severe asthma. Methods: This was a cross-sectional study involving a convenience sample of 200 asthma patients followed in the Department of Pharmaceutical Care of the Bahia State Asthma and Allergic Rhinitis Control Program Referral Center, located in the city of Salvador, Brazil. The patients were ≥ 18 years of age and had been using ICSs regularly for at least 6 months. Local adverse effects (irritation, pain, dry throat, throat clearing, hoarseness, reduced vocal intensity, loss of voice, sensation of thirst, cough during ICS use, altered sense of taste, and presence of oral candidiasis) were assessed using a 30-day recall questionnaire. Results: Of the 200 patients studied, 159 (79.5%) were women. The mean age was 50.7 ± 14.4 years. In this sample, 55 patients (27.5%) were using high doses of ICS, with a median treatment duration of 38 months. Regarding the symptoms, 163 patients (81.5%) reported at least one adverse effect, and 131 (65.5%) had a daily perception of at least one symptom. Vocal and pharyngeal symptoms were identified in 57 (28.5%) and 154 (77.0%) of the patients, respectively. The most commonly reported adverse effects were dry throat, throat clearing, sensation of thirst, and hoarseness. Conclusions: Self-reported adverse effects related to ICS use were common among the asthma patients evaluated here. Keywords: Asthma; Glucocorticoids; Administration, inhalation; Pharmaceutical services.

Resumo Objetivo: Descrever e caracterizar os eventos adversos locais na orofaringe e laringe associados ao uso de corticosteroide inalatório (CI) em pacientes com asma moderada ou grave. Métodos: Estudo de corte transversal, com amostra de conveniência composta por 200 pacientes acompanhados no Serviço de Assistência Farmacêutica da Central de Referência do Programa para Controle da Asma na Bahia, em Salvador (BA). Os pacientes tinham ≥ 18 anos e estavam em uso regular de CI por período ≥ 6 meses. Os eventos adversos locais (irritação, dor, garganta seca, pigarro, rouquidão, redução da potência da voz, perda de voz; sensação de sede, tosse durante inalação, alteração do paladar e presença de monilíase oral) foram avaliados por meio de um questionário com período recordatório de 30 dias. Resultados: Dos 200 pacientes estudados, 159 (79,5%) eram mulheres. A média de idade foi de 50,7 ± 14,4 anos. Nesta amostra, 55 pacientes (27,5%) utilizavam altas doses de CI, com mediana de duração de tratamento de 38 meses. Em relação aos sintomas, 163 pacientes (81,5%) reportaram ao menos um evento adverso, e 131 (65,5%) tinham a percepção diária de pelo menos um sintoma. Os sintomas de voz e de faringe foram identificados em 57 (28,5%) e 154 (77,0%) pacientes, respectivamente. Os eventos adversos mais frequentemente relatados foram garganta seca, pigarros, sensação de sede e rouquidão. Conclusões: Eventos adversos relacionados ao uso de CI foram queixas frequentemente referidas e percebidas por esta amostra de asmáticos. Descritores: Asma; Glucocorticoides; Administração por inalação; Assistência farmacêutica.

* Study carried out under of auspices of the Programa para o Controle da Asma na Bahia – ProAR, Bahia State Asthma Control Program – Salvador, Brazil.Tel. 55 71 3237-5353. E-mail: charlestonribeiro@gmail.com Financial support: None. Submitted: 2 January 2013. Accepted, after review: 23 May 2013.

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Pinto CR, Almeida NR, Marques TS, Yamamura LLL, Costa LA, Souza-Machado A

Introduction Inhaled corticosteroids (ICSs) are currently the most effective therapeutic strategy for asthma control and are recommended by national and international guidelines for the management of the disease. Maintenance treatment with ICSs reduces asthma symptoms, the frequency and severity of exacerbations, and the number of hospitalizations, as well as improving the quality of life of patients.(1-3) Despite their efficacy, ICSs can cause local and systemic adverse effects.(1-8) Their frequent use, for longer periods and in high doses, has been accompanied by concerns about their potential adverse effects in the oral cavity and pharynx, such as hoarseness, dysphonia, candidiasis, pharyngitis, and cough reflex.(3,5,7) Approximately 5-10% of subjects treated with ICSs report adverse effects in the oral cavity and pharynx, which are considered to be an immediate cause of clinical discomfort, with poorer patient adherence to treatment and a consequent increase in asthma morbidity.(3-6,9) Adverse effects resulting from the use of ICSs are underestimated by patients and physicians and often are not identified in daily clinical practice.(7,10-13) In addition, information about the frequency and intensity with which local adverse effects induced by ICSs strike patients is limited.(7) Patient reports about the adverse effects experienced are considered an important source of information on adverse effects in pharmacovigilance and in clinical practice.(14) The Programa para o Controle da Asma na Bahia (ProAR, Bahia State Asthma Control Program) is a project involving care, education, and research and aiming at ensuring concomitant control of asthma and allergic rhinitis by means of a multidisciplinary approach including medical care, nursing care, psychological follow-up, and pharmaceutical care. The objective of the present study was to describe and characterize local adverse effects (in the oral cavity, pharynx, and larynx) associated with the use of ICSs in patients with moderate or severe asthma and under treatment in the Department of Pharmaceutical Care of the ProAR Referral Center.

Methods The protocol for the treatment of ProAR patients includes non-pharmacological measures, such as asthma self-management plans, psychological support, and an education program J Bras Pneumol. 2013;39(4):409-417

for patients and their families, all of which are associated with the Department of Pharmaceutical Care, which provides access to medications at no cost and on a regular basis, including ICSs alone (budesonide, 200 µg; and beclomethasone, 250 µg and 400 µg), a long-acting β2 agonist combined with an ICS (formoterol + budesonide, 6/200 and 12/400 µg), and a short-acting β2 agonist (fenoterol, 100 µg). The patients are followed monthly at the Department of Pharmaceutical Care, in which the medications are dispensed and support is provided by means of strategic interventions designed to promote the effectiveness and safety of the pharmacological treatment, as well as adherence to it. These interventions include assessment of the level of asthma control, systematic guidance on the proper inhalation technique on a regular basis, intensive monitoring of adherence to treatment, use of a spacer, and oral hygiene after ICS use. This cross-sectional descriptive study was conducted between June of 2009 and January of 2010 and involved a convenience sample of 200 patients followed at the ProAR Referral Center, located in the city of Salvador, Brazil. We included male and female subjects (≥ 18 years of age) who had been diagnosed with moderate or severe persistent asthma,(1) were being regularly followed in the ProAR Department of Pharmaceutical Care, and had been using ICSs regularly for at least 6 months. Patients who used oral, parenteral, ocular, or topic corticosteroids in the last three months prior to the beginning of the study were not selected. A daily dose of 800 µg of beclomethasone was considered equivalent to a daily dose of 800 µg of budesonide. Daily doses of 400-800 µg of budesonide were considered medium doses, whereas daily doses above 800 µg of budesonide were considered high doses.(1) The devices evaluated were classified into two groups: metered dose inhalers (MDIs), with or without a spacer; and dry powder inhalers (DPIs), including Pulvinal®, Aerolizer®, and Turbohaler®. All patients were evaluated by a pulmonologist and a pharmacist, both of whom had been previously trained, after medical visits, in a room in the Department of Pharmaceutical Care. The interview elicited information about the patient (gender and age) and the characteristics of the ICS (formulation, daily dose, type of inhaler, and duration of

Local adverse effects associated with the use of inhaled corticosteroids in patients with moderate or severe asthma

use), as well as about the practice of oral hygiene after ICS use and about the use of nasal corticosteroids. The practice of oral hygiene was considered correct when the patients rinsed their mouths with water immediately after ICS use, gargled, and subsequently spat out the wash water. (1) Adverse effects were assessed using a 30-day recall questionnaire. The following parameters were evaluated: throat conditions, such as irritation, pain, dryness, and throat clearing; hoarseness; reduced vocal intensity and loss of voice; sensation of thirst; cough during ICS use; altered sense of taste; and presence of oral candidiasis. The frequency of adverse effects was classified into one of the following categories: never; occasionally; on most days; or daily. The present study was approved by the Research Ethics Committee of the Federal University of Bahia Climério de Oliveira Maternity Hospital. All patients gave written informed consent, and their personal data were kept confidential. Data were analyzed with the Statistical Package for the Social Sciences, version 17.0 (SPSS Inc., Chicago, IL, USA). Simple descriptive frequency statistics was used to determine the prevalence of each adverse effect and its degree of intensity. The overall prevalence of adverse effects was estimated on the basis of the cases with at least one adverse effect and the total number of asthma patients evaluated. Means and standard deviations were calculated for quantitative variables with normal distribution. Categorical variables are expressed as proportions. The chi-square test was used to assess the statistical significance between categorical variables, and the Student’s t-test was used to compare the means of quantitative data. The level of statistical significance was set at p < 0.05 for all tests.

Results We evaluated 200 patients, of whom 159 (79.5%) were female and 41 (20.5%) were male. The mean age was 50.7 ± 14.4 years. In this sample, 55 patients (27.5%) were using high doses of ICS (budesonide > 800 µg/day). The mean daily dose of ICS was 945 ± 345 µg, and 171 patients (85.5%) were found to be using budesonide. The duration of treatment with ICSs

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was long, with the median being 38 months (range, 6-84 months). Of the sample as a whole, 153 (76.5%) reported performing oral hygiene after ICS use. The general characteristics of the patients are shown in Table 1. In general, 95% of the patients used ICSs + long-acting β2 agonists (formoterol + budesonide, in 85.5%; formoterol + budesonide and beclomethasone, in 14.5%) and only 5% used an ICS alone (beclomethasone, in 3.0%; and budesonide, in 2.0%). We found that 149 patients (74.5%) used only one inhaler and 51 (25.5%) used two inhalers. Of the 200 patients, 162 (81.0%) used an Aerolizer® DPI, 45 (22.5%) used an MDI, 28 (14.0%) used a Turbohaler® DPI, and 17 (8.5%) used a Pulvinal® DPI. Approximately two thirds of the patients (65%) used a nasal corticosteroid (budesonide, in 91.5%, and beclomethasone, in 8.5%). Patient perception of adverse effects in the pharynx/larynx was found to be high among the subjects with severe asthma, with at least one effect being observed in 81.5% of them, one to three effects being observed in 51.5%, and four to six effects being observed in 23.5%. Table 1 - General characteristics of the 200 patients with moderate or severe asthma evaluated.a Characteristic Result Gender Female Male Age, yearsb Daily dose of ICS = 800 µg > 800 µg Treatment duration, monthsb

159 (79.5) 41 (20.5) 50.7 ± 14.4 145 (72.5) 55 (27.5) 38

ICS Budesonide

171 (85.5)

Beclomethasone

6 (3.0)

Budesonide + beclomethasone

23 (11.5)

Type of inhaler DPI

144 (72)

DPI + MDI

51 (25.5)

MDI

5 (2.5)

ICS: inhaled corticosteroid; DPI: dry powder inhaler; and MDI: metered dose inhaler with or without a spacer. aValues expressed as n (%), except where otherwise indicated. bValues expressed as mean ± SD or as median.

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Table 2 - Frequency of adverse effects (in the oral cavity and pharynx) reported by the 200 patients studied.a Adverse effects Frequency Total Occasionally On most days Daily Vocal symptoms Reduced vocal intensity 16 (8.0) 5 (2.5) 2 (1.0) 23 (11.5) Loss of voice 6 (3.0) 5 (2.5) − 11 (5.5) Hoarseness 32 (16.0) 11 (5.5) 9 (4.5) 52 (26.0) Pharyngeal symptoms Irritated throat 32 (16.0) 8 (4.0) 11 (5.5) 51 (25.5) Sore throat 10 (5.0) 4 (2.0) 4 (2.0) 17 (9.0) Dry throat 42 (21.0) 19 (9.5) 33 (16.5) 83 (47.0) Need for throat clearing 51 (25.5) 14 (7.0) 23 (11.5) 88 (44.0) Sensation of thirst 36 (18.0) 11 (5.5) 36 (18.0) 83 (41.5) Cough during ICS use 36 (18.0) 6 (3.0) 8 (4.0) 50 (25.0) Anosmia 14 (7.0) 4 (2.0) 5 (2.5) 23 (11.5) Oral candidiasis 16 (10.5) 3 (1.5) − 19 (12.0) ICS: inhaled corticosteroid. aValues expressed as n (%).

Table 3 - Frequency of local adverse effects in the patients studied, by use of mediuminhaled corticosteroids. a Daily dose of ICS Characteristic Medium (= 800 µg) High (> 800 µg) (n = 145) (n = 55) Duration of ICS use, monthsb 41.59 ± 18.73 36.65 ± 16.56 Number of adverse effectsb 2.52 ± 2.21 2.76 ± 2.33 Report of at least 1 adverse effect 116 (80.0) 47 (85.5) Vocal symptoms Reduced vocal intensity 16 (11) 7 (12.7) Loss of voice 6 (4.1) 5 (9.1) Hoarseness 37 (25.5) 15 (27.3) Pharyngeal symptoms Irritated throat 34 (23.4) 17 (30.9) Sore throat 10 (6.9) 8 (14.5) Dry throat 67 (46.2) 27 (49.1) Need for throat clearing 65 (44.8) 23 (41.8) Sensation of thirst 57 (39.3) 26 (47.3) Cough during ICS use 35 (24.1) 15 (27.3) Anosmia 18 (12.4) 5 (9.1) Oral candidiasis 20 (13.8) 4 (7.3)

or high-dose

p* 0.088 0.513 0.375 0.738 0.170 0.800 0.280 0.091 0.715 0.702 0.308 0.648 0.511 0.205

ICS: inhaled corticosteroid. aValues expressed as n (%), except where otherwise indicated. bValues expressed as mean ± SD. *Student’s t-test or chi-square test.

Of the patients evaluated, 58 (29.0%) perceived at least one vocal symptoms, with 37 (18.5%) reporting at least one voice-related adverse effect, 14 (7.0%) reporting two adverse effects, and 7 (3.5%) reporting three adverse effects. The prevalence of vocal symptoms found in the study was 26.0% for hoarseness and 11.5% for reduced J Bras Pneumol. 2013;39(4):409-417

vocal intensity. The proportion of patients with the symptom of loss of voice was found to be low (5.0%; Table 2). Pharyngeal adverse effects induced by the use of ICSs were found to be the most prevalent. In 77% of the patients, there was at least one pharyngeal effect. The symptoms of dry throat

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Table 4 - Comparison of general characteristics between patients with and without at least one self-reported local adverse effect.a Characteristic Presence of local adverse effects p* No Yes (n = 37) (n = 163) Age, yearsb 48.59 ± 12.86 51.13 ± 14.74 0.296 Female gender

27 (73)

132 (80.9)

0.276

908.10 ± 304.02

953.98 ± 320.34

0.416

Use of high doses of ICS

8 (21.6)

47 (28.8)

0.375

Use of DPI + MDI

5 (13.5)

33 (20.2)

0.346

Dose of ICS, µgb

Duration of ICS use, months

41.05 ± 20.84

40.09 ± 17.68

0.787

Nasal corticosteroid use

20 (54.1)

110 (67.5)

0.122

Oral hygiene after ICS use

29 (78.4)

124 (76.1)

0.765

and throat clearing were observed in 47% and 44% of the patients, respectively. Of the patients who reported adverse effects related to ICS use, 131 (65.5%) had a daily perception of symptoms, with the most commonly perceived effects being sensation of thirst, in 36 (18.0%); dry throat, in 33 (16.5%); and throat clearing, in 23 (11.5%). The frequencies of local symptoms reported by patients using medium and high doses of ICS are shown in Table 3. Although no statistically significant differences were identified between the two groups, the patients using high doses were more commonly affected by adverse effects than were those using medium doses (frequency of patients with one or more effects, 85.5% vs. 80.0%), as well as having reported a larger number of effects (mean number by patient, 2.76 effects vs. 2.52 effects). In addition, we observed that, for most of the adverse effects evaluated, prevalence increased as the daily dose of ICS was increased, especially for loss of voice (9.1% vs. 4.1%) and sore throat (14.5% vs. 6.9%). Although no statistically significant differences were identified between the groups of patients with and without self-reported adverse effects for any of the characteristics evaluated (Table 4), the former group included older patients (mean age, 51.13 years vs. 48.59 years), as well as higher proportions of females (80.9% vs. 73.0%), patients who used high doses of ICS (28.8% vs. 21.6%), and patients who used a combination of two inhalers (DPI + MDI; (20.2% vs. 13.5%).

Discussion In the present study, patient perception of adverse effects in the oral cavity and pharynx was found to be high among the subjects with moderate or severe asthma being evaluated in clinical practice. Approximately 80% of the patients reported at least one local adverse effect, which confirms the high prevalence of these effects. More than half of the patients (65.5%) had a daily perception of at least one symptom. The most prevalent symptoms were dry throat, need for throat clearing, and sensation of thirst, the last being the most commonly reported adverse effect, affecting approximately one quarter of the subjects daily. The high frequency of local adverse effects induced by ICSs found in the present study is in agreement with the findings of various authors who used structured questionnaires.(6-10,15,16) It is possible that our results are due to the fact that our sample comprised patients with moderate or severe asthma who had been using medium or high doses of ICS for extended periods of time, as well as to the fact that the adverse effects experienced by the patients were assessed using a structured questionnaire. The frequency of adverse effects in the oral cavity and pharynx varies widely. Reviews on the subject describe symptoms that vary widely in frequency, such as candidiasis (in 0-70% of patients), dysphonia (in 5-58%), and pharyngitis (in 4-25%).(3-5,12) This variation has been associated with differences in the study designs, as well as in J Bras Pneumol. 2013;39(4):409-417

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the length of the observation period and in the method of collecting data on adverse effects, which usually involves using questionnaires or clinical tests. (5,11) Although several clinical trials have estimated that these symptoms affect 5-10% of the treated population, there is no scientific evidence from real-life studies to support those findings.(5) However, some questionnaire-based studies have estimated the prevalence of local adverse effects at 24-81%. (6,12) In the present study, the prevalence of symptoms in the oral cavity and pharynx in asthma patients is at the upper end of this range. The frequency of these local effects can vary depending on the ICS dose and potency, as well as on the type of inhaler used. (3,5,7,10,11) Pharyngeal symptoms affected more than half of the patients. The study revealed that approximately half (47%) of the asthma patients had the symptom of dry throat and that 33 (16%) had a daily perception of this symptom. The high frequency and intensity of this adverse effect was also observed in a recent study evaluating the prevalence of potential adverse effects associated with the use of ICSs combined with long-acting Î˛2 agonists in asthma patients and COPD patients. (17) The authors observed that the symptom of dry throat was reported by 52% of the patients and that it was perceived, on average, 14 days per month. In addition, a reduction in the total dose of ICS was responsible for a 47% reduction in patient perception of this symptom, suggesting the dose-dependent nature of this adverse effect.(17) A large proportion of patients (44%) reported the need for throat clearing, this being the second most prevalent pharyngeal symptom. Throat clearing is a very common adverse effect, affecting 24-65% of ICS users(6,7,15,16) and being more prevalent in patients using high daily doses. This local adverse effect is defined as laryngitis caused by ICSs, which act by inducing a form of chemical laryngopharyngitis, mimicking the clinical profile of laryngopharyngeal reflux.(18) Sensation of thirst after ICS use was found in more than 40% of the subjects evaluated in our study. This local symptom can correspond to a manifestation of oral candidiasis or be caused by throat irritation.(3,5,9) In a cross-sectional questionnaire-based study, the prevalence of this symptom ranged from 42% to 60% and was found to be dose-dependent.(6) In contrast, in J Bras Pneumol. 2013;39(4):409-417

another study, involving children with asthma and also using a questionnaire, this symptom was present in 21.9% of ICS users, and combination therapy with ICSs and long-acting Î˛2 agonists was found to be the only risk factor for the onset of this symptom.(5,9) The impact of ICSs on voice production has received considerable attention in recent studies.(6-8,10,16,18) Vocal symptoms affect 39-83% of ICS users, (6,7,10,15,16) and the magnitude and extent of these symptoms have been found to be dose-dependent. (6,7,15,16,18) In our study, we observed a lower frequency of vocal complaints than that reported by other authors (28.5% in our study vs. 39-83% in other studies). (6,10,15,16) Hoarseness was found to be most common vocal symptom reported by the patients (in 26%). In three questionnaire-based studies using methodologies similar to that used in our study, the prevalence of hoarseness ranged from 10% to 57%.(8,9,11,15,16) According to a study, hoarseness is a local adverse effect dependent on factors such as ICS formulation, type of inhaler, frequency of use, total daily dose, ICS particle size, and local effect of the lactose contained in DPIs. (18) The exact mechanism leading to hoarseness is unknown; however, hoarseness can be attributed to steroid myopathy affecting the vocal muscles, which causes a bilateral adduction deformity and bowing of the vocal cords during phonation. (4,5,9,18,19) Although the mechanisms by which ICSs cause local adverse effects have yet to be clarified, they appear to be related to the deposition of the active ICS into the oral cavity, pharynx, and larynx during drug administration.(3,8,10) Several factors can affect the fraction of an inhaled dose that is deposited in the oral cavity. These factors include ICS formulation, type of drug delivery system, and patient adherence to the instructions for use.(3) Our results showed no significant differences in the frequency of adverse events between the groups being treated with moderate or high daily doses of ICS; however, we observed an overall increase in the frequency of local effects, including vocal symptoms, sore throat, and sensation of thirst, as the daily dose was increased. According to one group of authors, high doses of ICS are associated with a higher intensity and frequency of patient-perceived adverse events. (7)

Local adverse effects associated with the use of inhaled corticosteroids in patients with moderate or severe asthma

Although no significant differences were found in the general characteristics between the patients who reported at least one adverse event and those who perceived no adverse events, previous studies have demonstrated that the chronic use of ICSs, usually in high doses, for long periods, and via different inhalers, is an important risk factor for the incidence of adverse effects in the oral cavity and pharynx.(1,2,8,15) One of the aspects that should be considered in the present study is the fact that our sample of patients, who have moderate or severe asthma, participate in a multidisciplinary outpatient care program in which there is good communication between patients and health professionals, particularly regarding the cost-benefit ratio of the treatment for asthma control. The good relationship between the health care team and the patient makes it possible for the asthma patients in our study to discuss their symptoms and their concerns regarding the pharmacological treatment more frequently, and this favors spontaneous reporting of adverse effects of medications. According to one group of authors, open and honest communication with patients, taking their concerns seriously, can reduce the impact caused by adverse reactions to medications.(20) A previous qualitative study involving patients who reported suspected reactions to paroxetine has suggested that understanding how the medication produced the symptom can bring relief to the patient. (20,21) Assessment of the local adverse effects of ICSs, using a multidisciplinary approach supported by a pharmaceutical care service, can be a useful tool in monitoring the safety of use of these medications, since, in clinical practice, such effects tend to be seen as â&#x20AC;&#x153;side effectsâ&#x20AC;? and, therefore, as deviations from the priorities of patients and physicians. A previous study has demonstrated that asthma patients prefer not to discuss their concerns regarding ICS use with their physicians. (13) According to one group of authors, of 24% of patients who experienced symptoms in the oral cavity and pharynx, only 16% reported their symptoms to their physicians, and this might be associated with the existing communication gap between patients and physicians.(12) In contrast, physicians tend not to discuss the potential adverse effects associated with the use of the prescribed

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medications with their patients.(22,23) Good safety monitoring encourages health professionals to take full responsibility for the medications they prescribe, improving clinical effectiveness and increasing the confidence with which they and their patients use these medications.(24) With regard to the local symptoms (in the oral cavity, pharynx, and larynx) associated with the use of ICSs, as well as to management recommendations and preventive measures, the educational approach provided by the ProAR Department of Pharmaceutical Care appears not to be sufficient for ensuring a lesser impact of these symptoms, although it favors an improvement in patient perception of local adverse effects. A study conducted in Canada showed that, although some recommendations for the management of symptoms in the oral cavity and pharynx made by family physicians are logical, they can be insufficient in some situations.(12) In the present study, we observed that more than 70% of the patients reported performing oral hygiene after ICS use. Although the practice of oral hygiene after ICS use is an important measure to remove ICSs from the oral cavity, this measure is ineffective in cleaning the larynx. (18) Previous studies have demonstrated that rinsing the mouth after ICS use reduces the incidence of candidiasis; however, this does not have an impact on voice or throat symptoms. (9,15,18,19) Although the questionnaire used in the present study was designed to assess the occurrence of local symptoms associated with the use of ICSs, we cannot absolutely rule out the possibility that, for some patients, these symptoms were related to other alternative causes, such as comorbidities and continuous use of other medications. The study design allowed us to control the use of systemic corticosteroids in the three months preceding the study; however, we could not control their use beyond this point. In addition, it was not possible to control the use of nasal corticosteroids, the use of which was identified in more than half of the patients evaluated. Nasal corticosteroids can penetrate the pharynx and larynx, and, consequently, they have the potential to cause symptoms in the oral cavity and pharynx. In conclusion, patient perception of local adverse effects associated with the use of ICSs, J Bras Pneumol. 2013;39(4):409-417

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especially pharyngeal symptoms, including dry mouth and need for throat clearing, is high among the asthma patients followed in the ProAR Department of Pharmaceutical Care. This high frequency of local symptoms might be associated with the use of medium and high doses of ICS, as well as with long-term exposure to ICSs. Assessment of asthma patient perception of local adverse effects of ICSs could provide a greater understanding of the extent and severity of these effects and could aid in determining the risk-benefit ratio of the use of ICSs in clinical practice. Although ICSs are highly effective in the treatment of asthma, their rational use, on the basis of a step-down therapeutic approach, must be ensured in order to reach the lowest maintenance dose consistent with the best level of disease control.

References 1. Global Initiative for Asthma [homepage on the Internet]. Bethesda: Global Initiative for Asthma. [cited 2013 Feb 08]. Global Strategy for Asthma Management and Prevention 2012. [Adobe Acrobat document, 128p.]. Available from: http://www.ginasthma.org/local/uploads/ files/GINA_Report_March13.pdf 2. Sociedade Brasileira de Pneumologia e Tisiologia. Diretrizes da Sociedade Brasileira de Pneumologia e Tisiologia para o Manejo da Asma 2012. J Bras Pneumol. 2012;38(Suppl 1):S1-S46. 3. Buhl R. Local oropharyngeal side effects of inhaled corticosteroids in patients with asthma. Allergy. 2006;61(5):518-26. http://dx.doi.org/10.1111/j.13989995.2006.01090.x PMid:16629778 4. Hanania NA, Chapman KR, Kesten S. Adverse effects of inhaled corticosteroids. Am J Med. 1995;98(2):196-208. http://dx.doi.org/10.1016/S0002-9343(99)80404-5 5. Roland NJ, Bhalla RK, Earis J. The local side effects of inhaled corticosteroids: current understanding and review of the literature. Chest. 2004;126(1):213-9. http:// dx.doi.org/10.1378/chest.126.1.213 PMid:15249465 6. Foster JM, van Sonderen E, Lee AJ, Sanderman R, Dijkstra A, Postma DS, et al. A self-rating scale for patientperceived side effects of inhaled corticosteroids. Respir Res. 2006;7:131. http://dx.doi.org/10.1186/1465-99217-131 PMid:17062139 PMCid:1637103 7. Foster JM, Aucott L, van der Werf RH, van der Meijden MJ, Schraa G, Postma DS, et al. Higher patient perceived side effects related to higher daily doses of inhaled corticosteroids in the community: a cross-sectional analysis. Respir Med. 2006;100(8):1318-36. http:// dx.doi.org/10.1016/j.rmed.2005.11.029 PMid:16442275 8. Bhalla RK, Jones AS, Roland NJ. Prevalence of pharyngeal and laryngeal complications in adult asthmatics using inhaled corticosteroids. J Laryngol Otol. 2008;122(10):1078-83. http://dx.doi.org/10.1017/ S0022215107001272 PMid:18201390 9. Dubus JC, Marguet C, Deschildre A, Mely L, Le Roux P, Brouard J, et al. Local side-effects of inhaled corticosteroids in asthmatic children: influence of drug, dose, age,

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and device. Allergy. 2001;56(10):944-8. http://dx.doi. org/10.1034/j.1398-9995.2001.00100.x PMid:11576072 10. Ivanova JI, Birnbaum HG, Hsieh M, Yu AP, Seal B, van der Molen T, et al. Adherence to inhaled corticosteroid use and local adverse events in persistent asthma. Am J Manag Care. 2008;14(12):801-9. PMid:19067497 11. Molimard M, Le Gros V, Robinson P, Bourdeix I. Prevalence and associated factors of oropharyngeal side effects in users of inhaled corticosteroids in a real-life setting. J Aerosol Med Pulm Drug Deliv. 2010;23(2):91-5. http:// dx.doi.org/10.1089/jamp.2009.0762 PMid:19778267 12. Fitzgerald JM, Chan CK, Holroyde MC, Boulet LP. The CASE survey: patient and physician perceptions regarding asthma medication use and associated oropharyngeal symptoms. Can Respir J. 2008;15(1):2732. PMid:18292850 PMCid:2677852 13. Boulet LP. Perception of the role and potential side effects of inhaled corticosteroids among asthmatic patients. Chest. 1998;113(3):587-92. http://dx.doi.org/10.1378/ chest.113.3.587 PMid:9515829 14. Foster JM, van der Molen T, de Jong-van den Berg L. Patient-reporting of side effects may provide an important source of information in clinical practice. Eur J Clin Pharmacol. 2007;63(10):979-80; author reply 981. http://dx.doi.org/10.1007/s00228-007-0339-8 PMid:17618426 PMCid:2039823 15. Williamson IJ, Matusiewicz SP, Brown PH, Greening AP, Crompton GK. Frequency of voice problems and cough in patients using pressurized aerosol inhaled steroid preparations. Eur Respir J. 1995;8(4):590-2. PMid:7664859 16. Ihre E, Zetterström O, Ihre E, Hammarberg B. Voice problems as side effects of inhaled corticosteroids in asthma patients--a prevalence study. J Voice. 2004;18(3):403-14. http://dx.doi.org/10.1016/j. jvoice.2003.05.003 PMid:15331115 17. Korsgaard J, Ledet M. Potential side effects in patients treated with inhaled corticosteroids and long-acting beta2-agonists. Respir Med. 2009;103(4):566-73. http:// dx.doi.org/10.1016/j.rmed.2008.10.028 PMid:19136239 18. Gallivan GJ, Gallivan KH, Gallivan HK. Inhaled corticosteroids: hazardous effects on voice-an update. J Voice. 2007;21(1):101-11. http://dx.doi.org/10.1016/j. jvoice.2005.09.003 PMid:16442776 19. Williams AJ, Baghat MS, Stableforth DE, Cayton RM, Shenoi PM, Skinner C. Dysphonia caused by inhaled steroids: recognition of a characteristic laryngeal abnormality. Thorax. 1983;38(11):813-21. http://dx.doi.org/10.1136/ thx.38.11.813 PMid:6648863 PMCid:459669 20. Lorimer S, Cox A, Langford NJ. A patient’s perspective: the impact of adverse drug reactions on patients and their views on reporting. J Clin Pharm Ther. 2012;37(2):148-52. http://dx.doi.org/10.1111/j.13652710.2011.01258.x PMid:21592157 21. Medawar C, Herxheimer A, Bell A, Jofre S. Paroxetine, panorama and user reporting of ADRs: consumer intelligence matters in clinical practice and post-marketing surveillance. Int J Risk Saf Med. 2002;15:161–9. 22. Britten N, Stevenson F, Gafaranga J, Barry C, Bradley C. The expression of aversion to medicines in general practice consultations. Soc Sci Med. 2004;59(7):1495503. http://dx.doi.org/10.1016/j.socscimed.2004.01.019 PMid:15246177 23. Lamb GC, Green SS, Heron J. Can physicians warn patients of potential side effects without fear of causing those side effects? Arch Intern Med. 1994;154(23):2753-6.

Local adverse effects associated with the use of inhaled corticosteroids in patients with moderate or severe asthma

http://dx.doi.org/10.1001/archinte.1994.00420230150018 PMid:7993161 24. Organização Pan-Americana da Saúde Brasil [homepage on the Internet]. Brasília: Organização Pan-Americana

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da Saúde Brasil. [cited 2012 Oct 20]. A importância da Farmacovigilância. Available from: http://new.paho. org/bra/index.php?option=com_docman&task=doc_ details&gid=745&Itemid=423

About the authors Charleston Ribeiro Pinto

Assistant Professor. Undergraduate Course in Pharmacy, Department of Chemistry and Exact Sciences, Southwestern Bahia State University, Jequié, Brazil.

Natalie Rios Almeida

Medical Student. Bahia School of Medicine and Public Health, Salvador, Brazil.

Thamy Santana Marques

Resident in General Surgery. Roberto Santos General Hospital, Salvador, Brazil.

Laira Lorena Lima Yamamura

Pharmacist. Bahia State Health Department, Salvador, Brazil.

Lindemberg Assunção Costa

Assistant Professor. Federal University of Bahia School of Pharmacy, Salvador, Brazil.

Adelmir Souza-Machado

Adjunct Professor. Institute of Health Sciences, Federal University of Bahia; and Coordinator. Programa para o Controle da Asma na Bahia – ProAR, Bahia State Asthma Control Program – Salvador, Brazil.

J Bras Pneumol. 2013;39(4):409-417

Original Article Congenital lobar emphysema: 30-year case series in two university hospitals* Enfisema lobar congênito: série de casos de 30 anos em dois hospitais universitários

Daniele Cristina Cataneo, Olavo Ribeiro Rodrigues, Erica Nishida Hasimoto, Aurelino Fernandes Schmidt Jr, Antonio José Maria Cataneo

Abstract Objective: To review the cases of patients with congenital lobar emphysema (CLE) submitted to surgical treatment at two university hospitals over a 30-year period. Methods: We reviewed the medical records of children with CLE undergoing surgical treatment between 1979 and 2009 at the Botucatu School of Medicine Hospital das Clínicas or the Mogi das Cruzes University Hospital. We analyzed data regarding symptoms, physical examination, radiographic findings, diagnosis, surgical treatment, and postoperative follow-up. Results: During the period studied, 20 children with CLE underwent surgery. The mean age at the time of surgery was 6.9 months (range, 9 days to 4 years). All of the cases presented with symptoms at birth or during the first months of life. In all cases, chest X-rays were useful in defining the diagnosis. In cases of moderate respiratory distress, chest CT facilitated the diagnosis. One patient with severe respiratory distress was misdiagnosed with hypertensive pneumothorax and underwent chest tube drainage. Only patients with moderate respiratory distress were submitted to bronchoscopy, which revealed no tracheobronchial abnormalities. The surgical approach was lateral muscle-sparing thoracotomy. The left upper and middle lobes were the most often affected, followed by the right upper lobe. Lobectomy was performed in 18 cases, whereas bilobectomy was performed in 2 (together with bronchogenic cyst resection in 1 of those). No postoperative complications were observed. Postoperative follow-up time was at least 24 months (mean, 60 months), and no late complications were observed. Conclusions: Although CLE is an uncommon, still neglected disease of uncertain etiology, the radiological diagnosis is easily made and surgical treatment is effective. Keywords: Respiratory system abnormalities; Congenital abnormalities; Pulmonary surgical procedures; Pulmonary emphysema.

Resumo Objetivo: Revisar os casos de enfisema lobar congênito (ELC) operados nos últimos 30 anos em dois hospitais universitários. Métodos: Foram revistos os prontuários médicos das crianças com ELC operadas no Hospital das Clínicas da Faculdade de Medicina de Botucatu e no Hospital da Universidade de Mogi das Cruzes entre 1979 e 2009. Dados sobre sintomas, exame físico, achados radiológicos, diagnóstico, tratamento cirúrgico e seguimento pós-operatório mediato e tardio foram analisados. Resultados: Durante o período estudado, 20 crianças com ELC foram submetidas a tratamento cirúrgico. A média de idade dos pacientes no momento da cirurgia foi 6,9 meses (variação, 9 dias a 4 anos). Todos os casos apresentaram sintomas ao nascimento ou nos primeiros meses de vida. Em todos os casos, a radiografia simples de tórax foi importante na definição do diagnóstico. Em casos de dificuldade respiratória moderada, a TC de tórax auxiliou no diagnóstico. Um paciente com desconforto respiratório grave foi diagnosticado erroneamente com pneumotórax hipertensivo e submetido a drenagem torácica. A broncoscopia só foi realizada nos pacientes com dificuldade respiratória moderada e não foram encontrados sinais de anomalias traqueobrônquicas. A abordagem cirúrgica foi realizada através de toracotomia lateral poupadora de músculo. O lobo superior esquerdo e o lobo médio foram os mais afetados, seguidos pelo lobo superior direito. A lobectomia foi realizada em 18 casos, enquanto a bilobectomia foi realizada em 2 casos (com ressecção de cisto broncogênico em 1 desses). Complicações pós-operatórias não foram observadas. O acompanhamento pós-operatório foi de pelo menos 24 meses (média, 60 meses) e não foram observadas complicações tardias nesta série. Conclusões: O ELC é uma doença pouco comum, ainda negligenciada, de etiologia incerta, mas de fácil diagnóstico radiológico e tratamento cirúrgico eficaz. Descritores: Anormalidades do sistema respiratório; Anormalidades congênitas; Procedimentos cirúrgicos pulmonares; Enfisema pulmonar. *Study carried out under the auspices of the Graduate Program in the Fundamentals of Surgery, São Paulo State University Botucatu School of Medicine, Botucatu, Brazil, and at the University of Mogi das Cruzes, Mogi das Cruzes, Brazil. Correspondence to: Daniele Cristina Cataneo. Disciplina de Cirurgia Torácica, Departamento de Cirurgia e Ortopedia, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, Distrito de Rubião Jr, s/n, CEP 18618-970, Botucatu, SP, Brasil. Tel. 55 14 3811-6091. Fax: 55 14 3815-7615. E-mail: dcataneo@fmb.unesp.br Financial support: None. Submitted: 22 January 2013. Accepted, after review: 27 May 2013.

J Bras Pneumol. 2013;39(4):418-426

Congenital lobar emphysema: 30-year case series in two university hospitals

Introduction Congenital lobar emphysema (CLE) was first described in 1932, by Nelson,(1) and was so designated in 1951, by Robertson and James. It is a rare disease, its incidence being 1 per 20-30 thousand births.(2) However, the prevalence of CLE during pregnancy is uncertain.(3) The abnormality is defined by hyperinflation of one or more lung lobes in the absence of extrinsic bronchial obstruction. Although the etiology has yet to be fully understood, many authors have reported it as being the result of bronchial abnormalities(4) or alveolar defects.(5) Some theories include bronchial collapse resulting from inadequate cartilaginous support. In 1970, Hislop and Reid(5) found an increase in the number of alveoli in the affected lobe and were the first to describe polyalveolar lobe. Subsequent studies conducted in the 1980s and 1990s re-evaluated and confirmed polyalveolar lobe in CLE.(6) Some Brazilian authors have also reported polyalveolar lobe as the cause of CLE on the basis of histological studies involving alveolar counts, having shown an increase in the number of alveoli per area of lung tissue.(7) It is difficult to differentiate between CLE and hyperinflation resulting from extrinsic bronchial obstruction (lymph nodes, vessels, masses, or cysts) that compresses the bronchus and produces valve obstruction. In such cases, hyperinflation should be designated acquired lobar emphysema; however, more than 50% of all CLE cases are unrelated to airway abnormalities. The left upper lobe is usually the most frequently affected, followed by the middle and right upper lobes, the lower lobes being rarely affected. It is known that CLE can occur in association with other malformations, especially cardiac malformations, which occur in 20% of cases.(8) The most common clinical presentation is neonatal acute respiratory distress, which is caused by localized air trapping that compresses the ipsilateral and contralateral normal lungs. The diagnosis is made by clinical examination and routine chest X-rays and can be confirmed by CT. Although bronchoscopy can be an important tool in the differential diagnosis, it is not a primary screening test, being indicated for children whose symptoms appear later, with the objective of excluding acquired bronchial obstruction. Surgery is the treatment of choice(9) and has been recommended since 1945, when Gross and

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Lewis(10) reported the first case of CLE successfully treated by lobectomy. The prognosis is good even when more than one lobe is resected and probably reflects the potential for compensatory alveolar growth in children.(9,11-13) The objective of the present study was to show the clinical and radiographic findings, the approach adopted, and the early and late postoperative outcomes in children with CLE undergoing surgical treatment at either of two university hospitals in the state of São Paulo, Brazil, over a 30-year period.

Methods The study was approved by the Research Ethics Committee of the São Paulo State University Botucatu School of Medicine (Protocol no. 268/08-CEP). We reviewed the medical records of children with CLE undergoing surgical treatment between 1979 and 2009 at the São Paulo State University Botucatu School of Medicine Hospital das Clínicas or the Mogi das Cruzes University Hospital. The diagnosis was confirmed by the presence of respiratory symptoms, typical radiographic findings, and pathological findings. We analyzed the following parameters: age at the onset of symptoms; clinical findings; age at surgery; radiographic findings (on routine chest X-rays and on chest CT scans); bronchoscopic findings (when bronchoscopy was performed); affected lobes; presence of other malformations; type of surgery; pathological findings; and early and late postoperative outcomes. Early postoperative outcome was evaluated on the basis of the following: time to extubation; time to recovery from anesthesia; re-expansion of the remaining lung; and resolution of the symptoms. Late postoperative outcome was evaluated on the basis of respiratory symptoms and findings on routine chest X-rays.

Results Between 1979 and 2009, 20 children with CLE underwent surgery. Of those, 15 underwent surgery at the Botucatu School of Medicine Hospital das Clínicas and 5 underwent surgery at the Mogi das Cruzes University Hospital. The time elapsed between the first case and the second case was greater than 8 years. The mean age at surgery was 6.9 months (range, 9 days to 4 years), and J Bras Pneumol. 2013;39(4):418-426

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Cataneo DC, Rodrigues OR, Hasimoto EN, Schmidt Jr AF, Cataneo AJM

all of the children were White (Table 1). The age at onset of respiratory symptoms ranged from 0 (i.e., symptoms at birth) to 12 months. Symptoms of respiratory distress (dyspnea, wheezing, and cyanosis) were present in 60% of the cases, with no evidence of infection. Recurrent pneumonia (fever, cough, tachypnea, and a history of antibiotic therapy) was observed in 50% of the cases. The time elapsed between the onset of symptoms and the surgical procedure ranged from 1 day to 36 months. The test that raised the diagnostic suspicion of CLE was a routine chest X-ray, which showed lobar hyperinflation and compression of the ipsilateral and contralateral parenchyma in all cases (Figure 1). A CT scan of the chest was performed in 18 (90%) of the cases, and the findings consisted of hyperinflation of the affected lobe, contralateral herniation of the affected lobe through the anterior mediastinum, mediastinal shift, and collapse of the healthy lobes due to compression (Figure 2). Rigid bronchoscopy was performed in 7 children (35%), although only in those over 6 months of age. Although there was no acute respiratory impairment, most of those children had recurrent pneumonia. In the first case, in 1979, bronchoscopy was performed in a child who was younger than 6 months of age because of the difficulty in establishing the diagnosis.

All of the tests showed that the bronchial tree was within normal limits. In 1 case, CLE was misdiagnosed as tension pneumothorax at birth, and the child underwent emergency pleural drainage, without success (Figure 3). In 2 cases, CLE was found in association with other malformations (hydrocephalus in 1 and bronchogenic cyst in 1). In the case of the patient with CLE and bronchogenic cyst, both defects were treated during the same procedure. The most commonly affected lobes were the left upper lobe (in 7 patients) and the middle lobe (in 7 patients), followed by the right upper lobe (in 6 patients) and the right lower lobe (in 2 patients). Two children had involvement of two ipsilateral lobes. Lobectomy and bilobectomy were performed in 18 and 2 patients, respectively. In 1 case, bilobectomy was performed in conjunction with bronchogenic cyst resection. In 15 cases, a lateral thoracotomy was performed, and, in 5 cases, thoracotomy was performed via the triangle of auscultation; in all cases, the surgical approach was lateral muscle-sparing thoracotomy. In all procedures, the affected lung herniated through the pleural cavity immediately after it had been opened (Figure 4).

Figure 1 - Chest X-ray showing hyperinflation of the left upper lobe, with compression of the lower lobe and mediastinal shift to the right leading to compression of the entire right lung.

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Congenital lobar emphysema: 30-year case series in two university hospitals

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Figure 2 - Chest CT scan showing hyperinflation of the left upper lobe (in A) and right upper lobe (in B), with contralateral mediastinal shift and compression of the contralateral lung in both cases.

Figure 3 - Chest X-ray of a child with congenital lobar emphysema misdiagnosed as right tension pneumothorax. The child was referred to the facility with a right pleural tube already in place.

Figure 4 - Hyperinflated left upper lobe (in A) and right upper lobe (in B) with herniation through the chest incision.

J Bras Pneumol. 2013;39(4):418-426

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Cataneo DC, Rodrigues OR, Hasimoto EN, Schmidt Jr AF, Cataneo AJM

Table 1 - Characteristics of the patients diagnosed with congenital lobar emphysema and treated surgically at either of two hospitals between 1979 and 2009. Patient Year in Gender Age at Symptoms Age at CT Bronchoscopy Affected which symptom surgery lobes surgery was onset performed 1

1979

Female

3 months

NARDS

4 months

Normal

1988

Male

Neonate

NARDS

10 days

RUL

1991

Male

Neonate

NARDS

9 days

Yes

LUL

1995

Female

Neonate

Recurrent pneumonia

3 months

Yes

RLL

1995

Female

12 months

Recurrent pneumonia

48 months

Yes

Normal

RUL

1995

Male

4 months

Recurrent pneumonia

7 months

Yes

Normal

RUL/ML

1996

Female

2 months

Recurrent pneumonia

5 months

Yes

RUL

1996

Male

30 days

1 months

Yes

1999

Female

Neonate

NARDS and recurrent pneumonia NARDS

3 months

Yes

LUL

2000

Male

Neonate

NARDS

1 months

Yes

2000

Male

Neonate

Recurrent pneumonia

14 months

Yes

Normal

LUL

2001

Female

Neonate

NARDS

2 months

Yes

LUL

2001

Female

Neonate

NARDS

30 days

Yes

2002

Female

Neonate

24 months

Yes

Normal

RLL

2002

Male

Neonate

NARDS and recurrent pneumonia NARDS

30 days

Yes

RUL/ML

2003

Female

Neonate

NARDS

6 months

Yes

Normal

RUL

2004

Male

Neonate

NARDS

21 days

Yes

LUL

2004

Male

6 months

Recurrent pneumonia

12 months

Yes

Normal

LUL

2004

Male

30 days

Recurrent pneumonia

4 months

Yes

2008

Female

30 days

Recurrent pneumonia

2 months

Yes

LUL

NARDS: neonatal acute respiratory distress syndrome; ML: middle lobe; NP: not performed; RUL: right upper lobe; LUL: left upper lobe; and RLL: right lower lobe.

J Bras Pneumol. 2013;39(4):418-426

Congenital lobar emphysema: 30-year case series in two university hospitals

A pathological diagnosis of CLE was established in all of the cases, although there were no cartilaginous changes or confirmed polyalveolar lobe in any, and the only possible etiology was a small bronchogenic cyst compressing the upper and middle lobe bronchi. All of the patients progressed well, being weaned from mechanical ventilation shortly after surgery. Chest tube removal and discharge occurred within up to 4 and 5 days after surgery, respectively. Late postoperative outcomes were satisfactory, and postoperative follow-up time was at least 24 months (mean, 60 months), 3 patients having been followed for more than 10 years. No late complications were observed.

Discussion Although the incidence of CLE is possibly underestimated, it ranges from 1:20,000 births to 1:30,000 births in the literature,(2) CLE being more common in White boys.(11,14,15) However, in our sample, there was no predominance of CLE in males, and although all of the children were White, the predominance of CLE in White patients no longer seems to hold true, one study having shown a high incidence of CLE in non-White children in Oman.(16) The fact that the incidence of CLE is low has been confirmed by studies conducted in Brazil: at a referral facility for pediatric thoracic surgery in the city of Porto Alegre, 13 patients with CLE underwent surgery over a 10-year period,(17) and at a university hospital in the city of S達o Paulo, 14 patients with CLE underwent surgery over a 35-year period.(18) Although the diagnosis of CLE can be made by routine chest X-rays, it continues to be delayed; this suggests that the low incidence of CLE and the difficulty in diagnosing the disease in the presence of infection contribute to delayed diagnosis and treatment, resulting in recurrent and frequent complications.(18) Before the early 1990s, only 2 patients with CLE had undergone surgery at one of the hospitals under study. This shows that the disease was poorly understood in primary health care settings in Brazil. All of the patients analyzed in the present study had been diagnosed after birth; however, some authors have reported that CLE can be prenatally diagnosed by ultrasound on the basis of the difference in echogenicity and reflectivity between healthy and affected lobes.(15,19,20) Currently, the

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routine use of prenatal ultrasound allows early diagnosis of all lung malformations. We do not believe that this can increase our sample size, because none of the patients analyzed in the present study had been diagnosed with CLE before birth. However, several other, cystic, malformations were diagnosed by prenatal ultrasound. This might be due to the fact that the sensitivity of ultrasound diagnosis of CLE is lower than is that of ultrasound diagnosis of cystic diseases. The onset of signs and symptoms of respiratory impairment usually occurs in the first days of life, occurring before the age of 6 months in 90% of cases, when approximately half of all cases are diagnosed; however, the onset of signs and symptoms of respiratory impairment can occur as late as the age of 5 years.(21) According to the literature, 12% of all patients with CLE develop severe acute respiratory impairment, a proportion that is consistent with the proportion that we found in our sample. Radiographic images can sometimes confuse physicians because healthy lobes can appear opaque as a result of their being compressed by the affected lobe. This, in association with symptoms of respiratory distress, can mimic pneumonia, thus delaying diagnosis. The main differential diagnosis on routine chest X-rays is still tension pneumothorax, which is evidenced by the high radiolucency of the affected lung and which can, in association with respiratory distress, lead to unnecessary invasive procedures(6,21,22) that can worsen the condition of patients. In such cases, chest CT is useful in order to confirm the X-ray findings, to determine the affected lobe more accurately, and to exclude other malformations, such as vascular ring, masses, and cysts, which can compress the bronchi.(16) In most of the cases in which the onset of symptoms was immediately after birth, early tracheal intubation and mechanical ventilation contributed to greater air retention in the affected lung, urgent intervention being therefore required. In such cases, some authors have suggested the use of high-frequency ventilation,(23) selective intubation,(24) or endoscopic decompression of the emphysematous lobe(25) for preoperative and perioperative optimization. In cases in which the onset of symptoms is after the sixth month of life or in oligosymptomatic patients, conservative treatment is an option and has been widely discussed in the literature.(26) However, attention J Bras Pneumol. 2013;39(4):418-426

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Cataneo DC, Rodrigues OR, Hasimoto EN, Schmidt Jr AF, Cataneo AJM

should be paid to deterioration of respiratory function leading to urgent interventions. Regarding the affected lobes, our findings were consistent with those reported in the literature. However, the proportion of lower lobe involvement was higher in our case series than in other case series. In 2 cases, more than one lobe was affected. In both cases, the upper right and middle lobes in the right hemithorax were affected. This facilitated the surgical approachâ&#x20AC;&#x201D;as previously discussed by other authors(15,22)â&#x20AC;&#x201D;which would have been more difficult had there been bilateral involvement.(27) Some authors have reported that the symptoms are more intense when there is upper lobe involvement than when there is middle lobe involvement.(15,16,22) However, no such difference was found in our sample of patients. Although CLE has been shown to be significantly associated with cardiac malformations, we found no cardiac malformations in our sample. Our screening for cardiac malformations was carried out exclusively by echocardiography and chest CT because cardiac catheterization and cineangiography(28) seemed extremely invasive and unnecessary. The intraoperative period is generally made difficult by mechanical ventilation and the use of inhaled anesthetics, such as nitric oxide, which can increase the retention of air in the affected lobe, increasing hyperinflation during the entire procedure and making ventilation and surgical manipulation even more difficult.(8) However, the literature shows that the surgical treatment of CLE is safe, the morbidity and mortality from the procedure being low in most studies.(2,17,18) In our case series, all of the procedures were successful and the surgical approach was lateral muscle-sparing thoracotomy followed by the affected lung being pulled out of the pleural cavity in order to facilitate ventilation. The use of video-assisted thoracoscopic lobectomy(29) for congenital lung malformations has been reported in the literature; however, this surgical approach is difficult in patients with CLE because the pleural cavity is mostly occupied by the affected lobe (which generally remains inflated), and this makes it difficult to create a pneumothorax with the purpose of creating a virtual cavity. Although pain or the cosmetic appearance of the chest wall can justify the use of video-assisted thoracoscopy, none of our patients had such complications. J Bras Pneumol. 2013;39(4):418-426

Although more than 50% of all CLE cases have no clear etiology, several theories have been proposed to explain the mechanism of air trapping in the emphysematous lung, including the presence of bronchial cartilage dysplasia,(7,30) accumulation of mucus or redundant mucosa leading to valve obstruction, extrinsic compression by aberrant bronchi or vascular structures, infection-related abnormalities,(14) and polyalveolar lobe.(5,6) Contrary to what many authors have reported, we found no cartilaginous changes in the bronchi of the emphysematous lobe. However, such changes cannot be completely ruled out, because it is possible that there was a change in the emergence of the bronchus, which was not resected with the specimen. However, 35% of the patients who underwent bronchoscopy had no intrinsic or extrinsic central bronchial obstruction. Although bronchoscopy is not a primary screening test, it was used only in patients over 6 months of age, age at which the onset of CLE symptoms is less common. The objective of the procedure was to exclude obstruction by a foreign body or thick secretion plugs and avoid inappropriate surgery, in accordance with the algorithm proposed by Karnak et al.(9) Regarding polyalveolar lobe, although the pathological findings were not consistent with it, we cannot state that it did not occur. Therefore, in one of the cases, the only possible etiology found was bronchogenic cyst compressing the emergence of two lobes. In conclusion, CLE is an uncommon disease, and it is still difficult to diagnose it in neonatal ICU and infant care settings. Therefore, CLE should be suspected in neonates with respiratory distress. Although the etiology of CLE remains uncertain, the radiological diagnosis is easily made, and surgical treatment is effective and safe.

References 1. Nelson RL. Congenital cystic disease of the lung: Report of a case. J Pediatr. 1932;1(2):233-8. http://dx.doi. org/10.1016/S0022-3476(32)80105-8 2. Andrade CF, Ferreira HP, Fischer GB. Congenital lung malformations. J Bras Pneumol. 2011;37(2):259-71. http://dx.doi.org/10.1590/S1806-37132011000200017 PMid:21537663 3. Pariente G, Aviram M, Landau D, Hershkovitz R. Prenatal diagnosis of congenital lobar emphysema: case report and review of the literature. J Ultrasound Med. 2009;28(8):1081-4. PMid:19643792 4. Warner JO, Rubin S, Heard BE. Congenital lobar emphysema: a case with bronchial atresia and abnormal bronchial cartilages. Br J Dis Chest. 1982;76(2):17784. http://dx.doi.org/10.1016/0007-0971(82)90032-8

Congenital lobar emphysema: 30-year case series in two university hospitals

5. Hislop A, Reid L. New pathological findings in emphysema of childhood. 1. Polyalveolar lobe with emphysema. Thorax. 1970;25(6):682-90. http://dx.doi.org/10.1136/ thx.25.6.682 PMid:5494677 PMCid:472210 6. Tapper D, Schuster S, McBride J, Eraklis A, Wohl ME, Williams A, et al. Polyalveolar lobe: anatomic and physiologic parameters and their relationship to congenital lobar emphysema. J Pediatr Surg. 1980;15(6):931-7. http://dx.doi.org/10.1016/S0022-3468(80)80306-X 7. Giudici R, Leão LE, Moura LA, Wey SB, Ferreira RG, Crotti PL. Polialveolose: patogênese do enfisema lobar congênito? Rev Assoc Med Bras. 1998;44(2):99-105. http://dx.doi.org/10.1590/S0104-42301998000200006 PMid:9699326 8. Moideen I, Nair SG, Cherian A, Rao SG. Congenital lobar emphysema associated with congenital heart disease. J Cardiothorac Vasc Anesth. 2006;20(2):239-41. http:// dx.doi.org/10.1053/j.jvca.2006.01.019 PMid:16616669 9. Karnak I, Senocak ME, Ciftci AO, Büyükpamukçu N. Congenital lobar emphysema: diagnostic and therapeutic considerations. J Pediatr Surg. 1999;34(9):1347-51. http://dx.doi.org/10.1016/S0022-3468(99)90009-X 10. Gross RE, Lewis JE. Defect of the anterior mediastinum successful surgical repair. Surg Gynecol Obstet. 1945;80:549-54. 11. Lacquet LK, Lacquet AM. Congenital lobar emphysema. Prog Pediatr Surg. 1977;10:307-20. PMid:866684 12. Haller JA Jr, Golladay ES, Pickard LR, Tepas JJ 3rd, Shorter NA, Shermeta DW. Surgical management of lung bud anomalies: lobar emphysema, bronchogenic cyst, cystic adenomatoid malformation, and intralobar pulmonary sequestration. Ann Thorac Surg. 1979;28(1):33-43. http://dx.doi.org/10.1016/S0003-4975(10)63389-9 13. Schwartz MZ, Ramachandran P. Congenital malformations of the lung and mediastinum--a quarter century of experience from a single institution. J Pediatr Surg. 1997;32(1):44-7. http://dx.doi.org/10.1016/ S0022-3468(97)90090-7 14. Leape LL, Longino LA. Infantile lobar emphysema. Pediatrics. 1964;34:246-55. PMid:14211085 15. Ozçelik U, Göçmen A, Kiper N, Doğru D, Dilber E, Yalçin EG. Congenital lobar emphysema: evaluation and long-term follow-up of thirty cases at a single center. Pediatr Pulmonol. 2003;35(5):384-91. http://dx.doi. org/10.1002/ppul.10240 PMid:12687596 16. Thakral CL, Maji DC, Sajwani MJ. Congenital lobar emphysema: experience with 21 cases. Pediatr Surg Int. 2001;17(2-3):88-91. http://dx.doi.org/10.1007/ s003830000506 PMid:11315310 17. Ferreira HP, Fischer GB, Felicetti JC, Camargo Jde J, Andrade CF. Surgical treatment of congenital lung malformations in pediatric patients. J Bras Pneumol. 2010;36(2):175-80. http://dx.doi.org/10.1590/S180637132010000200004 PMid:20485937

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18. Costa Júnior Ada S, Perfeito JA, Forte V. Surgical treatment of 60 patients with pulmonary malformations: what have we learned? J Bras Pneumol. 2008;34(9):661-6. PMid:18982202 19. Lacy DE, Shaw NJ, Pilling DW, Walkinshaw S. Outcome of congenital lung abnormalities detected antenatally. Acta Paediatr. 1999;88(4):454-8. http://dx.doi. org/10.1111/j.1651-2227.1999.tb01139.x PMid:10342547 20. Olutoye OO, Coleman BG, Hubbard AM, Adzick NS. Prenatal diagnosis and management of congenital lobar emphysema. J Pediatr Surg. 2000;35(5):792-5. http:// dx.doi.org/10.1053/jpsu.2000.6084 PMid:10813352 21. Man DW, Hamdy MH, Hendry GM, Bisset WH, Forfar JO. Congenital lobar emphysema: problems in diagnosis and management. Arch Dis Child. 1983;58(9):709-12. http://dx.doi.org/10.1136/adc.58.9.709 PMid:6625632 PMCid:1628259 22. Choudhury SR, Chadha R, Mishra A, Kumar V, Singh V, Dubey NK. Lung resections in children for congenital and acquired lesions. Pediatr Surg Int. 2007;23(9):851-9. http:// dx.doi.org/10.1007/s00383-007-1940-8 PMid:17671788 23. Goto H, Boozalis ST, Benson KT, Arakawa K. Highfrequency jet ventilation for resection of congenital lobar emphysema. Anesth Analg. 1987;66(7):684-6. http://dx.doi.org/10.1213/00000539-198707000-00022 PMid:3605681 24. Glenski JA, Thibeault DW, Hall FK, Hall RT, Germann DR. Selective bronchial intubation in infants with lobar emphysema: indications, complications, and long-term outcome. Am J Perinatol. 1986;3(3):199-204. http:// dx.doi.org/10.1055/s-2007-999867 PMid:3718641 25. Phillipos EZ, Libsekal K. Flexible bronchoscopy in the management of congenital lobar emphysema in the neonate. Can Resp J. 1998; 5:219-21. PMid:9707469 26. Mei-Zahav M, Konen O, Manson D, Langer JC. Is congenital lobar emphysema a surgical disease? J Pediatr Surg. 2006;41(6):1058-61. http://dx.doi.org/10.1016/j. jpedsurg.2006.02.011 PMid:16769334 27. Maiya S, Clarke JR, More B, Desai M, Parikh D. Bilateral congenital lobar emphysema: how should we proceed? Pediatr Surg Int. 2005;21(8):659-61. http://dx.doi. org/10.1007/s00383-005-1425-6 PMid:15918044 28. Roguin N, Peleg H, Lemer J, Naveh Y, Riss E. The value of cardiac catheterization and cineangiography in infantile lobar emphysema. Pediatr Radiol. 1980;10(2):71-4. http://dx.doi.org/10.1007/BF01001742 PMid:7454424 29. Rahman N, Lakhoo K. Comparison between open and thoracoscopic resection of congenital lung lesions. J Pediatr Surg. 2009;44(2):333-6. http://dx.doi.org/10.1016/j. jpedsurg.2008.10.081 PMid:19231529 30. Doull IJ, Connett GJ, Warner JO. Bronchoscopic appearances of congenital lobar emphysema. Pediatr Pulmonol. 1996;21(3):195-7. http://dx.doi.org/10.1002/ (SICI)1099-0496(199603)21:3<195::AID-PPUL9>3.0.CO;2-P

J Bras Pneumol. 2013;39(4):418-426

426

Cataneo DC, Rodrigues OR, Hasimoto EN, Schmidt Jr AF, Cataneo AJM

About the authors Daniele Cristina Cataneo

Adjunct Professor. Thoracic Surgery Section, Department of Surgery and Orthopedics, S達o Paulo State University Botucatu School of Medicine, Botucatu, Brazil.

Olavo Ribeiro Rodrigues

Adjunct Professor. Department of Thoracic Surgery, University of Mogi das Cruzes, Mogi das Cruzes, Brazil.

Erica Nishida Hasimoto

Doctoral Student. Graduate Program in the Fundamentals of Surgery, S達o Paulo State University Botucatu School of Medicine, Botucatu, Brazil.

Aurelino Fernandes Schmidt Jr

Assistant Professor. Department of Thoracic Surgery, University of Mogi das Cruzes, Mogi das Cruzes, Brazil.

Antonio Jos辿 Maria Cataneo

Full Professor. Thoracic Surgery Section, Department of Surgery and Orthopedics, S達o Paulo State University Botucatu School of Medicine, Botucatu, Brazil.

J Bras Pneumol. 2013;39(4):418-426

Original Article Reliability of the Brazilian Portuguese version of the fatigue severity scale and its correlation with pulmonary function, dyspnea, and functional capacity in patients with COPD* Reprodutibilidade da versão brasileira da escala de gravidade da fadiga e sua correlação com função pulmonar, dispneia e capacidade funcional em pacientes com DPOC

Silvia Valderramas, Aquiles Assunção Camelier, Sinara Alves da Silva, Renata Mallmann, Hanna Karine de Paulo, Fernanda Warken Rosa

Abstract Objective: To describe the intra-rater and inter-rater reliability of the Brazilian Portuguese version of the fatigue severity scale (FSS) in patients with COPD and to identify the presence of its association with parameters of pulmonary function, dyspnea, and functional capacity. Methods: This was an observational cross-sectional study involving 50 patients with COPD, who completed the FSS in interviews with two researchers in two visits. The FSS scores were correlated with those of the Medical Research Council (MRC) scale, as well as with FEV1, FVC, and six-minute walk distance (6MWD). Results: The mean age of the patients was 69.4 ± 8.23 years, whereas the mean FEV1 was 46.5 ± 20.4% of the predicted value. The scale was reliable, with an intraclass correlation coefficient of 0.90 (95% CI, 0.81-0.94; p < 0.01). The FSS scores showed significant correlations with those of MRC scale (r = 0.70; p < 0.01), as well as with 6MWD (r = −0.77; p < 0.01), FEV1 (r = −0.38; p < 0.01), FVC (r = −0.35; p < 0.01), and stage of the disease in accordance with the Global Initiative for Chronic Obstructive Lung Disease criteria (r = 0.37; p < 0.01). Conclusions: The Brazilian Portuguese version of the FSS proved reliable for use in COPD patients in Brazil and showed significant correlations with sensation of dyspnea, functional capacity, pulmonary function, and stage of the disease. Keywords: Fatigue; Pulmonary disease, chronic obstructive; Reproducibility of results; Validation studies.

Resumo Objetivo: Descrever a reprodutibilidade intra e interobservador da versão brasileira da escala de gravidade da fadiga (EGF) em pacientes com DPOC e verificar a presença de sua associação com parâmetros de função pulmonar, dispneia e capacidade funcional. Métodos: Estudo observacional de corte transversal no qual 50 pacientes com DPOC responderam a EGF em forma de entrevista a dois pesquisadores em duas visitas. Os escores da EGF foram correlacionados aos da escala Medical Research Council (MRC), VEF1, CVF e a distância percorrida no teste da caminhada de seis minutos (DTC6). Resultados: A média de idade dos pacientes foi de 69,4 ± 8,23 anos, enquanto a de VEF1 foi de 46,5 ± 20,4% do previsto. A EGF foi considerada reprodutível, com um coeficiente de correlação intraclasse de 0,90 (IC95%, 0,81-0,94; p < 0,01). Os escores da EGF mostraram correlações significantes com os da escala MRC (r = 0,70; p < 0,01), DTC6 (r = −0,77; p < 0,01), VEF1 (r = −0,38; p < 0,01), CVF (r = −0,35; p < 0,01) e a estágio da doença pela Global Initiative for Chronic Obstructive Lung Disease (r = 0,37; p < 0,01). Conclusões: A versão brasileira da EGF mostrou-se reprodutível para uso em pacientes com DPOC no Brasil e apresentou correlações significantes com a sensação de dispneia, capacidade funcional, função pulmonar e estágio da doença. Descritores: Fadiga; Doença pulmonar obstrutiva crônica; Reprodutibilidade dos testes; Avaliação; Estudos de validação.

*Study carried out at the Faculdade Evangélica do Paraná, Curitiba, Brazil. Correspondence to: Silvia Valderramas. Rua Paulo Martins, 298, CEP 81710-000, Curitiba, PR, Brasil. Tel. 55 41 3218-5550. E-mail: svalderramas@uol.com.br Financial support: This study received financial support from the Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB, Bahia Research Foundation). Submitted: 29 April 2013. Accepted, after review: 18 July 2013.

J Bras Pneumol. 2013;39(4):427-433

428

Valderramas S, Camelier AA, Silva AS, Mallmann R, de Paulo HK, Rosa FW

Introduction Fatigue is a major symptom and is present in 43-58% of patients with COPD,(1-5) having a major impact on the functional capacity and quality of life of COPD patients.(6,7) Fatigue is currently defined as a subjective, unpleasant symptom that incorporates total body feelings ranging from tiredness to exhaustion creating an unrelenting overall condition that interferes with the ability of individuals to function to their normal capacity.(8) In patients with COPD, fatigue limits the motivation, concentration, and willingness to perform work and social activities,(9) often leading to deep frustration and depression, as well as to a deep sense of loss of emotional control.(5) The Borg scale(10) has been routinely used in order to quantify the perception of leg fatigue during physical exertion or functional capacity tests. However, an instrument quantifying fatigue during activities of daily living should also be considered an important tool in the evaluation and treatment of patients with COPD. The fatigue severity scale (FSS),(11) previously translated into Brazilian Portuguese, has been widely used in order to assess fatigue in patients with neurological diseases,(12-14) in the elderly,(15) and in patients with neoplasia.(16,17) The FSS is a self-report scale comprising nine statements describing the severity of fatigue and the impact of fatigue on activities of daily living in the last two weeks. The researchers hypothesized that the FSS would show good reliability, internal consistency, and validity, i.e., that it would correlate with lung function, perception of dyspnea, and the six-minute walk distance (6MWD). They also hypothesized that patients with fatigue would have more severe clinical and functional limitations (severity of airway obstruction, disease stage, dyspnea, and functional exercise capacity). The objective of the present study was to evaluate the intra-rater and inter-rater reliability of the FSS and determine whether the degree of fatigue correlated with lung function, perception of dyspnea, and functional exercise capacity in patients with COPD.

Methods This was a cross-sectional study evaluating clinically stable patients with COPD staged in J Bras Pneumol. 2013;39(4):427-433

accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (18) and with no medication changes for at least three months before the beginning of the study. Patients were selected from among those treated at a university medical center between October and December of 2011. We excluded those who had been involved in any type of physical activity before the beginning of the study, those who had any extrapulmonary disease causing functional limitation and fatigue (such as severe cardiovascular disease), and those who had difficulty understanding the scale items (as determined by the interviewers on the basis of subjective criteria). The present study was approved by the local research ethics committee, and all participants gave written informed consent. The FSS comprises nine statements, and, for each item, patients are instructed to choose a score ranging from 1 to 7, 7 representing the highest level of agreement with a given statement. The total FSS score is obtained by calculating the mean of all items, a score ≥ 4 indicating the presence of fatigue. (11) In order to determine the reliability of the FSS, the scale was administered by two interviewers on two different occasions, two weeks apart. The evaluations were designated interview 1 (I1, intra-rater reliability assessment) and interview 2 (I2, inter-rater reliability assessment). The interviews were conducted independently by two raters, with a 30-min interval between interviews. (19) Although the patients were literate, we followed the methodology used in other studies (13,14); that is, the interviewers read the questions aloud and marked the answers given by patients. Additionally, we assessed the degree of dyspnea—using the Medical Research Council (MRC) scale, (20) previously translated into Brazilian Portuguese and validated for use in Brazil (21)—the 6MWD, (22) and lung function parameters (FVC and FEV 1). (23) Data analysis was performed with the Statistical Package for the Social Sciences, version 16.0 for Windows (SPSS Inc., Chicago, IL, USA). Descriptive statistics (frequency, mean, standard deviation, median, and interquartile range) were calculated for demographic, anthropometric, and clinical characteristics, depending on the type of variable and the

Reliability of the Brazilian Portuguese version of the fatigue severity scale and its correlation with pulmonary function, dyspnea, and functional capacity in patients with COPD

data distribution. The intraclass correlation coefficient (ICC) and its 95% CI were used in order to assess inter-rater reliability at I1 and I2, and the Wilcoxon test was used in order to determine whether there were differences between I1 and I2. The intra-rater reliability at I1 and I2 and inter-rater reliability were visually assessed by Bland & Altman plots. Bland & Altman plots display the differences, the overall mean and variance are calculated, and the 95% CI is constructed around the mean, a normal distribution of the data being assumed. We used Spearman’s test in order to determine the association of the FSS score with the degree of dyspnea as assessed by the MRC scale score, 6MWD, disease severity, FEV1, and FVC. The level of statistical significance was set at p < 0.05.

Results Our study included 50 patients. Of those, all were literate and 28 (56%) were male. No significant differences were found between the genders regarding any of the study variables. All patients were using bronchodilators. General, sociodemographic, and clinical data are shown in Table 1. There were no significant differences in FSS scores between I1 and I2 in the intra-rater reliability assessment (p = 0.76) or in the interrater reliability assessment (p = 0.67). Intra-rater and inter-rater ICCs were significant for the FSS (0.90 [0.81-0.94]; p < 0.01; and 0.95 [0.92-0.98]; p < 0.01, respectively). Cronbach’s alpha coefficient was 0.90. The test-retest reliability of the FSS was demonstrated by Bland & Altman plots between I1 and I2, as well as between the two raters (Figure 1). The correlations of FSS scores with disease severity (GOLD criteria), SpO2, FEV1, FVC, MRC scale scores, and 6MWD are shown in Table 2. The median FSS score was 5.33 (range, 1-7). The prevalence of fatigue in the study sample was 60% (n = 30); consequently, it was possible to divide the sample into two groups: patients with fatigue (n = 30) and patients without fatigue (n = 20). When compared, the groups showed significant differences regarding FSS scores, spirometric parameters (FEV1, FVC, and FEV1/FVC), GOLD stages, MRC scale scores, and 6MWD (Table 3).

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Discussion The results of the present study show that the Brazilian Portuguese version of the FSS is reliable for use in the evaluation of fatigue in patients with COPD. In addition, FSS scores Table 1 - Characteristics of the patients evaluated (n = 50).a Variable Mean, SD Age, years

69.4 ± 8.23

BMI, kg/m2

25.7 ± 4.54

FVC, % of predicted

65.9 ± 20.4

FEV1, % of predicted

46.5 ± 20.4

FEV1/FVC

65.9 ± 25.3

SpO2, %

92.4 ± 3.13

MRC scale score

3 (2-3)

GOLD stage, I/II/III/IVc 6MWD, m

5/15/14/16 357.2 ± 92.6

6MWD, % of predicted EGF

77 ± 22 5.33 (3.50-6.00)

BMI: body mass index; GOLD: Global Initiative for Chronic Obstructive Lung Disease; 6MWD: six-minute walk distance; MRC: Medical Research Council; and EGF: escala de gravidade da fadiga (Brazilian Portuguese version of the fatigue severity scale). aValues expressed as mean ± SD, except where otherwise indicated. bValues expressed as median (interquartile range). c Values expressed as n of patients.

Table 2 - Correlations of fatigue severity scale scores with the study variables. Variable r p GOLD stage

0.37

0.01

SpO2

−0.38

0.03

FEV1, % of predicted

−0.38

0.01

FVC, % of predicted

−0.35

0.01

FEV1/FVC

−0.30

0.03

MRC scale score

0.69

< 0.01

6MWD, m

−0.77

< 0.01

6MWD, % of predicted

−0.54

< 0.01

GOLD: Global Initiative for Chronic Obstructive Lung Disease; MRC: Medical Research Council; and 6MWD: six-minute walk distance.

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Valderramas S, Camelier AA, Silva AS, Mallmann R, de Paulo HK, Rosa FW

Table 3 - Differences between the groups of patients with and without fatigue as assessed by fatigue severity scale scores.a Variable Group p With fatigue Without fatigue (n = 30) (n = 20) EGFb 6.0 (4.6-7.0) 3.0 (1.0-4.0) < 0.01 Age, years 70.1 ± 7.9 68.4 ± 8.8 0.42 Female/male genderc 15/15 7/13 0.30 BMI, kg/m2 25.20 ± 4.94 26.50 ± 3.84 0.33 FVC, % of predicted 62.40 ± 21.90 71.00 ± 17.21 0.04 FEV1, % of predicted 40.18 ± 16.30 56.00 ± 22.60 < 0.01 FEV1/FVC 58.00 ± 22.00 76.45 ± 26.30 0.01 SpO2 92.10 ± 3.17 92.90 ± 3.00 0.27 MRC scale scoreb 3 (1-4) 2 (0-4) < 0.01 GOLD stage, I/II/III/IVc 1/7/10/12 4/8/4/4 < 0.01 6MWD, m 323.1 ± 78.2 408.4 ± 90.5 < 0.01 6MWD, % of predicted 68.80 ± 18.70 89.40 ± 21.15 < 0.01 EGF: escala de gravidade da fadiga (Brazilian Portuguese version of the fatigue severity scale); BMI: body mass index; MRC: Medical Research Council; GOLD: Global Initiative for Chronic Obstructive Lung Disease; and 6MWD: six-minute walk distance. aValues expressed as mean ± SD, except where otherwise indicated. bValues expressed as median (interquartile range). cValues expressed as n of patients.

+1.96 SD 2,0

2 1

Mean -0,1

0 -1

-1,96 SD -2,3

-2 -3 -4 -5 -6 -7 1

2 3 4 5 6 8 7 Mean of the results obtained at interviews 1 and 2

3 Difference between raters 1 and 2

Difference between interviews 1 and 2

+1.96 SD 1,4

Mean -0,0

0 -1

-1,96 SD -1,4

-2 -3 1

Mean of the results obtained by raters 1 and 2

Figura 1 - Disposições gráficas de Bland & Altman comparando os resultados obtidos nas entrevistas 1 e 2 (à esquerda) e entre os entrevistadores 1 e 2 (à direita).

correlated strongly and significantly with the degree of dyspnea and the 6MWD, and the FSS scores allowed us to divide the sample into two groups of patients (with and without fatigue) and detect differences between the two groups in terms of the parameters evaluated. For instruments (such as scales and questionnaires) to be considered suitable for use in clinical practice or research in countries other than those in which they were originally developed, it is necessary to evaluate their reliability.(11) Reliability is defined as the ability of an instrument to show little or no variability J Bras Pneumol. 2013;39(4):427-433

when it is used by different researchers or at different time points. The absence of a statistically significant difference in test-retest reliability, together with the high ICC and excellent internal consistency (Cronbach’s alpha coefficient = 0.90), demonstrate the reliability of the FSS in patients with COPD. The reliability of the FSS was visually assessed by analyzing Bland & Altman plots, which showed that the bias ratio (difference between I1 and I2) was nearly zero. This showed good concordance between the interviews and between the two raters.

Reliability of the Brazilian Portuguese version of the fatigue severity scale and its correlation with pulmonary function, dyspnea, and functional capacity in patients with COPD

Regarding the FSS test time, there was no statistically significant difference between I1 and I2 (5 ± 3 min and 3 ± 2 min, respectively), although the test time was shorter at I2. We believe that this minimal difference is due to the fact that the patients had a better understanding of the questions. The FSS test time was shorter in the present study than in a study in which the FSS was administered to patients with Parkinson’s disease in Brazil.(13) We believe that this difference is due to the fact that the cognitive status is more severely impaired in patients with Parkinson’s disease. Regarding construct validity, the FSS score correlated strongly and significantly with the degree of dyspnea as assessed by the MRC scale score (r = 0.69) and with the 6MWD (r = −0.77), as well as having correlated moderately with disease stage, SpO2, and the spirometric parameters FEV1, FVC, and FEV1/FVC. Some studies have investigated the prevalence of fatigue and the association between fatigue and functional and clinical parameters in patients with COPD using, however, scales or questionnaires other than the FSS, including the fatigue impact scale,(24) the multidimensional fatigue inventory,(25) the chronic respiratory disease questionnaire,(26) and the functional assessment of chronic illness therapy-fatigue scale.(27) Only one study(20) used the FSS, showing that the presence of fatigue was correlated with age (r = −0.31), the degree of dyspnea as assessed by the MRC scale score (r = 0.27), and the quality of sleep (r = 0.37). Our results showed a stronger correlation between FSS scores and MRC scale scores. This might be due to the fact that our study sample comprised a large number of patients with advanced disease. In a study validating the MRC scale for use in Brazil, (21) the results showed a weak correlation between MRC scale scores and the 6MWD (r = −0.33). The MRC scale is an instrument that assesses the limitations imposed by dyspnea, (29) being therefore less sensitive in identifying fatigue than is the FSS. Our results confirm that fatigue is a common symptom in patients with COPD, affecting 60% of the study sample. There were no differences between the groups of patients with and without fatigue regarding age, gender, body mass index, or SpO2. Most of those with fatigue had advanced COPD (GOLD stages III and IV) and a higher

431

degree of dyspnea, as well as having shown more severely impaired lung function and lower 6MWD (Table 3). The median FSS score in the present study was 5.33, being higher than those found by other authors using the FSS in patients with COPD (median score, 3.91)(27) and in patients with Parkinson’s disease (median score, 4.6).(11) The fact that the FSS score was highest in our study can be explained by the presence of a high number of patients with advanced disease. Our sample size was larger than was that in another study validating the FSS,(13) as well as being larger than was that in studies validating other scales or questionnaires, such as the Saint George’s Respiratory Questionnaire,(29) the MRC scale, and the Pulmonary Functional Status and Dyspnea Questionnaire - Modified version.(21) This demonstrates the reliability and external validity of the FSS. The FSS is a simple instrument that is useful for the assessment of fatigue, which is a very common symptom in patients with COPD. More specifically, the FSS can contribute to the evaluation of the effectiveness of a clinical (physical and pharmacological) intervention for COPD patients with fatigue. In addition, the identification of an association between fatigue and the main clinical and functional features of patients with COPD, such as the presence of dyspnea and decreased functional exercise capacity, can lead to interventions that are more specific in the rehabilitation process. The results of the present study showed that the Brazilian Portuguese version of the FSS is reliable for use in patients with COPD in Brazil and correlated strongly with the degree of dyspnea and the 6MWD.

Acknowledgments We would like to thank Professor L. B. Krupp for having given us permission to use the FSS.

References 1. Kinsman RA, Yaroush RA, Fernandez E, Dirks JE, Schocket M, Fukuhara J. Symptoms and experiences in chronic bronchitis and emphysema. Chest. 1983;83(5):755-61. http://dx.doi.org/10.1378/chest.83.5.755 PMid:6839816 2. Walke LM, Byers AL, Tinetti ME, Dubin JA, McCorkle R, Fried TR. Range and severity of symptoms over time among older adults with chronic obstructive pulmonary disease and heart failure. Arch Intern Med. 2007;167(22):2503-8. http://dx.doi.org/10.1001/archinte.167.22.2503 PMid:18071174 PMCid:PMC2196402

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3. Gift AG, Shepard CE. Fatigue and other symptoms in patients with chronic obstructive pulmonary disease: do women and men differ? J Obstet Gynecol Neonatal Nurs. 1999;28(2):201-8. http://dx.doi. org/10.1111/j.1552-6909.1999.tb01985.x 4. Graydon JE, Ross E. Influence of symptoms, lung function, mood, and social support on level of functioning of patients with COPD. Res Nurs Health. 1995;18(6):525-33. http://dx.doi.org/10.1002/nur.4770180608 5. Reishtein JL. Relationship between symptoms and functional performance in COPD. Res Nurs Health. 2005;28(1):39-47. http://dx.doi.org/10.1002/nur.20054 PMid:15625710 6. Oga T, Nishimura K, Tsukino M, Hajiro T, Sato S, Ikeda A, et al. Longitudinal changes in health status using the chronic respiratory diseases questionnaire and pulmonary function in patients with stable chronic obstructive pulmonary disease. Qual Life Res. 2004;13(6):1109-16. http://dx.doi.org/10.1023/B:QURE.0000031345.56580.6a PMid:15287277 7. Cramer JA, Spilker B. Quality of Life and Pharmacoeconomics: An Introduction. Philadelphia: Lippincott-Raven; 1998. 8. Ream E, Richardson A. Fatigue in patients with cancer and chronic obstructive airways disease: A phenomenological enquiry. Int J Nurs Stud. 1997;34(1):44-53. http://dx.doi. org/10.1016/S0020-7489(96)00032-6 9. Small S, Lamb M. Fatigue in chronic illness: the experience of individuals with chronic obstructive pulmonary disease and with asthma. J Adv Nurs. 1999;30(2):469-78. http:// dx.doi.org/10.1046/j.1365-2648.1999.01102.x 10. Borg G. A category scale with ratio properties for intermodal and interindividual comparisons. In: Geissler HG, Petzol P, editors. Psychophysical Judgement and the Process of Perception. Proceedings of the 22nd International Congress of Psychology. Amsterdam, The Netherlands: North Holland Publishing Co; 1980. p. 25-34. 11. Krupp LB, Pollina DA. Mechanisms and management of fatigue in progressive neurological disorders. Curr Opin Neurol 1996;9(6):456-60. http://dx.doi. org/10.1097/00019052-199612000-00011 PMid:9007405 12. Friedman JH, Alves G, Hagell P, Marinus J, Marsh L, Martinez-Martin P, et al. Fatigue ranking scales critique and recommendations by the Movement Disorders Society Task Force on rating scales for Parkinson’s Disease. Mov Disord. 2010;25(7):805-22. http://dx.doi.org/10.1002/ mds.22989 PMid:20461797 13. Valderramas S, Feres AC, Melo A. Reliability and validity study of a Brazilian-Portuguese version of the fatigue severity scale in Parkinson’s disease patients. Arq Neuropsiquiatr. 2012;70(7):497-500. http://dx.doi.org/10.1590/S0004282X2012000700005 PMid:22836454 14. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46(10):1121-3. http://dx.doi.org/10.1001/ archneur.1989.00520460115022 PMid:2803071 15. Poluri A, Mores J, Cook DB, Findley TW, Cristian A. Fatigue in the elderly population. Phys Med Rehabil Clin N Am. 2005; 16(1):91-108. http://dx.doi.org/10.1016/j. pmr.2004.06.006 PMid:15561546 16. Stone P, Richards M, Hardy J. Fatigue in patients with cancer. Eur J Cancer. 1998;34(11):1670-6. http://dx.doi. org/10.1016/S0959-8049(98)00167-1 17. Stone P, Richards M, A’Hern R, Hardy J. A study to investigate the prevalence, severity and correlates of fatigue among patients with cancer in comparison

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with a control group of volunteers without cancer. Ann Oncol. 2000;11(5):561-7. http://dx.doi. org/10.1023/A:1008331230608 PMid:10907949 18. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532-55. http://dx.doi.org/10.1164/ rccm.200703-456SO PMid:17507545 19. Guillemin F, Bombardier C, Beaton D. Crosscultural adaptation of health-related quality of life measures: literature review and proposed guidelines. J Clin Epidemiol. 1993;46(12):1417-32. http://dx.doi. org/10.1016/0895-4356(93)90142-N 20. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax. 1999;54(7): 581-6. http://dx.doi.org/10.1136/thx.54.7.581 PMid:10377201 PMCid:PMC1745516 21. Kovelis D, Segretti NO, Probst VS, Lareau SC, Brunetto AF, Pitta F. Validation of the Modified Pulmonary Functional Status and Dyspnea Questionnaire and the Medical Research Council scale for use in Brazilian patients with chronic obstructive pulmonary disease. J Bras Pneumol. 2008;34(12):1008-18. http://dx.doi.org/10.1590/S180637132008001200005 PMid:19180335 22. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-7. http://dx.doi.org/10.1164/ ajrccm.166.1.at1102 PMid:12091180 23. Sociedade Brasileira de Pneumologia e Tisiologia. Diretrizes para Testes de Função Pulmonar. J Pneumol. 2002;28(Suppl 3):S1-S238. 24. Theander K, Unosson M. Fatigue in patients with chronic obstructive pulmonary disease. J Adv Nurs. 2004;45(2):172-7. http://dx.doi.org/10.1046/j.1365-2648.2003.02878.x 25. Breslin E, van der Schans C, Breukink S, Meek P, Mercer K, Volz W, et al. Perception of fatigue and quality of life in patients with COPD. Chest. 1998;114(4):958-64. http://dx.doi.org/10.1378/chest.114.4.958 PMid:9792561 26. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease. Thorax. 1987;42(10):773-8. http://dx.doi.org/10.1136/thx.42.10.773 PMid:3321537 PMCid:PMC460950 27. Baghai-Ravary R, Quint JK, Goldring JJ, Hurst JR, Donaldson GC, Wedzicha JA. Determinants and impact of fatigue in patients with chronic obstructive pulmonary disease. Respir Med. 2009;103(2): 216-23. http://dx.doi.org/10.1016/j. rmed.2008.09.022 PMid:19027278 28. Cavalcante AG, de Bruin PF, de Bruin VM, Pereira ED, Cavalcante MM, Nunes DM, et al. Restless legs syndrome, sleep impairment, and fatigue in chronic obstructive pulmonary disease. Sleep Med. 2012;13(7):842-7. http:// dx.doi.org/10.1016/j.sleep.2012.03.017 PMid:22727926 29. Camelier A, Rosa FW, Salim C, Nascimento OA, Cardoso F, Jardim JR. Using the Saint George’s Respiratory Questionnaire to evaluate quality of life in patients with chronic obstructive pulmonary disease: validating a new version for use in Brazil. J Bras Pneumol. 2006;32(2):11422. http://dx.doi.org/10.1590/S1806-37132006000200006 PMid:17273580

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About the authors Silvia Valderramas

Professora, Faculdade Dom Bosco e Faculdade Evangélica do Paraná, Curitiba (PR) Brasil.

Aquiles Assunção Camelier

Professor, Escola Bahiana de Medicina e Saude Publica/Hospital Português, Salvador (BA) Brasil.

Sinara Alves da Silva

Fisioterapeuta, Universidade do Estado da Bahia – UNEB – Salvador (BA) Brasil.

Renata Mallmann

Fisioterapeuta, Faculdade Evangélica do Paraná, Curitiba (PR) Brasil.

Hanna Karine de Paulo,

Fisioterapeuta, Faculdade Evangélica do Paraná, Curitiba (PR) Brasil.

Fernanda Warken Rosa

Professora. Universidade do Estado da Bahia – UNEB – Salvador (BA) Brasil.

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Original Article Effect of tramadol on lung injury induced by skeletal muscle ischemia-reperfusion: an experimental study* Efeito do tramadol na lesão pulmonar induzida por isquemia-reperfusão de músculo esquelético: um estudo experimental

Mohammad Ashrafzadeh Takhtfooladi, Amirali Jahanshahi, Amir Sotoudeh, Gholamreza Jahanshahi, Hamed Ashrafzadeh Takhtfooladi, Kimia Aslani

Abstract Objective: To determine whether tramadol has a protective effect against lung injury induced by skeletal muscle ischemia-reperfusion. Methods: Twenty Wistar male rats were allocated to one of two groups: ischemia-reperfusion (IR) and ischemia-reperfusion + tramadol (IR+T). The animals were anesthetized with intramuscular injections of ketamine and xylazine (50 mg/kg and 10 mg/kg, respectively). All of the animals underwent 2-h ischemia by occlusion of the femoral artery and 24-h reperfusion. Prior to the occlusion of the femoral artery, 250 IU heparin were administered via the jugular vein in order to prevent clotting. The rats in the IR+T group were treated with tramadol (20 mg/kg i.v.) immediately before reperfusion. After the reperfusion period, the animals were euthanized with pentobarbital (300 mg/kg i.p.), the lungs were carefully removed, and specimens were properly prepared for histopathological and biochemical studies. Results: Myeloperoxidase activity and nitric oxide levels were significantly higher in the IR group than in the IR+T group (p = 0.001 for both). Histological abnormalities, such as intra-alveolar edema, intra-alveolar hemorrhage, and neutrophil infiltration, were significantly more common in the IR group than in the IR+T group. Conclusions: On the basis of our histological and biochemical findings, we conclude that tramadol prevents lung tissue injury after skeletal muscle ischemia-reperfusion. Keywords: Tramadol; Muscle, skeletal; Ischemic attack, transient; Lung Injury.

Resumo Objetivo: Investigar se o tramadol tem um efeito protetor contra a lesão pulmonar induzida por isquemia-reperfusão de músculo esquelético. Métodos: Vinte ratos Wistar machos foram divididos em dois grupos: grupo isquemiareperfusão (IR) e grupo isquemia-reperfusão + tramadol (IR+T). Os animais foram anestesiados com cetamina e xilazina (i.m., 50 mg/kg e 10 mg/kg, respectivamente). Todos os animais foram submetidos a 2 h de isquemia por oclusão da artéria femoral e 24 h de reperfusão. Antes da oclusão da artéria femoral, foram administrados 250 UI de heparina pela veia jugular para impedir a coagulação. Os ratos do grupo IR+T foram tratados com tramadol (20 mg/kg i.v.) imediatamente antes da reperfusão. Após o período de reperfusão, os animais foram sacrificados com pentobarbital (300 mg/kg i.p.), os pulmões foram removidos cuidadosamente, e os espécimes foram preparados adequadamente para estudos histopatológicos e bioquímicos. Resultados: A atividade de mieloperoxidase e os níveis de óxido nítrico foram significativamente maiores no grupo IR que no grupo IR+T (p = 0,001 para ambos). Anormalidades histológicas, como edema intra-alveolar, hemorragia intra-alveolar e infiltração neutrofílica, foram significativamente mais frequentes no grupo IR que no grupo IR+T. Conclusões: Com base nos resultados histológicos e bioquímicos deste estudo, concluímos que o tramadol tem um efeito protetor contra o dano ao tecido pulmonar após isquemia-reperfusão de músculo esquelético. Descritores: Tramadol; Músculo esquelético; Ataque isquêmico transitório; Lesão pulmonar.

*Study carried out in the Department of Veterinary Surgery, Faculty of Specialized Veterinary Science, Science and Research Branch, Islamic Azad University, Hesarak, Tehran, Iran. Correspondence to: Mohammad Ashrafzadeh Takhtfooladi. Department of Veterinary Surgery, Faculty of Specialized Veterinary Science, Science and Research Branch, Islamic Azad University, Hesarak, Tehran, Iran. Tel. 00989121590428. E-mail: dr_ashrafzadeh@yahoo.com Financial support: None. Submitted: 5 December 2012. Accepted, after review: 14 May 2013.

J Bras Pneumol. 2013;39(4):434-439

Effect of tramadol on lung injury induced by skeletal muscle ischemia-reperfusion: an experimental study

Introduction Ischemia-reperfusion injury is one of the most common types of cell injury that occurs in a variety of surgical practices. Reperfusion of ischemic organs can result in tissue injury, which manifests as microvascular and parenchymal cell dysfunction. The mechanisms underlying ischemiareperfusion injury have been previously described; polymorphonuclear leukocytes and reactive oxygen metabolites have been indicated to have pivotal roles in the etiology.(1-3) Skeletal muscle ischemia-reperfusion resulting from trauma, limb revascularization, orthopedic surgery, free flap reconstruction, or any other etiology not only leads to muscle damage itself but also causes injury involving a severe destruction of remote organs. Considerable advances have been made in the understanding of the mechanisms of this systemic response regarding the skeletal muscle ischemia-reperfusion sequence. Remote organs with intense microcapillary systems, such as the lungs, are prone to developing this type of systemic injury.(3,4) Various investigators have demonstrated that the opioid pathway is involved in tissue preservation during hypoxia or ischemia, and this protection is mediated via the delta opioid receptor.(5,6) Tramadol hydrochloride is an effective analgesic drug used for severe acute and chronic pain conditions. It has a weak affinity to the Îź-opioid receptor and inhibits the reuptake of monoamines in the central nervous system, thereby activating the descending inhibitory systems.(7,8) Recent research discloses that tramadol decreases lipid peroxidation and regulates noradrenalin uptake, and, therefore, these therapeutic properties are used for the management of myocardial ischemia.(9) The aim of the present study was to investigate the potential protective effect of tramadol hydrochloride on lung ischemia-reperfusion injury induced by the hind limb model by means of histopathological evaluation and determination of inflammatory responses via myeloperoxidase (MPO) activity and nitric oxide (NO) levels in the lung tissue of rats.

Methods All of the animals used in the present research were properly cared in accordance with the norms of the Laboratory of Animal Experimentation at the Islamic Azad University Faculty of Specialized Veterinary

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Sciences, in Tehran, Iran. The study was approved by the Animal Research Ethics Committee of the Department of Veterinary Surgery of the university. Twenty Wistar male rats, weighing 250-300 g (12-15 weeks old), were used in the present study. All of the rats were maintained under constant room temperature and standard conditions, with ad libitum access to water and commercial food, and placed in individual plastic cages with soft bedding. The animals were divided randomly into two experimental groups of ten rats each: ischemia-reperfusion (IR) group and ischemiareperfusion + tramadol (IR+T) group. Anesthesia was induced using ketamine and xylazine (i.m., 50 mg/kg and 10 mg/kg, respectively). After induction of anesthesia, the left hind limb was completely clipped. After clipping, disinfecting, and dropping, a skin incision was made on the medial surface of the left hind limb. The femoral artery and vein were isolated from the surrounding tissues, and the femoral artery was exposed and clamped with a mini bulldog forceps. Prior to the occlusion of the femoral artery, 250 IU heparin was administered via the jugular vein in order to prevent clotting. All of the animals underwent 2-h ischemia by the occlusion femoral artery with a vascular clamp and 24-h reperfusion. The animals were maintained in dorsal recumbency and kept anesthetized throughout the duration of the ischemic period. Additional doses of the anesthetics were given as necessary in order to maintain anesthesia during the experiment. Body temperature was maintained with a heating pad under anesthesia. The animals in the IR+T group were administered tramadol i.v. (20 mg/kg)(10) immediately before reperfusion. Following the ischemic period, the vascular clamp was removed, and the surgical site was routinely closed. After the surgery, fluid losses were replaced by intraperitoneal administration of 5-mL warm isotonic saline, and the rats were returned to their cages with ad libitum access to commercial food and water during the reperfusion period. After 24 h of reperfusion, the rats were euthanized with an overdose of intraperitoneal pentobarbital injection (300 mg/kg), and the left lungs were harvested and fixed in 10% formaldehyde for histopathological examination under light microscopy. The right lungs were removed and stored at â&#x2C6;&#x2019;20Â°C for analysis. The lung tissue homogenate and supernatant samples were prepared as described by Yildirim et al.(11) The biochemical assay consisted of determining MPO activity and NO levels in lung tissue. The activity J Bras Pneumol. 2013;39(4):434-439

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of MPO(12) was analyzed spectrophotometrically as described elsewhere, whereas NO levels in lung tissue were measured by the Griess reaction.(13) All of the left lung tissue samples were fixed in 10% formalin solution and processed routinely (embedded in paraffin blocks, the anterior lung region being sectioned into 6-μm sections, and stained with H&E). The severity of lung injury was determined by a pathologist who was blinded to the experiment. Lung injury was classified into four levels, as follows: level 0, no diagnostic change; level 1, mild neutrophil leukocyte infiltration and mild to moderate interstitial congestion; level 2, moderate neutrophil leukocyte infiltration, perivascular edema formation, and partial destruction of pulmonary architecture; and level 3, dense neutrophil leukocyte infiltration and complete destruction of pulmonary structure.(14) A total of four slides from each lung sample were randomly screened, and the mean level was considered representative of the sample. Statistical analyses were carried out with the Statistical Package for the Social Sciences, version 11.2 (SPSS Inc., Chicago, IL, USA). The distribution of the groups was analyzed with one-sample Kolmogorov-Smirnov test. Biochemical results showed normal distribution, and one-way ANOVA was used. Histopathological results were analyzed using Kruskal-Wallis and Mann-Whitney U tests. Values of p < 0.05 were considered as statistically significant.

Results All of the rats survived until the end of the study period. Regarding biochemical results, NO levels were significantly higher in the lungs of the rats in the IR group than in those of the rats in the IR+T group (p = 0.001; Figure 1). Likewise, MPO activity, a novel indicator for neutrophil function, was significantly higher in the IR group than in the IR+T group (p = 0.001; Figure 2). Figure 3 illustrates a representative photomicrograph of lung tissue of the rats in the IR group 24 h after reperfusion. Histological changes in the IR group included intra-alveolar edema, intra-alveolar hemorrhage, and neutrophil infiltration. The mean level of lung injury in the IR group was 2.10 ± 0.89. These pathological changes, particularly neutrophil infiltration, were much less common in the IR+T group (Figure 4). One animal in the IR+T group presented no injury, whereas the level of lung injury in the other animals ranged from 1 to 2 (mean, 1.70 J Bras Pneumol. 2013;39(4):434-439

± 0.23). Histopathologically, there was a significant difference between two groups (p = 0.035).

Figure 1 - Levels of nitric oxide (NO) in lung tissue between the groups studied (p = 0.001).

IR: ischemia-reperfusion; and IR+T: ischemia-reperfusion + tramadol.

Figure 2 - Myeloperoxidase (MPO) activity in lung tissue between the groups studied (p = 0.001).

IR: ischemia-reperfusion; and IR+T: ischemia-reperfusion + tramadol.

Figure 3 - Photomicrograph under light microscopy. Lung tissue of a rat in the ischemia-reperfusion group showing extensive intra-alveolar hemorrhage (H&E; magnification, ×40).

Effect of tramadol on lung injury induced by skeletal muscle ischemia-reperfusion: an experimental study

Figure 4 - Photomicrograph under light microscopy. Lung tissue of a rat in the ischemia-reperfusion + tramadol group showing fewer histological changes and better preserved, practically normal structures (H&E; magnification, Ă&#x2014;40).

Discussion The lung is one of the most important target organs in multiple organ dysfunction syndrome or multiple system organ failure caused by severe injury. Lungs can be damaged by indirect injuries caused by the intestine, liver, and skeletal muscle reperfusion, as well as by circulatory shock.(15,16) The mechanism of respiratory failure after ischemiareperfusion injury is a complex process which is associated with the activation of systemic inflammatory mediators, including bacteriotoxins, immunocytokines, and inflammatory mediators, such as TNF and interleukins.(17,18) TNF and NO are significant determinants of the lung injury process, which is caused by lower extremity ischemia-reperfusion,(19,20) whereas MPO is an index for the accumulation of activated leukocytes in tissues and is associated with an overproduction of reactive oxygen species (ROS); therefore, leukocyte accumulation, high MPO activity, and excessive ROS production exist together in the inflammatory process. Overproduction of ROS results in a quick depletion of antioxidant capacity of the body, which consequently leads to the damage of target organs.(21,22) Animal studies showed that opioids can act as a trigger for both phases of ischemic preconditioning,(23) and serotonin augments(24) or attenuates(25) this phenomenon depending on the concentration. Mayfield et al. (6) and Chien et al.(5) have demonstrated that the opioid pathway is involved in tissue preservation during

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hypoxia or ischemia. It has been proven that morphine has cardioprotective effects during ischemia-reperfusion. (26,27) Factors such as respiratory depression and histamine release are the disadvantages of morphine usage during the postoperative period.(28) Tramadol is a centrally acting analgesic drug with negligible respiratory depressant action, very low tolerance, and physical dependence liability. The use of tramadol (10 and 20 mg/kg) showed a protective effect against transient forebrain ischemia in rats.(10) In the present study, we tested the hypothesis that 20 mg/kg of tramadol could protect the lungs from remote organ injury after skeletal muscle ischemia-reperfusion. Higher doses of tramadol should be investigated in order to determine whether higher doses would have a higher protective effect. The present study, in concert with previous ones,(29-31) confirmed that lower limb ischemiareperfusion could induce acute lung injury in rats. We demonstrated that the acute lung injury induced by lower limb ischemia-reperfusion could be mitigated by tramadol. Our data demonstrate that tramadol significantly decreases the severity of acute lung injury, the infiltration of macrophages and polymorphonuclear leukocytes in the lungs, pulmonary vascular permeability, and intra-alveolar hemorrhage, as well as inhibiting cellular apoptosis in the lungs after skeletal muscle ischemiareperfusion injury. These results suggest the possibility of clinical application of tramadol in ischemia-reperfusion injury of the lung. Different dosages, alternative time protocols, and forms of tramadol administration for lung injury induced by skeletal muscle ischemia-reperfusion should be investigated in future studies.

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19. Welbourn R, Goldman G, O’Riordain M, Lindsay TF, Paterson IS, Kobzik L, et al. Role for tumor necrosis factor as mediator of lung injury following lower torso ischemia. J Appl Physiol. 1991;70(6):2645-9. PMid:1885460 20. Tassiopoulos AK, Carlin RE, Gao Y, Pedoto A, Finck CM, Landas SK, et al. Role of nitric oxide and tumor necrosis factor on lung injury caused by ischemia/reperfusion of the lower extremities. J Vasc Surg. 1997;26(4):647-56. http://dx.doi.org/10.1016/S0741-5214(97)70065-X 21. Crinnion JN, Homer-Vanniasinkam S, Gough MJ. Skeletal muscle reperfusion injury: pathophysiology and clinical considerations. Cardiovasc Surg. 1993;1(4):317-24. PMid:8076053 22. Carden DL, Granger DN. Pathophysiology of ischaemiareperfusion injury. J Pathol. 2000;190(3):255-66. http:// dx.doi.org/10.1002/(SICI)1096-9896(200002)190:3 <255::AID-PATH526>3.0.CO;2-6 23. Fryer RM, Hsu AK, Eells JT, Nagase H, Gross GJ. Opioidinduced second window of cardioprotection: potential role of mitochondrial KATP channels. Circ Res. 1999;84(7):846-51. http://dx.doi.org/10.1161/01.RES.84.7.846 PMid:10205153 24. Nebigil CG, Etienne N, Messaddeq N, Maroteaux L. Serotonin is a novel survival factor of cardiomyocytes: mitochondria as a target of 5-HT2B receptor signaling. FASEB J. 2003;17(10):1373-5. PMid:12738797 25. Bianchi P, Pimentel DR, Murphy MP, Colucci WS, Parini A. A new hypertrophic mechanism of serotonin in cardiac myocytes: receptor-independent ROS generation. FASEB J. 2005;19(6):641-3. PMid:15703274 26. Groban L, Vernon JC, Butterworth J. Intrathecal morphine reduces infarct size in a rat model of ischemiareperfusion injury. Anesth Analg. 2004;98(4):903-9. http://dx.doi.org/10.1213/01.ANE.0000105878.96434.05 PMid:15041570 27. McPherson BC, Yao Z. Signal transduction of opioidinduced cardioprotection in ischemia-reperfusion. Anesthesiology. 2001;94(6):1082-8. http://dx.doi. org/10.1097/00000542-200106000-00024 28. Ellmauer S, Dick W, Otto S, Müller H. Different opioids in patients at cardiovascular risk. Comparison of central and peripheral hemodynamic adverse effects [Article in German]. Anaesthesist. 1994;43(11):743-9. http://dx.doi. org/10.1007/s001010050117 PMid:7840403 29. Yassin MM, Barros D’Sa AA, Parks G, Abdulkadir AS, Halliday I, Rowlands BJ. Mortality following lower limb ischemia-reperfusion: a systemic inflammatory response? World J Surg. 1996;20(8):961-6; discussion 966-7. http:// dx.doi.org/10.1007/s002689900144 PMid:8798348 30. Yassin MM, Harkin DW, Barros D’Sa AA, Halliday MI, Rowlands BJ. Lower limb ischemia-reperfusion injury triggers a systemic inflammatory response and multiple organ dysfunction. World J Surg. 2002;26(1):115-21. http:// dx.doi.org/10.1007/s00268-001-0169-2 PMid:11898044 31. Sirmali M, Uz E, Sirmali R, Kilbaş A, Yilmaz HR, Ağaçkiran Y, et al. The effects of erdosteine on lung injury induced by the ischemia-reperfusion of the hind-limbs in rats. J Surg Res. 2008;145(2):303-7. http://dx.doi.org/10.1016/j. jss.2007.02.027 PMid:17574582

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About the authors Mohammad Ashrafzadeh Takhtfooladi

Doctoral Fellow. Department of Veterinary Surgery, Faculty of Specialized Veterinary Science, Science and Research Branch, Islamic Azad University, Tehran, Iran.

Amirali Jahanshahi

Doctoral Fellow. Department of Veterinary Surgery, Faculty of Specialized Veterinary Science, Science and Research Branch, Islamic Azad University, Tehran, Iran.

Amir Sotoudeh

Assistant Professor. Faculty of Veterinary Science, Kahnooj Branch, Islamic Azad University, Kerman, Iran.

Gholamreza Jahanshahi

Associate Professor. Department of Oral & Maxillofacial Pathology, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran.

Hamed Ashrafzadeh Takhtfooladi

Graduate Student. Faculty of Veterinary Science, Karaj Branch, Islamic Azad University, Alborz, Iran.

Kimia Aslani

Graduate Student. Faculty of Veterinary Science, Science and Research Branch, Islamic Azad University, Tehran, Iran.

J Bras Pneumol. 2013;39(4):434-439

Original Article Oxygen desaturation in healthy subjects undergoing the incremental shuttle walk test* Dessaturação em indivíduos saudáveis submetidos ao incremental

shuttle walk test

Daniel Machado Seixas, Daniela Miti Tsukumo Seixas, Monica Corso Pereira, Marcos Mello Moreira, Ilma Aparecida Paschoal

Abstract Objective: To determine the probability of oxygen desaturation in healthy individuals undergoing the incremental shuttle walk test (ISWT). Methods: We enrolled 83 healthy subjects: 55 males (including 1 smoker) and 28 females. We determined pre-ISWT FEV1, FEV6, HR and SpO2, as well as post-ISWT HR and SpO2. Results: Mean values overall were as follows: age, 35.05 ± 12.53 years; body mass index, 24.30 ± 3.47 kg/m2; resting HR, 75.12 ± 12.48 bpm; resting SpO2, 97.96 ± 1.02%; FEV1, 3.75 ± 0.81 L; FEV6, 4.45 ± 0.87 L; FEV1/FEV6 ratio, 0.83 ± 0.08 (no restriction or obstruction); incremental shuttle walk distance, 958.30 ± 146.32 m; post-ISWT HR, 162.41 ± 18.24 bpm; and post-ISWT SpO2, 96.27 ± 2.21%. In 11 subjects, post-ISWT SpO2 was higher than was pre-ISWT SpO2. In 17 subjects, there was a 4% decrease in SpO2 after the ISWT. There were no statistically significant differences between the groups with and without post-ISWT oxygen desaturation in terms of age, gender, FEV1, FEV6, FEV1/FEV6, pre-ISWT SpO2, incremental shuttle walk distance, HR, or percentage of maximal HR. In the individuals with post-ISWT oxygen desaturation, the body mass index was higher (p = 0.01) and post-ISWT SpO2 was lower (p = 0.0001). Conclusions: Healthy individuals can present oxygen desaturation after the ISWT. Using the ISWT to predict subtle respiratory abnormalities can be misleading. In healthy subjects, oxygen desaturation is common after the ISWT, as it is during any intense physical activity. Keywords: Heart function tests; Respiratory function tests; Body mass index; Oximetry

Resumo Objetivo: Determinar a probabilidade de dessaturação arterial em indivíduos saudáveis submetidos ao incremental shuttle walk test (ISWT). Métodos: Foram estudados 83 indivíduos saudáveis, dos quais 55 eram homens (1 deles fumante) e 28 eram mulheres. Foram determinados VEF1 e VEF6 antes da realização do ISWT, assim como FC e SpO2 antes e depois do ISWT. Resultados: As médias gerais foram as seguintes: idade, 35,05 ± 12,53 anos; índice de massa corporal, 24,30 ± 3,47 kg/m2; FC em repouso, 75,12 ± 12,48 bpm; SpO2 em repouso, 97,96 ± 1,02%; VEF1, 3,75 ± 0,81 L; VEF6, 4,45 ± 0,87 L; relação VEF1/VEF6, 0,83 ± 0,08 (sem restrição ou obstrução); distância percorrida no ISWT, 958,30 ± 146,32 m; FC pós-ISWT, 162,41 ± 18,24 bpm e SpO2 pós-ISWT, 96,27 ± 2,21% Em 11 indivíduos, houve um aumento da SpO2 após o ISWT, ao passo que em 17 houve uma queda de 4%. Não houve diferença estatística entre os grupos com e sem dessaturação após o ISWT no tocante às variáveis idade, gênero, VEF1, VEF6, VEF1/VEF6, SpO2 basal, distância percorrida no ISWT, FC e porcentagem da FC máxima. Nos indivíduos que apresentaram dessaturação, o índice de massa corporal foi maior (p = 0,01) e a SpO2 pós-ISWT foi menor (p = 0,0001). Conclusões: Indivíduos saudáveis podem apresentar dessaturação após o ISWT. O uso do ISWT para prever a presença de problemas respiratórios sutis pode ser enganador. Em indivíduos saudáveis, a dessaturação é um evento comum após o ISWT, assim como o é durante a atividade física intensa. Descritores: Testes de função cardíaca; Testes de função respiratória; Índice de massa corporal; Oximetria.

*Study carried out at the State University at Campinas, Campinas, Brazil. Correspondence to: Ilma Aparecida Paschoal. Cidade Universitária “Zeferino Vaz”, Disciplina de Pneumologia, FCM-UNICAMP, Distrito de Barão Geraldo, CEP 13083-888 Campinas, SP, Brasil. Tel. 55 19 3521-7948. E-mail: ilma@fcm.unicamp.br Financial support: None. Submitted: 23 April 2013. Accepted, after review: 9 July 2013.

J Bras Pneumol. 2013;39(4):440-446

Oxygen desaturation in healthy subjects undergoing the incremental shuttle walk test

Introduction Although patients with interstitial pulmonary fibrosis or pulmonary arterial hypertension can have normal SpO2 at rest, some will show oxygen desaturation after submaximal exercise. (1,2) End-exercise PaO2 decreases after maximal exercise, and submaximal steady-state exercise was found to be an important measure of disease severity in interstitial pulmonary fibrosis.(3,4) Lama et al. demonstrated that patients with usual interstitial pneumonia who developed oxygen desaturation during and after a six-minute walk test (6MWT)—a ≥ 4% decrease in oxygen saturation from baseline (Δsat ≥ 4%)—were more than four times more likely to die during follow-up.(5) The abovementioned findings led us to hypothesize that a decrease in oxygen saturation during selfpaced walking (a submaximal exercise test) is a meaningful measure of disease status in patients with scleroderma. Our results showed that, in the multiple logistic regression analysis, the variable Δsat ≥ 4% was significantly associated with age, dyspnea, and two other variables related to pulmonary involvement, i.e., FVC < 80% of the predicted value (as assessed by spirometry) and positivity for the Scl-70 antibody, which is a marker of pulmonary disease in scleroderma. However, the statistical model applied to the data did not indicate which of the dependent variables analyzed (Δsat ≥ 4% or the distance walked) was better at predicting pulmonary disease. Nevertheless, Δsat ≥ 4% appeared to be able to provide more information on this issue than did the distance walked.(6) Another study conducted by our research group and involving patients with systemic lupus erythematosus showed that those with post-6MWT Δsat ≥ 4% (as assessed by pulse oximetry) showed a significant reduction in the six-minute walk distance (6MWD), which was 443 m in the group of patients who developed oxygen desaturation and 497 m in that of those who did not (p = 0.0291). However, both 6MWDs were well above the lower limit of the normal range. In addition, when compared with the patients who did not develop oxygen desaturation, those who did had a higher post-6MWT HR (p = 0.0170), a lower MEP (p = 0.0282), a lower MIP (p = 0.0504), and a restrictive pattern of lung disease (as determined by spirometry). These findings suggest that oxygen desaturation is more sensitive in detecting the presence of respiratory abnormalities in patients

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with systemic lupus erythematosus than is the 6MWD (unpublished data). Therefore, oxygen desaturation during submaximal exercise seems to be a more sensitive endpoint to detect subtle respiratory abnormalities in pulmonary diseases and in systemic diseases that affect respiration. Maximal exercise tests, such as cardiopulmonary exercise tests, can provide important information on the integration between the cardiovascular and respiratory systems during exercise. Although cardiopulmonary exercise tests have been extensively used in order to investigate various lung diseases, they are complex tests that require expensive equipment. The incremental shuttle walk test (ISWT) is a maximal exercise test that provides data that correlate well with measurements made during incremental cardiopulmonary exercise testing, being simpler and less expensive than the latter. The fact that even patients with few symptoms and mild pulmonary involvement can present with a decrease in oxygen saturation in a submaximal test led to us inquire how oxygen saturation would behave during a maximal walk test, such as the ISWT. Could it improve the sensitivity of the 6MWT in detecting respiratory impairment? With the objective of exploring this hypothesis, we decided to perform the ISWT in healthy individuals in order to determine the probability of oxygen desaturation at the end of the test.

Methods This was a cross-sectional study involving healthy subjects who attended a private fitness center in the city of Campinas, Brazil. All of the enrolled subjects attended the fitness center in order to keep physically active and in good health, and none were professional athletes. They were invited to participate in the study and agreed to perform the tests included in the protocol. The study was approved by the Research Ethics Committee of the Universidade Estadual de Campinas (Unicamp, State University at Campinas) Hospital de Clínicas, located in the city of Campinas, Brazil, and all participants gave written informed consent. Subjects were considered ineligible for the ISWT if they had a history of lung or heart disease or any other health condition that might preclude the performance of the ISWT. A standard questionnaire was applied to all participants to ensure that they did not meet any of the exclusion criteria. J Bras Pneumol. 2013;39(4):440-446

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Seixas DM, Seixas DMT, Pereira MC, Moreira MM, Paschoal IA

A digital peak flow meter (Koko Peak Pro 6; Ferraris Cardiorespiratory PDS Healthcare Products Inc., Louisville, CO, USA) was used in order to determine pre-ISWT FEV1 and FEV6. The FEV1/ FEV6 ratio was calculated by the device and was displayed on the screen. Each subject performed at least three forced expiratory maneuvers after maximal inspiratory maneuvers, the best maneuver being automatically chosen by the peak flow meter. Pre-ISWT HR and oxygen saturation were determined with a pulse oximeter equipped with a finger probe (Nonin Medical, Inc., Plymouth, MN, USA). Fingernail polish, if worn by the subject, was removed before testing. In order to guarantee an accurate assessment of oxygen saturation, the principal investigator checked that the pulse oximeter showed an acceptable pulse signal and that the oximeter light was green and pulsing in synchrony with the HR before the beginning of the tests. The protocol used for the ISWT was the 12-level version proposed by Singh et al.(7) for functional capacity evaluation in patients with COPD. All participants were tested under standardized conditions by the same investigator. The walking course was level, being 10 m in length. It was delimited by two cones inset 0.5 m from either end to avoid the need for abrupt changes in

direction. The speed at which subjects walked was dictated by an audio signal played on a portable microcomputer. Each participant received a standardized explanation (“you should walk at a steady pace, aiming to turn around whenever you hear the signal; you should continue to walk until you feel that you are unable to maintain the required speed”). At the first level of the test, the calculated walking speed was 0.5 m/s and the number of expected shuttles was 3; at the twelfth level, walking speed was 2.37 m/s and 14 shuttles were expected. All subjects were carefully observed during the test so that they would not exceed their exercise limit. Oxygen saturation was also measured immediately after the end of the ISWT. For the purpose of data analysis, oxygen desaturation was defined as a ≥ 4% decrease in oxygen saturation (SpO2) from baseline (Δsat = oxygen saturation at rest − oxygen saturation immediately after the ISWT). This 4% decrease in oxygen saturation was validated in studies of exercise-induced hypoxemia during maximal exercise tests in athletes. (8) Maximum incremental shuttle walk distance (ISWD) was defined as the maximum distance that the subjects were able to walk during the ISWT.

Table 1 - Comparison between the two groups (with and without oxygen desaturation).a Variable OD No OD (n = 17) (n = 66) Age 38.65 ± 13.77 34.12 ± 12.13

p NS

BMI

26.59 ± 3.85

23.71 ± 3.14

0.01

FEV1

3.53 ± 0.67

3.80 ± 0.84

FEV6

4.34 ± 0.56

4.48 ± 0.93

FEV1/FEV6

0.83 ± 0.11

0.84 ± 0.08

LLN

3.95 ± 0.68

3.82 ± 0.78

Initial HR, bpm

73.76 ± 10.16

75.47 ± 13.06

Final HR, bpm

160.47 ± 20.59

162.91 ± 17.72

Initial SpO2,%

97.88 ± 0.99

97.99 ± 1.03

Final SpO2,%

93.12 ± 1.76

97.08 ± 1.46

0.0001

∆ SpO2

4.77 ± 1.15

0.91 ± 1.27

0.0001

ISWD

956.50 ± 127.10

958.80 ± 151.80

Maximal HR, bpm

181.53 ± 13.96

185.88 ± 12.13

Maximal HR, %

88.29 ± 9.34

87.64 ± 9.62

Recovery HR, %

91.24 ± 15.16

92.24 ± 17.93

Recovery SpO2, %

97.29 ± 0.99

97.70 ± 1.07

OD: oxygen desaturation; BMI: body mass index; ISWD: incremental shuttle walk distance; LLN: lower limit of normality; and NS: not significant. aValues expressed as mean ± SD.

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Oxygen desaturation in healthy subjects undergoing the incremental shuttle walk test

Table 2 - Proportions of individuals who reached more than 85% or 85% or less of the predicted maximal HR in the two groups.a Maximal HR OD No OD > 85% 12 (71) 47 (71) ≤ 85% 5 (29) 19 (29) Total 17 (100) 66 (100) OD: oxygen desaturation. aValues expressed as n (%).

A ≥ 4% decrease in oxygen saturation was used in order to divide the study population into two groups. The Anderson-Darling test was applied to the measured variables and the demographic characteristics of the two groups to determine their distribution. Variables with normal distribution were analyzed with the Student’s t-test. Variables with non-normal distribution were analyzed with the Wilcoxon test. Categorical data were compared by the chi-square test or Fisher’s exact test. The statistical analysis was performed with the SAS software, version 8 (SAS Institute, Inc., Cary, NC, USA). Differences were considered significant at p < 0.05.

Results Eighty-three individuals who attended a fitness center in the city of Campinas, Brazil, were invited and agreed to participate in the study. Of those, 55 were male and 28 were female. Only 1 was a smoker. The mean age was 35.05 ± 12.53 years, the median being 32 years. The mean body mass index (BMI) was 24.30 ± 3.47 kg/m2, the median being 24.5 kg/m2. The mean resting HR was 75.12 ± 12.48 bpm, the median being 73 bpm. The mean pre-ISWT SpO2 was 97.96 ± 1.02%, the median being 98%. The mean FEV1 was 3.75 ± 0.81 L, the median being 3.65 L. The mean FEV6 was 4.45 ± 0.87 L, the median being 4.38 L. The mean FEV1/FEV6 ratio was 0.83 ± 0.08, the median being 0.82. In all enrolled subjects, measured FEV6 was above the lower limit of the predicted FVC (as determined by the equations devised for the Brazilian population), and all subjects had a FEV1/FEV6 ratio ≥ 0.8. These findings allow the assumption that none of the participants had restrictive or obstructive lung disease (Table 1). The mean ISWD was 958.30 ± 146.32 m, the median being 1,020 m. The mean postISWT HR was 162.41 ± 18.24 bpm, the median being 166 bpm. The mean post-ISWT SpO2 was 96.27 ± 2.21%. In 11 subjects, post-ISWT oxygen saturation values were higher than pre-ISWT

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oxygen saturation values. In 17 subjects, oxygen saturation had decreased by ≥ 4% by the end of the test. In 2 subjects, SpO2 was < 92% (Table 2). The study population was divided into two groups on the basis of the presence of a postISWT oxygen desaturation ≥ 4%. No differences were found between the two groups regarding age, gender, FEV1, FEV6, FEV1/FEV6, initial oxygen saturation (pre-ISWT SpO2), ISWD, pre-ISWT HR, post-ISWT HR, or percentage of maximal HR (Table 1). The BMI was significantly higher in those who developed oxygen desaturation (p = 0.01), and post-ISWT SpO2 was significantly different between the two groups (p < 0.0001).

Discussion In 66 subjects, post-ISWT oxygen saturation values were quite similar to pre-ISWT oxygen saturation values, a finding that was expected because of the intensity of the exercise performed. In 11 subjects, post-ISWT SpO2 values were higher than pre-ISWT SpO2 values. This finding is not unusual, given that physical activity improves ventilation and alveolar recruitment. However, 17 (20.7%) of the 83 individuals in the study sample showed a significant drop in oxygen saturation during the ISWT (Δsat ≥ 4%). This was an unexpected finding, and there is little information in the literature regarding what happens with oxygen saturation after the ISWT in healthy subjects. Exercise-induced hypoxemia in athletes is arbitrarily defined as a decrease in PaO2 of approximately 7.5 mmHg,(7) an SaO2 below 95%, or both; extreme cases will show an SaO2 of less than 88%.(9) Oxygen uptake increases during exercise in order to meet the needs imposed by an increased metabolic rate and correlate with work intensity until all subjects achieve maximal oxygen uptake. (10) Each step of oxygen transport from ambient air to the cells can limit whole-body oxygen uptake, and circulation has been considered the most important factor limiting maximal oxygen uptake during large muscle mass exercise. A decrease in PaO2 and SaO2 is quite common during maximal ergometer rowing.(11) In such subjects, cardiac output can exceed 30 L/min; under such circumstances, the ability to renew alveolar air and maintain high oxygen partial pressures, the diffusion resistance to oxygen at the alveolar-capillary membrane, the reduction in red blood cell transit time in the pulmonary capillary, J Bras Pneumol. 2013;39(4):440-446

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Seixas DM, Seixas DMT, Pereira MC, Moreira MM, Paschoal IA

and the increased probability of ventilation/ perfusion mismatch are critically important to oxygen uptake.(12) The prevalence of exercise-induced hypoxemia seems to be as high as 50%.(13) Exercise intensity determines the degree of hypoxemia.(14) Oxygen desaturation is also more pronounced during whole-body exercise, such as rowing or running, than during leg exercise, and leg exercise is more capable of inducing hypoxemia than is arm exercise. (14) This suggests that the amount of muscle mass involved in the exercise influences the development of oxygen desaturation. In 1984, Dempsey et al.(15) studied the incidence of exercise-induced arterial hypoxemia in 16 highly trained healthy runners who were capable of achieving and sustaining very high metabolic rates, including a maximal oxygen uptake of 72 Âą 2 mL/kg. Arterial blood gases and acid-base status were determined at each load of a progressive short-term exercise test and repeatedly determined during constant-load treadmill running. Three types of response were encountered and were quite reproducible within subjects: four runners maintained PaO2 within 10 mmHg of resting values; another four showed a decrease of 10-15 mmHg in PaO2; and the remaining eight runners showed remarkably decreased PaO2. The decrease in PaO2 ranged from 21 mmHg to 35 mmHg, PaO2 having decreased to less than 75 mmHg in all cases and to less than 60 mmHg in two cases. During constant-load exercise, PaO2 was often maintained during the initial 30 s, when hyperventilation was greatest; subsequently, hypoxemia occurred, the severity of hypoxemia having either remained the same or worsened over the ensuing 3-4 min in most of the cases. The most severe hypoxemia during heavy exercise was associated with an (estimated) alveolar oxygen tension to a (measured) PaO2 difference in excess of 40 mmHg. The analysis of all of the variables measured during the investigation led the authors to hypothesize that the observed hypoxemia was attributable to a diffusion limitation secondary to very short red cell transit times in at least a portion of the pulmonary circulation; such short transit times can occur at high metabolic rates. Tidal breathing during heavy exercise can frequently exceed the maximal flow-volume curve, and hyperventilation can be limited by the mechanical load on the chest wall secondary to increased J Bras Pneumol. 2013;39(4):440-446

pulmonary impedance, a situation that can also impair the renewal of alveolar air. Although it has been described as an incremental field walking test that produces a symptomlimited maximal performance, the ISWT cannot be compared with the maximal exercise tests cited above. Nevertheless, 17 healthy subjects showed oxygen desaturation after the ISWT in the present study. The only significant difference between the individuals who developed oxygen desaturation and those who did not was that the BMI was higher in the former. This finding is consistent with the hypothesis that the lungs, during physical activities that cause the HR to get closest to the maximal HR expected for a given subject, are unable to arterialize the fast flowing blood, especially in those subjects whose needs are amplified because of a higher body mass. Although Durand et al.(16) found no differences in height, weight, or lung volume between athletes who developed oxygen desaturation and those who did not, it can be argued that the proportions of those variables are more important than their absolute values. Our findings and the data from the literature lead to a worrisome possibility: oxygen desaturation during aerobic activity is probably more common than previously thought and can pose a threat to high-performance athletes that has been systematically overlooked. Although the occurrence of oxygen desaturation is acknowledged in studies that date back to the second half of the last century, none of those studies elaborated on the potential harmful effects of such periods of intermittent hypoxemia. We are unaware of any evaluation protocol for high-performance aerobic training that includes the determination of exercise-induced oxygen desaturation. Given that sudden death is relatively common in athletes, screening for oxygen desaturation seems justified. Sudden cardiac death (SCD) is considered the leading cause of death in young athletes. The true incidence of SCD is unknown and highly underestimated. The studies reporting the highest incidence estimated that up to 110 deaths occur each year in young athletes, which is equivalent to 1 death every 3 days in the United States. (17) The available evidence points to a structural cardiac abnormality as the underlying cause of SCD. Hypertrophic cardiomyopathy and coronary artery anomalies account for approximately 25% and 14%, respectively, of all SCDs in the

Oxygen desaturation in healthy subjects undergoing the incremental shuttle walk test

United States.(18) Arrhythmogenic right ventricular cardiomyopathy/dysplasia is a cardiac disease characterized by myocardial necrosis followed by fibrofatty replacement. These altered myocardial areas constitute the anatomical substrate for reentry circuits that propitiate the onset of ventricular arrhythmias.(19) This last condition can be particularly significant in the context of the present study. Oxygen desaturation during intense physical activity can cause repeated episodes of hypoxic pulmonary vascular constriction and pulmonary hypertension. The walls of the right ventricle can suffer during these episodes, to the point of myocardial necrosis, fibrofatty replacement being the expected consequence of this kind of stress. Another common cause of SCD is Brugada syndrome,(20) which is characterized by an ST-segment elevation in the right precordial electrocardiogram leads followed by a negative T wave. The worldwide prevalence of Brugada syndrome is estimated at 1-5 per 10,000 population, although it is higher in Southeast Asia.(21) Brugada syndrome is traditionally thought of as a primary electrical cardiac disease arising in myocardium that is otherwise structurally normal. However, magnetic resonance imaging, positron emission tomography, and pathological evaluation of biopsy specimens have identified structural abnormalities in many patients with a diagnosis of Brugada syndrome, including fibrofatty replacement of the right ventricular free wall and fibrotic disruption of the right bundle branch. It is established in the literature that Brugada syndrome is the result of an autosomal dominant mutation in the SCN5A gene on chromosome 3, resulting in a loss of function sodium channel abnormality.(22) It has become increasingly clear that ion channel gene expression is highly dynamic and can respond to many environmental stimuli. (23) Hypoxemia is possibly one of these stimuli. Therefore, a genetic predisposition to cardiac arrhythmia does not preclude the superimposition of hypoxemia causing the sudden deaths of young people or athletes. The data in the present study and the accumulated knowledge regarding oxygen desaturation during physical activity raise the hypothesis that hypoxemia during exercise can be dangerous and suggest that it is advisable to include a screening test for oxygen desaturation in the evaluation protocols for endurance athletes. Further studies are needed in order to explore this hypothesis.

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In conclusion, because of the possibility of oxygen desaturation in healthy individuals undergoing the ISWT, the use of the ISWT to predict the presence of subtle respiratory abnormalities undetected by submaximal tests such as the 6MWT can be misleading. The finding that oxygen desaturation is common in healthy subjects undergoing the ISWT adds to the knowledge that oxygen desaturation during intense physical activity is quite common and can have deleterious effects.

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11. Nielsen HB, Madsen P, Svendsen LB, Roach RC, Secher NH. The influence of PaO2, pH and SaO2 on maximal oxygen uptake. Acta Physiol Scand. 1998;164(1):89-7. http://dx.doi. org/10.1046/j.1365-201X.1998.00405.x PMid:9777029 12. N ielsen HB. pH after competitive rowing: the lower physiological range? Acta Physiol Scand. 1999.;165(1):113-4. http://dx.doi.org/10.1046/j.1365-201x.1999.00485.x PMid:10072104 13. Powers SK, Dodd S, Lawler J, Landry G, Kirtley M, McKnight T, et al. Incidence of exercise induced hypoxemia in elite endurance athletes at sea level. Eur J Appl Physiol Occup Physiol. 1988;58(3):298-302. http://dx.doi.org/10.1007/ BF00417266 PMid:3220070 14. Nielsen HB. Arterial desaturation during exercise in man: implication for O2 uptake and work capacity. Scand J Med Sci Sports. 2003;13(6):339-58. http://dx.doi.org/10.1046/ j.1600-0838.2003.00325.x PMid:14617055 15. D empsey JA, Hanson PG, Henderson KS. Exerciseinduced arterial hypoxaemia in healthy human subjects at sea level. J Physiol. 1984;355:161-75. PMid:6436475 PMCid:PMC1193484 16. Durand F, Mucci P, PrĂŠfaut C. Evidence for an inadequate hyperventilation inducing arterial hypoxemia at submaximal exercise in all highly trained endurance athletes. Med Sci Sports Exerc. 2000;32(5):926-32. http://dx.doi. org/10.1097/00005768-200005000-00008 PMid:10795782 17. Casa DJ, Guskiewicz KM, Anderson SA, Courson RW, Heck JF, Jimenez CC, et al. National athletic trainersâ&#x20AC;&#x2122;

association position statement: preventing sudden death in sports. J Athl Train. 2012;47(1):96-118. PMid:22488236 PMCid:PMC3418121 18. Maron BJ. Sudden death in young athletes. N Engl J Med. 2003;349(11):1064-75. http://dx.doi.org/10.1056/ NEJMra022783 PMid:12968091 19. Bauce B, Daliento L, Frigo G, Russo G, Nava A. Pregnancy in women with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Eur J Obstet Gynecol Reprod Biol. 2006;127(2):186-9 http://dx.doi.org/10.1016/j. ejogrb.2005.10.011 PMid:16337730 20. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. 1992;20(6):1391-6. http://dx.doi. org/10.1016/0735-1097(92)90253-J 21. Antzelevitch C. Brugada syndrome. Pacing Clin Electrophysiol. 2006;29(10):1130-59. http://dx.doi.org/10.1111/j.15408159.2006.00507.x PMid:17038146 PMCid:PMC1978482 22. Walker J, Calkins H, Nazarian S. Evaluation of cardiac arrhythmia among athletes. Am J Med. 2010;123(12):107581. http://dx.doi.org/10.1016/j.amjmed.2010.05.008 PMid:20870195 PMCid:PMC3010317 23. Hilber K. Skeletal myocyte plasticity: basis for improved therapeutic potential? Curr Opin Pharmacol. 2008;8(3):32732. http://dx.doi.org/10.1016/j.coph.2008.01.007 PMid:18329336 PMCid:PMC2957812

About the authors Daniel Machado Seixas Professor of Physical Education. State University at Campinas, Campinas, Brazil.

Daniela Miti Tsukumo Seixas

Physician. State University at Campinas, Campinas, Brazil.

Monica Corso Pereira

Physician. State University at Campinas, Campinas, Brazil.

Marcos Mello Moreira

Respiratory Diseases Service. State University at Campinas, Campinas, Brazil.

Ilma Aparecida Paschoal

Associate Professor. State University at Campinas, Campinas, Brazil.

J Bras Pneumol. 2013;39(4):440-446

Original Article Contribution of flow-volume curves to the detection of central airway obstruction* Contribuição da curva de fluxo-volume na detecção de obstrução da via aérea central Liliana Bárbara Perestrelo de Andrade e Raposo, António Bugalho, Maria João Marques Gomes

Abstract Objective: To assess the sensitivity and specificity of flow-volume curves in detecting central airway obstruction (CAO), and to determine whether their quantitative and qualitative criteria are associated with the location, type and degree of obstruction. Methods: Over a four-month period, we consecutively evaluated patients with bronchoscopy indicated. Over a one-week period, all patients underwent clinical evaluation, flow-volume curve, bronchoscopy, and completed a dyspnea scale. Four reviewers, blinded to quantitative and clinical data, and bronchoscopy results, classified the morphology of the curves. A fifth reviewer determined the morphological criteria, as well as the quantitative criteria. Results: We studied 82 patients, 36 (44%) of whom had CAO. The sensitivity and specificity of the flow-volume curves in detecting CAO were, respectively, 88.9% and 91.3% (quantitative criteria) and 30.6% and 93.5% (qualitative criteria). The most prevalent quantitative criteria in our sample were FEF50%/FIF50% ≥ 1, in 83% of patients, and FEV1/PEF ≥ 8 mL . L−1 . min−1, in 36%, both being associated with the type, location, and degree of obstruction (p < 0.05). There was concordance among the reviewers as to the presence of CAO. There is a relationship between the degree of obstruction and dyspnea. Conclusions: The quantitative criteria should always be calculated for flow-volume curves in order to detect CAO, because of the low sensitivity of the qualitative criteria. Both FEF50%/FIF50% ≥ 1 and FEV1/PEF ≥ 8 mL . L−1 . min−1 were associated with the location, type and degree of obstruction. Keywords: Bronchoscopy; Maximal expiratory flow-volume curves; Sensitivity and specificity; Lung neoplasms.

Resumo Objetivo: Verificar a sensibilidade e especificidade das curvas de fluxo-volume na detecção de obstrução da via aérea central (OVAC), e se os critérios qualitativos e quantitativos da curva se relacionam com a localização, o tipo e o grau de obstrução. Métodos: Durante quatro meses foram selecionados, consecutivamente, indivíduos com indicação para broncoscopia. Todos efetuaram avaliação clínica, preenchimento de escala de dispneia, curva de fluxo-volume e broncoscopia num intervalo de uma semana. Quatro revisores classificaram a morfologia da curva sem conhecimento dos dados quantitativos, clínicos e broncoscopicos. Um quinto revisor averiguou os critérios morfológicos e quantitativos. Resultados: Foram incluídos 82 doentes, 36 (44%) com OVAC. A sensibilidade e especificidade da curva de fluxovolume na detecção de OVAC foram, respectivamente, de 88,9% e 91,3% (critérios quantitativos) e de 30,6% e 93,5% (critérios qualitativos). Os critérios quantitativos mais frequentes na amostra foram o FEF50%/FIF50% ≥ 1 em 83% e o VEF1/PFE ≥ 8 mL . L−1 . min−1 em 36% dos doentes, e ambos se relacionaram com o tipo, a localização e o grau de obstrução (p < 0,05). Houve concordância dos revisores quanto à existência ou não de OVAC. Existe relação entre o grau de obstrução e o de dispneia. Conclusões: Os critérios quantitativos devem ser sempre calculados nas curvas de fluxo-volume de forma a detectar OVAC, dado a baixa sensibilidade dos critérios qualitativos. Os critérios FEF50%/ FIF50% ≥ 1 e VEF1/PFE ≥ 8 mL . L−1 . min−1 foram relacionados com a localização, o tipo e o grau de obstrução. Descritores: Broncoscopia; Curvas de fluxo-volume expiratório máximo; Sensibilidade e especificidade; Neoplasias pulmonares.

*Study carried out at the Respiratory Pathophysiology Section, Department of Pulmonology, Northern Lisbon Hospital Center, Lisbon, Portugal. Correspondence to: Liliana Andrade e Raposo. Rua Cesário Verde, 39, 2º Direito, Queijas, 2790-491, Oeiras, Portugal. Tel. 351 21 754-8547. E-mail: liliana.raposo@cardiocvp.net Financial support: None. Submitted: 31 January 2013. Accepted, after review: 16 July 2013.

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Introduction Central airway obstruction (CAO) is a pathological process that leads to airflow limitation at the level of the glottis, subglottis, trachea, and main bronchi. Correct diagnosis and treatment of CAO is an area of interest and concern for health professionals, given that this disease has the potential to cause significant morbidity and mortality. The incidence and prevalence of CAO are unknown; however, the epidemiological characteristics of lung cancer worldwide and the increase in survival resulting from the use of treatments that are more efficient indicate that there is an increasing number of patients with invasion of the proximal airway. Ernst et al.(1) emphasize that 20-30% of patients with lung cancer develop complications related to CAO, whereas Cavaliere et al.(2) estimate that 35% of lung neoplasms cause obstruction of the trachea and main bronchi. Worrisome values have been published by Miyazawa et al., who state that CAO can affect 50% of patients with lung cancer.(3) In Portugal, the number of deaths from malignant tumors of the lung, trachea, and main bronchi increased from 1.5%, in 1981, to 2.28%, in 2008, which allows for speculation about an increase in the incidence of CAO.(4) Given the absence of specificity and the subjectivity of the symptoms that characterize CAO, there is a need to implement diagnostic methods that are efficient in evaluating this disease. Several studies have shown that rigid or flexible bronchoscopy is necessary for the definitive diagnosis of CAO, and that only by using these techniques is it possible to visualize and characterize the nature, degree, and extent of the lesions directly.(5−7) Although these tests make it possible to acquire knowledge about the etiology and the structural nature of CAO, they are invasive and provide no information about the pathophysiological impact. Respiratory function testing, by means of analysis of flowvolume curves obtained from forced maneuvers, is the most appropriate method.(1,8,9) Flow-volume curves are a graphic representation of airflow determined at different volumes, having been used for detecting CAO since the late 1960s. They became a subject of interest when some authors proposed the ratio between forced expiratory and inspiratory flows at 50% of FVC (FEF50%/FIF50%) ≥ 1 as the first quantitative diagnostic criterion for CAO.(10,11) J Bras Pneumol. 2013;39(4):447-454

Subsequently, other criteria were made available, namely FEV1/PEF ≥ 10 mL . L−1 . min−1, FIF50% < 100 mL, and FEV1/FEV0.5 ≥ 1.5.(12,13) In 2005, Pellegrino et al. suggested that FEV1/PEF ≥ 8 mL . L−1 . min−1 can indicate the presence of CAO and recommended performing ancillary tests to confirm the disease.(14) Likewise, there are qualitative or morphological changes obtained from visual analysis of flow-volumes curves that can contribute to the diagnosis of CAO and that include the presence of a plateau on the inspiratory portion of the flow-volume curve (variable extrathoracic obstruction), a plateau on the expiratory portion of the curve (variable intrathoracic obstruction), and a plateau on the inspiratory and expiratory portions (fixed obstruction).(11,12) Most studies on this topic were published many years ago, have methodological flaws, and show a lack of standardization. In addition, recent technological developments, namely those related to the diagnostic methods and the sophistication of the new spirometers, have not produced significant advances in this area. The generalized notion that the presence of the quantitative and qualitative criteria always raises the suspicion of CAO needs confirmation. The primary objective of the present study was to determine whether flow-volume curves are a sensitive and specific method for detecting CAO. As secondary objectives, we sought to establish whether the quantitative criteria are associated with the location, type, and degree of obstruction; whether there is a criterion that best identifies the presence of CAO; whether CAO can be present without affecting the morphology of the curve; and whether there is an association between the degree of obstruction and the degree of dyspnea.

Methods Between November of 2009 and April of 2010, we conducted a prospective, observational, cross-sectional study. The target population consisted of patients for whom bronchoscopy was clinically indicated. The patients were consecutively selected for the sample on the basis of the following inclusion criteria: being clinically indicated for bronchoscopy (with or without suspected CAO); being able to undergo respiratory function tests, especially flow-volume curve measurement; and giving written informed consent. The exclusion criteria included having

Contribution of flow-volume curves to the detection of central airway obstruction

hemodynamic instability; being unable to undergo flow-volume curve measurement, meeting quality control standards; being under 18 years of age; having contraindications to undergoing bronchoscopy or flow-volume curve measurement; and declining to participate in the study. The study was approved by the Health Ethics Committee of the Northern Lisbon Hospital Center, and all of the patients gave written informed consent after the objectives of the study were explained to them, verbally and in writing. Each patient underwent a brief physical examination, and the degree of dyspnea was determined by the Medical Research Council (MRC) 5-point scale.(15) Bronchoscopy was performed with a flexible bronchoscope (BF-P180, Olympus, Tokyo, Japan), which was introduced into the nasal or oral cavity and advanced to the vocal folds and lower airway, with the bronchial tree reached by the device being seen throughout its length, bilaterally. The changes were recorded according to the classification proposed by Freitag et al. to describe the degree, type, and location of obstruction. (16) The flow-volumes curves were measured by a cardiorespiratory technician with a previously calibrated plethysmograph (Vmax 6200; SensorMedics, Yorba Linda, CA, USA). The procedures were performed in accordance with the guidelines proposed by the American Thoracic Society/European Respiratory Society Task Force in 2005.(14) At least three flowvolume curves were measured, two of which were reproducible, meeting the recommended quality control criteria. The best curve was chosen on the basis of the sum of the best FVC and the best FEV1. Inspiratory values were calculated using the curve that obtained the best inspiratory effort, i.e., the greatest FIF50%. For each patient, the maximum interval between functional, clinical, and endoscopic evaluation was one week. The collected data were recorded on a form designed specifically for this study. Subsequently, copies of the morphology of the flow-volume curves (without the quantitative parameters) were made, being compiled randomly. In order to determine agreement between the morphology of the curve and the identification or exclusion of CAO, four reviewers, who were experienced in performing respiratory function

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tests and interpreting their results and who were blinded to the results of the remaining evaluations (quantitative or bronchoscopic), were requested to classify the curves in terms of their morphology by means of a Likert scale: 1) not at all suggestive of CAO; 2) slightly suggestive of CAO; 3) reasonably suggestive of CAO and 4) highly suggestive of CAO. A fifth independent reviewer performed all quantitative and qualitative calculations for the curves. The Statistical Package for the Social Sciences, version 17.0 (SPSS Inc., Chicago, IL, USA), was used for data treatment. The tests used included the nonparametric Mann-Whitney test (for ordinal variables measured in two independent samples) and Pearsonâ&#x20AC;&#x2122;s and Spearmanâ&#x20AC;&#x2122;s correlation coefficients (for nominal and ordinal variables). A binomial regression analysis was performed to determine the sensitivity and specificity of the flow-volume curves, with obstruction confirmed by bronchoscopy being the dependent variable and each of the quantitative and qualitative criteria of the curve being the independent variables. The sample was characterized using descriptive statistics. When applicable, the 95% or 99% confidence intervals of the tests used in this study were calculated.

Results Over a four-month period, we consecutively evaluated 107 patients. Of those, 25 (23%) were excluded because they did not meet the inclusion criteria: 8 (32%) because it was not possible to determine the degree of obstruction; 6 (24%) because their flow-volume curve measurements failed to meet quality standards; 9 (36%) because they had hemodynamic instability; and 2 (8%) because they declined to participate in the study. Of the remaining 82 patients, 36 (44%) had CAO confirmed by bronchoscopy. The patients were divided into two groups: those with and those without CAO. The demographic characteristics are described in Table 1, which shows the lack of statistically significant differences between the two groups in mean age, gender, and smoking history. Regarding the reasons (i.e., diagnoses) motivating bronchoscopy, the group of patients with CAO included 30 (83%) with malignant lung cancer and 6 (17%) with benign disease, whereas the group without CAO included 26 (56.5%) for whom malignant cancer was confirmed and 20 (43.5%) for whom benign disease was confirmed. J Bras Pneumol. 2013;39(4):447-454

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Table 1 - Demographic characteristics of the study sample.a Variable Bronchoscopy showing CAO

Bronchoscopy showing no CAO

(n = 36) Age, years

Male/female gender

64.5

61.7 34 (74)/12 (26)

23 (64)

29 (63)

30 (83.0)/6 (17.0)

26 (56.5)/20 (43.5)

Smoker Smoking history, pack-yearsb Malignant/benign etiology

(n = 46)

23 (64)/13 (36)

CAO: central airway obstruction. Values expressed as n (%), except where otherwise indicated. bValues expressed as mean. a

Table 2 - Sensitivities and specificities of the criteria of flow-volume curves. Criteria Sensitivity, % Specificity, % Positive predictive value, % Quantitative 88.9 91.3 88.9 Qualitative 30.6 93.5 78.6 Quantitative + 93.9 89.8 86.1 Qualitative

Negative predictive value, % 91.3 63.2 95.6

Table 3 - Correlation of the quantitative and Quantitative criteria Upper third of the trachea r p FEF50%/FIF50% ≥ 1 −3.327 0.001

qualitative criteria with the location of obstruction. Middle third Lower third of RMB LMB of the trachea the trachea r p r p r p r p −1.317 0.188 2.309 0.021 −3.781 0.000 2.500 0.012

FEV1/PEF ≥ 10 mL . L−1 . min−1 −0.400 0.690

−0.158 0.874 −7.393 0.000 −2.569 0.010 0.615 0.539

FEV1/PEF ≥ 8 mL · L−1 . min−1

−0.070 0.944

−0.434 0.664 −2.478 0.013 −3.166 0.002 0.629 0.529

FEV1/FEV0.5 ≥ 1.5

−0.927 0.354

−3.559 0.000 −4.051 0.000 −1.811 0.070 1.093 0.274

Qualitative criteria Morphology

0.257

0.020

0.386

0.001 0.490

0.000

FEF50%: forced expiratory flow at 50% of FVC; FIF50%: forced inspiratory flow at 50% of FVC; RMB: right main bronchus; and LMB: left main bronchus.

Table 4 - Association of the quantitative and qualitative criteria with the type of obstruction. Quantitative criteria Intraluminal Extraluminal Mixed r

FEF50%/FIF50% ≥ 1

0.491

0.000

0.361

0.001

−0.019

0.866

FEV1/PEF ≥ 10 mL . L−1 . min−1

0.057

0.608

0.334

0.002

0.259

0.019

FEV1/PEF ≥ 8 mL . L−1 . min−1

0.264

0.016

0.226

0.041

0.134

0.228

FEV1/FEV0.5 ≥ 1.5

0.002

0.983

0.230

0.037

0.101

0.367

0.313

0.004

0.126

0.260

0.137

0.219

Qualitative criteria Morphology

FEF50%: forced expiratory flow at 50% of FVC; and FIF50%: forced inspiratory flow at 50% of FVC.

J Bras Pneumol. 2013;39(4):447-454

Contribution of flow-volume curves to the detection of central airway obstruction

Table 5 - Association of the quantitative and qualitative criteria with the degree of obstruction. Quantitative criteria r p FEF50%/FIF50% ≥ 1 0.673 0.000 FEV1/PEF ≥ 8 mL . L−1 . min−1

0.325

0.003

0.271

0.014

Qualitative criteria Morphology

FEF50%: forced expiratory flow at 50% of FVC; and FIF50%: forced inspiratory flow at 50% of FVC.

The sensitivity and specificity of the flowvolume curves were determined, and, at this point, the quantitative and qualitative criteria were used alone and in combination (Table 2). The combined use of all of the quantitative and qualitative criteria was found to keep specificity high (89.8%), allowing an increase in sensitivity (93.9%). With the purpose of determining whether professionals are attentive to the morphological aspects of flow-volume curves, a frequency count test and Spearman’s correlation were used to assess agreement among the reviewers. The results show that the reviewers agreed among themselves, heading in the same direction with a 95% CI, i.e., they either headed in favor of or against the presence of obstruction. The correlation of the quantitative and qualitative criteria with the location of obstruction was studied with the nonparametric Mann-Whitney test and Pearson’s correlation (Table 3). Statistically significant differences were found among the patients who met the criterion of having an FEF50%/FIF50% ≥ 1 for all locations, except for that in the middle third of the trachea. Both FEV1/PEF ≥ 10 mL . L−1 . min−1 and FEV1/PEF ≥ 8 mL . L−1 . min−1 were present when the obstruction was located in the lower third of the trachea or in the right main bronchus (RMB; p < 0.05). When the obstruction was located in the middle and lower thirds of the trachea, FEV1/FEV0.5 ≥ 1.5 was present (p < 0.01). The qualitative criteria were associated with the obstruction being located in the middle and lower thirds of the trachea and in the RMB (p < 0.01). Pearson’s and Spearman’s correlations were used to investigate a possible association of the quantitative and qualitative criteria with the type of obstruction (Table 4). The results showed that FEF50%/FIF50% ≥ 1 and FEV1/PEF ≥ 8 mL . L−1 . min−1 were associated with intraluminal and extraluminal obstruction. The criterion of having an FEV1/

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PEF ≥ 10 mL . L−1 . min−1 was found in the presence of extraluminal or mixed obstruction (p < 0.05), and FEV1/FEV0.5 ≥ 1.5 was found in the presence of extraluminal obstruction. Regarding the qualitative criteria, morphological changes in the curve were found in the presence of intraluminal obstruction (p < 0.01). Regarding the correlation of the quantitative and qualitative criteria with the degree of obstruction, Spearman’s correlation was used (Table 5). We found that the two criteria that were most associated with the degree of obstruction were FEF50%/FIF50% ≥ 1 and FEV1/PEF ≥ 8 mL . L−1 . min−1. For the quantitative and qualitative (morphological) criteria, this correlation was positive, i.e., a higher degree of obstruction translated to an increased likelihood of finding the aforementioned morphological changes and quantitative criteria. Spearman’s correlation was used to assess the presence of dyspnea and the location of obstruction. The presence of dyspnea was found to correlate with the obstruction being located in the upper third of the trachea (p < 0.05), as well as with the degree of obstruction (p < 0.05), this correlation being positive, i.e., a higher degree of obstruction translated to a higher patientreported degree of dyspnea.

Discussion The present study demonstrated that the quantitative criteria of flow-volume curves have high sensitivity and high specificity in detecting CAO, and that the morphological criteria have low sensitivity but high specificity. These data underscore the need for careful inspection of the morphology of the curves, although the need for a quantitative evaluation of the values for all curves is mandatory. The evaluation and treatment of patients with CAO require in-depth knowledge of its etiology, physiology, diagnosis, and treatment options. The study of each individual should include multiple aspects, chief among which are the clinical component (signs and symptoms), the pathophysiological impact (respiratory function), and imaging studies (chest CT and techniques for airway endoscopy). The compilation of such data, together with etiology, is an important factor in establishing prognosis, determining the need for treatment, or planning a future therapeutic intervention. Regarding etiology, J Bras Pneumol. 2013;39(4):447-454

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the study population included patients with CAO due to benign stenosis, in most cases following intubation, and due to malignant stenosis, in the context of tumor invasion of the proximal airway, which confirms the high prevalence of these diseases.(1,2) From a pathophysiological standpoint, the literature reports that, when CAO is mild, there can be little or no reduction in airflow, with the patient remaining asymptomatic at rest or dyspneic on exertion, and that, in the presence of marked obstruction of the trachea, symptoms occur at rest.(1,5,9) Likewise, our results confirm an association between the degree of dyspnea and that of obstruction. In addition, we found that there is an association between any given degree of dyspnea, as measured by the MRC scale, and the presence of obstruction in the upper third of the trachea. A factor of great importance is that this symptom is common to many diseases of the cardiorespiratory system, which is why the hypothesis of CAO is not often raised. The request of flow-volume curves is common in these patients, and our study shows the presence of CAO with no qualitative changes in the curve. We can speculate that this result is due to the number of smokers included in the group of patients with CAO. A significant smoking history can translate to underlying chronic obstructive pulmonary disease, which is likely to cause changes in the morphology of flow-volume curves, and this is consistent with the international literature.(1,16) Quantitative calculations, performed systematically, would make it possible to increase the diagnostic yield for CAO. There was good agreement among the individuals who reviewed the morphology of the flow-volume curves as to the presence or absence of CAO, which demonstrates that they were sensitized to the presence of morphological changes that could lead to the identification of CAO. These results are in line with those of Watson et al., who used a similar methodology to detect morphological changes in the flowvolume curve that were consistent with vocal cord dysfunction.(17) Recently, Sterner et al. evaluated 2,662 flow-volume curves in order to determine whether the changes of the inspiratory phase would be consistent with the presence of CAO.(18) In only 50% of the patients was the presence of CAO confirmed. Once again, this draws attention to the need to meet the J Bras Pneumol. 2013;39(4):447-454

quality criteria by means of the quantitative determination for all flow-volume curves. Although the qualitative criteria were identified nearly 40 years ago, we found only two other studies conducted in order to assess the sensitivity of flow-volume curves in detecting CAO: that of Miller et al.(19) and that of Modrykamien et al.(20) The first study reports sensitivity values of 100% and specificity values of 78% for the qualitative criteria. The difference in the methodology used, namely the study population (100% of patients with goiter and extrinsic compression), could explain the observed difference from our results, because our patients mostly had intraluminal disease of malignant origin. The second study demonstrates that the qualitative criteria have a sensitivity of 5.5% and a specificity of 93.6%. These results are in line with those found in our study. The methodological similarity shared by the two studies, namely the characteristics of the study population, may have led to this closeness of results. When the morphological changes were associated with the location of obstruction, the results indicate a correlation of the quantitative criteria with obstruction in the lower two-thirds of the trachea and in the RMB. These data are in line with those of a study by Hira & Sing,(21) who found morphological changes in the curve that were associated with obstruction at the level of the trachea. Regarding the association with the type of obstruction, it was only possible to find it in the presence of intraluminal obstruction. Most patients with CAO (75%) had this type of obstruction, and, finding no studies in the literature that support these results, one can infer that, because of the small number of patients with this type of changes in our sample, other associations were not found. Our results showed that FEF50%/FIF50% â&#x2030;Ľ 1 was the most common quantitative criterion in patients with CAO (in 83%), similarly to what was published in the studies of Miller & Hyatt,(10) of Yernault et al.,(11) and also of Das et al.,(22) who found this criterion in 86.5% of their sample. In addition, this criterion was found to be associated with all locations of CAO, except for that in the middle third of the trachea. The study of Rotman et al.(13) and that of Hira & Sing(21) were similar, associating this criterion with the presence of extrathoracic obstruction.

Contribution of flow-volume curves to the detection of central airway obstruction

The second most prevalent criterion in this study was FEV1/PEF ≥ 8 mL . L−1 . min−1 (in 36% of our sample). Previous studies suggest that this criterion is extremely important in detecting CAO, as in the study of Miller et al.,(21) who found a specificity of 94% and a specificity of 64% in patients with CAO due to goiter. Similar results were also found by Brooks & Fairfax,(23) who identified the presence of this criterion in a study presenting three cases of patients with CAO confirmed by flexible bronchoscopy. Similarly to the previous criterion, FEV1/PEF ≥ 8 mL . L−1 . min−1 was associated with CAO in the lower third of the trachea or in the RMB, as well as with intraluminal and extraluminal obstruction. Once again, we emphasize that our results are original, given that there are no other studies in the scientific literature that have sought to answer this question. We underscore the need for future studies on this topic. Some of our questions of investigation could not be compared with those of previous studies because there are no such studies. It is possible that the methodology of the present study, namely the sample size, which did not allow us to assess a significant number of patients with each degree of obstruction and each location of obstruction, may have contributed to our results. In the future, we suggest a study involving a larger sample size in order to form significant groups of patients with CAO in different locations. The present study showed that flow-volume curves contribute significantly to the detection of CAO, and that these curves can lead to a more rapid diagnosis, translating to economic benefits and predominantly to benefits in patient quality of life.

References 1. Ernst A, Feller-Kopman D, Becker HD, Mehta AC. Central airway obstruction. Am J Resp Crit Care Med. 2004;169(12):1278-97. http://dx.doi.org/10.1164/ rccm.200210-1181SO PMid:15187010 2. Cavaliere S, Venuta F, Foccoli P, Toninelli C, La Face B. Endoscopic treatment of malignant airway obstruction in 2,008 patients. Chest. 1996; 12;110(6):1536-42. 3. Miyazawa T, Miyazu Y, Iwamoto Y, Ishida A, Kanoh K, Sumiyoshi H, et al. Stenting at the flow-limiting segment in tracheobronchial stenosis due to lung cancer. Am J Respir Crit Care Med. 2004;169(10):1096-102. PMid:15132959 4. Oliveira, I. Mortalidade: Compressão, Deslocamento e Causas de Morte. Rev Estudos Demográficos. 2008;48(1):35-76. 5. Jeon K, Kim H, Yu CM, Koh WJ, Suh GY, Chung MP, et al. Rigid bronchoscopic intervention in patients

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with respiratory failure caused by malignant central airway obstruction. J Thorac Oncol. 2006;1(4):319-23. http://dx.doi.org/10.1097/01243894-200605000-00009 PMid:17409877 6. Ernst A, Silvestri GA, Johnstone D; American College of Chest Physicians. Interventional pulmonary procedures: Guidelines from the American College of Chest Physicians. Chest. 2003;123(5):1693-717. http://dx.doi.org/10.1378/ chest.123.5.1693 7. Asimakopoulos G, Beeson J, Evans J, Maiwand MO. Cryosurgery for malignant endobronchial tumors: analysis of outcome. Chest. 2005;127(6):2007-14. http://dx.doi. org/10.1378/chest.127.6.2007 PMid:15947313 8. Kvale PA, Selecky PA, Prakash UB; American College of Chest Physicians. Palliative care in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):368S-403S. 9. Herzog H, Keller R, Allgöwer M. Special methods of diagnosing and treating obstructive diseases of the central airways. Chest. 1971;60(1):49-67. http://dx.doi. org/10.1378/chest.60.1.49 PMid:5571274 10. Miller RD, Hyatt RE. Obstructing lesions of larynx and trachea: clinical and physiologic characteristics. Mayo Clin Proc. 1969;44(3):145-61. PMid:5776050 11. Yernault JC, Englert M, Sergysels R, De Coster A. Upper airway stenosis: a physiologic study. Am Rev Respir Dis. 1973;108(4):996-1000. PMid:4741896 12. Empey DW. Assessment of upper airway obstruction. Br Med J. 1972;3(5825):503-5. http://dx.doi.org/10.1136/ bmj.3.5825.503 PMid:5069620 PMCid:PMC1785761 13. Rotman HH, Liss HP, Weg JG. Diagnosis of upper airway obstruction by pulmonary function testing. Chest. 1975;68(6):796-9. http://dx.doi.org/10.1378/ chest.68.6.796 PMid:1192859 14. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26(5):948-68. http://dx.doi. org/10.1183/09031936.05.00035205 PMid:16264058 15. Nouraei SA, Nouraei SM, Randhawa PS, Butler CR, Magill JC, Howard DJ, et al. Sensitivity and responsiveness of de Medical Research Council dyspnoea scale to the presence and treatment of adult laryngotracheal stenosis. Clin Otolaryngol. 2008;33(6):575-80 http://dx.doi. org/10.1111/j.1749-4486.2008.01832.x PMid:19126132 16. Freitag L, Ernst A, Unger M, Kovitz K, Marquette CH. A proposed classification system of central airway stenosis. Eur Respir J. 2007;30(1):7-12. http://dx.doi. org/10.1183/09031936.00132804 PMid:17392320 17. Watson MA, King CS, Holley AB, Greenburg DL, Mikita JA. Clinical and lung-function variables associated with vocal cord dysfunction. Respir Care. 2009;54(4):467-73. PMid:19327181 18. Sterner JB, Morris MJ, Sill JM, Hayes JA. Inspiratory flow-volume curve evaluation for detecting upper airway disease. Respir Care. 2009;54(4):461-6. PMid:19327180 19. Miller MR, Pincock AC, Oates GD, Wilkinson R, Skene-Smith H. Upper airway obstruction due to goitre: detection, prevalence and results of surgical management. Q J Med. 1990;74(274):177-88. PMid:2345786 20. Modrykamien AM, Gudavalli R, McCarthy K, Liu X, Stoller JK. Detection of upper airway obstruction with spirometry results and the flow-volume loop: a comparison of quantitative and visual inspection criteria. Respir Care. 2009;54(4):474-9. PMid:19327182

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21. Hira HS, Singh H. Assessment of upper airway obstruction by pulmonary function testing. J Assoc Physicians India. 1994;42(7):531-4. PMid:7868521 22. Das AK, Davanzo LD, Poiani GJ, Zazzali PG, Scardella AT, Warnock ML et al. Variable extrathoracic airflow obstruction and chronic laryngotracheitis in Gulf War

veterans. Chest. 1999;115(1):97-101. http://dx.doi. org/10.1378/chest.115.1.97 PMid:9925068 23. Brookes GB, Fairfax AJ. Chronic upper airway obstruction: value of flow volume loop examination in assessment and management. J R Soc Med. 1982;75(6):425-34. PMid:7086791 PMCid:PMC1437964

About the authors Liliana Bárbara Perestrelo de Andrade e Raposo

Cardiorespiratory Diseases Technician. Respiratory Pathophysiology Section, Department of Pulmonology, Northern Lisbon Hospital Center and Portuguese Red Cross School of Health, Lisbon, Portugal.

António Bugalho

Pulmonologist and Coordinator. Interventional Pulmonology Section, Beatriz Ângelo Hospital, Loures, Portugal; and Centro de Estudo de Doenças Crônicas – CEDOC, Center for the Study of Chronic Diseases – Universidade Nova de Lisboa School of Medical Sciences, Lisbon, Portugal.

Maria João Marques Gomes

PhD in Pulmonology. Universidade Nova de Lisboa School of Medical Sciences, Lisbon, Portugal.

J Bras Pneumol. 2013;39(4):447-454

Original Article Lung function in post-poliomyelitis syndrome: a cross-sectional study* Função pulmonar em pessoas com síndrome pós-poliomielite: um estudo transversal

Abstract Objective: To compare lung function between patients with post-poliomyelitis syndrome and those with sequelae of paralytic poliomyelitis (without any signs or symptoms of post-poliomyelitis syndrome), as well as between patients with post-poliomyelitis syndrome and healthy controls. Methods: Twenty-nine male participants were assigned to one of three groups: control; poliomyelitis (comprising patients who had had paralytic poliomyelitis but had not developed post-poliomyelitis syndrome); and post-poliomyelitis syndrome. Volunteers underwent lung function measurements (spirometry and respiratory muscle strength assessment). Results: The results of the spirometric assessment revealed no significant differences among the groups except for an approximately 27% lower mean maximal voluntary ventilation in the post-poliomyelitis syndrome group when compared with the control group (p = 0.0127). Nevertheless, the maximal voluntary ventilation values for the post-poliomyelitis group were compared with those for the Brazilian population and were found to be normal. No significant differences were observed in respiratory muscle strength among the groups. Conclusions: With the exception of lower maximal voluntary ventilation, there was no significant lung function impairment in outpatients diagnosed with post-poliomyelitis syndrome when compared with healthy subjects and with patients with sequelae of poliomyelitis without post-poliomyelitis syndrome. This is an important clinical finding because it shows that patients with post-poliomyelitis syndrome can have preserved lung function. Keywords: Respiratory function tests; Postpoliomyelitis syndrome; Muscle strength.

Resumo Objetivo: Comparar a função pulmonar de pacientes com síndrome pós-poliomielite à de pacientes com sequelas de poliomielite paralítica (sem quaisquer sinais ou sintomas de síndrome pós-poliomielite) e à de sujeitos saudáveis. Métodos: Vinte e nove sujeitos do sexo masculino foram divididos em três grupos: controle, poliomielite (pacientes que sofreram de poliomielite paralítica, mas que não apresentaram síndrome pós-poliomielite) e síndrome pós-poliomielite. Os voluntários foram submetidos a avaliações da função pulmonar (espirometria e avaliação da força muscular respiratória). Resultados: Os resultados da espirometria não revelaram diferenças significantes entre os grupos, à exceção da ventilação voluntária máxima, cuja média no grupo síndrome pós-poliomielite foi aproximadamente 27% mais baixa que no grupo controle (p = 0,0127). No entanto, os valores de ventilação voluntária máxima observados no grupo pós-poliomielite foram comparados aos da população brasileira e se apresentaram dentro da faixa normal. Não foram observadas diferenças significantes entre os grupos no tocante à força muscular respiratória. Conclusões: À exceção da ventilação voluntária máxima mais baixa, não houve comprometimento significante da função pulmonar em pacientes ambulatoriais com diagnóstico de síndrome pós-poliomielite quando comparados a pacientes com sequelas de poliomielite, mas sem a síndrome pós-poliomielite e a sujeitos saudáveis. Trata-se de um importante achado clínico, pois mostra que pacientes com síndrome pós-poliomielite podem apresentar função pulmonar preservada. Descritores: Testes de Função Respiratória; Síndrome pós-poliomielite; Força muscular.

*Study carried out at the Federal University of São Paulo, São Paulo, Brazil. Correspondence to: Claudio Andre Barbosa de Lira. Setor de Fisiologia Humana e do Exercício, Universidade Federal de Goiás, Campus Jataí, Unidade Jatobá, Rodovia BR364, km 192, no. 3800, Parque Industrial, CEP 75801-615 Jataí, GO, Brasil. Tel. 55 64 3606-8301. E-mail: andre.claudio@gmail.com Financial support: This study was partially supported by Laboratórios Baldacci S/A. Claudio A. B. de Lira is the recipient of a fellowship from the Brazilian Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education). Submitted: 11 November 2012. Accepted, after review: 22 July 2013.

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de Lira CA, Minozzo, FC, Sousa, BS, Vancini, RL, Andrade, MS, Quadros, AAJ, Oliveira, ASB, da Silva, AC

Introduction

Methods

Paralytic poliomyelitis, an acute disease caused by poliovirus, has been part of human history for thousands of years. In the mid-twentieth century, after the introduction of an effective vaccination program, the number of new cases dramatically dropped. Wild-type poliovirus was eliminated from the western hemisphere, and the number of new cases continues to drop in the rest of the world.(1) Some of the patients with a history of poliomyelitis report late-onset neuromuscular symptoms and a decline in functional capacity. These late symptoms are referred to as postpoliomyelitis syndrome (PPS). The syndrome is characterized by new and increased muscle weakness, fatigue, muscle pain, joint pain, muscle cramps, cold intolerance, and lung problems.(2,3) Although PPS is a common neurological disorder affecting a large proportion of those who have recovered from paralytic poliomyelitis, the causes of PPS remain unclear. The most widely accepted hypothesis, proposed by Wiechers and Hubbell,(4) attributes the symptoms to a distal degeneration of axons from the greatly enlarged motor units that develop during recovery from acute paralytic poliomyelitis. Patients with PPS have reported respiratory symptoms that include exertional dyspnea and reduced physical endurance.(5-7) Respiratory problems can result from impairment of medullary centers, impairment of cranial nerves, impairment of respiratory muscles, or any combination of the three.(8) The World Health Organization estimates that there are 20 million polio survivors,(9) and new cases of poliomyelitis have been reported in certain African and Asian countries. Therefore, knowledge of lung function in such patients is important in clinical practice in order to provide adequate information regarding their functional status. The primary objective of the present study was to determine whether individuals with PPS can present with lung function abnormalities. A secondary objective was to compare lung function between patients with PPS and those with sequelae of paralytic poliomyelitis (without any signs or symptoms of PPS), as well as between patients with PPS and healthy controls. Given that patients with PPS commonly experience a significant loss of muscle strength, we hypothesized that they would also show drastic changes in lung function.

The present study had a cross-sectional design. Twenty-nine male participants were assigned to one of three groups: control (n = 10; mean age, 49.8 ± 2.3 years; body mass, 88.4 ± 5.0 kg; and height, 175.4 ± 1.6 cm); poliomyelitis, composed of patients who had had paralytic poliomyelitis but had not developed PPS (n = 9; mean age, 47.9 ± 2.1 years; body mass, 81.9 ± 5.1 kg; and height, 169.0 ± 2.8 cm); and PPS, composed of patients who had been diagnosed with PPS (n = 10; mean age, 50.2 ± 2.3 years; body mass, 71.1 ± 4.5 kg; and height, 162.9 ± 2.3 cm). Age, body mass, and height were expressed as mean ± SE. In the poliomyelitis and PPS groups, height was measured with a flexible tape measure, with the patients in the supine position. There were no significant differences among the groups except for lower body mass and height in the PPS group when compared with the control group (p < 0.05). The diagnosis of PPS was based on the method developed by Borg,(10) all patients having been diagnosed by the same neurologist, who has extensive experience in treating patients with PPS. The patients in the poliomyelitis and PPS groups were recruited from among those treated at the Post-Polio Clinic of the Neuromuscular Diseases Section of the Federal University of São Paulo, located in the city of São Paulo, located in the city of São Paulo, Brazil. The clinical profiles of the patients with poliomyelitis sequelae are presented in Table 1. Healthy controls were recruited from among members of the university community by advertisements placed on the website of the Federal University of São Paulo, located in the city of São Paulo, Brazil, and in local newspapers. All individuals were disease-free except for the residual effects of poliomyelitis, and none were receiving respiratory care. In addition, none of the patients in the poliomyelitis group and only one of those in the PPS group had respiratory complaints. The participants were fully informed of any risks and discomfort associated with the experiments before giving their written consent to participate in the present study, which was approved by the Research Ethics Committee of the Federal University of São Paulo. All procedures were in accordance with the principles of the Declaration of Helsinki.

J Bras Pneumol. 2013;39(4):455-460

Lung function in post-poliomyelitis syndrome: a cross-sectional study

We assessed lung function by spirometry and by assessing respiratory muscle strength. All lung function tests were performed with the subjects sitting upright. A trained laboratory technician demonstrated each respiratory maneuver to each subject before initiating the test. Spirometry was performed using a K4b2 spirometer (Cosmed, Rome, Italy) attached to a computer. Our interpretation was based on the American Thoracic Society/European Respiratory Society guidelines.(11) On the day of the test, the volunteers did not undergo any physical exercise. They were instructed to perform 3-5 maximal forced expiratory maneuvers, a 3-min interval being allowed between trials. The outcomes of interest were FVC, FEV1, the FEV1/FVC ratio, PEF, FEF25-75%, and maximal voluntary ventilation (MVV), the highest value for each being used for data analysis. In order to measure MVV, subjects were required to breathe as deeply and rapidly as possible for 12 s. The respiratory volume values were then extrapolated to 1 min. Our spirometer was calibrated at least daily with a 3-L syringe (Hans Rudolf, Inc., Shawnee, KS, USA). All calibrations were within 1% measurement error. All volumes were corrected for body temperature, ambient pressure, and saturation with water vapor. Spirometric variables were compared with reference values for the Brazilian population.(12,13) Respiratory muscle strength was assessed by measuring MIP and MEP with a manometer (GerAr, São Paulo, Brazil), resolution being 1 cmH2O and capacity being 300 cmH2O. A small (< 2 mm) opening close to the mouthpiece was used in order to decrease mouth pressure and prevent patients from using their cheeks to generate pressure. For the measurement of MIP, participants emptied their lungs by blowing as hard as possible and exhaling as much air as possible to RV, subsequently inhaling up to TLC. The highest recorded value was used for analysis. For the measurement of MEP, participants were asked to fill their lungs with as much air as possible up to TLC and then rapidly breathe out. The measurements were repeated with 1-min intervals between trials. The highest pressure of each set of 3 trials was recorded. The obtained values

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were expressed in cmH2O and compared with reference values for the Brazilian population.(13) Regarding statistical analysis, normal distribution and homogeneity of variance were determined by the Kolmogorov-Smirnov test and the Levene test, respectively. The values obtained in the lung function tests were converted to percentages of the predicted values. To that end, the reference values for FVC, FEV1, the FEV1/FVC ratio, PEF, and FEF25-75% were based on those used by Pereira et al. for the Brazilian population,(12) whereas those for MVV, MIP, and MEP were based on values used by Neder et al.(13) The age at onset of acute poliomyelitis and the number of years of functional stability were compared between the poliomyelitis and PPS groups by the Student’s t-test for unpaired samples. Another Student’s t-test for unpaired samples was performed in order to compare the obtained and predicted values for the following respiratory variables: FVC, FEV1, the FEV1/FVC ratio, PEF, FEF25-75%, MVV, MIP, and MEP. Subsequently, a one-way ANOVA was performed in order to detect differences in respiratory variables among the groups. When a significant effect was achieved, Tukey’s post hoc test was performed in order to detect differences among the means. Data are presented as mean ± SE. The significance level was set at 0.05 for all statistical procedures.

Table 1 - Clinical profiles of patients with poliomyelitis sequelae. a Variable Poliomyelitis PPS group group (n = 9)

(n = 10)

Age at onset (years)

1.6 ± 0.4

1.5 ± 0.3

Years of functional stability Years of PPS

40.0 ± 3.0

35.3 ± 3.0

N/A

7.3 ± 1.4

Monoparesis

Diparesis

Triparesis

Quadriparesis

Hemiparesis

Physical sequelae

PPS: post-poliomyelitis syndrome. aValues expressed as mean ± SE.

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de Lira CA, Minozzo, FC, Sousa, BS, Vancini, RL, Andrade, MS, Quadros, AAJ, Oliveira, ASB, da Silva, AC

Table 2 - Spirometric assessment in controls and patients with poliomyelitis sequelae.a Variable CG (n = 10) PG (n = 9) PPSG (n = 10) FVC Obtained (L) 4.75 ± 0.23 4.20 ± 0.16 3.91 ± 0.34 Predicted (L) 4.64 ± 0.14 4.30 ± 0.17 3.89 ± 0.16 % of predicted 102.80 ± 5.28 98.45 ± 4.25 100.70 ± 8.52 FEV1 Obtained (L) 3.81 ± 0.19 3.47 ± 0.15 3.20 ± 0.24 Predicted (L) 3.75 ± 0.12 3.51 ± 0.13 3.15 ± 0.14 % of predicted 101.80 ± 4.27 99.81 ± 4.65 102.30 ± 7.58 FEV1/FVC Obtained (%) 80.72 ± 2.63 82.77 ± 2.36 83.08 ± 2.15 Predicted (%) 80.79 ± 0.45 81.51 ± 0.56 80.80 ± 0.57 % of predicted 99.87 ± 3,06 101.5 ± 2.45 102.8 ± 2.38 FEF25-75% Obtained (L/s) 4.18 ± 0.44 3.93 ± 0.44 3.51 ± 0.28 Predicted (L/s) 3.69 ± 0.18 3.51 ± 0.12 3.17 ± 0.16 % of predicted 112.60 ± 10.03 111.60 ± 11.32 111.90 ± 8.01 PEF Obtained (L/s) 10.17 ± 0.45 10.03 ± 0.48 9.22 ± 0.68 Predicted (L/s) 9.37 ± 0.22 8.87 ± 0.26 8.21 ± 0.26 % of predicted 108.60 ± 4.43 113.00 ± 3.91 112.90 ± 8.47 MVV Obtained (L/min) 168.90 ± 10.00 150.50 ± 10.70 123.50 ± 10.00* Predicted (L/min) 143.40 ± 2.50 146.00 ± 2.50 142.90 ± 2.60 % of predicted 117.40 ± 5.60 103.00 ± 6.90 86.50 ± 6.90* CG: control group; PG: poliomyelitis group; PPSG: post-poliomyelitis syndrome group; and MVV: maximal voluntary ventilation. aData expressed as mean ± SE. *p < 0.05, significantly different from the control group.

Table 3 - Respiratory muscle strength in controls and patients with poliomyelitis sequelae.a Variable CG (n = 10) PG (n = 9) PPSG (n = 10) MIP

MEP

Obtained (cmH2O)

150 ± 14

136 ± 13

118 ± 12

Predicted (cmH2O)

116 ± 2

117 ± 2

115 ± 2

% of predicted

130 ± 12

115 ± 10

103 ± 11

Obtained (cmH2O)

181 ± 17

180 ± 11

146 ± 15

Predicted (cmH2O)

125 ± 2

127 ± 2

125 ± 2

% of predicted

144 ± 13

142 ± 9

118 ± 13

CG: control group; PG: poliomyelitis group; and PPSG: post-poliomyelitis syndrome group. Data expressed as mean ± SE. a

Results

Discussion

No significant differences were observed between the poliomyelitis and PPS groups regarding the age at onset of acute poliomyelitis or the number of years of functional stability (Table 1). The results of the spirometric assessment are shown in Table 2. No significant differences were observed among the groups except for an approximately 27% lower mean MVV in the PPS group when compared with the control group (p = 0.0127). Nevertheless, the MVV values obtained in the PPS group were compared with those for the Brazilian population and were found to be normal. Regarding respiratory muscle strength, no significant differences were observed among the groups (Table 3).

After the implementation of an effective worldwide vaccination program, paralytic poliomyelitis was virtually forgotten by the medical community. However, millions of polio survivors still need special care and clinical assistance. These survivors have complained about new signs and symptoms, which are collectively known as PPS. Because the major polio epidemics occurred in the 1950s in many western countries and in the 1980s in Latin American countries, and considering that late-onset neurological changes typically do not appear until 30-50 years after infection, millions of polio survivors had not experienced problems related to their poliomyelitis sequelae

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Lung function in post-poliomyelitis syndrome: a cross-sectional study

until the late 1970s and early 1980s. People experiencing these symptoms are now receiving attention from the medical community in several parts of the world. In fact, as a result of an initiative led by professionals from the Federal University of S達o Paulo, PPS was included in the International Classification of Diseases. Additionally, new cases of polio have been reported in certain African and Asian countries. Therefore, studies investigating the clinical profile of PPS are important to elucidate the pathological mechanisms and clinical impact of this neuromuscular disease. In the present study, we investigated the lung function of patients with sequelae of paralytic poliomyelitis with and without PPS. Our results showed that there were no significant differences among the groups (control, poliomyelitis, and PPS). To our knowledge, this is the first study to investigate lung function in patients with paralytic poliomyelitis divided into groups of patients with PPS (the PPS group) and without PPS (the poliomyelitis group). Previously, many studies investigating lung function in patients with poliomyelitis sequelae (8,14-18) and other neuromuscular diseases (19) were controversial because of the differences among patients in terms of their characteristics, which are usually dependent on the degree of impairment, the origin of the patients (outpatients having less disease progression), gender, and the presence of respiratory complaints. Our results showed no lung function impairment due to late sequelae of paralytic poliomyelitis. They are in disagreement with those of previous studies evaluating respiratory function in the same types of patients. (8,15,18) However, those studies evaluated patients with a history of poliomyelitis and respiratory problems, in whom lung function was found to be markedly lower. In our study, none of the patients in the poliomyelitis group had any respiratory complaints and only one of those in the PPS group complained of dyspnea on exertion. It is known that MVV is partially dependent on respiratory muscle strength and endurance.(20) In fact, Knobil et al.(17) reported the case of a patient with decreased MVV associated with low MIP. In our study, MVV was significantly lower in the PPS group than in the control group. However, the

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MVV values found in the PPS group were found to be normal after having been compared with those for the Brazilian population. We found no significant differences in respiratory muscle strength (as assessed by MIP and MEP) among the groups. This might explain why the MVV values in our study were not significantly different from the reference values for the Brazilian population. In general, lung function was not affected in the patients with poliomyelitis sequelae investigated in our study, a finding that is in disagreement with those of a previous study.(21) In that study, lung function impairment in those patients was associated with hospitalization, need for mechanical ventilation during the acute stage of the disease, age at disease acquisition (10 years or older), presence of quadriparesis, and time of exposure to the disease. In our study, only one of the individuals in the PPS group and two of those in the poliomyelitis group required hospitalization and respiratory support. In addition, none of the affected individuals had had poliomyelitis at an age older than 10 years (the mean age at disease acquisition being 1.6 in the poliomyelitis group and 1.5 years in PPS group), and only two of the individuals in the poliomyelitis group and three of those in the PPS group had quadriparesis. Lung function impairment has been strongly correlated with dyspnea. (8) In our study, none of the patients in the poliomyelitis group and one of those in the PPS group complained of dyspnea on exertion, having no other respiratory complaints. In conclusion, with the exception of lower MVV, there were no significant differences in lung function between the group of patients with PPS and that of those with poliomyelitis or between the former and healthy controls. This is an important clinical finding because it shows that patients with PPS can have preserved lung function.

Acknowledgments We thank the multidisciplinary team at the Neuromuscular Diseases Section of the Federal University of S達o Paulo Department of Neurology and Neurosurgery for the patient referrals. We also thank all of the individuals who volunteered to participate in the present study. J Bras Pneumol. 2013;39(4):455-460

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References 1. John TJ. The final stages of the global eradication of polio. N Engl J Med. 2000;343(11):806-7. http://dx.doi. org/10.1056/NEJM200009143431111 PMid:10984572 2. Trojan DA, Cashman NR. Post-poliomyelitis syndrome. Muscle Nerve. 2005;31(1):6-19. http://dx.doi.org/10.1002/ mus.20259 PMid:15599928 3. Tiffreau V, Rapin A, Serafi R, Percebois-Macadré L, Supper C, Jolly D, et al. Post-polio syndrome and rehabilitation. Ann Phys Rehabil Med. 2010;53(1):42-50. http://dx.doi. org/10.1016/j.rehab.2009.11.007 PMid:20044320 4. Wiechers DO, Hubbell SL. Late changes in the motor unit after acute poliomyelitis. Muscle Nerve. 1981;4(6):524-8. http://dx.doi.org/10.1002/mus.880040610 PMid:6273721 5. Cosgrove JL, Alexander MA, Kitts EL, Swan BE, Klein MJ, Bayer RE. Late effects of poliomyelitis. Arch Phys Med Rehabil. 1987;68(1):4-7. PMid:3800623 6. Fischer DA. Poliomyelitis: late respiratory complications and management. Orthopedics. 1985;8(7):891-4. PMid:3867866 7. Hamilton EA, Nichols PJ, Tait GB. Late onset of respiratory insufficiency after poliomyelitis. Ann Phys Med. 1970;10(5):223-9. PMid:4392215 8. Dean E, Ross J, Road JD, Courtenay L, Madill KJ. Pulmonary function in individuals with a history of poliomyelitis. Chest. 1991;100(1):118-23. http://dx.doi.org/10.1378/ chest.100.1.118 PMid:2060329 9. Aylward RB, Hull HF, Cochi SL, Sutter RW, Olivé JM, Melgaard B. Disease eradication as a public health strategy: a case study of poliomyelitis eradication. Bull World Health Organ. 2000;78(3):285-97. PMid:10812724 PMCid:PMC2560720 10. Borg K. Post-polio muscle dysfunction 29th ENMC workshop 14-16 October 1994, Naarden, the Netherlands. Neuromuscul Disord. 1996;6(1):75-80. http://dx.doi. org/10.1016/0960-8966(95)00013-5 11. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. http://dx.doi.org/10.118 3/09031936.05.00034805 PMid:16055882

12. Pereira CAC, Barreto SP, Simões JG, Pereira FWL, Gerstler JG, Nakatani J. Valores de referência para espirometria em uma amostra da população brasileira adulta. J Pneumol 1992,18(1):10-22. 13. Neder JA, Andreoni S, Lerario MC, Nery LE. Reference values for lung function tests. II. Maximal respiratory pressures and voluntary ventilation. Braz J Med Biol Res. 1999;32(6):719-27. http://dx.doi.org/10.1590/ S0100-879X1999000600007 PMid:10412550 14. Borg K, Kaijser L. Lung function in patients with prior poliomyelitis. Clin Physiol. 1990;10(2):201-12. http:// dx.doi.org/10.1111/j.1475-097X.1990.tb00254.x 15. Blomstrand A, Bake B. Post-polio lung function. Scand J Rehabil Med. 1992;24(1):43-9. PMid:1604261 16. Stanghelle JK, Festvåg L, Aksnes AK. Pulmonary function and symptom-limited exercise stress testing in subjects with late sequelae of poliomyelitis. Scand J Rehabil Med. 1993;25(3):125-9. PMid:8248763 17. Knobil K, Becker FS, Harper P, Graf LB, Wolf GT, Martinez FJ. Dyspnea in a patient years after severe poliomyelitis. The role of cardiopulmonary exercise testing. Chest. 1994;105(3):777-81. http://dx.doi.org/10.1378/ chest.105.3.777 PMid:8131540 18. Soliman MG, Higgins SE, El-Kabir DR, Davidson AC, Williams AJ, Howard RS. Non-invasive assessment of respiratory muscle strength in patients with previous poliomyelitis. Respir Med. 2005;99(10):1217-22. http:// dx.doi.org/10.1016/j.rmed.2005.02.035 PMid:16140221 19. Paschoal IA, Villalba Wde O, Pereira MC. Chronic respiratory failure in patients with neuromuscular diseases: diagnosis and treatment. J Bras Pneumol. 2007;33(1):81-92. http://dx.doi.org/10.1590/S1806-37132007000100016 PMid:17568873 20. Heliopoulos I, Patlakas G, Vadikolias K, Artemis N, Kleopa KA, Maltezos E, et al. Maximal voluntary ventilation in myasthenia gravis. Muscle Nerve. 2003;27(6):715-9. http://dx.doi.org/10.1002/mus.10378 PMid:12766983 21. Halstead LS, Rossi CD. New problems in old polio patients: results of a survey of 539 polio survivors. Orthopedics. 1985;8(7):845-50. PMid:3867865

About the authors Claudio Andre Barbosa de Lira

Adjunct Professor. Federal University of Goiás at Jataí, Jataí, Brazil.

Fábio Carderelli Minozzo

Postdoctoral Fellow. McGill University, Montreal, Canada.

Bolivar Saldanha Sousa

Physician. Faculdade de Ciências Médicas da Santa Casa de São Paulo and Instituto Israelita de Ensino e Pesquisa Albert Einstein, São Paulo, Brazil.

Rodrigo Luiz Vancini

Adjunct Professor. Federal University of Goiás at Jataí, Jataí, Brazil.

Marília dos Santos Andrade

Adjunct Professor. Department of Physiology, Federal University of São Paulo, São Paulo, Brazil.

Abrahão Augusto Juviniano Quadros

Physiotherapist. Department of Neurology and Neurosurgery, Federal University of São Paulo, São Paulo, Brazil.

Acary Souza Bulle Oliveira

Physician. Department of Neurology and Neurosurgery, Federal University of São Paulo, São Paulo, Brazil.

Antonio Carlos da Silva

Associate Professor. Department of Physiology, Federal University of São Paulo, São Paulo, Brazil.

J Bras Pneumol. 2013;39(4):455-460

Original Article Psychological morbidity as a moderator of intention to quit smoking: a study of smokers and former smokers* Morbidade psicológica como moderador da intenção para deixar de fumar: um estudo com fumantes e ex-fumantes

Maria Fernanda Besteiro Afonso, Maria Graça Pereira Alves

Abstract Objective: To analyze psychological morbidity as a moderator of the relationship between smoking representations and quality of life in smokers and former smokers, as well as to determine which psychological variables discriminate between smokers with and without the intention to quit smoking. Methods: This was a quantitative, correlational cross-sectional study involving a convenience sample of 224 smokers and 169 former smokers. Results: In smokers and former smokers, psychological morbidity had a moderating effect on the relationship between mental/physical quality of life and smoking representations (cognitive representations, emotional representations, and comprehensibility). Smokers with the intention to quit smoking more often presented with low comprehensibility, threatening emotional representations, behavioral beliefs, and perceived behavioral control, as well as with normative/control beliefs, than did those without the intention to quit. Conclusions: The results of this study underscore the importance of the moderating effect exerted by psychological morbidity, as well as that of sociocognitive variables, among smokers who have the intention to quit smoking. Keywords: Smoking/psychology; Smoking cessation; Smoking/prevention & control.

Resumo Objetivo: Analisar a morbidade psicológica como um moderador na relação entre as representações do tabaco e a qualidade de vida em fumantes e ex-fumantes, assim como conhecer as variáveis psicológicas que discriminam os fumantes com e sem intenção para deixar de fumar. Métodos: Estudo quantitativo, correlacional e transversal com uma amostra de conveniência constituída por 224 fumantes e 169 ex-fumantes. Resultados: Verificou-se um efeito moderador da morbidade psicológica na relação entre a qualidade de vida (física e mental) e as representações do tabaco (representações cognitivas e emocionais e compreensão) nos fumantes e nos ex-fumantes. Os fumantes com intenção para deixar de fumar apresentavam menor compreensão, representações emocionais mais ameaçadoras, mais crenças de comportamento, maior controle comportamental percebido e mais crenças normativas/controle do que aqueles sem essa intenção. Conclusões: Os resultados deste estudo enfatizam a importância da morbidade psicológica como moderadora, bem como das variáveis sociocognitivas, junto dos fumantes que querem deixar de fumar. Descritores: Hábito de fumar/psicologia; Abandono do hábito de fumar; Hábito de fumar/prevenção & controle.

*Study carried out at the University of Minho School of Psychology, Braga, Portugal. Correspondence to: Fernanda Afonso. Rua dos Passionistas, 110, 4º Esquerdo, 4520-292, Santa Maria da Feira, Portugal. Tel. 351917400290. E-mail: fernandafonso@gmail.com Financial support: None. Submitted: 29 January 2013. Accepted, after review: 16 May 2013.

J Bras Pneumol. 2013;39(4):461-468

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Introduction The literature on smoking has underscored that tobacco consumption is potentially fatal and that nicotine in particular is highly addictive.(1) Successful smoking cessation requires a structured intervention, this type of intervention being more effective in helping smokers to quit.(2) The literature shows a relationship between psychological morbidity (depression, anxiety, and stress) and the use of substances, including nicotine.(3) It is a relationship between smoking and the presence of symptoms related to depression,(3) anxiety,(4) and stress.(5) In terms of quality of life, the literature shows that smoking is a risk behavior that has a major impact on health.(6) In contrast, not smoking is associated with better physical and mental quality of life.(7) Many smokers do not regard smoking as a health problem and minimize their nicotine dependence; that is, they harbor misconceptions about smoking.(8) According to the literature, the way individuals perceive their health and disease has important implications for their behavior,(9) as is the case with smoking. Smoking representations are categorized into cognitive representations (which evaluate the perceived health effects of smoking, the duration of smoking, control, the effectiveness of smoking cessation treatment, and how smokers identify smoking-related symptoms); emotional representations (which evaluate smokingrelated concerns and how smokers feel emotionally affected); and comprehensibility (i.e., individualsâ&#x20AC;&#x2122; level of understanding of their smoking behavior). Threatening cognitive representations, emotional representations, and comprehensibility indicate an increased perception that smoking is harmful to health and bring into question the quality of life of smokers.(10) Regarding sociocognitive variables, smoking is a behavior in which intention is influenced by the social dimension. Intention is a key aspect of the theory of planned behavior (TPB) and is an important predictor of smoking behavior.(11,12) The TPB(11) developed from the theory of reasoned action, to which the concept of perceived behavioral control was added. The TPB proposes that an individualâ&#x20AC;&#x2122;s intention to engage in a certain behavior is the key determinant of that behavior, because it reflects the individualâ&#x20AC;&#x2122;s level of motivation and readiness to make efforts to engage in the behavior. Therefore, according to the TPB, behavioral intentions are influenced by three aspects: attitudes toward the behavior; subjective norms; and perceived behavioral J Bras Pneumol. 2013;39(4):461-468

control. The TPB states that increasingly favorable attitudes and subjective norms regarding a certain behavior translate to a higher intention to engage in that behavior, as does higher perceived behavioral control.(11) The intention to quit smoking is important, moderating smoking cessation interventions and the effect of medical advice.(13) Therefore, according to the TPB, the most important proximal determinant of behavior is the intention that results from the combination of attitudes toward the behavior, subjective norms, and perceived behavioral control. Beliefs are a central element in the TPB and are considered solid cognitive and affective foundations for the construction of attitudes, subjective norms, and perceived behavioral control. According to the stress-coping model,(14) in the presence of a stressor (as is the case of smoking), smokers evaluate their characteristics and how they can influence their external or internal resources. These resources will enable smokers to organize appropriate coping strategies to obtain a result, such as quitting smoking. The objective of the present study was to analyze psychological morbidity as a moderator of the relationship between smoking representations and quality of life in smokers and former smokers, as well as to determine which psychological variables discriminate between smokers with and without the intention to quit smoking.

Methods Our study sample was a convenience sample of individuals recruited from among those in the Braga region, in northern Portugal. The participants were recruited during medical consultations (in a central hospital and a private company), in which they were informed of the nature and purpose of the study by the physicians. In the university, the professors were contacted and were asked to inform their students about the study. Subsequently, the participants signed up for the study. Data were collected over a one-year period, and all of the data collection instruments were completed at a single time point. Participation was voluntary, volunteers consenting to participate after having received information on the scope and purpose of the study. The inclusion criteria were being over 18 years of age, being a daily smoker, and having been a former smoker for at least three months. There were no conflicts of interest, and the study was approved by the research ethics committees of the data collection sites.

Psychological morbidity as a moderator of intention to quit smoking: a study of smokers and former smokers

With the objective of analyzing the moderating effect of psychological morbidity on the relationship between smoking representations and quality of life in smokers and former smokers, we used the regression model proposed by Baron and Kenny(15) and simple slopes analysis in order to determine the significance of the interaction among (t) variables. (16) In order to determine which psychological variables discriminate between smokers with and without the intention to quit smoking, we used discriminant analysis.(17) We used the following instruments: • A sociodemographic questionnaire to obtain information to characterize the study sample in terms of group, marital status, gender, level of education, age, age at smoking onset, attempts to quit smoking, type of treatment, and smoking status of the partner. • The brief illness perception questionnaire,(10,18) an instrument composed of nine items, which are used in order to assess emotional representations (five items), cognitive representations (two items), and the comprehensibility of the disease (one item). The instrument scores the items on a scale of zero to ten (with the exception of item 9). In terms of internal consistency, given that each scale is composed of only one item and that it is a revised version of the original instrument, it is impossible to calculate Cronbach’s alpha coefficient based on factor analysis. The original version refers only to test-retest reliability, which is high. In our study sample, the subscales were moderately correlated with one another, as occurred in the original version. Regarding the scales of cognitive representations, emotional representations, and comprehensibility, high scores indicate threatening cognitive and emotional representations and poorer comprehensibility of the disease. • The Partner Interaction Questionnaire,(19,20) an instrument composed of one positive scale (eight items) and one negative scale (eleven items), which assess the support that smokers received in the last three months when attempting to quit smoking. This adapted version was developed for a sample of smokers and former smokers, who completed the same questionnaire items. A higher score translates to greater (positive or negative) support from partners.

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• The Depression, Anxiety, and Stress Scale,(21,22) an instrument composed of 21 items organized into three subscales (i.e., anxiety, depression, and stress), each subscale comprising seven items. A higher score translates to greater psychological morbidity. • Medical Outcomes Study 36-item Short-form Health Survey,(23,24) an instrument composed of eight dimensions grouped into two general components (i.e., physical quality of life, comprising 21 items, and mental quality of life, comprising 14 items). A higher score translates to a better perceived quality of life. Rather than an overall scale score, two summary scores are obtained, corresponding to physical quality of life and mental quality of life. • A TPB questionnaire to assess the intention to quit smoking,(25) which was constructed on the basis of the guidelines proposed by Ajzen(26) and Francis et al.(27) The adapted version of the questionnaire is composed of seven subscales— action and coping planning; behavioral beliefs; attitudes toward the behavior; perceived behavioral control; subjective norms; normative/ control beliefs; and intention. A high score on the questionnaire indicates a higher value on each scale.

Results We recruited 224 daily smokers (52.7% of whom were males) and 169 former smokers who had quit smoking at least three months prior (68.6% of whom were males). Of the smokers, 49.1% were single and 61.6% had attended the third year of high school. The mean age of the smokers was 28.58 ± 8.69 years (range, 18-58 years). Most of the smokers had been smoking for more than three years, and the age at smoking onset was 14-18 years. Of the smokers, 60% had made at least one attempt to quit smoking, 96% had never undergone any smoking cessation treatment, and 56.7% had a partner who did not smoke. Of the former smokers, 72.8% were married and 39% had attended high school. The mean age was 43.10 ± 13.02 years (range, 19-63 years). Most of the former smokers had started smoking at the age of 12-18 years. All former smokers had made at least one attempt to quit smoking, 32% having sought smoking cessation treatment. J Bras Pneumol. 2013;39(4):461-468

Afonso MFB, Alves MGP

J Bras Pneumol. 2013;39(4):461-468

Mental quality of life

In the group of former smokers, cognitive representations had a negative predictive effect on physical quality of life (β = −0.128; p ≤ 0.050), and the interaction between psychological morbidity and cognitive representations was significant (β 68 67.5 67 66.5 66 65.5 65 64.5 64 63.5 63 62.5

77 76.5 76 75.5 75 74.5 74 73.5 73 72.5 72 71.5

t = 2.348; p = 0.019

High PM Low PM t = 1.002; p = 0.82

Low Emotional representations High

t = 1.875; p < 0.001

High PM Low PM t = 1.186; p = 0.75

Low Cognitive representations High

Mental quality of life

In the group of smokers, comprehensibility had a positive predictive effect on mental quality of life (β = 0.207; p ≤ 0.001). The interactions between psychological morbidity and emotional representations (β = 0.129; p ≤ 0.001), between psychological morbidity and cognitive representations (β = 0.281; p ≤ 0.001), and between psychological morbidity and comprehensibility (β = −0.446; p ≤ 0.050) were significant. Our results showed that psychological morbidity had a moderating effect on the relationship between mental quality of life and emotional representations (t = −2.348; p = 0.019) and on the relationship between mental quality of life and cognitive representations (t = −1.875; p < 0.001), the relationship being negative when psychological morbidity is low. Psychological morbidity also had a moderating effect on the relationship between mental quality of life and comprehensibility (t = 4.57; p ≤ 0.001), the relationship being positive when psychological morbidity is high (Figure 1). In the group of former smokers, comprehensibility had a positive predictive effect on mental quality of life (β = 0.207; p ≤ 0.001). The interaction between psychological morbidity and cognitive representations was significant (β = 0.333; p ≤ 0.001). Our results showed that psychological morbidity had a moderating effect on the relationship between mental quality of life and cognitive representations (t = −1.255; p = 0.001), the relationship being negative when psychological morbidity is low (Figure 2). Psychological morbidity was found to have no moderating effect on the relationship between mental quality of life and emotional representations or on the relationship between mental quality of life and comprehensibility. In the group of smokers, emotional representations had a negative predictive effect on physical quality of life (β = −0.263; p ≤ 0.001), and the interaction between psychological morbidity and emotional representations was significant (β = 0.215; p ≤ 0.001). Our results showed that psychological morbidity had a moderating effect on the relationship between physical quality of life and emotional representations (t = −1.956; p = 0.005), the relationship being negative when psychological morbidity is low (Figure 3). Psychological morbidity was found to have no moderating effect on the relationship between physical quality of life and cognitive representations or on the relationship between physical quality of life and comprehensibility.

54.5 54 53.5

t = 4.48; p = 1.17

High PM

52.5

Low PM

52 51,5 51

t = 4.57; p < 0.001

Low Comprehensibility High

Figure 1 - Moderating effect of psychological morbidity (PM) on the relationship between mental quality of life and and smoking representations in smokers: emotional representations (A), cognitive representations (B), and comprehensibility (C).

Mental quality of life

464

77 76.5 76 75.5 75 74.5 74 73.5 73 72.5 72 71.5

t = −1.255; p = 0.001

High PM Low PM t = 1.720; p = 0.60

Low Cognitive representations High

Figure 2 - Moderating effect of psychological morbidity (PM) on the relationship between mental quality of life and cognitive representations in former smokers.

Psychological morbidity as a moderator of intention to quit smoking: a study of smokers and former smokers

Physical quality of life

60.5 60 59.5 59 58.5

t = −1.956; p = 0.005

High PM

58 57.5 57

Low PM t = 2.585; p = 0.150

56.5 56

Low Emotional representations High

Figure 3 - Moderating effect of psychological morbidity (PM) on the relationship between physical quality of life and emotional representations in smokers. 60.5

a canonical discriminant variable, with results of significance (Wilk’s lambda = 0.495; chi-square = 71.778; p ≤ 0.001) and a canonical correlation of 0.715. These results showed that the discriminatory power of the function is significant and that the two groups (smokers with and without the intention to quit smoking) are significantly different on the basis of the study variables. The results of the functional classification matrix for smokers with and without the intention to quit smoking showed that 77% of cases are correctly classified, and the proportion of unexplained variance was 49.5%.

Discussion

Physical quality of life

465

59.5 59 58.5

t = −1.875; p = 0.001

High PM

58 57.5 57

Low PM t = 3.195; p = 0.165

56.5 56

Low Cognitive representations High

Figure 4 - Moderating effect of psychological morbidity (PM) on the relationship between physical quality of life and cognitive representations in former smokers.

= 0.329; p ≤ 0.001). Psychological morbidity had a moderating effect on the relationship between physical quality of life and cognitive representations (t = −1.875; p = 0.001), the relationship being negative when psychological morbidity is low (Figure 4). Psychological morbidity was found to have no moderating effect on the relationship between physical quality of life and emotional representations or on the relationship between physical quality of life and comprehensibility. The results of the discriminant analysis showed that 59.8% of the smokers had the intention to quit smoking, whereas 40.1% did not. Regarding the variables discriminating between the two groups, the results showed that the smokers who had the intention to quit smoking more often presented with low comprehensibility, threatening emotional representations, behavioral beliefs, and perceived behavioral control, as well as with normative/ control beliefs, than did those who did not. The relationship between the discriminant function and the original variable, in the case of intention to quit smoking, allowed us to see the contribution of each variable to group discrimination and showed that the most important variable is perceived behavioral control, followed by emotional representations. The discriminant function analysis allowed us to obtain

The negative relationship between mental quality of life and threatening emotional and cognitive representations of smoking indicates that perceived quality of life decreased as the perceived threat posed by smoking increased. These results can be explained by the literature, which shows that threatening representations are associated with poorer perceived quality of life.(28) By relating this information to the results of our study, we found that threatening (cognitive and emotional) representations of smoking translate to an increased perception that smoking is harmful to health and, consequently, decreased mental quality of life. The literature shows how psychological morbidity is related to smoking behavior,(3) psychological morbidity having physical consequences at the level of decreased mental quality of life.(2,9) According to the stress-coping model,(13) psychological morbidity can be viewed as an emotional response that can have a direct impact on the outcome measure, i.e., mental quality of life. Also according to the stress-coping model, smoking can be viewed as a stressor that has a direct effect of increasing psychological morbidity and the perceived threat posed by smoking. Therefore, smokers, in the presence of lower psychological morbidity associated with smoking, more often present with low mental quality of life and threatening emotional and cognitive representations; that is, mental quality of life decreases as the perception that smoking is harmful to health increases. Interestingly, the relationship between mental quality of life and comprehensibility is positive. This indicates that, in the presence of higher psychological morbidity, a poorer comprehensibility of the reasons for smoking translates to better mental quality of life as perceived by smokers. Comprehensibility refers J Bras Pneumol. 2013;39(4):461-468

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to smokers knowing why they smoke and what the symptoms related to smoking are. Therefore, psychological morbidity can have a protective effect that will probably maintain smoking behavior in order to protect smokers, giving them the perception of good mental quality of life. For the former smokers in the present study, psychological morbidity had a moderating effect (which was similar to that observed in the smokers) on the relationship between mental quality of life and cognitive representations. The relationship between quality of life and cognitive representations was negative. This indicates that, in the presence of lower psychological morbidity, the former smokers had shown poorer perceived mental quality of life and threatening cognitive representations when they were smokers. The relationship between physical quality of life and the emotional and cognitive representations of smoking was found to be negative in the smokers and former smokers investigated in the present study; that is, in the presence of fewer symptoms of psychological morbidity in smokers and former smokers, physical quality of life is lower when cognitive and emotional representations of smoking are more threatening. Therefore, threatening cognitive and emotional representations of smoking are associated with lower perceived quality of life, which is in agreement with the literature.(28) The discriminant analysis showed that the smokers who had the intention to quit smoking more often presented with low comprehensibility, threatening emotional representations, behavioral beliefs, and perceived behavioral control, as well as with normative/control beliefs, than did those who did not. According to the literature,(29) smokers who have the intention to quit smoking are in a stage of preparation for quitting smoking. In our study, those who had the intention to quit smoking had a poorer understanding of the reasons for smoking (comprehensibility), showed greater concern with the fact that they smoked, and felt emotionally affected by the threat that smoking posed to their health (emotional representations). These results suggest that smokers in whom the perception that smoking poses a health threat is increased are more motivated to quit smoking. According to the TPB,(30) smokers who have the intention to quit smoking are aware of their control over quitting (perceived behavioral control), take into account what others expect from them (i.e., more often present with normative/control beliefs), and consider the likely J Bras Pneumol. 2013;39(4):461-468

outcomes of quitting (i.e., more often present with behavioral beliefs). In fact, the TPB states that beliefs are important in the construction of attitudes, subjective norms, and perceived behavioral control, beliefs being implicated in behavioral intention (to quit smoking).(30) The sociocognitive variables (perceived behavioral control, behavioral beliefs, and normative/control beliefs) are important in the context of devising a smoking cessation plan. Therefore, threatening emotional representations of smoking and a poorer understanding of smoking lead smokers to believe that smoking is harmful to their health; to show a poorer understanding of the reasons for smoking; and to believe that quitting smoking can be important to their health.(10) The sociocognitive variables in the present study show that perceived behavioral control, normative/control beliefs, and behavioral beliefs play an important role in the intention to quit smoking.(20) The fact that the study sample was a convenience sample of individuals recruited exclusively from among those in northern Portugal limits the generalization of the results to other regions of the country, given that the social and cultural characteristics of each region should be taken into consideration. Future studies should examine the role of sociocognitive variables, particularly in intention, in samples that are more diverse, as well as evaluating the role of family coping as a moderating variable in the relationship between smoking representations and the intention to quit smoking. The present study underscored the importance of the moderating effect of psychological morbidity on mental and physical quality of life in smokers and former smokers, as well as underscoring the importance of sociocognitive variables in the intention to quit smoking. The results obtained contribute to informing smoking cessation programs regarding a reduction in psychological morbidity and the inclusion of sociocognitive variables (TPB).(12,13)

References 1. Viegas CA. Noncigarette forms of tobacco use. J Bras Pneumol. 2008;34(12):1069-73. http://dx.doi.org/10.1590/ S1806-37132008001200013 PMid:19180343 2. Reichert J, AraĂşjo AJ, GonĂ§alves CM, Godoy I, Chatkin JM, Sales MP, et al. Smoking cessation guidelines--2008. J Bras Pneumol. 2008;34(10):845-80. Erratum in: J Bras Pneumol. 2008;34(12):1090. http://dx.doi.org/10.1590/ S1806-37132008001000014 PMid:19009219 3. Aubin HJ, Bobak A, Britton JR, Oncken C, Billing CB Jr, Gong J, et al. Varenicline versus transdermal nicotine

Psychological morbidity as a moderator of intention to quit smoking: a study of smokers and former smokers

patch for smoking cessation: results from a randomised open-label trial. Thorax. 2008;63(8):717-24. http:// dx.doi.org/10.1136/thx.2007.090647 PMid:18263663 PMCid:2569194 4. Calheiros P, Andretta I, Oliveira M. Avaliação da motivação para mudança nos comportamentos aditivos. In: Werlang BS, Oliveira MS, editors. Temas em Psicologia Clínica. São Paulo: Casa do Psicólogo; 2006. 5. Magid V, Colder CR, Stroud LR, Nichter M, Nichter M; TERN Members. Negative affect, stress, and smoking in college students: unique associations independent of alcohol and marijuana use. Addict Behav. 2009;34(11):973-5. http:// dx.doi.org/10.1016/j.addbeh.2009.05.007 PMid:19523773 6. Miller KE. Quality of life impairment in healthy young smokers. Am Fam Physician. 2004;70(9):1785-6. 7. Sales MP, Oliveira MI, Mattos IM, Viana CM, Pereira ED. The impact of smoking cessation on patient quality of life. J Bras Pneumol. 2009;35(5):436-41. http://dx.doi. org/10.1590/S1806-37132009000500008 PMid:19547852 8. Trigo M. O que provoca realmente a mudança nos fumadores? Algumas reflexões. Rev Port Clin Geral. 2005;21:161-82. 9. Arjonilla S, Pelcastre B Orozco E. Representación social del consumo de tabaco en una institución de salud. Salud Ment. 2000;23(3):2-12. 10. Broadbent E, Petrie KJ, Main J, Weinman J. The brief illness perception questionnaire. J Psychosom Res. 2006;60(6):631-7. http://dx.doi.org/10.1016/j.jpsychores.2005.10.020 PMid:16731240 11. Ajzen I. From intentions to actions: A theory of planned behavior. In: Kuhl J, Beckmann J, editors. Action control: From cognition to behavior. Heidelberg: Springer-Verlag; 1985. p. 11-39. 12. Ajzen I, Madden TJ. Prediction of goal-directed behavior: Attitudes, intentions, and perceived behavioral control. J Exp Soc Psychol. 1986;2:453-74. http://dx.doi. org/10.1016/0022-1031(86)90045-4 13. Haug S, Meyer C, Ulbricht S, Schorr G, Rüge J, Rumpf HJ, et al. Predictors and moderators of outcome in different brief interventions for smoking cessation in general medical practice. Patient Educ Couns. 2010;78(1):57-64. http:// dx.doi.org/10.1016/j.pec.2009.07.005 PMid:19660890 14. Maes S, Leventhal H, de Ridder D. Coping with chronic diseases. In: Ziender M, Endler N, editors. Handbook of Coping. New York: Wiley; 1996. p. 221-45. 15. Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol. 1986;51(6):117382. http://dx.doi.org/10.1037/0022-3514.51.6.1173 16. Curran PJ, Bauer DJ, Willoughby MT. Testing main effects and interactions in latent curve analysis. Psychol Methods. 2004;9(2):220-37. http://dx.doi.org/10.1037/1082989X.9.2.220 PMid:15137890 17. Burns RB, Burns RA, editors. Business Research Methods and Statistics using SPSS. London: SAGE Publications Ltd; 2008.

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18. Figueiras M, Marcelino DS, Claudino A, Cortes MA, Maroco J, Weinman J. Patients’ illness schemata of hypertension: the role of beliefs for the choice of treatment. Psychol Health. 2010;25(4):507-17. http:// dx.doi.org/10.1080/08870440802578961 PMid:20204931 19. Cohen S, Lichtenstein E. Partner behaviors that support quitting smoking. J Consult Clin Psychol. 1990;58(3):304-9. http://dx.doi.org/10.1037/0022-006X.58.3.304 20. Pereira MG, Afonso F. Partner Interaction Questionnaire. Versão de Investigação. Braga: Universidade do Minho; 2006. 21. Lovibond PF, Lovibond SH. The structure of negative emotional states: comparison of the Depression Anxiety Stress Scales (DASS) with the Beck Depression and Anxiety Inventories. Behav Res Ther. 1995;33(3):335-43. http:// dx.doi.org/10.1016/0005-7967(94)00075-U 22. Pais-Ribeiro J, Honrado A, Leal, I. Contribuição para o estudo da adaptação portuguesa das escalas de ansiedade, depressão e stress de Lovibond e Lovibond. Psic., Saúde & Doenças. 2004;5(2):229-39. 23. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473-83. http://dx.doi. org/10.1097/00005650-199206000-00002 PMid:1593914 24. Ferreira PL, Santana P. Perceção de estado de saúde e de qualidade de vida da população ativa: Contributos para a definição de normas portuguesas. Rev Port Saúde Publica. 2003;21(2):15-30. 25. Pereira MG, Afonso F. Questionário Sociocognitivo. Versão de Investigação. Braga: Universidade do Minho; 2010. 26. APCC [homepage on the Internet]. Lisboa: APCC [cited 2007 Dec 20]. Ajzen I. Constructing a TpB Questionnaire: conceptual and Methodological Considerations; 2002. [Adobe Acrobat document, 14p.] Available from: http:// www.apcc.online.pt/upload/membro.id/ficheiros/i005562. pdf 27. Icek Ajzen [homepage on the Internet]. Amherst: University of Massachusetts [cited 2007 Nov 20]. Francis JJ, Eccles MP, Johnston M, Walker A, Grinshaw J, Foy R, et al. Constructing questionnaires based on the theory of planned behavior: A manual for health services researchers; 2004. Available from: http://people.umass.edu/aizen/tpb.html 28. Sampaio RS, Pereira MG, Winck JC. Adaptation of the sleep apnea quality of life index (SAQLI) to Portuguese obstructive sleep apnea syndrome patients [Article in Portuguese]. Rev Port Pneumol. 2012;18(4):166-74. http:// dx.doi.org/10.1016/j.rppneu.2012.02.009 PMid:22541672 29. Prochaska JO, DiClemente CC. Transtheorical therapy: towards a more integrative model of change. Psychol Psychother Theor Res Pract. 1982;19(3):276-88. 30. Ajzen I. The theory of planned behavior. Organ Behav Hum Dec. 1991;50:179-211. http://dx.doi. org/10.1016/0749-5978(91)90020-T

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Afonso MFB, Alves MGP

About the authors Maria Fernanda Besteiro Afonso

Researcher. University of Minho School of Psychology, Braga, Portugal.

Maria Graรงa Pereira Alves

Associate Professor. University of Minho School of Psychology, Braga, Portugal.

J Bras Pneumol. 2013;39(4):461-468

Original Article Adaptation to different noninvasive ventilation masks in critically ill patients* Adaptação a diferentes interfaces de ventilação mecânica não invasiva em pacientes críticos

Renata Matos da Silva, Karina Tavares Timenetski, Renata Cristina Miranda Neves, Liane Hirano Shigemichi, Sandra Sayuri Kanda, Carla Maekawa, Eliezer Silva, Raquel Afonso Caserta Eid

Abstract Objective: To identify which noninvasive ventilation (NIV) masks are most commonly used and the problems related to the adaptation to such masks in critically ill patients admitted to a hospital in the city of São Paulo, Brazil. Methods: An observational study involving patients ≥ 18 years of age admitted to intensive care units and submitted to NIV. The reason for NIV use, type of mask, NIV regimen, adaptation to the mask, and reasons for non-adaptation to the mask were investigated. Results: We evaluated 245 patients, with a median age of 82 years. Acute respiratory failure was the most common reason for NIV use (in 71.3%). Total face masks were the most commonly used (in 74.7%), followed by full face masks and near-total face masks (in 24.5% and 0.8%, respectively). Intermittent NIV was used in 82.4% of the patients. Adequate adaptation to the mask was found in 76% of the patients. Masks had to be replaced by another type of mask in 24% of the patients. Adequate adaptation to total face masks and full face masks was found in 75.5% and 80.0% of the patients, respectively. Non-adaptation occurred in the 2 patients using near-total facial masks. The most common reason for non-adaptation was the shape of the face, in 30.5% of the patients. Conclusions: In our sample, acute respiratory failure was the most common reason for NIV use, and total face masks were the most commonly used. The most common reason for non-adaptation to the mask was the shape of the face, which was resolved by changing the type of mask employed. Keywords: Intermittent positive-pressure ventilation; Masks; Respiratory insufficiency.

Resumo Objetivo: Identificar as interfaces de ventilação não invasiva (VNI) mais utilizadas e os eventuais problemas relacionados a sua adaptação em pacientes críticos internados em um hospital na cidade de São Paulo, SP. Métodos: Estudo observacional, com pacientes acima de 18 anos admitidos nas unidades de pacientes graves que usaram VNI. Foram coletados a causa de uso da VNI, interface utilizada, esquema de uso da VNI, adaptação e motivos para a falta de adaptação à interface. Resultados: Avaliamos 245 pacientes, com média de idade de 82 anos. A insuficiência respiratória aguda foi a causa mais frequente de uso da VNI (71,3%). A interface mais utilizada foi a máscara facial total (74,7%), seguida por máscara facial e máscara facial quase total (24,5% e 0,8%, respectivamente). Em 82,4% dos pacientes, a VNI foi utilizada por períodos. A adaptação adequada à interface ocorreu em 76% dos pacientes. As máscaras tiveram de ser trocadas em 24% dos pacientes. Houve adaptação adequada à máscara facial total e à máscara facial em 75,5% e em 80,0% dos pacientes, respectivamente. A adaptação foi inadequada nos 2 pacientes que utilizaram a máscara facial quase total. A causa mais frequente da falta de adaptação foi o formato da face, em 30,5% dos pacientes. Conclusões: Nesta amostra, a insuficiência respiratória aguda foi a causa mais frequente de uso da VNI, e a máscara facial total foi a interface mais utilizada. A causa mais comum da falta de adaptação à máscara foi o formato da face, que foi resolvida após a troca da interface. Descritores: Ventilação com pressão positiva intermitente; Máscaras; Insuficiência respiratória.

* Study carried out in the Department of Intensive Care – Critically Ill Patients, Hospital Israelita Albert Einstein, São Paulo, Brazil. Correspondence to: Renata Matos da Silva. Hospital Israelita Albert Einstein, Unidade Morumbi, Departamento de Fisioterapia de Pacientes Graves, Avenida Albert Einstein, 627/701, 5º andar, Bloco B, CEP 05651-901, São Paulo, SP, Brasil. Tel. 55 11 99459-3581. Fax: 55 11 2151-9411. E-mail: renatams@einstein.br Financial support: None. Submitted: 28 September 2012. Accepted, after review: 5 April 2013.

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Introduction Acute respiratory failure (ARF) causes severe deterioration of gas exchange, which can result in the need for ventilatory support via orotracheal intubation (OTI). Ventilatory support via OTI is associated with a high risk of complications, such as tracheal stenosis and pneumonia. In contrast, noninvasive ventilation (NIV) has proven to be an effective modality in the treatment of respiratory failure of various causes. The use of NIV for the treatment of patients with ARF or chronic respiratory failure has certainly been one of the greatest advances in mechanical ventilation in recent decades.(1-3) A safe and effective method in correcting the pathophysiological mechanisms of ARF, NIV reduces the work of breathing and improves oxygenation while simultaneous treatments address the causes of ARF.(4,5) In some patients, however, NIV has limited effectiveness because of non-adaptation to the masks, significant air leaks, feelings of claustrophobia, aerophagy, and presence or risk of facial injuries.(6) In addition, the time spent by nurses and therapists on frequent mask adjustments, with the objective of preventing excessive leaks and providing adequate monitoring, generates an additional workload for the team.(7) An effective NIV program must pay attention to detail, such as provision of training in NIV monitoring for caregivers and professionals, selection of an appropriate ventilatory strategy for each condition, and use of an appropriate mask for each patient.(7) Few studies have compared the effectiveness of different types of masks in NIV. In addition, the appropriate mask for use in NIV has yet to be defined.(8,9) A recent study evaluated the use of three different masks—nasal masks, face masks, total face masks (TFMs)—by using an analog scale with questions related to comfort. In terms of leaks and nasal pain, TFMs showed better performance; however, there was a higher incidence of feelings of claustrophobia. It is of note that the study involved healthy individuals, which does not allow a full extrapolation of the results to patients whose clinical situation could also affect the adaptation to the masks.(10) Another study examined the physiological effects of different masks in patients with either hypoxemic or hypercapnic ARF. Four different J Bras Pneumol. 2013;39(3):469-475

masks (two types of face masks, one type of TFM, and a mouthpiece) were considered, and patient respiratory effort during the use of each mask was evaluated on the basis of the dead space in each one. Although the researchers concluded that there were no major differences between the masks in terms of the work of breathing, they did not evaluate patient adaptation to the masks; rather, they evaluated patient respiratory effort. In addition, the masks used in that study are different from those used in our institution.(11) Nasal and oronasal masks are the ones most commonly used for application of NIV in the hospital environment. In an attempt to improve patient comfort with and tolerance of NIV, new masks have become available in recent years, among which are TFMs, also known as “full face masks”.(1) Because of their greater contact area with the face of the patient, TFMs have the advantage of minimizing air leak and allowing the use of higher inspiratory pressures, as well as minimizing skin injury associated with prolonged use of NIV, making it more comfortable for the patient to use them.(1) In our institution, during patient care, we observed a considerable reduction in the rates of complications related to the use of TFMs, these being the masks of choice by the staff of the institution and also being the preferred masks by patients, with exceptions in case of intolerance or better adaptation to another type of mask, because many patients already received NIV at home and chose to use the same type of device. In a pilot study conducted in the units for critically ill patients in our institution, we observed that even TFMs caused adaptation problems, making it necessary to replace them by another type of mask in order to achieve better adaptation and, consequently, allow patients to take full advantage of NIV. A relevant finding in that pilot study was the fact that there was greater NIV mask use compliance in the ICU than in semi-intensive care departments, such as the coronary care unit and the semi-intensive care unit, although the level of interference of the clinical status of the patient with this adaptation was not determined. In this context, we collected information about the use of NIV masks in our institution in order to identify the main types of patientventilator interface used by our patients, as well

Adaptation to different noninvasive ventilation masks in critically ill patients

as the problems related to the adaptation to such masks, on the basis of the views of the therapists who were responsible for monitoring patients and adapting them to their masks.

Methods After the study design had been approved by the local ethics committee, all patients 18 years of age or older who received NIV in the ICUs, coronary care unit, or semi-intensive unit of the Hospital Israelita Albert Einstein, located in the city of São Paulo, Brazil, between August of 2009 and July of 2011, were included in the study. Data were obtained by using a data collection form with specific questions, which were answered by the therapists who were responsible for monitoring patients and adapting them to their masks. Patients were not asked any questions, and this was an observational study, in which only those involved in the investigation were aware of its objectives. Therefore, for the physical therapists who were responsible for the direct care of patients, this was a blind study. A data collection form was filled out for each patient; however, the patients for whom NIV use was discontinued and, after some time, resumed were included again, since their clinical status was different. In addition, if a given patient did not adapt to a given mask and this mask was replaced by another type of mask, the same criteria were reevaluated. The data collection form addressed the following items: patient age; reason for NIV use; type of mask; NIV regimen (continuous, intermittent, or nocturnal-only use); adaptation to the mask (adequate or inadequate); complications; and need to replace the mask by another type of mask. The data obtained were entered into and analyzed by using Excel spreadsheets, and all printed documents were filed in a folder specific to the study. Initially, with the objective of identifying the main types of masks used and the problems related to the adaptation to such masks, we conducted a descriptive exploratory analysis of all observed variables. Qualitative variables are expressed as absolute and relative frequencies. Quantitative variables are expressed as mean and standard deviation (normal distribution) or as median and range (non-normal distribution).

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In order to investigate the relationship between the variables age, reason for NIV use, type of mask, NIV regimen, and adaptation to the mask, we generated scatterplots and calculated Pearson correlation coefficients, for variables with normal distribution, and Spearman’s correlation coefficients, for variables with non-normal distribution. In order to study the influence of age, reason for NIV use, and NIV regimen on the likelihood of adequate adaptation to the masks, we adjusted these variables by using a multiple logistic regression model. All variables with a descriptive level of less than 0.20 in the univariate approach were included in the initial model. The level of significance was set at 0.05. The statistical program used was the Statistical Package for the Social Sciences, version 16.0 (SPSS Inc., Chicago, IL, USA).

Results We evaluated 245 patients, with a median age of 82 years (range, 20-107 years; Table 1). The most common reason for NIV use was a diagnosis of ARF (in 71.3%), followed by a need for exercise or lung expansion (in 10.2%), use after weaning from invasive mechanical ventilation (in 6.1%), and obstructive sleep apnea (in 8.6%), as shown in Table 1. The most commonly used masks were TFMs (Philips Respironics, Murrysville, PA, USA), in 74.7%; followed by face masks (Comfo mask; HSINER Co. LTD., Taichung, Taiwan—Mirage; ResMed Corp., San Diego, CA, USA—and Comfort full; Philips Respironics), in 24.5%; and by neartotal face masks (PerforMax; Philips Respironics), in 0.8% (Figure 1). Regarding the NIV regimen, intermittent NIV was the most commonly used (in 82.4%), followed by continuous NIV (in 10.6%) and nocturnalonly NIV (in 6.9%; Table 2). Adequate adaptation to the mask was found in 76% of the patients (Figure 1). Non-adaptation to the mask (in 24%) caused the type of mask to be changed until adequate adaptation was achieved. Adequate adaptation to TFMs was found in 75.5% of the patients, whereas adequate adaptation to face masks was found in 80.0% of the patients. Adequate adaptation to neartotal face masks did not occur, perhaps due to J Bras Pneumol. 2013;39(3):469-475

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the fact they were seldom used, in only two patients (Figure 1). We found that the shape of the face, especially the nose contour, was the most common reason for non-adaptation, in 30.5% of the cases; followed by patient-reported discomfort, in 28.8%; air leaks around the mask, in 27;7%; feelings of claustrophobia, in 18.6%; patient non-cooperation, in 10.1%; patient agitation, in 6.7%; facial trauma or injury, in 1.7%; type of fixation device or â&#x20AC;&#x153;halterâ&#x20AC;?, in 1.7%; and other reasons, in 1.7% (Table 2).

Discussion The use of NIV for the control and treatment of ARF or chronic respiratory failure has certainly Table 1 - Characteristics of the 245 patients evaluated.a Characteristic Result Age, yearsb 82 (20-107) Gender Male 130 (53) Female 115 (47) Reason for noninvasive ventilation use Acute respiratory failure 170 (69.4) Lung expansion 44 (18.0) Use after weaning from mechanical 15 (6.1) ventilation Obstructive sleep apnea 37 (15.0)

been one of the greatest advances in the care of critically ill patients in recent years. The use of NIV leads to re-expansion of collapsed areas, improved gas exchange, and reduced work of breathing while simultaneous treatments address the causes of the respiratory failure. Our study showed that respiratory failure was the main reason for NIV use. However, NIV was also indicated for other purposes, such as lung expansion, being used as a thoracic expansion exercise for short periods during the Table 2 - Noninvasive ventilation (NIV) regimen and reasons for non-adaptation to the mask. Variable Patients NIV regimen Intermittent 202 (82.4) Continuous 26 (10.6) Nocturnal 17 (7.0) Reason for non-adaptation Shape of the face 75 (30.5) Discomfort 70 (28.8) Leaks 68 (27.7) Claustrophobia 45 (18.6) Non-cooperation 24 (10.0) Agitation 16 (6.7) Facial trauma 4 (1.7) Type of fixation device 4 (1.7) Others 4 (1.7)

Values expressed as n (%), except where otherwise indicated. Value expressed as median (range).

90 80 70

60 50

Frequency

Adaptation

30 20 10 0 Total face mask

Face mask

Near-total face mask

Figure 1 - Frequency of use and adequate adaptation to different masks.

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day and being used in the evening for improving gas exchange or for re-expansion of collapsed lung areas. In addition, in our study, nocturnal use of NIV was mentioned as being indicated to minimize sleep apnea syndrome, as well as being indicated immediately after extubation, acting as an adjuvant in weaning from invasive mechanical ventilation. It is known that, for each purpose, a NIV regimen is tailored on the basis of its indication and the clinical status of the patient. In our study, intermittent NIV, which consists of use for longer than one-hour periods in the morning, afternoon, and evening, was the most common regimen. The clinical status of the patients who used continuous NIV was more severe, and removal of NIV was allowed only for feeding, oral hygiene, expectoration, and aspiration of secretions. The nocturnal regimen was administered only to patients who had been diagnosed with obstructive sleep apnea and presented with an indication for NIV use. These findings are important in order to understand the major indications for NIV use and its frequency of use. However, it is of note that an inappropriate choice of the mask or poor adaptation of patients to their masks might affect treatment outcomes. An effective treatment plan using NIV must pay attention to detail, one of which is the use of an appropriate type of mask for each patient.(7) Our study focused on adequate adaptation of patients to their masks, considering their comfort, because adequate adaptation to the mask allows higher compliance with the NIV program proposed, positively contributing to the clinical course. Mask intolerance can be an important factor in NIV failure, as demonstrated in a study by Conti et al.,(12) who compared the efficacy of NIV delivered via a face mask with that of NIV delivered via a helmet in ARF patients after abdominal surgery. Regardless of the type of mask used, oxygenation improved, as did RR, HR, systolic blood pressure, and ventilation parameters. However, the incidence of NIV complications, such as mask intolerance, leaks that compromise ventilation, and ventilator-associated pneumonia, was higher in the group using face masks than in the group using helmets. In another study, Kwork et al.(13) evaluated tolerance of oronasal and nasal masks in patients

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with ARF. The success rate tended to be higher with the use of oronasal masks, but without statistical significance. Once again, oxygenation, RR, and HR improved in both groups; however, intolerance of or non-adaptation to the mask was higher in the group using nasal masks. Chacur et al.(14) compared the use of TFMs with that of traditional face masks in terms of changes in clinical parameters, oxygenation parameters, levels of ventilatory support, and incidence of OTI. The group using TFMs showed better adaptation and therefore tolerated NIV for longer periods than did the group using face masks. In contrast, there were no significant differences in clinical course. Recent guidelines for the use of NIV mention two randomized controlled studies that compared the use of nose masks with that of orofacial masks, and, although no differences were found in the rates of OTI or mortality, oronasal masks were better tolerated by patients.(15) In our study, adequate adaptation to the mask employed was found in 76% of the cases. For the patients (24%) who did not adapt to the mask of choice, the type of mask was changed until adequate adaptation was achieved. The most commonly used type of mask was TFMs, which is an expected finding, because, in our institution, TFMs have been defined as the mask of choice by the staff on the basis of care observation. Analyzing adaptation to the types of mask separately, we found adequate adaptation to TFMs in 75.5% of the cases and adequate adaptation to face masks in 80.0% of the cases. Therefore, we observed that both types of mask are options that can be used in NIV, and that the acceptance of either one can vary with each patient, depending on their clinical and physical status, or even on their personal preferences. Considering that the shape of the face was the main reason for non-adaptation, we found that it is difficult to define a type or standard of mask that can fit all anatomical variations. Face masks are available on the market in various types and sizes; however, TFMs are available in a limited range of sizes, which made it difficult for patients with smaller- or larger-than-average faces to adapt to their masks. We found that some reasons for non-adaptation to the mask, such as respiratory distress, air leaks around the mask, type of fixation device, and facial trauma or injury, were associated with the J Bras Pneumol. 2013;39(3):469-475

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use of a type or size of mask that was inadequate to fit the face of the patient. In addition, we found that feelings of claustrophobia, patient agitation, and patient non-cooperation because of their personal situation or condition can be resolved, in most cases, by changing the type of mask employed. In conclusion, it is important to evaluate patient adaptation to their masks in order to ensure an effective NIV compliance program and treatment success. In the present study, ARF was the main reason for NIV use, and TFMs were the most commonly used, with satisfactory patient adaptation, followed by face masks. The main reasons for non-adaptation to NIV were the shape of the face of the patient, patient-reported discomfort with the use of the mask, respiratory distress, and air leaks around the mask. These problems were resolved by changing the type of mask employed.

References 1. Schettino GP, Reis MA, Galas F, Park M, Franca S, Okamoto V. Ventilação mecânica não invasiva com pressão positiva. J Bras Pneumol. 2007;33(Suppl 2):S92-S105. http://dx.doi.org/10.1590/S1806-37132007000800004 PMid:18026667 2. Organized jointly by the American Thoracic Society, the European Respiratory Society, the European Society of Intensive Care Medicine, and the Société de Réanimation de Langue Française, and approved by ATS Board of Directors, December 2000. International Consensus Conferences in Intensive Care Medicine: noninvasive positive pressure ventilation in acute Respiratory failure. Am J Respir Crit Care Med. 2001;163(1):283-91.http:// dx.doi.org/10.1164/ajrccm.163.1.ats1000 PMid:11208659 3. British Thoracic Society Standards of Care Committee. Non-invasive ventilation in acute respiratory failure. Thorax. 2002;57(3):192-211. http://dx.doi.org/10.1136/ thorax.57.3.192 PMid:11867822 PMCid:1746282 4. Antonelli M, Pennisi MA, Montini L. Clinical review: noninvasive ventilation in the clinical setting--experience from the past 10 years. Crit Care. 2005;9(1):98-103. http://dx.doi.org/10.1186/cc2933 PMid:15693991 PMCid:1065090 5. Caples SM, Gay PB. Noninvasive positive pressure ventilation in the intensive care unit: a concise review. Crit Care

J Bras Pneumol. 2013;39(3):469-475

Med. 2005;33(11):2651-8. http://dx.doi.org/10.1097/01. CCM.0000186768.61570.69 6. Criner GJ, Travaline JM, Brennan KJ, Kreimer DT. Efficacy of a new full face mask for noninvasive positive pressure ventilation. Chest. 1994;106(4):1109-15. http://dx.doi. org/10.1378/chest.106.4.1109 PMid:7924481 7. Kacmarek RM. Noninvasive positive pressure ventilation: the little things do make the difference! Respir Care. 2003;48(10):919-21.PMid:14525627 8. Willson GN, Piper AJ, Norman M, Chaseling WG, Milross MA, Collins ER, et al. Nasal versus full face mask for noninvasive ventilation in chronic respiratory failure. Eur Respir J. 2004;23(4):605-9. http://dx.doi.org/10.1 183/09031936.04.00051604 PMid:15083762 9. Navalesi P, Fanfulla F, Frigerio P, Gregoretti C, Nava S. Physiologic evaluation of noninvasive mechanical ventilation delivered with three types of masks in patients with chronic hypercapnic respiratory failure. Crit Care Med. 2000;28(6):1785-90. http://dx.doi.org/10.1097/00003246200006000-00015 PMid:10890620 10. Holanda MA, Reis RC, Winkeler GF, Fortaleza SC, Lima JW, Pereira ED. Influence of total face, facial and nasal masks on short-term adverse effects during noninvasive ventilation. J Bras Pneumol. 2009;35(2):164-73. http:// dx.doi.org/10.1590/S1806-37132009000200010 PMid:19287920 11. Fraticelli AT, Lellouche F, L’her E, Taillé S, Mancebo J, Brochard L. Physiological effects of different interfaces during noninvasive ventilation for acute respiratory failure. Crit Care Med. 2009;37(3):939-45. Erratum in: Crit Care Med. 2009;37(4):1537. http://dx.doi.org/10.1097/ CCM.0b013e31819b575f PMid:19237900 12. Conti G, Cavaliere F, Costa R, Craba A, Catarci S, Festa V, et al. Noninvasive positive-pressure ventilation with different interfaces in patients with respiratory failure after abdominal surgery: a matched-control study. Respir Care. 2007;52(11):1463-71. PMid:17971249 13. Kwok H, McCormack J, Cece R, Houtchens J, Hill NS. Controlled trial of oronasal versus nasal mask ventilation in the treatment of acute respiratory failure. Crit Care Med, 2003;31(2):468-73. http://dx.doi.org/10.1097/01. CCM.0000045563.64187.20 PMid:12576953 14. Chacur FH, Vilella Felipe LM, Fernandes CG, Lazzarini LC. The total face mask is more comfortable than the oronasal mask in noninvasive ventilation but is not associated with improved outcome. Respiration. 2011;82(5):426-30. http://dx.doi.org/10.1159/000324441 PMid:21846957 15. Keenan SP, Sinuff T, Burns KE, Muscedere J, Kutsogiannis J, Mehta S, et al. Clinical practice guidelines for the use of noninvasive positive-pressure ventilation and noninvasive continuous positive airway pressure in the acute care setting. CMAJ. 2011;183(3):E195-E214. http://dx.doi.org/10.1503/cmaj.100071 PMid:21324867 PMCid:3042478

Adaptation to different noninvasive ventilation masks in critically ill patients

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About the authors Renata Matos da Silva

Physical Therapist. Hospital Israelita Albert Einstein, São Paulo, Brazil.

Karina Tavares Timenetski

Physical Therapist. Hospital Israelita Albert Einstein, São Paulo, Brazil.

Renata Cristina Miranda Neves

Physical Therapist. Hospital Israelita Albert Einstein, São Paulo, Brazil.

Liane Hirano Shigemichi

Physical Therapist. Hospital Israelita Albert Einstein, São Paulo, Brazil.

Sandra Sayuri Kanda

Physical Therapist. Hospital Israelita Albert Einstein, São Paulo, Brazil.

Carla Maekawa

Physical Therapist. Hospital Israelita Albert Einstein, São Paulo, Brazil.

Eliezer Silva

Medical Manager in Intensive Care. Hospital Israelita Albert Einstein, São Paulo, Brazil.

Raquel Afonso Caserta Eid

Coordinator of Physical Therapy. Hospital Israelita Albert Einstein, São Paulo, Brazil.

J Bras Pneumol. 2013;39(3):469-475

Original Article Prevalence of nutritional deficiency in patients with pulmonary tuberculosis* Prevalência de deficiência nutricional em pacientes com tuberculose pulmonar*

Silvana Gomes Nunes Piva, Maria da Conceição Nascimento Costa, Florisneide Rodrigues Barreto, Susan Martins Pereira

Abstract Objective: To determine the prevalence of nutritional deficiency among patients with pulmonary tuberculosis. Methods: This was a cross-sectional study using data obtained from the Brazilian Case Registry Database and from the medical records of patients diagnosed with pulmonary tuberculosis (15-59 years of age) residing in one of the municipalities that make up the 16th Regional Health District of the state of Bahia. We calculated the incidence, lethality, and mortality rates, as well as the prevalence of nutritional deficiency, as evaluated by body mass index. Demographic, social, clinical, and epidemiological data were collected. Results: Of the 72 confirmed cases of tuberculosis, 59 (81.9%) were in males, and 21 (29.2%) of the patients were in the 40-49 year age bracket. The majority (85.3%) described themselves as Mulatto or Black; 55.2% reported using alcohol; and approximately 90% were treated as outpatients. In the district and age bracket studied, the incidence of pulmonary tuberculosis was 30.6/100,000 population. Among the 72 patients, data regarding nutritional status was available for 34. Of those, 50% and 25%, respectively, presented nutritional deficiency at the beginning and at the end of treatment. No statistically significant differences were found between normal-weight and malnourished patients regarding the characteristics studied. Conclusions: The prevalence of nutritional deficiency was high among our sample of patients with pulmonary tuberculosis. This underscores the importance of nutritional follow-up for the assessment of tuberculosis treatment in the decision-making process regarding therapeutic interventions. Keywords: Malnutrition; Tuberculosis; Body mass index; Malnutrition/epidemiology.

Resumo Objetivo: Determinar a prevalência de deficiência nutricional entre pacientes com tuberculose pulmonar. Métodos: Estudo transversal tendo como fontes de dados o Sistema de Informação de Agravos de Notificação e prontuários médicos de pacientes diagnosticados com tuberculose pulmonar (15-59 anos de idade) e residentes nos municípios da 16a Regional de Saúde do estado da Bahia. Foram calculados os coeficientes de incidência, letalidade e mortalidade por tuberculose e a prevalência de deficiência nutricional, avaliada pelo índice de massa corpórea. Características demográficas, sociais e clínico-epidemiológicas foram coletadas. Resultados: Dos 72 casos confirmados de tuberculose, 59 (81,9%) eram do sexo masculino, e 21 (29,2%) tinham 40-49 anos de idade. A maioria declarou-se como pardo ou preto (85,3%). O tratamento foi ambulatorial em aproximadamente 90% dos casos, e 55,2% referiram uso de álcool. A incidência de tuberculose pulmonar foi de 30,6/100.000 habitantes no distrito e faixa etária estudados. Dos 72 pacientes, 34 apresentavam dados relativos ao estado nutricional. Desses, 50% e 25%, respectivamente, apresentavam deficiência nutricional ao início e ao final do tratamento. Não houve diferenças estatisticamente significantes entre pacientes eutróficos e desnutridos quanto às características estudadas. Conclusões: A prevalência de deficiência nutricional foi elevada em nossa amostra de pacientes com tuberculose pulmonar. Isso reforça a importância do acompanhamento nutricional para a avaliação do tratamento da tuberculose para a tomada de decisão quanto a intervenções terapêuticas. Descritores: Desnutrição; Tuberculose; Índice de massa corporal; Desnutrição/epidemiologia.

*Study carried out at the Collective Health Institute, Federal University of Bahia, Salvador, Brazil. Correspondence to: Maria da Conceição Nascimento Costa. Rua Basílio da Gama, s/n, Canela, CEP 40110-040, Salvador, BA, Brasil. Tel. 55 71 3283-7373. Fax: 55 71 3293-7460. E-mail: mcncosta@ufba.br Financial support: None. Submitted: 31 January 2013. Accepted, after review: 5 June 2013.

J Bras Pneumol. 2013;39(4):476-483

Prevalence of nutritional deficiency in patients with pulmonary tuberculosis

Introduction Tuberculosis, a disease that is considered neglected, affects large population groups, especially in developing countries, where it is of significant magnitude and social importance; therefore, it is a major public health problem. Approximately 95% of the estimated number of tuberculosis cases occur in resource-poor countries, and 82% are concentrated in 22 of these countries, among which is Brazil, which ranks 17th.(1) Estimates indicate that, in 2010, approximately 270,000 new cases of tuberculosis were in the Americas,(2) which corresponds to an incidence rate of 28.9 per 100,000 population. Brazil, a country considered a priority in the fight against tuberculosis in the continent, was among those that reached the target detection rate set by the World Health Organization (WHO), since it identified 88% of new active cases. However, it achieved a cure rate of only 72%, a value that is lower than the recommended target rate of 85% for successful treatment.(1) In 2011 in Brazil, 71,337 new cases of tuberculosis were reported, corresponding to an incidence of 37.1/100,000 population, and 4,600 deaths from tuberculosis were registered. The states of Rio de Janeiro, Amazonas, Pernambuco, Pará, Rio Grande do Sul, São Paulo, Ceará, and Acre had values above the national average, whereas Tocantins (14.1/100,000), Goiás (13.6/100,000), and the Federal District of Brasília (11.1/100,000) have historically registered the lowest rates.(3) In the state of Bahia, there has been a gradual decline in the incidence of tuberculosis. This indicator decreased by 29.6%, from 51.0/100,000 to 35.9/100,000 population, between 2003 and 2011.(3) It is possible that improved living conditions and the increased effectiveness of the tuberculosis control program in this period contributed to this trend. Despite this decline, the disease rates remained equal to or greater than 30/100,000 population in nearly 45% of the Regional Health Districts in 2009. In the 16th Regional Health District, the incidence was, on average, 25.3/100,000 population between 2004 and 2009, with the highest rates in the period (around 30.0/100,000) being registered in 2005, 2006, and 2009.(4) The association between tuberculosis, malnutrition, and poverty is well established. However, this relationship is known to be

477

bidirectional, because the clinical course of the disease leads to secondary malnutrition, and malnutrition is also a risk factor for the disease. (5) Depending on the severity and/or duration of nutritional imbalance, a patient’s nutritional status can deteriorate.(6) Another aspect that must also be considered is the interaction of drugs and nutrients. In the presence of nutrients, the drugs might not reach effective levels in the blood, their effects might be prolonged by their slow absorption, or they might cause nutrient depletion, leading to nutritional deficiencies.(7) On the basis of this knowledge, the four drugs used for the treatment of tuberculosis (pyrazinamide, rifampin, isoniazid, and ethambutol) are administered orally, in a single daily dose before breakfast, to increase their absorption.(8) Therefore, the importance of assessing the nutritional status of patients with tuberculosis is evident. Investigations of the nutritional status of tuberculosis patients conducted in Brazil have shown varying results. An evaluation of 31 women with tuberculosis reported that 61.3% had protein-energy malnutrition,(5) whereas another investigation found similar values (33.3% and 31.3%, respectively) for the prevalence of underweight among men and women.(9) The objective of the present study was to determine the prevalence of nutritional deficiency in patients with pulmonary tuberculosis in order to produce information that can help ensure quality follow-up care for patients being treated for this disease, as well as their recovery.

Methods This was a cross-sectional descriptive study using data obtained from the Brazilian Case Registry Database of the 16th Regional Health District of the state of Bahia and from the medical records of patients in whom the diagnosis of pulmonary tuberculosis had been confirmed, in accordance with the recommendation of the Brazilian National Ministry of Health.(10) This Regional Health District, the headquarters of which are in the municipality of Jacobina, includes 19 municipalities that comprise the Chapada Norte (Northern Plateau) of the state and has 377,710 inhabitants.(11) All of the 159 primary health care clinics, as well as 93.5% of the 957 hospital beds, are part of the Brazilian Unified Health Care System, which employs more than 90% of the health professionals in the region. J Bras Pneumol. 2013;39(4):476-483

478

Piva SGN, Costa MCN, Barreto FR, Pereira SM

The study population consisted of individuals, aged 15-59 years, residing in one of the municipalities that make up the 16th Regional Health District. We considered all of the reported cases of tuberculosis for which, upon the diagnosis being confirmed, initiated treatment in April of 2008 and completed it by March of 2009. Elderly individuals were not included because, in general, they exhibit aging-related characteristics, such as progressive decrease in height and progressive increase in weight and body mass index (BMI) up to 65-70 years of age, from which point on the body composition changes are reduced.(12) The collected data was recorded on a form with closed questions related to the variables, such as age, gender, height, weight at treatment initiation, weight over the six months of treatment, etc. We calculated the incidence rate of confirmed cases of tuberculosis and the prevalence of nutritional deficiency among these patients for the regional district as a whole and for each of its municipalities. Nutritional deficiency was defined a BMI < 18.5 kg/m2,(13) and, for the calculation of this indicator, only consistent and complete information was considered. We analyzed the frequency distribution of the demographic, social, clinical, and epidemiological characteristics of the patients and conducted statistical testing of differences between proportions. The level of significance was set at 0.05. We calculated tuberculosis mortality and lethality rates for the regional district. The study project was approved by the Research Ethics Committee of the Collective Health Institute of the Federal University of Bahia (CEP/ISC no. 47/2010).

Results In 4 of the 19 municipalities that make up the 16th Regional Health District, no confirmed cases of pulmonary tuberculosis were reported during the study period. In the remaining municipalities, 102 cases were reported, of which 72 were confirmed. Of those 72, most (81.9%) were in males, and most of the patients (57.0%) were in the 30-49 year age bracket (Table 1). The mean age was 39.8 ± 10.8 years for the sample as a whole, 40.8 ± 10.7 years for males, and 34.2 ± 9.8 years for females. Of the total number of patients, 75.5% had had up to four years of schooling, 64.7% were Mulatto, and 20.6% were Black. J Bras Pneumol. 2013;39(4):476-483

Table 2 shows that 77.8% of the confirmed cases were admitted to tuberculosis facilities as new cases, and that 90.7% of the patients were treated as outpatients. Transfer to other facilities and recurrence accounted for 12.5% and 8.3% of the cases, respectively. Smear microscopy/first sample was positive in 70.8% of the cases, and 5.6% patients did not undergo the test. Data regarding smear microscopy/second sample was available for 54 patients, of whom 22.2% did not undergo the test and 61.1% had a positive result. Comorbidities were reported in 29 cases (40.3%). Of those patients, 55.2% reported using alcohol and 24.1% reported having diabetes. Testing for HIV was performed in 44.4% of the cases, and, for the remaining cases, no data regarding HIV testing results was available by treatment completion. At 9 months of follow-up, when the case is considered closed, 75.0% of the patients were cured, 5.6% had been noncompliant with the treatment, and 2.8% had died from tuberculosis. For 6.8%, no outcome data was available. Malnourished and normal-weight patients differed in terms of the frequency of transfer (15.4% vs. 0.0%), positive smear microscopy/ first sample (69.2% vs. 61.9%), positive smear microscopy/second sample (77.8% vs. 46.7%), and treatment noncompliance (15.4% vs. 9.4%). Although there were no statistically significant differences between malnourished and normalweight patients regarding alcohol consumption (50.0% vs. 66.7%) or cure (76.9% vs. 81.0%), the latter had higher rates. Table 1- Confirmed new cases of pulmonary tuberculosis in patients between 15 and 59 years of age by gender and age bracket between April of 2008 and March of 2009 in the 16th Regional Health District of the state of Bahia. Age bracket, Gender Total years Male Female n % n % n % 15-19 2 3.4 1 7.7 3 4.2 20-29

11.9 3

23.1 10

13.9

30-39

23.7 6

46.2 20

27.8

40-49

32.2 2

15.4 21

29.2

50+

28.8 1

7.7

25.0

Total

81.9 13

18.1 72

100.0

Prevalence of nutritional deficiency in patients with pulmonary tuberculosis

479

Table 2 - Confirmed new cases of pulmonary tuberculosis in patients between 15 and 59 years of age by selected characteristics and nutritional status between April of 2008 and March of 2009 in the 16th Regional Health District of the state of Bahia.a Characteristic Nutritional status* Total Normal-weight

Malnourished

(n = 21)

(n = 13)

(n = 72)

New case

15 (71.4)

10 (76.9)

56 (77.8)

Transfer

2 (15.4)

9 (12.5)

Recurrence

5 (23.8)

1 (7.7)

6 (8.3)

Readmission for noncompliance

1 (4.8)

1 (1.4)

(n = 16)

(n = 13)

(n = 54)

14 (87.5)

12 (92.3)

49 (70.7)

1 (1.9)

Type of admission

Institutionalization Non-institutionalized Prison Others

2 (12.5)

1 (7.7)

4 (7.4)

(n = 21)

(n = 13)

(n = 72)

Positive

13 (61.9)

9 (69.2)

51 (90.7)

Negative

7 (33.3)

4 (30.8)

17 (23.6)

Diagnostic smear microscopy: 1st sample

Not performed

1 (4.8)

4 (5.6)

(n = 15)

(n = 9)

(n = 54)

Positive

7 (46.7)

7 (77.8)

33 (61.1)

Negative

3 (20.0)

1 (11.1)

9 (16.7)

Not performed

5 (33.3)

1 (11.1)

12 (22.2)

Diagnostic smear microscopy: 2nd sample

Comorbidities

(n = 6)

(n= 29)

Alcoholism

4 (66.7)

3 (50.0)

16 (55.2)

Diabetes

2 (33.3)

7 (24.1)

1 (16.7)

1 (3.4)

Mental illness Others (smoking, lung tumor, etc.) HIV serology

5 (17.2)

(n = 21)

(n = 13)

(n = 63)

Positive

Negative

13 (61.9)

7 (53.8)

28 (44.4)

In progress

8 (38.1)

6 (46.2)

35 (55.6)

Status at 9 months

(n = 21)

(n = 13)

(n = 72)

17 (81.0)

10 (76.9)

54 (75.0)

Cure Noncompliance

2 (9.4)

2 (15.4)

4 (5.6)

Death from tuberculosis

2 (2.8)

Death from other causes

1 (1.4)

Transfer within the same city

2 (2.8)

Transfer to another city

1 (1.4)

Transfer to another state

1 (1.4)

Change in regimen because of drug intolerance

1 (1.4)

Is still under treatment

1 (4.8)

1 (1.4)

No data

1 (4.8)

5 (6.8)

Source: Sistema de Informação de Agravos de Notificação (SINAN, Brazilian Case Registry Database) – 16ª Diretoria Regional de Saúde-Bahia (16ª DIRES-BA, 16th Regional Health Board of the state of Bahia). ND: no data. aValues expressed as n (%). *No statistically significant differences were found between malnourished and normal-weight individuals regarding the variables studied.

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Piva SGN, Costa MCN, Barreto FR, Pereira SM

Table 3 - Confirmed new cases of pulmonary tuberculosis in patients between 15 and 59 years of age by nutritional status and results of follow-up smear microscopy during treatment between April of 2008 and March of 2009 in the 16th Regional Health District of the state of Bahia.a Smear microscopy resultsb Nutritional status* Total Normal-weight Malnourished At 2 months (n = 18) (n = 12) (n = 62) Positive 1 (5.6) 1 (8.3) 6 (9.7) Negative 13 (72.2) 8 (66.7) 37 (59.7) Not performed 4 (22.2) 3 (25.0) 19 (30.6) At 4 months (n = 17) (n = 11) (n = 53) Positive ND ND 1 (1.8) Negative 11 (64.8) 7 (63.6) 26 (49.1) Not performed 6 (35.2) 4 (36.4) 26 (49.1) At 6 months (n = 16) (n = 11) (n = 57) Positive ND ND 2 (3.5) Negative 14 (87.5) 8 (72.7) 46 (80.7) Not performed 2 (12.5) 3 (27.3) 9 (15.8) Source: Sistema de Informação de Agravos de Notificação (SINAN, Brazilian Case Registry Database) – 16ª Diretoria Regional de Saúde-Bahia (16ª DIRES-BA, 16th Regional Health Board of the state of Bahia). ND: no data. aValues expressed as n (%). bThere were no records of results of follow-up smear microscopy at 2, 4, and 6 months, respectively, for 10 (14.0%), 19 (26.4%), and 15 (20.8%) of the patients. *No statistically significant differences were found between malnourished and normal-weight individuals regarding the variables studied.

Table 4 - Incidence rate of pulmonary tuberculosis (per 100,000 population) and prevalence of malnutrition in patients between 15 and 59 years of age by municipality of residence, from baseline to the sixth month of treatment, in the 16th Regional Health District of the state of Bahia. Municipality Incidence Prevalence of malnutrition by month of treatmenta rate Baseline 1 2 3 4 5 6 Caem

34,0

Caldeirão Grande

89.3

2 (33.3)

1 (16.7)

Capim Grosso

123.3

3 (0)

1 (0)

2 (0)

3 (0)

0 (0)

Jacobina

40.6

2 (28.6)

3 (42.8)

2 (50.0)

4 (50.0)

2 (33.3)

1 (16.7)

Mairi

8.7

Miguel Calmon

17.8

1 (100)

Mirangaba

9.3

1 (0)

0 (0)

Morro do Chapéu

14.8

1 (33.3)

3 (0.0)

2 (0.0)

0 (0.0)

Ourolândia

29.1

3 (100.0)

2 (66.7)

1 (33.3)

2 (66.7)

1 (33.3)

2 (66.7)

Saúde

13.6

1 (100)

Serrolândia

25.9

1 (100)

1 (0)

1 (50)

1 (0)

1 (50)

Umburanas

19.5

1 (0)

0 (0)

Várzea da Roça

22.4

Várzea do Poço

18.1

Várzea Nova

11.5

TOTAL

30.6

9 (50.0)

15 (60.0)

11 (55.0)

14 (60.9)

15 (62.5)

12 (52.1)

6 (50.0)

Source: Sistema de Informação de Agravos de Notificação (SINAN, Brazilian Case Registry Database) – 16ª Diretoria Regional de Saúde-Bahia (16ª DIRES-BA, 16th Regional Health Board of the state of Bahia) and forms containing data obtained from the medical records of patients residing in one of the 15 municipalities. ND: no data. aValues expressed as n (%).

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Prevalence of nutritional deficiency in patients with pulmonary tuberculosis

At 2 months, 59.7% and 30.6% of the 62 patients for whom data regarding follow-up smear microscopy during treatment were available had negative results and did not undergo the test, respectively (Table 3). At 4 months of treatment, 1.8%, 49.1%, and 49.1% of the 53 patients for whom these data were available had positive results, had negative results, and did not undergo the test, respectively. At 6 months, 3.5%, 80.7%, and 15.8% of the 57 patients for whom these data were available had positive results, had negative results, and did not undergo the test, respectively. The greatest differences between malnourished and normal-weight patients were found in the proportion of positive smear microscopy (8.3% vs. 5.6%) and negative smear microscopy (72.7% vs. 87.5%) at 2 months. Although there were no records of positive smear microscopy at 4 or 6 months of treatment, the proportion of patients who did not undergo the test was high in the two groups. The differences found were not statistically significant. The incidence of pulmonary tuberculosis for the 16th Regional Health District was 30.6/100,000 population aged 15-59 years. In the municipalities of Caldeirão Grande, Capim Grosso, and Jacobina, the value of this indicator (per 100,000 population) was 89.3, 123.3, and 40.6, respectively, whereas in the municipalities of Mairi and Mirangaba, the incidence rate was lowest (8.7 and 9.3, respectively). The prevalence of malnutrition among the cases of pulmonary tuberculosis was 50.0% at treatment initiation, 60.0% at 1 month of follow-up, and 50.0% at 6 months of follow-up. At these same time points, the BMI means were 17.7 ± 3.2 kg/m2, 17.3 ± 3.4 kg/m2, and 21.0 ± 3.3 kg/m2, respectively, among the cases for which data regarding weight and height were available. In 10 (66.7%) of the 15 municipalities in which cases were reported, data regarding these two variables were available for at least a treatment month. Throughout the period analyzed, variation in BMI occurred in only 29 cases. The prevalence of nutritional deficiency at baseline was 33.3% in Caldeirão Grande; 28.6% in Jacobina; and 100% in Ourolândia, Saúde, and Serrolândia (Table 4). During the study period, lethality from pulmonary tuberculosis was 3%, whereas the mortality rate was 0.84/100,000 population. No deaths from tuberculosis occurred among malnourished patients.

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Discussion The findings of the present study are suggestive of the existence of a high prevalence (50%) of malnutrition among patients with pulmonary tuberculosis in the 16th Regional Health District, this prevalence being even higher than that found in Rio de Janeiro (32%)(9) and São Paulo (34.9%).(14) This problem has also been found to be very common in hospitalized patients with tuberculosis in São Paulo and northeastern Brazil.(15,16) Likewise, underweight was present in 49% of 49 indigenous subjects under 15 years of age diagnosed with tuberculosis in Mato Grosso do Sul between 2007 and 2010.(17) Although, perhaps because of the small numbers, no statistically significant differences were found between malnourished and normal-weight patients regarding the characteristics analyzed, the rate of treatment noncompliance (15.4%), almost twice as high among malnourished patients, is of note, exceeding 5%, the value considered acceptable.(18) This may be related to the higher frequency of side effects of chemotherapy among patients with this condition,(19) especially gastric intolerance, because it complicates the continuity of treatment. In fact, the nutritional status of patients is reported as one of the factors that may be related to the side effects of tuberculosis treatment(20) and as a reason for noncompliance,(21) i.e., contributing to nonadherence to treatment. In addition, malnourished patients have alterations in immune mechanisms,(22) and this is a possible hypothesis to explain the higher frequency of positive smear microscopy among these patients. In 2009, the incidence of pulmonary tuberculosis (30.6/100,000 population) in the population of the regional health district investigated was lower than that found in Salvador (58.9/100,000), the capital of the state of Bahia, for that same year,(23) which may be a result of the possible occurrence of greater underreporting of tuberculosis in the interior of this state. The predominance of the disease in males and adults is consistent with the literature,(24,25) as is the lower level of education(26) and the predominance of cases among Mulattos and Blacks.(27) In addition, alcohol consumption was very common among patients with tuberculosis, which is similar to results reported by other authors.(28,29) Factors related to lifestyle and habits, as well as to socioeconomic and cultural conditions, are offered as possible explanations. The noncompliance J Bras Pneumol. 2013;39(4):476-483

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rate (5.6%) found for the group of patients with pulmonary tuberculosis in this regional district was close to the value considered acceptable, which represents a positive result. However, the cure rate (75%) is slightly below the 85% rate set by the WHO,(1) indicating the existence of a deficiency that needs to be identified and resolved. We emphasize that, because the present study was based on secondary data that may present problems related to its scope and quality, our findings should be interpreted with caution. It is possible that limitations, such as underreporting of tuberculosis cases and incorrect and/or incomplete entries in some fields on the forms for data collection by health care facilities, affected the results presented. In the municipality of Belford Roxo, located in the state of Rio de Janeiro, a study on the quality of data regarding tuberculosis found a 6.4% underreporting rate in the triennium 2006-2008.(30) We understand that the reduced number of tuberculosis cases for which data regarding weight and height were available is the major limitation of this investigation, making it impossible to obtain conclusive information about the true prevalence of malnutrition among patients. There is no doubt that underreporting of these data is a cause for concern, both because it is suggestive of the poor quality of health care provided and because of the importance of nutritional assessment for the analysis of treatment of this mycobacterial disease in the decision-making process regarding therapeutic interventions aimed at these patients.(6) In view of the possibility that there is a high prevalence of nutritional deficiency among patients with pulmonary tuberculosis, and considering similar findings reported by other studies conducted in Brazil, we suggest that a specific field for recording weight, height, and BMI be added to the Follow-up Report Form of tuberculosis cases.

References 1. World Health Organization [homepage on the Internet]. Geneva: World Health Organization. [cited 2013 Jan 29]. Global tuberculosis report 2012. [Adobe Acrobat document, 98p.]. Available from: http://www.who.int/ tb/publications/global_report/gtbr12_main.pdf 2. Pan American Health Organization [homepage on the Internet]. Washington, D.C: Pan American Health Organization. [cited 2013 Sep 26]. World TB Day, 24 March 2012: “Stop TB in my lifetime”. Available from: http://new.paho.org/hq/index.php?option=com_conten t&task=view&id=6529&Itemid=3511&lang=en

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3. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2012 Dec 28]. Boletim Epidemiológico. Especial Tuberculose. Volume 43 março, 2012. [Adobe Acrobat document, 12p.]. Available from: http://portal.saude.gov.br/portal/arquivos/pdf/ bolepi_v43_especial_tb_correto.pdf 4. Secretaria da Saúde do Estado da Bahia [homepage on the Internet]. Salvador: Secretaria da Saúde do Estado da Bahia. [cited 2012 Nov 15]. Casos de Tuberculose confirmados e notificados no SinanNET - Bahia. Available from: http://www3.saude.ba.gov.br/cgi/deftohtm. exe?tabnet/sinan/tube.def 5. Nogueira CR, Chaves GV, Teixeira MT, Franca CA, Ramalho R. Aspectos antropométricos, bioquímicos e sintomatológicos em mulheres com tuberculose pulmonar. Rev Cienc Med Campinas. 2006;15(4):281-8. 6. Vannucchi H, Unamuno MR, Marchini JS. Avaliação do estado nutricional. Medicina (Rib Preto). 1996;29(1):5-18. 7. Cuppari L, organizer. Guias de Medicina Ambulatorial e Hospitalar UNIFESP/EPM - Nutrição Clínica no Adulto. São Paulo: Editora Manole; 2002. 8. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2010 Aug 10]. Tratamento diretamente observado (TDO) da tuberculose na atenção básica: protocolo de enfermagem. [Adobe Acrobat document, 168p.]. Available from: http://portal.saude. gov.br/portal/arquivos/pdf/manual_tdo_tb.pdf 9. Ramalho RA, Costa RS da, Vieira AC, Silva LB da, Machado FC, Menezes EM, et al. Avaliação nutricional de pacientes com tuberculose pulmonar atendidos na UISHL. Bol Pneumol Sanit. 2000;8(2):13-20. 10. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2012 Sep 05]. Vigilância em Saúde: Dengue, Esquistossomose, Hanseníase, Malária, Tracoma e Tuberculose. Available from: http://portal. saude.gov.br/portal/arquivos/pdf/abcad21.pdf 11. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2010 Sep 08]. Análise da disponibilidade domiciliar de alimentos e do estado nutricional no Brasil. Rio de Janeiro. Available from: http://www.ibge.gov.br/home/estatistica/populacao/ condicaodevida/pof/2002analise/default.shtm 12. Acu-a K, Cruz T. Avaliação do estado nutricional de adultos e idosos e situação nutricional da população brasileira. Arq Bras Endocrinol Metab. 2004;48(3):345-61. http://dx.doi.org/10.1590/S0004-27302004000300004 13. World Health Organization [homepage on the Internet]. Geneva: World Health Organization. [cited 2010 Aug 08]. Physical Status: The Use and Interpretation of Anthropometry - Report of a WHO Expert Committee. Available from: http://helid.digicollection.org/en/d/ Jh0211e/1.html#Jh0211e.1 14. Souza AL, Ribeiro AS, Tudisco ES. Avaliação nutricional de pacientes tuberculosos em tratamento ambulatorial. J Pneumol. 1992;18(4):167-70. 15. Nogueira PA. Motivos e tempo de internação e o tipo de saída em hospitais de tuberculose do Estado de São Paulo, Brasil – 1981 a 1995. J Pneumol. 2001;27(3):123-9. http://dx.doi.org/10.1590/S0102-35862001000300001 16. Pinheiro VG, Barroso EC, Ramos LA, Monteiro HS, Lima AM, Cordeiro JI, et al. Estado nutricional de pacientes com tuberculose pulmonar hospitalizados no Nordeste do Brasil. J Pneumol. 2002;28(Suppl 2): 645. 17. dos Santos SC, Marques AM, de Oliveira RL, da Cunha RV. Scoring system for the diagnosis of tuberculosis in

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indigenous children and adolescents under 15 years of age in the state of Mato Grosso do Sul, Brazil. J Bras Pneumol. 2013;39(1):84-91. PMid:23503490 18. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Manual de recomendações para o controle da tuberculose no Brasil. Brasília: Ministério da Saúde; 2011. 19. Brólio R. Quimioterapia da tuberculose. Rev Saude Publ. 1975;9(1):71-85. http://dx.doi.org/10.1590/ S0034-89101975000100011 20. Brasil. Ministério da Saúde. Fundação Nacional de Saúde. Centro de Referência Prof. Hélio Fraga. Sociedade Brasileira de Pneumologia e Tisiologia. Controle da tuberculose: uma proposta de integração ensino-serviço. Rio de Janeiro: FUNASA/CRPHF/SBPT; 2002. 21. Mendes AM, Fensterseifer LM. Tuberculose: porque os pacientes abandonam o tratamento? Bol Pneumol Sanit. 2004;12(1):27-38. 22. Alam I, Larbi A, Pawelec G. Nutritional status influences peripheral immune cell phenotypes in healthy men in rural Pakistan. Immun Ageing. 2012;9(1):16. http:// dx.doi.org/10.1186/1742-4933-9-16 PMid:22863368 PMCid:3488561 23. Secretaria de Saúde do Estado da Bahia [homepage on the Internet]. Salvador: Secretaria de Saúde do Estado da Bahia. [cited 2012 Sep 19]. Diretoria de Informações em Saúde 2009. Available from: http://www.saude.ba.gov. br/cgi/tabcgi.exe?.tabnet/sinan/tube.def 24. Silveira MP, de Adorno RF, Fontana T. Profile of patients with tuberculosis: evaluation of the Brazilian national tuberculosis control program in Bagé, Brazil. J Bras

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Pneumol. 2007;33(2):199-205. http://dx.doi.org/10.1590/ S1806-37132007000200015 PMid:17724540 25. Mendes JM, Fonseca Lde S, Lourenço MC, Ferreira RM, Saad MH. A retrospective study of the epidemiological aspects of tuberculosis in the Complexo de Manguinhos, an urban slum area in Rio de Janeiro, Brazil, 20002002. J Bras Pneumol. 2007;33(4):443-7. http://dx.doi. org/10.1590/S1806-37132007000400014 PMid:17982537 26. Maciel EL, Guidoni LM, Favero JL, Hadad DJ, Molino LP, Jonhson JL, et al. Adverse effects of the new tuberculosis treatment regimen recommended by the Brazilian Ministry of Health. J Bras Pneumol. 2010;36(2):232-8. PMid:20485945 27. de Oliveira HB, Moreira Filho Dde C. Tuberculosis recurrence and its risk factors [Article in Portuguese]. Rev Panam Salud Publica. 2000;7(4):232-41. PMid:10846926 28. Severo NP, Leite CQ, Capela MV, Simões MJ. Clinical and demographic characteristics of patients hospitalized with tuberculosis in Brasil between 1994 and 2004. J Bras Pneumol. 2007;33(5):565-71. http://dx.doi.org/10.1590/ S1806-37132007000500012 PMid:18026655 29. Paixão LM, Gontijo ED. Profile of notified tuberculosis cases and factors associated with treatment dropout [Article in Portuguese]. Rev Saude Publica. 2007;41(2):205-13. http://dx.doi.org/10.1590/S0034-89102007000200006 PMid:17384794 30. Medeiros D, Sucupira ED, Guedes RM, Costa AJ. Análise da qualidade das informações sobre tuberculose no município de Belford Roxo, Rio de Janeiro, 2006 a 2008. Cad Saude Colet. 2012;20(2):146-52.

About the authors Silvana Gomes Nunes Piva

Assistant Professor. University of the State of Bahia, Campus VII, Senhor do Bonfim, Brazil.

Maria da Conceição Nascimento Costa

Professor of Epidemiology. Collective Health Institute, Federal University of Bahia, Salvador, Brazil.

Florisneide Rodrigues Barreto

Professor of Epidemiology. Collective Health Institute, Federal University of Bahia, Salvador, Brazil.

Susan Martins Pereira

Professor of Epidemiology. Collective Health Institute, Federal University of Bahia, Salvador, Brazil.

J Bras Pneumol. 2013;39(4):476-483

Original Article Pulmonary tuberculosis and lung cancer: simultaneous and sequential occurrence* Tuberculose pulmonar e câncer de pulmão: ocorrência simultânea ou sequencial

Denise Rossato Silva, Dirceu Felipe Valentini Junior, Alice Mânica Müller, Carlos Podalirio Borges de Almeida, Paulo de Tarso Roth Dalcin

Resumo Objetivo: O câncer de pulmão (CP) é o tipo mais letal de câncer na população mundial e representa um importante problema de saúde pública. A tuberculose é outra causa significativa de morbidade e mortalidade, especialmente em países em desenvolvimento. A ocorrência de tuberculose pulmonar e CP no mesmo paciente, simultaneamente ou não, tem sido descrita em diversas séries de casos e estudos de caso-controle. O objetivo deste estudo foi descrever as características de pacientes com tuberculose e CP, com apresentação simultânea ou sequencial. Métodos: Estudo transversal, realizado através de revisão de prontuários. Resultados: Foram incluídos no estudo 24 pacientes com diagnósticos de tuberculose e CP no período entre 2009 e 2012. Os diagnósticos de tuberculose e CP ocorreram simultaneamente em 10 pacientes, enquanto a tuberculose foi diagnosticada antes do CP em 14. A mediana do tempo entre os diagnósticos foi de 5 anos (variação interquartil: 1-30 anos). Quatorze pacientes (58,3%) eram do sexo masculino, 20 (83,3%) eram brancos, e 22 (91,7%) eram tabagistas ativos ou ex-tabagistas. O tipo histológico mais comum foi o adenocarcinoma, em 14 casos (58,3%), seguido de carcinoma epidermoide, em 6 (25,0%). Sete pacientes (29,2%) já apresentavam metástases à distância no momento do diagnóstico; desses 7, 5 (71%) tiveram o diagnóstico de CP e TB simultaneamente. Conclusões: Neste estudo, a maioria dos pacientes com tuberculose e CP eram tabagistas ou ex-fumantes e a tuberculose foi diagnosticada tanto antes quanto simultaneamente ao diagnóstico de CP. O carcinoma brônquico não pequenas células, em especial o adenocarcinoma, foi o tipo histológico mais comum. Descritores: Tuberculose/diagnóstico; Neoplasias Pulmonares/diagnóstico; Comorbidade.

Abstract Objective: Lung cancer (LC) is the leading cause of cancer-related death and represents a major public health problem worldwide. Another major cause of morbidity and mortality, especially in developing countries, is tuberculosis. The simultaneous or sequential occurrence of pulmonary tuberculosis and LC in the same patient has been reported in various case series and case-control studies. The objective of this study was to describe the characteristics of patients developing tuberculosis and LC, either simultaneously or sequentially. Methods: This was a cross-sectional study based on the review of medical charts. Results: The study involved 24 patients diagnosed with tuberculosis and LC between 2009 and 2012. The diagnoses of tuberculosis and LC occurred simultaneously in 10 patients, whereas tuberculosis was diagnosed prior to LC in 14. The median time between the two diagnoses was 5 years (interquartile range: 1-30 years). Fourteen patients (58.3%) were male, 20 (83.3%) were White, and 22 (91.7%) were smokers or former smokers. The most common histological type was adenocarcinoma, identified in 14 cases (58.3%), followed by epidermoid carcinoma, identified in 6 (25.0%). Seven patients (29.2%) presented with distant metastases at diagnosis; of those 7 patients, 5 (71%) were diagnosed with LC and tuberculosis simultaneously. Conclusions: In the present study, most of the patients with tuberculosis and LC were smokers or former smokers, and tuberculosis was diagnosed either before or simultaneously with LC. Non-small cell lung cancer, especially adenocarcinoma, was the most common histological type. Keywords: Tuberculosis/diagnosis; Lung neoplasms/diagnosis; Comorbidity.

*Study carried out at the Federal University of Rio Grande do Sul School of Medicine, Porto Alegre, Brazil. Correspondence to: Denise Rossato Silva. Rua Ramiro Barcelos, 2350, Santa Cecília, CEP 90035-903, Porto Alegre, RS, Brasil. Tel. 55 51 3359-8241. E-mail: denise.rossato@terra.com.br Financial support: Dirceu Felipe Valentini Junior is the recipient of a Young Investigator Grant from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development). Submitted: 1 April 2013. Accepted, after review: 3 June 2013.

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Pulmonary tuberculosis and lung cancer: simultaneous and sequential occurrence

Introduction Lung cancer (LC) is the most deadly type of cancer and represents a major public health problem worldwide. It is the leading cause of cancer-related death in Brazil and in the world, with 1.3 million deaths annually.(1) Another major cause of morbidity and mortality, especially in developing countries, is tuberculosis.(2) It has been suggested that inflammation and pulmonary fibrosis caused by tuberculosis can induce genetic damage, which can increase LC risk.(3-5) The increased occurrence of LC in patients with tuberculosis can also be related to infection-induced immunosuppression.(6) In contrast, cancer-induced or chemotherapy-induced immunosuppression can also lead to increased rates of tuberculosis reactivation in patients with solid tumors.(7) The simultaneous or sequential occurrence of pulmonary tuberculosis and LC in the same patient has been reported in various case series and case-control studies.(8-13) The association between these two diseases is important, since both are quite prevalent and have a major impact on public health. In addition, considering that one study(10) demonstrated that the association between tuberculosis and LC varies in different ethnic groups and also in different regions, it is important to know the characteristics of these cases in Brazil. Therefore, the objective of this study was to describe the clinical characteristics of patients with pulmonary tuberculosis and LC.

Methods This was a cross-sectional study, involving retrospective data collection, conducted in order to determine the characteristics of patients with tuberculosis and LC who were treated at the Hospital de Clínicas de Porto Alegre (HCPA, Porto Alegre Hospital de Clínicas), located in the city of Porto Alegre, southern Brazil. The HCPA is a general tertiary university hospital with 750 beds and approximately 30,000 hospitalizations annually. The HCPA Research Ethics Committee granted permission for access to patient records. A waiver of informed consent was obtained, and the researchers signed a confidentiality agreement. The study involved patients diagnosed with tuberculosis and LC, either simultaneously or sequentially. We performed a search of the files of the pulmonology outpatient clinics

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for patients with tuberculosis and LC, and the electronic medical records of these patients were reviewed. A standardized form was completed for each patient included in the study. Demographic data and data relating to the diagnoses of tuberculosis and LC were collected, as were pulmonary function test results. The diagnosis of pulmonary tuberculosis was based on consensus criteria(14): positive ZiehlNeelsen staining for AFB (two positive smears); positive Ziehl-Neelsen staining for AFB (a positive smear and a positive culture for Mycobacterium tuberculosis); positive Ziehl-Neelsen staining for AFB and radiological findings consistent with pulmonary tuberculosis; a single positive culture for M. tuberculosis; or epidemiological, clinical, and radiological findings consistent with pulmonary tuberculosis, associated with a favorable response to treatment with antituberculosis drugs. The diagnosis of LC was based on anatomopathological findings. The diagnoses of LC and tuberculosis were classified by timing as follows: simultaneous—when the diagnoses of tuberculosis and LC occurred simultaneously or when the time between the two diagnoses was < 2 months; sequential (LC first)—when tuberculosis was diagnosed ≥ 2 after LC diagnosis and within 12 months of completion of LC treatment; sequential (tuberculosis first)—when LC is diagnosed ≥ 2 months after tuberculosis diagnosis, indefinitely, because of the possibility of scar cancer.(10,15,16) The data were entered into Microsoft Excel spreadsheets, after which they were processed and analyzed with the Statistical Package for the Social Sciences, version 18.0 (SPSS Inc., Chicago, IL, USA). We carried out a descriptive analysis of the study variables. Quantitative data are presented as mean ± SD. Qualitative data are expressed as n (%).

Results The study involved 24 patients diagnosed with tuberculosis and LC between 2009 and 2012. The principal characteristics of the patients are shown in Table 1. In 10 of the 24 patients, the diagnoses of tuberculosis and LC occurred simultaneously, whereas, in 14, tuberculosis was diagnosed before LC. The median time between the two diagnoses was 5 years (interquartile range: 1-30 years). J Bras Pneumol. 2013;39(4):484-489

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Table 1 - Principal characteristics of the patients.a Characteristic Result Male gender 14 (58.3) Age, yearsb 62.8 ± 10.6 White race 20 (83.3) Smoker 11 (45.8) Former smoker 11 (45.8) History of TB contact 3 (12.5) Family history of LC 3 (12.5) Time of diagnoses TB and LC simultaneously 10 (41.7) TB before LC 14 (58.3) LC before TB 0 (0.0) Type of LC Adenocarcinoma 14 (58.3) Epidermoid carcinoma 6 (25.0) Others 4 (16.7) TB: tuberculosis; and LC: lung cancer. aValues expressed as n (%), except where otherwise indicated. bValue expressed as mean ± SD.

Three patients (12.5%) reported having had tuberculosis twice. The diagnosis of tuberculosis was established by the following methods: smear microscopy of spontaneous sputum, in 3 patients; culture of spontaneous sputum, in 2; smear microscopy of induced sputum, in 2; bronchoalveolar lavage (BAL) culture, in 2; PCR positivity for M. tuberculosis in BAL samples, in 4; and clinical and radiological findings consistent with tuberculosis, in 11. Tuberculosis treatment was as follows: a regimen consisting of rifampin, isoniazid, and pyrazinamide, in 11 patients (45.8%); and a regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol, in 7 (29.2%). In 6 patients (25.0%), data on treatment regimen were either not provided or unavailable. Only 1 patient (4.2%) reported noncompliance with tuberculosis treatment, 3 (12.5%) died, and 16 (66.7%) were discharged as cured. For 5 (20.8%) of the patients, no treatment outcome data were available. The mean age at LC diagnosis was 62.8 ± 10.6 years. Of the 24 patients, 7 (29.2%) presented with distant metastases at diagnosis; of those 7 patients, 71% were diagnosed with LC and tuberculosis simultaneously. The following LC treatments were performed: radiotherapy alone, in 6 patients (25.0%); chemotherapy and radiotherapy, in 4 (16.7%); surgery alone, in 3 (12.5%); chemotherapy alone, 2 (8.3%); J Bras Pneumol. 2013;39(4):484-489

surgery and radiotherapy, in 2 (8.3%); surgery and chemotherapy, in 2 (8.3%); and supportive treatment alone, in 5 (20.8%).

Discussion In this study, we described the characteristics of 24 patients developing tuberculosis and LC, either simultaneously or sequentially. Tuberculosis was diagnosed before LC in most of the patients, and in none of the cases was LC diagnosed before tuberculosis. Non-small cell lung cancer, especially adenocarcinoma, was the most common histological type. The coexistence of pulmonary tuberculosis and LC was first described in 1810, and it was demonstrated histologically a few years later.(9) Since then, several studies on this association have been published, most of which are case series and case-control studies.(8-13) However, it has always been questioned whether this association was casual or whether it could be explained by a plausible biological mechanism. One hypothesis would be that inflammation associated with infections can contribute to carcinogenesis.(4) Reactive oxygen or nitrogen species produced by activated neutrophils can bind to the DNA, inducing genetic damage and neoplastic transformation. (17,18) In fact, it has been shown that alterations of the fragile histidine triad gene might be involved in lung carcinogenesis in patients with chronic pulmonary tuberculosis.(19-21) In addition, during tissue repair, there is increased cell proliferation and angiogenesis, and the epithelium is more prone to metaplasia. Furthermore, carcinogens concentrate preferentially in hyperactive areas to induce neoplastic changes.(22,23) The cases described here are similar to those reported in previous studies.(8-13) Adenocarcinoma was the most common histological type in our case series. In a meta-analysis(10) of 37 case-control studies and 4 cohort studies, the association between tuberculosis and LC was significant for adenocarcinoma (relative risk = 1.6), but not for epidermoid carcinoma or small cell carcinoma. In a case series of LC in Japan,(24) adenocarcinoma was also the most common cancer. Another study(9) demonstrated that all scar carcinomas were adenocarcinomas, and that, even in cases in which there was no proximity between the scar and the neoplasm, adenocarcinoma was the most common histological type.

Pulmonary tuberculosis and lung cancer: simultaneous and sequential occurrence

The vast majority of the patients described here were smokers or former smokers. Despite the cumulative effects of tobacco as a carcinogen, the relationship between pulmonary tuberculosis and LC persists even after control for smoking, with cancer risk being 2.5-fold higher among patients with tuberculosis.(6,8,25) A meta-analysis(10) corroborated this evidence, showing that the association between tuberculosis and LC was not due to the effects of smoking, because, when considering only nonsmoking patients, there was a 1.78-fold increase in LC risk among patients with tuberculosis. That same metaanalysis demonstrated that the association between tuberculosis and LC was not due to the time since diagnosis of tuberculosis. Because the initial symptoms of LC can be mistaken for the symptoms of pulmonary tuberculosis, that analysis was restricted to studies in which tuberculosis was diagnosed more than 1 year before cancer, in order to minimize this bias. The studies were grouped by time between the two diagnoses (1-5, 6-10, 11-20, and more than 20 years). The increase in cancer risk was higher in the first 5 years after tuberculosis; diagnosis; however, the risk remained 1.99-fold higher among those for whom the time between the diagnoses was more than 20 years. This was true in our sample as well, given that the median time between the diagnoses of tuberculosis and LC was 5 years (interquartile range: 1-30 years). Another, more recent study(11) showed that LC risk was highest in the 2-year window after tuberculosis diagnosis (OR = 5.01) but remained elevated even 2 years after diagnosis (OR = 1.53). Approximately 30% of the patients presented with distant metastases at LC diagnosis. Of those, 71% were diagnosed with LC and tuberculosis simultaneously. Another case series found that 50% of the patients had stage IV LC.(24) Because the initial symptoms of these two diseases are similar, it should be considered that there can be a delay in the diagnosis of either condition and, consequently, patients can present with either LC or tuberculosis at a more advanced stage.(26) In none of our reported cases was LC diagnosed before pulmonary tuberculosis. In contrast, in a recent, retrospective case-control study(15) involving 36 patients with LC, 10 (27.8%) were diagnosed with tuberculosis and cancer concomitantly, whereas 26 (72.2%) were diagnosed with tuberculosis after being diagnosed with

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cancer. In a case series conducted in Japan,(24) the diagnoses were concomitant in 6 patients, tuberculosis was diagnosed before LC in 5 cases, and LC was diagnosed before tuberculosis in the remaining 5. It is possible that tuberculosis was diagnosed before LC more frequently because of a reverse causality bias, i.e., an occult cancer can reduce immunity and lead to reactivation of latent tuberculosis. Therefore, tuberculosis can present clinically before LC.(16,19) Our study has limitations that need to be considered. The major one is that the cases were identified retrospectively on the basis of a search of the files of the specialized outpatient clinics at our hospital. Retrospective studies are at risk of selection bias (cases lost to follow-up) and measurement bias (data obtained from medical records). We should also consider the Berkson bias, in which patients with an index diagnosis are more likely to be diagnosed with another disease than are those without an index diagnosis. For instance, patients with tuberculosis, at follow-up chest X-ray, are more prone to be diagnosed with cancer than are those not diagnosed with tuberculosis.(27) Nevertheless, because the occurrence of tuberculosis and LC, either simultaneously or not, may have different characteristics according to ethnic group and region,(10) it is relevant that cases identified locally be described. In addition, the importance of these cases lies in the fact that patients diagnosed with tuberculosis should be advised to avoid lung carcinogens, such as tobacco smoking, as much as possible, since these agents contribute to a substantial increase in LC risk. In conclusion, the present study demonstrated that most of the patients with tuberculosis and LC were smokers, and that tuberculosis was diagnosed either before or simultaneously with LC. Non-small cell lung cancer, especially adenocarcinoma, was the most common histological type.

References 1. INCA Instituto Nacional do C창ncer [homepage on the Internet]. Rio de Janeiro: INCA. [cited 2013 Apr 1]. Pulm찾o. Available from: www.inca.gov.br 2. World Health Organization [homepage on the Internet]. Geneva: World Health Organization. [cited 2013 Apr 1]. WHO REPORT 2009 Global Tuberculosis Control - Epidemiology, Strategy, Financing. [Adobe Acrobat document, 86p.]. Available from: http://whqlibdoc.who. int/publications/2009/9789241563802_eng_doc.pdf 3. Ballaz S, Mulshine JL. The potential contributions of chronic inflammation to lung carcinogenesis. Clin Lung

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Cancer. 2003;5(1):46-62. http://dx.doi.org/10.3816/ CLC.2003.n.021 PMid:14596704 4. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860-7. http://dx.doi.org/10.1038/ nature01322 PMid:12490959 PMCid:2803035 5. Engels EA. Inflammation in the development of lung cancer: epidemiological evidence. Expert Rev Anticancer Ther. 2008;8(4):605-15. http://dx.doi. org/10.1586/14737140.8.4.605 PMid:18402527 6. Rybacka-Chabros B, Mańdziuk S, Berger-Lukasiewicz A, Dańko-Mrozińska M, Milanowski J. The coexistence of tuberculosis infection and lung cancer in patients treated in pulmonary department of Medical Academy in Lublin during last ten years (1990-2000). Folia Histochem Cytobiol. 2001;39 Suppl 2:73-4. PMid:11820634 7. Kim HR, Hwang SS, Ro YK, Jeon CH, Ha DY, Park SJ, et al. Solid-organ malignancy as a risk factor for tuberculosis. Respirology. 2008;13(3):413-9. http://dx.doi. org/10.1111/j.1440-1843.2008.01282.x PMid:18399865 8. Brenner AV, Wang Z, Kleinerman RA, Wang L, Zhang S, Metayer C, et al. Previous pulmonary diseases and risk of lung cancer in Gansu Province, China. Int J Epidemiol. 2001;30(1):118-24. http://dx.doi.org/10.1093/ ije/30.1.118 PMid:11171871 9. Dacosta NA, Kinare SG. Association of lung carcinoma and tuberculosis. J Postgrad Med. 1991;37(4):185-9. PMid:1841965 10. Liang HY, Li XL, Yu XS, Guan P, Yin ZH, He QC, et al. Facts and fiction of the relationship between preexisting tuberculosis and lung cancer risk: a systematic review. Int J Cancer. 2009;125(12):2936-44. http://dx.doi. org/10.1002/ijc.24636 PMid:19521963 11. Shiels MS, Albanes D, Virtamo J, Engels EA. Increased risk of lung cancer in men with tuberculosis in the alpha-tocopherol, beta-carotene cancer prevention study. Cancer Epidemiol Biomarkers Prev. 2011;20(4):672-8. http://dx.doi.org/10.1158/1055-9965.EPI-10-1166 PMid:21335509 PMCid:3076700 12. Wu CY, Hu HY, Pu CY, Huang N, Shen HC, Li CP, et al. Pulmonary tuberculosis increases the risk of lung cancer: a population-based cohort study. Cancer. 2011;117(3):61824. http://dx.doi.org/10.1002/cncr.25616 PMid:20886634 13. Yu YH, Liao CC, Hsu WH, Chen HJ, Liao WC, Muo CH, et al. Increased lung cancer risk among patients with pulmonary tuberculosis: a population cohort study. J Thorac Oncol. 2011;6(1):32-7. http://dx.doi.org/10.1097/ JTO.0b013e3181fb4fcc PMid:21150470 14. Conde MB, Melo FA, Marques AM, Cardoso NC, Pinheiro VG, Dalcin Pde T, et al. III Brazilian Thoracic Association Guidelines on tuberculosis. J Bras Pneumol. 2009;35(10):1018-48. PMid:19918635 15. Cha SI, Shin KM, Lee JW, Lee SY, Kim CH, Park JY, et al. The clinical course of respiratory tuberculosis in lung cancer patients. Int J Tuberc Lung Dis. 2009;13(8):1002-7. PMid:19723381

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16. Libshitz HI, Pannu HK, Elting LS, Cooksley CD. Tuberculosis in cancer patients: an update. J Thorac Imaging. 1997;12(1):41-6. http://dx.doi.org/10.1097/00005382199701000-00006 PMid:8989758 17. Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007;117(5):1175-83. http://dx.doi.org/10.1172/JCI31537 PMid:17476347 PMCid:1857251 18. Rosin MP, Anwar WA, Ward AJ. Inflammation, chromosomal instability, and cancer: the schistosomiasis model. Cancer Res. 1994;54(7 Suppl):1929s-1933s. PMid:8137314 19. Nalbandian A, Yan BS, Pichugin A, Bronson RT, Kramnik I. Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control. Oncogene. 2009;28(17):1928-38. http://dx.doi.org/10.1038/onc.2009.32 PMid:19330024 20. Song L, Yan W, Deng M, Song S, Zhang J, Zhao T. Aberrations in the fragile histidine triad(FHIT) gene may be involved in lung carcinogenesis in patients with chronic pulmonary tuberculosis. Tumour Biol. 2004;25(5-6):270-5. http://dx.doi.org/10.1159/000081391 PMid:15627891 21. Song L, Yan W, Zhao T, Deng M, Song S, Zhang J, et al. Mycobacterium tuberculosis infection and FHIT gene alterations in lung cancer. Cancer Lett. 2005;219(2):15562. http://dx.doi.org/10.1016/j.canlet.2004.06.036 PMid:15723714 22. Dheda K, Booth H, Huggett JF, Johnson MA, Zumla A, Rook GA. Lung remodeling in pulmonary tuberculosis. J Infect Dis. 2005;192(7):1201-9. http://dx.doi. org/10.1086/444545 PMid:16136463 23. Limas C, Japaze H, Garcia-Bunuel R. “Scar” carcinoma of the lung. Chest. 1971;59(2):219-22. http://dx.doi. org/10.1378/chest.59.2.219 PMid:4322551 24. Watanabe A, Tokue Y, Takahashi H, Sato K, Nukiwa T, Honda Y, et al. Management of mycobacteriosis in general hospital without isolation ward for tuberculosis patients. Clinical study on pulmonary tuberculosis associated with lung cancer patients [Article in Japanese]. Kekkaku. 1999;74(2):157-62. PMid:10191612 25. Le CH, Ko YC, Cheng LS, Lin YC, Lin HJ, Huang MS, et al. The heterogeneity in risk factors of lung cancer and the difference of histologic distribution between genders in Taiwan. Cancer Causes Control. 2001;12(4):289300. http://dx.doi.org/10.1023/A:1011270521900 26. Singh VK, Chandra S, Kumar S, Pangtey G, Mohan A, Guleria R. A common medical error: lung cancer misdiagnosed as sputum negative tuberculosis. Asian Pac J Cancer Prev. 2009;10(3):335-8. PMid:19640168 27. Fontham ET, Correa P, Reynolds P, Wu-Williams A, Buffler PA, Greenberg RS, et al. Environmental tobacco smoke and lung cancer in nonsmoking women. A multicenter study. JAMA. 1994;271(22):1752-9. Erratum in: JAMA 1994;272(20):1578. http://dx.doi. org/10.1001/jama.1994.03510460044031 PMid:8196118

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About the Authors Denise Rossato Silva

Adjunct Professor of Pulmonology. Federal University of Rio Grande do Sul School of Medicine, Porto Alegre, Brazil.

Dirceu Felipe Valentini Junior

Medical Student. Federal University of Rio Grande do Sul School of Medicine, Porto Alegre, Brazil.

Alice Mânica Müller

Doctoral Student. Graduate Program in Pulmonology, Federal University of Rio Grande do Sul School of Medicine, Porto Alegre, Brazil.

Carlos Podalirio Borges de Almeida

Master’s Student. Graduate Program in Pulmonology, Federal University of Rio Grande do Sul School of Medicine, Porto Alegre, Brazil.

Paulo de Tarso Roth Dalcin

Associate Professor of Pulmonology. Federal University of Rio Grande do Sul School of Medicine, Porto Alegre, Brazil.

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Brief Communication Effectiveness of diaphragmatic stimulation with singlechannel electrodes in rabbits* Efetividade da estimulação diafragmática com eletrodos monocanais em coelhos

Rodrigo Guellner Ghedini, Julio de Oliveira Espinel, Elaine Aparecida Felix, Artur de Oliveira Paludo, Rodrigo Mariano, Arthur Rodrigo Ronconi Holand, Cristiano Feijó Andrade

Abstract Every year, a large number of individuals become dependent on mechanical ventilation because of a loss of diaphragm function. The most common causes are cervical spinal trauma and neuromuscular diseases. We have developed an experimental model to evaluate the performance of electrical stimulation of the diaphragm in rabbits using single-channel electrodes implanted directly into the muscle. Various current intensities (10, 16, 20, and 26 mA) produced tidal volumes above the baseline value, showing that this model is effective for the study of diaphragm performance at different levels of electrical stimulation. Keywords: Rabbits; Diaphragm; Electric stimulation; Models, animal.

Resumo A cada ano um grande número de pessoas perde a função do diafragma tornando-se dependentes de ventilação mecânica. As principais causas são o trauma raquimedular da região cervical e as doenças neuromusculares. Desenvolvemos um modelo experimental para avaliar o desempenho da estimulação elétrica do diafragma em coelhos com eletrodos monocanais implantados diretamente neste músculo. Foram aplicadas diferentes intensidades de correntes (10, 16, 20 e 26 mA), as quais geraram volumes correntes acima dos valores basais, mostrando que este modelo é eficaz para estudar o desempenho do diafragma sob diferentes tipos de estimulação elétrica. Descritores: Coelhos; Diafragma; Estimulação elétrica; Modelos animais.

The diaphragm is the muscle that is responsible for the proper functioning of the respiratory system. Upper cervical spine injuries can cause quadriplegia and lead to loss of diaphragm function, resulting in dependency on positive pressure ventilation. Neuromuscular diseases such as amyotrophic lateral sclerosis also lead to progressive and cumulative impairment of diaphragm function, death being due to respiratory failure in most cases.(1) The worldwide prevalence of amyotrophic lateral sclerosis is 3-8 cases per 100,000 population, the annual incidence being 2/100,000 population. Half of all affected patients live for at least three years after diagnosis.(2)

Approximately 20% live five years or more, and up to 10% survive for more than ten years. Because this is a problem of general interest, there is a need for studies providing diaphragmatic stimulation methods and devices that can benefit this population. The use of electrical currents in order to produce artificial ventilation has been described since the nineteenth century, generating nerve action potentials and direct contractions of the diaphragm and other respiratory muscles through different techniques.(3-5) An animal study comparing phrenic nerve stimulation and intramuscular stimulation showed similar results in terms of

*Study carried out in the Animal Experimentation Unit, Airways and Lung Laboratory, Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Hospital de Clínicas de Porto Alegre – HCPA, Porto Alegre Hospital de Clínicas – Porto Alegre, Brazil. Correspondence to: Cristiano Feijó Andrade. Hospital de Clínicas de Porto Alegre, Serviço de Cirurgia Torácica, Rua Ramiro Barcelos, 2350, CEP 90035-903, Porto Alegre, RS, Brasil. Tel. 55 51 3359-8684. E-mail: cristianofa@cirurgiatoracica.net Financial support: This study received financial support from the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, Rio Grande do Sul Research Foundation) and the Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE-HCPA, Research Incentive Fund of the Hospital de Clínicas de Porto Alegre). Submitted: 31 January 2013. Accepted, after review: 3 May 2013.

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Effectiveness of diaphragmatic stimulation with single-channel electrodes in rabbits

transdiaphragmatic pressure generation and latency of nerve conduction velocity.(6) The first studies used cervical or thoracic phrenic nerve stimulation in order to trigger action potentials. That technique proved to be clinically effective but was found to have limitations and pose a risk of mechanical nerve injury.(7,8) Technological evolution and development provided a major breakthrough in the development of diaphragmatic pacing through electrodes implanted directly into the muscle through laparotomy and, subsequently, laparoscopy.(9,10) Full activation of the diaphragm is related to electrodes implanted into the diaphragm motor points, where phrenic nerve fibers ramify.(11-13) The sites that are tested for motor points are chosen on the basis of anatomical landmarks on the abdominal surface of the diaphragm, and correct electrode placement is determined after diaphragm mapping and exploration, by observing the point at which muscle response to electrical stimulation is strongest.(14-16) We have previously described a model of electrical stimulation of the diaphragm in rabbits. Using that model, we tested two types of electrodes: bipolar electrodes, with the two poles of the current generator in the same electrode; and monopolar electrodes, with only one pole, depolarization occurring between the hemidiaphragms, with no dispersive electrode. Through laparotomy, the electrodes were placed at the motor points of both hemidiaphragms. We found that both types of electrodes were able to stimulate the diaphragm with different current intensities, producing tidal volumes that were similar to physiological volumes.(17) The objective of the present study was to evaluate the performance of electrical stimulation of the diaphragm with single-channel electrodes implanted directly into the diaphragm in rabbits. Seven healthy, female New Zealand rabbits weighing 2-3 kg were used. The animals were treated in accordance with the World Health Organization ethical code for animal experimentation. The study was approved by the Research Ethics Committee of the Hospital de Clínicas de Porto Alegre (Protocol no. 10,260). The animals received an intramuscular dose of ketamine, midazolam, and atropine, being subsequently shaved and submitted to peripheral venipuncture and orotracheal intubation. They were then placed

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on mechanical ventilation with a Nikkei ventilator (Takaoka Ind e Com Ltda., São Paulo, Brazil). Anesthesia was maintained with inhaled isoflurane. No neuromuscular blocking agents were used for anesthesia, because the myoneural junction had to remain functional.(18) After hemodynamic stabilization, the expiratory lung volume was measured at baseline for subsequent comparisons. An exploratory (longitudinal) laparotomy was performed for visualization of the diaphragm, followed by identification of the diaphragm motor points, into which the electrodes were implanted. The electrodes were implanted into both hemidiaphragms, and the wires were placed in the subcutaneous space of the abdominal wall (Figure 1). The animals were kept under observation for 15 days. After that period, the animals were intubated, mechanically ventilated, and anesthetized for electrical stimulation of the diaphragm at various current intensities (10, 16, 20, 26, and 32 mA), each being applied three times for ten respiratory cycles, with a 5-min recovery interval between each cycle. We obtained the mean values for each intensity, as previously described.(17) The means were analyzed by generalized estimating equations, being corrected by the Bonferroni method. To that end, the diaphragmatic electrode wires were connected to a Dualpex 961 Phrenics current generator (Quark Medical, São Paulo, Brazil), producing a depolarized current with a rectangular waveform, a symmetric alternating pulse, a frequency of 25 Hz (cycles/s), and a burst width of 0.07 ms. We evaluated the relationship between the volume of air exhaled and the current intensity applied using a flow sensor (Tracer 5; Intermed Ltda., São Paulo, Brazil) connected to the endotracheal tube. All measurements were performed with the animals in the supine position. All animals survived the procedure. However, one animal showed infection, an extensive area of fibrosis, and adhesions, which precluded the generation of an adequate tidal volume. The animal was therefore excluded from the study. In our study sample, the mean expiratory volume at baseline was 14.97 ± 1.75 mL, showing a proportional relationship between expiratory volume and current intensity. When an electrical current of 10 mA was applied, the mean expiratory volume was 15.72 ± 1.17 mL; when a current of 16 mA was applied, the mean expiratory volume was 18.86 ± 3.69 mL; when a current of 20 mA J Bras Pneumol. 2013;39(4):490-494

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electrodes

Figure 1 - In A, electrodes implanted directly into the diaphragm (arrows). In B, the abdominal wall is closed, but the skin and subcutaneous tissue are open and the wires are exteriorized for diaphragmatic stimulation after an observation period of 15 days.

Expiratory volume (ml)

15 10 5 0

baseline

Current intensity (mA) Figure 2 - Mean expiratory volumes at current intensities of 10, 16, 20, 26, and 32 mA. *Statistically significant differences between baseline volume and current intensities, as analyzed by generalized estimating equations and as corrected by the Bonferroni method. The error bar represents the standard error of the difference among the values obtained over three separate time periods, five minutes apart.

was applied, the mean expiratory volume was 19.69 ± 3.72 mL; when a current of 26 mA was applied, the mean expiratory volume was 22.01 ± 4.17 mL; and when a current of 32 mA was applied, the mean expiratory volume was 22.36 ± 2.77 mL (Figure 2). Electrical activation of the diaphragm by intramuscular electrodes is an alternative form of electroventilation for the restoration of respiratory capacity. The ideal electroventilation system is that which is capable of restoring respiratory muscle function and meeting the physiological J Bras Pneumol. 2013;39(4):490-494

demands of individuals. One of the challenges to be overcome in the development of an ideal model is the autonomy of current generators. Devices that have high power consumption are larger and heavier, requiring an external source of signal or power. In a previous study, our group examined the relationship between current intensity and expiratory volume using two different types of electrodes, and the responses were found to be similar. In the single-channel electrode model, both hemidiaphragms are depolarized with a single channel of the current generator. This

Effectiveness of diaphragmatic stimulation with single-channel electrodes in rabbits

reduces power consumption. Using that model, we were able to achieve expiratory volumes as high as 149% from baseline values. The findings are consistent with those of experimental and clinical studies.(5,6,9-11) Full activation of the diaphragm depends on proper electrode implantation into the diaphragm motor points, the entrance area, and the ramification of the phrenic nerves in the muscle; therefore, it is essential to explore the muscle and identify the points at which contraction is more consistent. One of the challenges was to design a specific electrode for diaphragmatic stimulation, given that, in rabbits, the diaphragm is thinner and more delicate than the peripheral muscles.(10) In the present study, we noted an important difference between the pattern of thoracoabdominal motion during spontaneous breathing and the pattern of thoracoabdominal motion during electrical stimulation of the diaphragm. During spontaneous breathing, the rib cage and the abdominal circumference increased in diameter during inhalation. When the diaphragm was stimulated, the circumference of the base of the rib cage decreased during inhalation, whereas the abdominal circumference increased. It is assumed that ventilation through the use of electrical currents is more physiological than positive pressure ventilation because patients can use the inspiratory muscles to inflate the lungs. There is currently no ideal model that can fully restore respiratory function, given that such models are not influenced by the respiratory centers and are therefore unable to meet the metabolic demands of individuals. The lack of synchrony between upper airway opening and diaphragmatic contraction leads to the need for tracheostomy. The animal model described herein proved to be effective for the study of diaphragm performance at different levels of electrical stimulation with a current generator and single-channel electrodes implanted directly into the muscle.

References 1. Oliveira AS, Pereira RD. Amyotrophic lateral sclerosis (ALS): three letters that change the peopleâ&#x20AC;&#x2122;s life. For ever. Arq Neuropsiquiatr. 2009;67(3A):750-82. http://dx.doi. org/10.1590/S0004-282X2009000400040 PMid:19722069 2. World Health Organization [homepage on the Internet]. Geneva: World Health Organization. [cited 2010 Apr 01]. World Health Statistics 2009. [Adobe Acrobat document, 149p.]. Available from: http://www.who.int/whosis/ whostat/EN_WHS09_Full.pdf

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3. Glenn WW, Holcomb WG, Gee JB, Rath R. Central hypoventilation; long-term ventilatory assistance by radiofrequency electrophrenic respiration. Ann Surg. 1970;172(4):755-73. http://dx.doi.org/10.1097/00000658197010000-00020 PMid:5458627 PMCid:1397282 4. Geddes LA, Voorhees WD, Babbs CF, Deford JA. Electroventilation. Am J Emerg Med. 1985;3(4):337-9. http://dx.doi.org/10.1016/0735-6757(85)90061-0 5. Geddes LA, Voorhees WD, Lagler R, Riscili C, Foster K, Bourland JD. Electrically produced artificial ventilation. Med Instrum. 1988;22(5):263-71. PMid:3054441 6. Reid WD, Blogg T, Wiggs BJ, ParĂŠ PD, Pardy RL. Diaphragmatic plate electrode stimulation of the hamster diaphragm. J Appl Physiol. 1989;67(4):1341-8. PMid:2676954 7. DiMarco AF. Phrenic nerve stimulation in patients with spinal cord injury. Respir Physiol Neurobiol. 2009;169(2):200-9. http://dx.doi.org/10.1016/j. resp.2009.09.008 PMid:19786125 8. Glenn WW, Phelps ML, Elefteriades JA, Dentz B, Hogan JF. Twenty years of experience in phrenic nerve stimulation to pace the diaphragm. Pacing Clin Electrophysiol. 1986;9(6 Pt 1):780-4. http://dx.doi.org/10.1111/j.1540-8159.1986. tb06627.x PMid:2432480 9. Onders RP, Elmo M, Khansarinia S, Bowman B, Yee J, Road J, et al. Complete worldwide operative experience in laparoscopic diaphragm pacing: results and differences in spinal cord injured patients and amyotrophic lateral sclerosis patients. Surg Endosc. 2009;23(7):1433-40. http:// dx.doi.org/10.1007/s00464-008-0223-3 PMid:19067067 10. Tedde ML, Onders RP, Teixeira MJ, Lage SG, Ballester G, Brotto MW, et al. Electric ventilation: indications for and technical aspects of diaphragm pacing stimulation surgical implantation. J Bras Pneumol. 2012;38(5):566-72 http://dx.doi.org/10.1590/S1806-37132012000500005 PMid:23147048 11. Peterson DK, Nochomovitz ML, Stellato TA, Mortimer JT. Long-term intramuscular electrical activation of the phrenic nerve: efficacy as a ventilatory prosthesis. IEEE Trans Biomed Eng. 1994;41(12):1127-35. http://dx.doi. org/10.1109/10.335861 PMid:7851914 12. Dunn RB, Walter JS, Walsh J. Diaphragm and accessory respiratory muscle stimulation using intramuscular electrodes. Arch Phys Med Rehabil. 1995;76(3):26671. http://dx.doi.org/10.1016/S0003-9993(95)80614-8 13. DiMarco AF, Onders RP, Kowalski KE, Miller ME, Ferek S, Mortimer JT. Phrenic nerve pacing in a tetraplegic patient via intramuscular diaphragm electrodes. Am J Respir Crit Care Med. 2002;166(12 Pt 1):1604-6. http:// dx.doi.org/10.1164/rccm.200203-175CR PMid:12471076 14. Peterson DK, Nochomovitz M, DiMarco AF, Mortimer JT. Intramuscular electrical activation of the phrenic nerve. IEEE Trans Biomed Eng. 1986;33(3):342-51. http:// dx.doi.org/10.1109/TBME.1986.325720 PMid:3957387 15. Schmit BD, Stellato TA, Miller ME, Mortimer JT. Laparoscopic placement of electrodes for diaphragm pacing using stimulation to locate the phrenic nerve motor points. IEEE Trans Rehabil Eng. 1998;6(4):382-90. http://dx.doi.org/10.1109/86.736152 PMid:9865885 16. Onders RP, Dimarco AF, Ignagni AR, Aiyar H, Mortimer JT. Mapping the phrenic nerve motor point: the key to a successful laparoscopic diaphragm pacing system in the first human series. Surgery. 2004;136(4):819-26. http:// dx.doi.org/10.1016/j.surg.2004.06.030 PMid:15467667

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18. Tedde ML, Vasconcelos Filho P, Hajjar LA, de Almeida JP, Flora GF, Okumura EM, et al. Diaphragmatic pacing stimulation in spinal cord injury: anesthetic and perioperative management. Clinics (Sao Paulo). 2012;67(11):1265-9. http://dx.doi.org/10.6061/ clinics/2012(11)07

About the authors Rodrigo Guellner Ghedini

Physical Therapist. Santa Casa Sisters of Mercy Hospital Complex; and Associate Researcher. Airways and Lung Laboratory, Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Hospital de Clínicas de Porto Alegre – HCPA, Porto Alegre Hospital de Clínicas – Porto Alegre, Brazil.

Julio de Oliveira Espinel

Thoracic Surgeon and Associate Researcher. Airways and Lung Laboratory, Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Hospital de Clínicas de Porto Alegre – HCPA, Porto Alegre Hospital de Clínicas – Porto Alegre, Brazil.

Elaine Aparecida Felix

Associate Professor of Anesthesiology. Department of Surgery, Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Porto Alegre, Brazil.

Artur de Oliveira Paludo

Associate Researcher. Airways and Lung Laboratory, Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Hospital de Clínicas de Porto Alegre – HCPA, Porto Alegre Hospital de Clínicas – Porto Alegre, Brazil.

Rodrigo Mariano

Arthur Rodrigo Ronconi Holand

Cristiano Feijó Andrade

Thoracic Surgeon. Santo Antônio Children’s Hospital and Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Hospital de Clínicas de Porto Alegre – HCPA, Porto Alegre Hospital de Clínicas – Porto Alegre, Brazil.

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Review Article Pseudomonas aeruginosa infection in patients with cystic fibrosis: scientific evidence regarding clinical impact, diagnosis, and treatment* Infecção por Pseudomonas aeruginosa em pacientes com fibrose cística: evidências científicas sobre o impacto clínico, diagnóstico e tratamento*

Luiz Vicente Ribeiro Ferreira da Silva Filho, Flavia de Aguiar Ferreira, Francisco José Caldeira Reis, Murilo Carlos Amorim de Britto, Carlos Emilio Levy, Otavio Clark, José Dirceu Ribeiro

Abstract Evidence-based techniques have been increasingly used in the creation of clinical guidelines and the development of recommendations for medical practice. The use of levels of evidence allows the reader to identify the quality of scientific information that supports the recommendations made by experts. The objective of this review was to address current concepts related to the clinical impact, diagnosis, and treatment of Pseudomonas aeruginosa infections in patients with cystic fibrosis. For the preparation of this review, the authors defined a group of questions that would be answered in accordance with the principles of PICO—an acronym based on questions regarding the Patients of interest, Intervention being studied, Comparison of the intervention, and Outcome of interest. For each question, a structured review of the literature was performed using the Medline database in order to identify the studies with the methodological design most appropriate to answering the question. The questions were designed so that each of the authors could write a response. A first draft was prepared and discussed by the group. Recommendations were then made on the basis of the level of scientific evidence, in accordance with the classification system devised by the Oxford Centre for Evidence-Based Medicine, as well as the level of agreement among the members of the group. Keywords: Cystic fibrosis/diagnosis; Cystic fibrosis/drug therapy; Pseudomonas aeruginosa; Evidence-based medicine.

Resumo As técnicas de medicina baseada em evidências são cada vez mais utilizadas para a construção de diretrizes clínicas e recomendações para a prática médica. O uso de níveis de evidências permite que o leitor identifique a qualidade da informação científica que sustenta as recomendações feitas pelos especialistas. Esta revisão teve por objetivo abordar conceitos atuais sobre o impacto clínico, diagnóstico e tratamento das infecções por Pseudomonas aeruginosa em pacientes com fibrose cística. Para a elaboração desta revisão, o grupo de autores definiu as perguntas que seriam respondidas, seguindo os preceitos de PICO, acrônimo baseado em perguntas referentes aos Pacientes de interesse, Intervenção a ser estudada, Comparação da intervenção e Outcome (desfecho) de interesse. Para cada pergunta, uma revisão estruturada da literatura foi realizada nas bases de dados do Medline, buscando identificar os estudos com desenho metodológico mais adequado para responder à questão. As perguntas foram designadas para que cada um dos autores redigisse uma resposta, e um primeiro rascunho foi elaborado e discutido pelo grupo em uma reunião presencial. Após essa discussão, recomendações foram emitidas com base na força das evidências e na concordância entre os membros do grupo segundo o sistema de classificação do Oxford Centre for Evidence Based Medicine. Descritores: Fibrose cística/diagnóstico; Fibrose cística/quimioterapia; Pseudomonas aeruginosa; Medicina baseada em evidências.

*Study carried out at the Institudo da Criança, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil. Correspondence to: Luiz Vicente Ribeiro Ferreira da Silva Filho. Rua Gregório Paes de Almeida, 1231, Vila Madalena, CEP 05450001, São Paulo, SP, Brasil. Tel. 55 11 5543-9677. Email: vicres@usp.br Financial support: This study received financial support from Novartis Brazil. Submitted: 11 February 2013. Accepted, after review: 17 April 2013.

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Introduction Cystic fibrosis (CF) is a complex genetic disease with multisystem involvement and pulmonary manifestations of a suppurative nature.(1) Patients with CF are born with structurally normal lungs, but develop a progressive respiratory disease with recurrent chronic infections that result in the formation of bronchiectasis and lead to respiratory failure, which is the leading cause of death in these subjects.(2) The basic defect in CF is related to chlorine transport through epithelial cell membranes by the cystic fibrosis transmembrane conductance regulator (CFTR) protein, the dysfunction of which was identified as being the principal mechanism of the disease in 1989.(3) There are more than 1,500 described mutations in the CFTR gene sequence, but most of them have very low prevalence, the Î&#x201D;F508 mutation (deletion of phenylalanine residue at position 508) being the most prevalent worldwide.(4) Patients with CF are peculiarly susceptible to infection and colonization of the respiratory tract with pathogens, such as Staphylococcus aureus, Haemophilus influenza, and glucose-nonfermenting gram-negative bacilli, including Pseudomonas aeruginosa, Burkholderia cepacia complex, and Stenotrophomonas maltophilia, among others.(5,6) The prevalence of these pathogens varies with age, with S. aureus infections usually occurring early (generally in the first months of life) and pathogens such as P. aeruginosa tending to appear a little later,(7) although this sequence of infections are greatly influenced by therapeutic and microbiological surveillance practices, as well as by hospitalizations, exposure to other patients with CF, and environmental conditions that have yet to be defined. The etiologic diagnosis of respiratory infections in patients with CF is habitually established through culture of respiratory tract samples, such as sputum and oropharyngeal swabs, the latter method generally being used in infants and children who are unable to expectorate sputum.(8) In recent years, some attention has been given to alternative methods of diagnosis, such as serology and molecular techniques, especially for early identification of infection with P. aeruginosa, a pathogen that has the greatest impact on this group of patients.(9) P. aeruginosa infections typically evolve to a pattern of persistence (chronicity), and J Bras Pneumol. 2013;39(4):495-512

strains undergo a phenotypic change, which is characterized by the production of a polysaccharide known as alginate.(6) This bacterial phenotype, known as the mucoid phenotype, is associated with the greater difficulty in (or near impossibility of) eradicating the pathogen, eliciting a major inflammatory response and resulting in accelerated functional loss and poorer prognosis.(6,10,11) Since the early 1990s, various treatment centers for patients with CF have recommended eradication therapies for initial P. aeruginosa infection, which is when strains are more susceptible to antimicrobials, in order to prevent the chronicity of the infection.(12) In addition, strategies to suppress P. aeruginosa (or to reduce the bacterial load) with the use of inhaled antibiotics are one of the major therapeutic resources in the management of patients chronically infected with P. aeruginosa, causing improvement in pulmonary function, reducing the frequency of respiratory exacerbations, and improving the quality of life of these patients.(2) Despite the growing knowledge in the field of respiratory infections in patients with CF, there are still many questions regarding the knowledge of the actual clinical impact, the most appropriate diagnostic methods, and the evidence on the treatment of P. aeruginosa infections. Evidencebased techniques have been increasingly used in the creation of clinical guidelines and the development of recommendations for medical practice. This type of approach allows the systematic use of available scientific information, with less emphasis on isolated experiences. The objective of the present review was to address current concepts related to the clinical impact, diagnosis, and treatment of P. aeruginosa infections in patients with CF.

Methods For the preparation of this study, the following steps were performed: 1. Question preparation: the authors, in a preliminary meeting, defined a group of questions that would be answered in accordance with the principles of PICOâ&#x20AC;&#x201D;an acronym based on questions regarding the Patients of interest, Intervention being studied, Comparison of the intervention, and Outcome of interest. The questions were designed so that one of the authors could write a response. 2. Search of the literature: an initial search of the literature was conducted using

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the Medline database and search terms related to each question. One of the authors, who is an expert in evidence-based medicine, made the initial selection of relevant studies, which were sent to each responsible author for preparing the responses. These authors then conducted their own search and added other references that were judged relevant. 3. First draft of responses: each author was responsible for writing responses that were subsequently discussed by the entire group at a face-to-face meeting. 4. Discussion meeting: the group had a face-to-face meeting to discuss and, if necessary, to make changes to the responses proposed by each author separately. In that meeting, new information was sought and added to the original text. In addition, there was an explicit discussion about the level of evidence (LE) of the information, in accordance with the criteria set out by the Oxford Centre for Evidence-Based Medicine in 2011,(13) which are shown in Chart 1.

5. Final draft: at the end of the meeting, each author sent the consensus response to the expert in evidence-based medicine, who was responsible for reviewing the LE, revising the text, and checking the references. 6. Revision: each author revised and approved the final draft of their responses and of the manuscript.

Questions addressed in the study 1. Does early P. aeruginosa colonization worsen the prognosis of patients with CF? 2. Can serologic testing for antiPseudomonas antibodies be useful for early detection of infection with this agent? 3. Does eradication of initial colonization with P. aeruginosa improve the prognosis in CF? 4. How does one identify and treat acute pulmonary exacerbations (APEs) in patients colonized with P. aeruginosa?

Chart 1 - Grades of recommendation and levels of evidence of scientific articles.a Grade of recommendation

A: More consistent experimental or observational studies B: Less consistent experimental or observational studies C: Case reports (uncontrolled studies) D: Opinion without critical appraisal, based on consensus, physiological studies, or animal models Strength of evidence Level of evidence Studies on prognosis Studies on treatment 1a Systematic review of cohort studies Systematic review of two or more (inception cohort), validated in different independent randomized studies rated as populations level 1b 1b Individual cohort studies (inception cohort) Randomized study of good methodological quality, including a sufficient number of patients 2a Systematic review of either retrospective Systematic review of level 2b cohort cohort studies or untreated control groups studies in randomized studies 2b Retrospective cohort studies or follow-up Individual cohort studies (including poor of untreated control groups in randomized quality randomized studies) studies 3a Systematic review of level 3b case-control studies 3b Case-control studies 4 Case series Case series 5 Expert opinions Expert opinions without explicit critical appraisal, or based on pathophysiology a

In accordance with the Oxford Centre for Evidence-Based Medicine.(13)

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5. When should chronic inhaled antibiotic therapy be initiated in CF? Which inhaled antibiotics can be used in the treatment of chronic P. aeruginosa infection in CF? 6. Does adherence to clinical treatment affect the prognosis of patients with CF? 7. Is azithromycin efficacious in slowing the progression of lung disease in CF patients colonized with P. aeruginosa? 8. Is there a good correlation between antibiogram results and clinical response in chronic P. aeruginosa infection? 9. Does multidrug-resistant P. aeruginosa infection worsen prognosis?

Does early P. aeruginosa colonization worsen the prognosis of patients with CF? Definitions Colonization means the presence of bacteria as detected by colony culture, i.e., by isolation of the bacterium in culture. Colonization can be initial (or acute)â&#x20AC;&#x201D;in the first bacterial isolationsâ&#x20AC;&#x201D;or chronic, in accordance with the referral center criteria: three or more positive cultures for P. aeruginosa within a 6-month period, with an interval of at least one month between them or more than 50% of positive cultures within 12 months. (14) Various parameters are used to characterize the prognosis in CF. The most common are pulmonary function testing and median survival: pulmonary function is in turn the best predictor of survival (LE 2b). (15) Initial colonization with P. aeruginosa in children under 2 years of age significantly increases morbidity, and its association with S. aureus from the beginning significantly increases the mortality rate in the first 10 years after diagnosis (LE 2b).(10,16) The radiographic score deteriorates significantly and the Tiffeneau index (FEV1/FVC ratio) falls more rapidly after P. aeruginosa acquisition in patients diagnosed by newborn screening (LE 2b). (17) Data from the U.S. Cystic Fibrosis Foundation national registry showed that, between 1990 and 1998, the presence of P. aeruginosa was the greatest predictor of morbidity and mortality in patients aged 1-5 years (n = 3,325)â&#x20AC;&#x201D;with the risk of death being 2.6 times higher in those with J Bras Pneumol. 2013;39(4):495-512

than in those without P. aeruginosa respiratory infection (LE 2b). (18) In a cohort study conducted in the USA, nonmucoid P. aeruginosa acquisition occurred in patients with a median age of 1 year, being observed in 29% of the patients under 6 months of age; identification of P. aeruginosa strains with a mucoid phenotype occurred in patients aged 4-16 years (median of 13 years). Eradication of nonmucoid P. aeruginosa, preventing chronicity and conversion to a mucoid phenotype, would allow a better prognosis (LE 2b).(7) Early P. aeruginosa colonization predisposes to chronic colonization with this pathogen. A low level of chronic colonization can be achieved with intermittent use of inhaled antibiotics and less use of intravenous antibiotics. A lower level of chronic P. aeruginosa colonization improves prognosis (LE 2b).(19)

Recommendation Early P. aeruginosa colonization, especially if associated with initial S. aureus colonization, worsens prognosis for morbidity and mortality (LE 2b; grade of recommendation [GR] B).

Can serologic testing for antiPseudomonas antibodies be useful for early detection of infection with this agent? Early identification of P. aeruginosa infection is essential for the initiation of eradication therapy, the goal of which is to prevent or delay chronic infection with the bacterium.(20) Respiratory infection with P. aeruginosa is routinely diagnosed by examination of sputum, oropharyngeal secretion, or laryngeal aspirates after respiratory therapy or inhalation of hypertonic sodium chloride solution (3-7%). Positive oropharyngeal secretion cultures have a high predictive value, although false-negative results can occur.(21) Other resources used for diagnosis are bronchoalveolar lavage (BAL) culture, serology for detection of specific antibodies in serum, and methods for the detection of bacterial DNA (by PCR) in respiratory secretion specimens.(9) The difficulty in obtaining representative respiratory specimens from the airways of infants and children under 6 years of age indicates the need for the use of methods that can complement or be an alternative to culture.(22) In the 1970s,

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the initial experience of a group of researchers in Denmark(23) regarding the use of serum precipitins to characterize stages of pulmonary infection with P. aeruginosa was the main incentive for the use of serological resources in early identification of infections with the pathogen.(24) West et al.(25) evaluated a cohort of 68 infants diagnosed by neonatal screening and described the natural history of P. aeruginosa infections over a 15-year period. The detection of anti-P. aeruginosa antibodies allowed the identification of infection with the pathogen before it was isolated from a culture, with bacterial anti-cell lysate antibodies being detected 12 months before culture. Significant P. aeruginosa anti-cell lysate antibody titers were detected before or simultaneously with the first isolation of the bacterium in approximately 60% of the patients (LE 2b).(25) In 2006, two studies reporting conflicting serological results were published in the same journal. Kappler et al.(26) used commercial ELISA kits in a prospective study involving 183 patients with CF and reported a sensitivity of 86%, a specificity of 96%, and a positive predictive value of 97%. Those authors propose P. aeruginosa eradication therapy in the event of a rise in antibody titers, even in the absence of positive cultures (LE 2b).(26) Tramper-Stranders et al.(27) used other ELISA kits in 220 CF patients with different P. aeruginosa infection status and found a sensitivity of 96% and a specificity of 79% for the combination of methods. The fact that 15 serological conversions were identified during the study period, with varying response patterns, draw attention to the possibility of failure in identifying early P. aeruginosa infection through the use of serological methods (LE 2b).(27) Subsequently, Ratjen et al.,(28) evaluating the usefulness of serological methods in initial P. aeruginosa infection in approximately 1,800 serum samples from 375 patients with CF, found inter-individual variability in antibody titers, but reported an association between the serological response and the intensity of the respiratory infection, which, according to the authors, suggested potential for the use of serological methods in conjunction with microbiology (LE 2b).(28) In 2007 in Brazil, da Silva Filho et al.,(22) in a study comparing single-sample PCR, culture, and serology in 87 patients with CF, reported that the combination of the three methods resulted in

higher positivity, PCR being the method with the highest positivity. Because the study was crosssectional, no further conclusions could be drawn (LE 3).(22) Methods for molecular identification of P. aeruginosa should be viewed with caution, because they do not depend on bacterial viability and they are affected by various technical aspects, such as DNA extraction methods, primers used, sample concentration, etc.(9) Another group of authors, seeking to establish whether it would be possible to use saliva as a tool for the detection of anti-P. aeruginosa antibodies in patients with CF and in normal individuals,(29) described significant titers in the oral fluids from 15 of the 17 patients with CF but in none from the healthy volunteers (LE 2b). Pressler et al.(30) comparatively analyzed three different serological methods (exotoxin A ELISA, CF-IgG ELISA, and counterimmunoelectrophoresis) in 791 Scandinavian patients with CF and concluded that the performance of the tests was very similar. Another relevant finding was the association between the antibody titers observed and the duration and characteristic of the infection, which means that serology could be used in characterizing the chronicity of the infection (LE 2b).(30) In another study conducted in Brazil, Milagres et al.(31) studied 51 patients with CF over a 2-year period, using two types of antigen (bacterial lysate and recombinant PcrV). For 44% of the patients with previously negative cultures or intermittent isolations, serology allowed the detection of P. aeruginosa, on average, 21 months before its detection by culture, suggesting that the method should be part of the routine follow-up of patients with CF (LE 2b).(31) More recently, two studies have generated more controversy on the subject. Hayes et al.,(32) in an approximately 6-year longitudinal study evaluating 69 children with CF diagnosed by newborn screening, reported that serology allowed the early identification of P. aeruginosa infection in those patients. In contrast, Douglas et al.(33) described paired BAL culture and serology results and found a low positive predictive value and a high negative predictive value using BALF culture as a reference. In view of these findings, there is questioning regarding the potential of serology for monitoring P. aeruginosa infection (LE 2b), although recently, the role of BALF culture as a decision-making tool in the treatment of J Bras Pneumol. 2013;39(4):495-512

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respiratory infection in patients with CF has also been questioned.(34)

Recommendation Positive serology results and culture-negative samples of respiratory secretion should alert health professionals to perform a more thorough search for a probable infection, by repeating the test or by using methods that are more sensitive and more specific. In contrast, increasing levels of antibodies are associated with a greater likelihood of persistent chronic infection with the bacterium. Their use in routine practice remains controversial (LE 2b; GR B).

Does eradication of initial colonization with P. aeruginosa improve the prognosis in CF? P. aeruginosa is the most common pathogen in lung infections in patients with CF. The importance of its early detection is due to its correlation with a more pronounced reduction in pulmonary function, which results in impaired quality of life and poorer prognosis of patients chronically colonized with the bacterium. Early identification of P. aeruginosa infection is essential for the initiation of eradication therapy, the goal of which is to prevent or delay chronic infection with the bacterium at a phase in which strains are more susceptible to antibiotics. Studies dating back to the 1980s investigated the effects of early treatment in patients infected with P. aeruginosa, suggesting that early eradication could lead to a decrease in the number of patients with chronic colonization. Since the initial studies by Littlewood et al.,(35) there has been growing evidence that the early initiation of antibiotic therapy is an effective strategy to delay chronic P. aeruginosa infection.(36-38) A broader assessment of the effects of eradication therapy was performed by Taccetti et al.,(12) who, in a study of 47 patients, showed that the early use of oral ciprofloxacin + inhaled colomycin resulted in reduced chronicity, causing no increase in bacterial resistance or in the emergence of other pathogens. In addition, those authors found a reduction in pulmonary function decline and in treatment costs.(12) In a recently published study,(39) the authors concluded that the implementation of an early intervention protocol led to decreased prevalence of J Bras Pneumol. 2013;39(4):495-512

chronic P. aeruginosa infection, improved pulmonary function, and decreased hospital costs (LE 1b). The decision on the best antimicrobial strategy for P. aeruginosa eradication remains controversial. In an open-label randomized multicenter study,(40) patients with CF (age â&#x2030;Ľ 6 months) and primary infection with P. aeruginosa were treated for 28 days or 56 days with inhaled tobramycin administered twice daily. The study showed that more than 90% of patients had negative cultures for P. aeruginosa one month after the end of treatment, and that most of those patients remained free from infection for up to 27 months. There was no significant difference when the period of treatment with inhaled tobramycin was extended to 56 days (LE 1b).(40) In another recent multicenter study,(41) the participants were randomized 1:1 to one of four treatment algorithms for 18 months. The treatment regimens were as follows: (a) intermittent courses (every 3 months) of inhaled tobramycin (300 mg twice daily) for 28 days + oral ciprofloxacin (15-20 mg/kg twice daily) for 14 days; (b) intermittent courses (every 3 months) of inhaled tobramycin for 28 days + oral placebo for 14 days; (c) inhaled tobramycin for 28 days + oral ciprofloxacin for 14 days in the presence of a positive culture for P. aeruginosa; and (d) inhaled tobramycin for 28 days + oral placebo for 14 days in the presence of a positive culture for P. aeruginosa. Those authors concluded that, after 18 months, there were no differences in the rates of exacerbation or prevalence of P. aeruginosa between prophylactic treatment and treatment based on positive cultures. There was no additional benefit from the addition of ciprofloxacin during that study (LE 1b).(41)

Recommendation Evidence suggests that the early initiation of inhaled antibiotic therapy, combined or not with oral antibiotics, is an efficient strategy to delay chronic P. aeruginosa infection. Studies suggest that short-term eradication can be achieved (LE 1b; GR A).(42)

How does one identify and treat acute pulmonary exacerbations (APEs) in patients colonized with P. aeruginosa? In patients with CF, APEs are a common complication. Although there are published

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guidelines for the management of APEs in patients with CF, it is not possible to know for sure which are the best treatment strategies, given the insufficient data.(2) Chronic P. aeruginosa infection becomes more common as patients grow older and is associated with increased morbidity and mortality. Chronic infection is interspersed with APEs, which require additional and more aggressive antibiotic therapy. There is evidence that APEs result in functional loss that often is not completely reversed by treatment.(43) In APEs with no obvious precipitating factor, several questions arise: a. How does one define an APE? b. Should intravenous therapy for an APE be administered in the home or in the hospital? c. Which antibiotic(s) should intravenous therapy for an APE include? d. Can (or should) aminoglycosides be used once daily? e. What should be the duration of intravenous therapy for an APE?

How does one define an APE? In 1994, Fuchs et al.(44) established criteria for defining APEs in CF, criteria that were subsequently used in a number of scientific studies in the field. According to those authors, an APE could be defined as the clinical need for intravenous antibiotics as indicated by the presence of at least 4 of the 12 signs or symptoms described below: • Change in sputum volume or color • Hemoptysis • Increased cough • Increased dyspnea • Increased malaise, fatigue, or lethargy • Temperature over 38°C • Anorexia or weight loss • Maxillary sinus pain or sensitivity • Change or increase in postnasal discharge • Change in chest physical examination findings • Decrease in FEV1 of 10% or higher • New radiographic changes Given that APEs have a negative impact on survival, quality of life, and costs (because of the high costs of hospitalizations and medications), they are an important outcome measure in clinical trials, and although various authors have proposed alternative methods for their objective

characterization in patients with CF,(45-47) this definition remains a source of controversy.(48) In 2011, a group of European experts met in Hamburg and proposed new consensus criteria for characterizing an APE(49): the need for antibiotic therapy resulting from a recent change in at least 2 of the following 7 items: • Change in sputum volume or color • Increased cough • Increased malaise, fatigue, or lethargy • Anorexia or weight loss • Decrease in FEV1 of 10% or higher • New radiographic changes • Increased dyspnea • Recommendation The criteria for defining an APE are derived from several studies, and there is a consensus among authors that most of the criteria are adopted on the basis of accumulated experience, although the scientific basis remains flimsy (LE 2b; GR B). (47) Should intravenous therapy for an APE be administered in the home or in the hospital? A cohort study conducted in the USA and involving twins and siblings with CF retrospectively analyzed APEs in 1,535 patients, comparing the FEV1 outcomes of approximately 5,000 courses of intravenous antibiotics administered in the hospital with those of the same number of courses administered in the home, and concluded that there was no difference in functional outcome between the two approaches (LE 2b).(43) A recent systematic review of the literature(50) evaluated whether or not home therapy can replace hospitalization in cases of APE. Although several databases were searched, only a small randomized study involving 17 patients was found. The authors concluded that the current evidence is too limited: the results of the only randomized study suggest that, in the short term, home therapy is efficient and cheaper, as well as resulting in reduced social costs. There are advantages and disadvantages in terms of quality of life. The decision to attempt treatment in the home should be made on a case-bycase basis. The authors concluded that further research is necessary (LE 3a).(50)

Recommendation There is insufficient evidence to recommend or refute intravenous home therapy for APEs, J Bras Pneumol. 2013;39(4):495-512

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and decisions should be made on a case-by-case basis (LE 5; GR D).

Which antibiotic(s) should intravenous therapy for an APE include? Traditionally, intravenous administration of beta-lactam antibiotics combined with aminoglycosides has been the most commonly used therapeutic regimen in the treatment of APEs in patients with CF.(51,52) Given that P. aeruginosa is a pathogen that develops resistance to antimicrobial agents relatively easily,(53) the combination of drugs with different mechanisms of action can contribute to minimizing this risk. In a study conducted in England, the researchers reported a high prevalence of ceftazidimeresistant P. aeruginosa strains, possibly due to the practice of monotherapy with this drug in the institution (LE 4).(54) A systematic review published in 2005(55) included 27 studies comparing monotherapy with combination antibiotic therapy in the treatment of APEs in patients with CF. The studies were mostly of questionable methodological quality and were quite heterogeneous, complicating the analysis and interpretation of results. In contrast, some randomized studies have shown that combination antibiotic therapy is effective in the treatment of APEs in patients with CF (NE 2a).(56,57) American guidelines(47) recognize the deficiency in information but recommend that combination drug therapy be instituted.

Recommendation There is evidence to recommend the combination of an aminoglycoside and a betalactam antibiotic for the treatment of APEs in patients with CF (LE 2a; GR B).

Can (or should) aminoglycosides be used once daily? Aminoglycosides were originally studied and approved for use as a three times-daily injection regimen.(58) The recognition that the maximum bactericidal effect of aminoglycosides results from the serum peak values achieved motivated researchers in the late 1980s to evaluate oncedaily aminoglycoside administration,(59) and this strategy was found to be effective and safe in various clinical settings. (60) In patients with CF, the results of a meta-analysis(61) and of a J Bras Pneumol. 2013;39(4):495-512

systematic review (62) indicate that once-daily aminoglycoside administration is effective and safer (LE 1a).

Recommendation Aminoglycosides should be administered in a single daily dose in order to reduce side effects (LE 1a; GR A).

What should be the duration of intravenous therapy for an APE? There are no clear guidelines on the optimal duration of intravenous antibiotic therapy in APEs in patients with CF. Treatment duration is currently based on the policies of each referral center and on individual response to treatment. Shorter treatment durations for APEs should improve the quality of life and satisfaction of patients and their families, as well as being less costly. However, this might not be sufficient to reduce the density of P. aeruginosa in the lungs significantly, potentially resulting in early recurrence of APE. Although a systematic review(63) concluded that there are insufficient data to recommend an appropriate treatment duration for an APE in patients with CF, most treatment regimens, in many centers worldwide, last 10-14 days (LE 4). Two more recent studies have provided some interesting data on the subject. VanDevanter et al., (64) in a retrospective study involving 95 hospitalized patients treated with two distinct antimicrobial regimens, found that the average time to the highest observed FEV1 during the hospitalizations was 8.7 days (median = 10 days), and also reported that, in patients who had poor baseline pulmonary function (FEV1 < 40%), the time to the highest observed FEV1 was significantly longer (LE 3b). In another recent study (also retrospective), which evaluated more than 10,000 courses of intravenous antibiotic therapy in approximately 1,500 patients with CF, Collaco et al. (43) showed that clinical and functional improvement was observed between day 7 and day 8 of therapy in most cases, indicating that shorter therapy durations can be used in some cases (LE 3b).

Recommendation There is no clear definition in the literature as to what the duration of therapy for APEs

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should be. However, the results suggest that antibiotics should be administered for at least 8-10 days, and patients who have worse baseline pulmonary function might require longer period of intravenous therapy (LE 3; GR C).

When should chronic inhaled antibiotic therapy be initiated in CF? Which inhaled antibiotics can be used in the treatment of chronic P. aeruginosa infection in CF? Chronic P. aeruginosa infections have a negative impact on the prognosis of patients with CF, and, since the 1980s, there has been evidence that the use of therapies that decrease the amount of P. aeruginosa in the bronchial tree contributes to the stabilization or improvement of the disease.(65,66) Tobramycin is the most studied inhaled antibiotic, since a specific formulation of tobramycin (Tobiﾂｮ; Novartis, Sﾃ｣o Paulo, Brazil) has been developed and tested in randomized, double-blind, placebo-controlled clinical trials involving a large number of patients with CF.(2) In the initial studies, inhaled tobramycin was compared with inhaled placebo or standard therapy in patients with moderate to severe lung disease (FEV1 < 70% of predicted), and the largest of them involved a sample of 520 patients (LE 1).(67) The three most significant studies had a total number of 619 randomized patients. The results showed statistically significant improvement in FEV1 in those who received tobramycin, with a 7.8-12.0% increase in pulmonary function (FEV1; LE 1b).(67-69) In addition, those three studies evaluated the influence of the use of inhaled tobramycin on the frequency of APEs, reporting a reduction in the number of hospitalizations and in the number of hospitalization days for the group treated with inhaled tobramycin (NE 1b).(67-69) The frequency of reported adverse events, especially those related to tinnitus, throat problems, and voice changes, was low in all studies. These results led to inhaled tobramycin being recommended by international guidelines as the primary treatment option for such cases.(2) Two studies,(38,70) involving a total number of 202 patients, evaluated the use of inhaled tobramycin in patients with CF and mild lung disease (FEV1 between 70% and 89% of predicted).

Gibson et al., in a sample of 21 patients under 6 years of age with CF and P. aeruginosa detected by BAL culture, reported that the use of inhaled tobramycin resulted in a reduction in the amount of P. aeruginosa in the airways (LE 2b).(38) Another study, involving 181 patients (6-15 years of age) with mild lung disease, compared the use of inhaled tobramycin with the use of standard therapy for 56 weeks and found a significant reduction in the occurrence of exacerbations requiring hospitalization (11.0% vs. 25.6%). The study was stopped early because of the magnitude of the observed impact (LE 1b).(70) There was no significant improvement in FEV1, but those treated with inhaled tobramycin showed a significant improvement (10%) in forced expiratory flow values窶認EF50% (LE 1b).(70) The quality of evidence for the use of inhaled tobramycin in patients with mild lung disease remains limited by the number of studies and by sample sizes, and the largest of those studies(70) was stopped early because of the magnitude of the impact observed for respiratory exacerbations. Other inhaled antibiotics are used in CF patients with chronic P. aeruginosa infection, but the amount of scientific evidence remains relatively sparse.(2) Inhaled colomycin remains the initial drug of choice for nebulization in patients with CF and chronic respiratory infection with P. aeruginosa in the United Kingdom.(71) A comparative study of inhaled tobramycin (300 mg twice daily) and nebulized colomycin (1,000,000 IU twice daily) involving 115 patients showed that both therapies reduced the bacterial content of sputum samples and increased FEV1 values by 6.7% and 0.37%, respectively (NE 2b).(72) There have been few studies on the use of other drugs, such as gentamicin, amikacin, and ceftazidime.(2) New drugs for inhalation have recently been tested in order to expand the range of therapeutic options, with benefits in the areas of tolerability, bacterial resistance, and practicality of administration, impacting patient safety and quality of life. Inhaled aztreonam, a single-ring beta-lactam antibiotic (a monobactam), is one of the recently introduced drugs.(73) One of the initial studies was a randomized, double-blind, placebo-controlled trial involving 211 patients over 6 years of age with CF, FEV1 between 25% and 75% of predicted, and chronic P. aeruginosa infection, all of whom J Bras Pneumol. 2013;39(4):495-512

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were using inhaled tobramycin regularly. The patients received 75 mg inhaled aztreonam or placebo, two or three times daily for 28 days, and were then monitored for another 56 days. The reported positive effects included a 21-day increase in the mean time to next respiratory exacerbation, improvement in mean quality of life scores, a 6.3% increase in VEF1 (p = 0.001), and a reduction in sputum P. aeruginosa density. Adverse events were comparable between the groups. There was no change in susceptibility to P. aeruginosa for aztreonam (LE 2b).(73) More recently, a study has been published that reports data on the use of inhaled aztreonam for a longer period of time (18 months).(74) The study included 274 patients (mean age, 26 years) who had participated in other studies with inhaled aztreonam. It was an open-label study involving two regimens (75 mg two or three times daily) in alternate months. In addition to high adherence to treatment, pulmonary function and qualityof-life data improved with each course of the drug, there being no significant increase in bacterial resistance rates. Patients treated with three times-daily nebulization showed more significant improvement in pulmonary function and respiratory symptoms (LE 2b).(74) A novel dry-powder formulation of tobramycin delivered via an innovative inhaler was compared, in a non-inferiority study, with the commercially available inhaled tobramycin preparation.(75) The study included 517 patients over 6 years of age with CF, FEV1 between 25% and 75% of predicted, and a history of chronic P. aeruginosa infection for the last 6 months. The dry-powder formulation of tobramycin and the inhaled tobramycin preparation had similar efficacy in terms of FEV1 and microbiological effect, although the former resulted in higher rates of adverse effects, such as dysphonia, cough, and dysgeusia. However, the dry-powder formulation of tobramycin resulted in higher scores on qualityof-life questionnaires (LE 1b).(75) A formulation of levofloxacin (MP-376, Aeroquin) was tested in 151 CF patients with chronic P. aeruginosa infection (LE 2b).(76) Three different doses (120 mg/day, 240 mg once daily, and 240 mg twice daily) were tested against placebo for 28 days. Sputum P. aeruginosa density was reduced by MP-376 treatment at all three different doses, and there was a dose-dependent increase (of up to 8.7%) in FEV1, as well as a J Bras Pneumol. 2013;39(4):495-512

significant reduction in the occurrence of APEs. The drug was generally well tolerated relative to placebo (LE 2b).(76) A systematic review of the literature, published in 2011,(77) summarized the available evidence on the use of inhaled antibiotics in patients with CF. The review made several comparisons using meta-analysis techniques. The conclusion was that inhaled antibiotics improve pulmonary function and reduce the rates of exacerbation of P. aeruginosa infection, and that the best evidence supports the use of inhaled tobramycin (LE 1a). (77)

Recommendation It is recommended that inhaled tobramycin be used in patients over 6 years of age with CF, chronic P. aeruginosa infection, and moderate or severe lung disease (FEV1 < 70%; LE 1; GR A). The use of inhaled tobramycin in patients over 6 years of age with CF, chronic P. aeruginosa infection, and mild lung disease (FEV1 between 70% and 89%) is recommended to reduce respiratory exacerbations (LE 2; GR B). The evidence for the use of inhaled tobramycin in the younger population (those under 6 years of age) remains too poor to allow any evidencebased recommendation. There are still few data on the use of other antibiotics, such as colomycin, gentamicin, and aztreonam, and there is no evidence to recommend that they be widely used.

Does adherence to clinical treatment affect the prognosis of patients with CF? The treatment of patients with CF is based on the prevention structural lung injury, the management of the nutritional status, with supplementation with enzymes and nutrients, the prevention of exacerbations, and the identification and treatment of comorbidities, allowing a good quality of life.(78) Among daily treatments, respiratory therapy plays a prominent role because of its complexity, since it usually requires the assistance of another individual and it is a procedure that has a significant impact on disease progression.(79,80) Given the complexity of the disease and the various objectives involved, it is clear that complex and aggressive treatment

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regimens are frequently used, which is very timeconsuming for patients and their families.(81) In this setting of complex treatments and no set deadline for their completion, adherence to the recommended treatment is a factor that greatly impacts the clinical outcomes and prognosis of such patients.(78) Nebulizations are the most complex part of the pharmacological treatment, because they are very time-consuming and are increasingly recommended in patients with mild disease.(2) In a recent study involving adult patients with CF, the mean reported time spent on treatment activities was 108 min/day, and nebulized therapies accounted for 41 min of that time.(81) Even in asthma patients, who spend much less time on drug administration, estimates of adherence to inhaled therapies range from 30% to 50%.(82) One of the reasons for poor adherence to treatment is lack of understanding of physician recommendations by patients and their families, who often also understand the same physician recommendation differently.(83) There is evidence that the low rates of adherence to medication use in CF are associated with poorer disease control, school absenteeism, and an increase in APEs (LE 2b).(84) In general, the onset of adolescence further worsens the scenario, because that is the time when the lung disease usually progresses and is precisely the time when adherence to treatment becomes poorer.(85) There is evidence that adherence is inversely proportional to patient age, as well as being intimately related to a more optimistic view of the disease.(86) Given that a study evaluating factors associated with poor adherence in children with asthma and CF identified common factors between the two diseases (forgetting, oppositional behaviors toward parents, difficulties with time management for procedures, side effects, difficulties swallowing pills, and taste of some medications), but also described many aspects that are specific to each disease, it is recommended that a disease-specific approach be applied to issues of adherence to treatment (LE 2b).(87) A study involving adult CF patients and self-reported adherence that was conducted in Brazil showed high adherence rates, which were higher than that perceived by the medical staff involved in the treatment of those individuals. (88) Using other tools to measure adherence, such

as pharmacy records, Eakin et al.(89) showed that poor adherence was associated with a higher risk of APE requiring the use of intravenous antibiotics (LE 4). Analyzing supplemental health care data on reimbursement for the purchase of inhaled tobramycin, Briesacher et al.(90) assessed the impact of adherence to this therapy on the clinical outcomes of patients with CF. Categorizing adherence as “low” (< 2 cycles/year), “medium” (2-3 cycles/year,) and “high” (≥ 4 cycles/year), those authors reported that high adherence was identified in only 7% of patients, and that low adherence was associated with an increased risk of hospitalization, with higher costs to the health care system (LE 3b). It is of note that the recommended treatment regimen is at least 6 cycles/year.

Recommendation Adherence to treatment in CF is related to the great treatment load required and is poorer in adolescence. Nebulized therapies and respiratory therapy have the worst rates of adherence, and there is evidence that these therapies affect relevant clinical outcomes, such as the need for hospitalization (LE 3; GR C).

Is azithromycin efficacious in slowing the progression of lung disease in CF patients colonized with P. aeruginosa? Macrolides are bacteriostatic drugs that act by inhibiting bacterial protein synthesis by binding to the 50S ribosomal unit.(91) In the 1980s, Japanese researchers described their experience in using low doses of erythromycin in diffuse panbronchiolitis, a disease that is accompanied by bronchiectasis and pulmonary suppuration.(92) That initial experience motivated further studies using different macrolides in the treatment of respiratory diseases, such as CF, asthma, and bronchiolitis obliterans.(91) Possible mechanisms of action of macrolides in CF include actions in the microorganism, such as reduced P. aeruginosa virulence, delayed bactericidal effects, reduced bacterial adherence to the respiratory epithelium, decreased bacterial motility, and impaired biofilm production. (91,93) Among the immunomodulatory actions of macrolides in the host are alteration in the neutrophil production of elastase, inhibition of J Bras Pneumol. 2013;39(4):495-512

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alveolar macrophage production of inflammatory cytokines, and decreased mucus hypersecretion.(91,93) Azithromycin is the most commonly used macrolide in patients with CF, and the first encouraging clinical trial was published in 2002: a 15-month randomized double-blind, placebo-controlled crossover trial evaluating 41 patients with CF.(94) The primary outcome measure was change in FEV1, and azithromycin was dosed by body weight: â&#x2030;¤ 40 kg (250 mg/ day) and > 40 kg (500 mg/day). The authors found significant improvement in pulmonary function (5.4%; 95% CI: 0.8-10.5%) in the group receiving azithromycin as compared with the group receiving placebo, and there was no significant difference in sputum bacterial concentration, exercise tolerance, or quality of life. In addition, treatment was well tolerated, with no significant adverse events (LE 2b).(94) Subsequently, a new, multicenter, randomized, double-blind, placebo-controlled trial involving 185 patients over 6 years of age who were chronically infected with P. aeruginosa was conducted in the USA.(95) The dose of azithromycin was the same as that of the previous study, although it was administered only three times weekly. The primary outcome measure was also FEV1, and the authors reported a significant difference between the treatment and placebo groups (6.2%; 95% CI: 2.6-9.8%). Other encouraging results were a 35% reduction in the risk of APE and significant weight gain among the patients receiving azithromycin (LE 1b).(95) The same group of authors assessed the effects of azithromycin in CF patients uninfected with P. aeruginosa(96); the use of azithromycin for 24 weeks did not result in significant improvement in FEV1 when compared with that of placebo, but there was a significant reduction in the occurrence of APEs in the group treated with azithromycin (LE 2b).(96) A recent meta-analysis evaluating the use of macrolides in patients with CF included 6 randomized placebo-controlled trials (654 patients).(97) Treatment with azithromycin resulted in significant improvement in FEV1 and FVC, especially in patients chronically infected with P. aeruginosa. The incidence of side effects was not significantly different between the placebo group and the azithromycin group (LE 1a).(97) A recent systematic review on the use of macrolides in CF included 10 studies (959 patients).(98) Four clinical trials (549 patients) J Bras Pneumol. 2013;39(4):495-512

reported significant improvement in pulmonary function by comparing azithromycin with placebo. The mean difference at 6 months was 3.97% (95% CI: 1.74-6.19%). Patients receiving azithromycin had a reduction in the occurrence of APEs, needed oral antibiotics less frequently, had greater weight gain, and had fewer respiratory secretion cultures positive for S. aureus. Adverse effects were uncommon, although there was an increase in resistance to macrolides. The authors concluded that azithromycin has a small beneficial effect in the treatment of patients with CF using a three times-weekly regimen for periods of 6 months. However, considering the limited long-term data available and the concern about the development of bacterial resistance to macrolides, the current evidence is not strong enough to recommend that azithromycin be used in all patients with CF (LE 1a).(98)

Recommendation The use of azithromycin in CF patients chronically infected with P. aeruginosa causes slight improvement in pulmonary function, reduces the frequency of APEs, and has no significant side effects (LE 1; GR A). Because most studies lasted approximately 6 months, long-term studies are needed to confirm the efficacy and safety of azithromycin.

Is there a good correlation between antibiogram results and clinical response in chronic P. aeruginosa infection? In initial infection with P. aeruginosa in patients with CF, nonmucoid forms are usually quite sensitive, there is a good correlation with antibiogram results, and treatment is usually successful. In chronic infections, mucoid forms of P. aeruginosa predominate, and higher concentrations of antibiotics are required; in addition, given the common occurrence of mixed populations of P. aeruginosa in the biofilm in the lung, the correlation between antibiogram results and clinical response might not be good.(71) There are reports of clinical success in the treatment of bacteria that are resistant in vitro, and, in a study involving treatment of APEs, clinical outcomes were not associated with the minimum inhibitory concentration values

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for P. aeruginosa of the antimicrobial agents used (LE 2b). (99) In a study addressing multidrug-resistant P. aeruginosa isolates, Aaron et al.(100) found no significant differences in clinical or bacteriological outcomes between the antimicrobial regimen chosen on the basis of standard sensitivity testing and that chosen on the basis of multiple combination bactericidal antibiotic testing (synergy testing; LE 2b). Despite the lack of correlation found between antibiogram results and clinical response in the treatment of P. aeruginosa infections, the recommendation is to perform cultures of respiratory secretions from CF patients periodically to detect the initial infection, as well as to monitor changes in sensitivity patterns or the presence of other pathogens, such as B. cepacia complex, Achromobacter xylosoxidans, Aspergillus spp., etc. (LE 5).(101)

Recommendation Despite the poor correlation between antibiogram results and clinical response in chronic P. aeruginosa infection, it is recommended that cultures of respiratory secretions from CF patients be performed periodically to identify different bacterial species, although P. aeruginosa treatment should not be directed solely by the sensitivity pattern in the antibiogram (LE 5; GR D).

Does multidrug-resistant P. aeruginosa infection worsen prognosis? As the mean survival of patients with CF increases and the population of adults with CF grows, there is increasing concern about multidrug-resistant P. aeruginosa infections. Multidrug-resistant P. aeruginosa has been defined as resistance to all drugs in at least two of the three following antimicrobial classes: fluoroquinolones; beta-lactam antibiotics; and aminoglycosides.(102) The major risk factors for multidrug-resistant P. aeruginosa infection are diabetes, long-term use of inhaled tobramycin, and frequent APEs requiring hospitalization or intravenous antibiotics. Receiving care at a treatment center with a high prevalence of resistant Pseudomonas spp. also increases the risk for acquiring multidrug-resistant P. aeruginosa (LE 2b).(103)

A study following 75 adult patients with CF over a 3-year period found that multidrugresistant P. aeruginosa infection was associated with greater lung disease severity, more rapid decline in FEV1, increased use of intravenous antibiotics, and increased frequency of medical visits (LE 2b).(104)

Recommendation Multidrug-resistant P. aeruginosa infection worsens the prognosis of patients with CF, as well as increasing the need for care and the use of medical and hospital resources (LE 2).

Final considerations There is a body of evidence that early P. aeruginosa colonization has a significant impact on the prognosis of patients with CF, and that eradication strategies should be used, although there is controversy as to what is the best treatment regimen for this purpose. Early diagnosis of P. aeruginosa infection remains a challenge in clinical practice, and the role of P. aeruginosa serology in routine practice has yet to be established. A major problem for patients with CF, APEs are difficult to identify and treat, which often results in significant functional loss. Maintenance treatment for patients with chronic P. aeruginosa infection includes drugs such as azithromycin and inhaled antibiotics and, despite the body of evidence supporting the use of inhaled tobramycin, there is a novel formulation of this drug, as well as other antimicrobial agents with potential for use in such cases.

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72. Hodson ME, Gallagher CG, Govan JR. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J. 2002;20(3):658-64. http://dx.doi. org/10.1183/09031936.02.00248102 PMid:12358344 73. McCoy KS, Quittner AL, Oermann CM, Gibson RL, RetschBogart GZ, Montgomery AB. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008;178(9):921-8. http:// dx.doi.org/10.1164/rccm.200712-1804OC PMid:18658109 PMCid:2577727 74. Oermann CM, Retsch-Bogart GZ, Quittner AL, Gibson RL, McCoy KS, Montgomery AB, et al. An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis. Pediatr Pulmonol. 2010;45(11):1121-34. http://dx.doi.org/10.1002/ ppul.21301 PMid:20672296 75. Konstan MW, Flume PA, Kappler M, Chiron R, Higgins M, Brockhaus F, et al. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros. 2011;10(1):54-61. http:// dx.doi.org/10.1016/j.jcf.2010.10.003 PMid:21075062 76. Geller DE, Flume PA, Staab D, Fischer R, Loutit JS, Conrad DJ, et al. Levofloxacin inhalation solution (MP-376) in patients with cystic fibrosis with Pseudomonas aeruginosa. Am J Respir Crit Care Med. 2011;183(11):1510-6. http:// dx.doi.org/10.1164/rccm.201008-1293OC PMid:21471106 77. Ryan G, Singh M, Dwan K. Inhaled antibiotics for longterm therapy in cystic fibrosis. Cochrane Database Syst Rev. 2011;(3):CD001021. PMid:21412868 78. Sawicki GS, Tiddens H. Managing treatment complexity in cystic fibrosis: challenges and opportunities. Pediatr Pulmonol. 2012;47(6):523-33. http://dx.doi.org/10.1002/ ppul.22546 PMid:22467341 79. Robinson P. Cystic fibrosis. Thorax. 2001;56(3):237-41. http://dx.doi.org/10.1136/thorax.56.3.237 PMid:11182019 PMCid:1758774 80. Bell SC, Robinson PJ. Exacerbations in cystic fibrosis: 2 . prevention. Thorax. 2007;62(8):723-32. http:// dx.doi.org/10.1136/thx.2006.060897 PMid:17687099 PMCid:2117269 81. Sawicki GS, Sellers DE, Robinson WM. High treatment burden in adults with cystic fibrosis: challenges to disease self-management. J Cyst Fibros. 2009;8(2):91-6. http:// dx.doi.org/10.1016/j.jcf.2008.09.007 PMid:18952504 PMCid:2680350 82. Milgrom H, Bender B, Ackerson L, Bowry P, Smith B, Rand C. Noncompliance and treatment failure in children with asthma. J Allergy Clin Immunol. 1996;98(6 Pt 1):1051-7. http://dx.doi.org/10.1016/S0091-6749(96)80190-4 83. Ievers CE, Brown RT, Drotar D, Caplan D, Pishevar BS, Lambert RG. Knowledge of physician prescriptions and adherence to treatment among children with cystic fibrosis and their mothers. J Dev Behav Pediatr. 1999;20(5):335-43. http://dx.doi.org/10.1097/00004703-199910000-00008 PMid:10533992 84. Rau JL. Determinants of patient adherence to an aerosol regimen. Respir Care. 2005;50(10):1346-56; discussion 1357-9. PMid:16185370 85. DiGirolamo AM, Quittner AL, Ackerman V, Stevens J. Identification and assessment of ongoing stressors in adolescents with a chronic illness: an application of the behavior-analytic model. J Clin Child Psychol. 1997;26(1):53-66. http://dx.doi.org/10.1207/ s15374424jccp2601_6 PMid:9118176

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controlled trial. JAMA. 2010;303(17):1707-15. http:// dx.doi.org/10.1001/jama.2010.563 PMid:20442386 97. Cai Y, Chai D, Wang R, Bai N, Liang BB, Liu Y. Effectiveness and safety of macrolides in cystic fibrosis patients: a metaanalysis and systematic review. J Antimicrob Chemother. 2011;66(5):968-78. http://dx.doi.org/10.1093/jac/dkr040 PMid:21393178 98. Southern KW, Barker PM, Solis-Moya A, Patel L. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2011;(12):CD002203. PMid:22161368 99. Smith AL, Fiel SB, Mayer-Hamblett N, Ramsey B, Burns JL. Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis. Chest. 2003;123(5):1495-502. http://dx.doi.org/10.1378/ chest.123.5.1495 PMid:12740266 100. Aaron SD, Vandemheen KL, Ferris W, Fergusson D, Tullis E, Haase D, et al. Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double-blind, controlled clinical trial. Lancet. 2005;366(9484):46371. http://dx.doi.org/10.1016/S0140-6736(05)67060-2 101. Cant贸n R, Cobos N, de Gracia J, Baquero F, Honorato J, Gartner S, et al. Antimicrobial therapy for pulmonary pathogenic colonisation and infection by Pseudomonas aeruginosa in cystic fibrosis patients. Clin Microbiol Infect. 2005;11(9):690-703. http://dx.doi.org/10.1111/j.14690691.2005.01217.x PMid:16104983 102. Saiman L, Mehar F, Niu WW, Neu HC, Shaw KJ, Miller G, et al. Antibiotic susceptibility of multiply resistant Pseudomonas aeruginosa isolated from patients with cystic fibrosis, including candidates for transplantation. Clin Infect Dis. 1996;23(3):532-7. http://dx.doi.org/10.1093/ clinids/23.3.532 PMid:8879776 103. Merlo CA, Boyle MP, Diener-West M, Marshall BC, Goss CH, Lechtzin N. Incidence and risk factors for multiple antibiotic-resistant Pseudomonas aeruginosa in cystic fibrosis. Chest. 2007;132(2):562-8. http://dx.doi. org/10.1378/chest.06-2888 PMid:17646236 104. Lechtzin N, John M, Irizarry R, Merlo C, Diette GB, Boyle MP. Outcomes of adults with cystic fibrosis infected with antibiotic-resistant Pseudomonas aeruginosa. Respiration. 2006;73(1):27-33. http://dx.doi.org/10.1159/000087686 PMid:16113513

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About the authors Luiz Vicente Ribeiro Ferreira da Silva Filho

Médico Assistente Doutor. Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil.

Flavia de Aguiar Ferreira

Gerente Médica. Novartis Brasil, São Paulo (SP) Brasil.

Francisco José Caldeira Reis

Presidente. Grupo Brasileiro de Estudos em Fibrose Cística, Belo Horizonte (MG) Brasil.

Murilo Carlos Amorim de Britto

Médico. Instituto Materno Infantil de Pernambuco, Recife (PE) Brasil.

Carlos Emilio Levy

Diretor. Divisão de Patologia Clínica, Hospital das Clínicas, Universidade Estadual de Campinas, Campinas (SP) Brasil.

Otavio Clark

Diretor. Evidências Consultoria, Campinas (SP) Brasil.

José Dirceu Ribeiro

Professor Titular de Pediatria. Universidade Estadual de Campinas, Campinas (SP) Brasil.

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Case Report Transdiaphragmatic intercostal hernia: imaging aspects in three cases* Hérnia intercostal transdiafragmática: aspectos de imagem em três casos

Ana Carolina Sandoval Macedo, Fernando Uliana Kay, Ricardo Mingarini Terra, José Ribas Milanez de Campos, André Galante Alencar Aranha, Marcelo Buarque de Gusmão Funari

Abstract Transdiaphragmatic intercostal hernia is uncommon and mostly related to blunt or penetrating trauma. We report three similar cases of cough-induced transdiaphragmatic intercostal hernia, highlighting the anatomic findings obtained with different imaging modalities (radiography, ultrasonography, CT, and magnetic resonance) in each of the cases. Keywords: Hernia, diaphragmatic; Radiography; Ultrasonography; Tomography; Magnetic resonance imaging.

Resumo Hérnias intercostais transdiafragmáticas são eventos raros e são geralmente relacionadas a traumas abertos ou fechados, com risco de complicações. Relatamos três casos semelhantes, decorrentes de crises de tosse, destacando o aspecto das alterações anatômicas nos exames de imagem obtidos em cada situação (radiografia, ultrassonografia, TC e ressonância magnética). Descritores: Hérnia diafragmática; Radiografia; Ultrassonografia; Tomografia; Imagem por ressonância magnética.

Introduction The occurrence of herniation of abdominal contents through the diaphragm and intercostal muscles is an uncommon phenomenon, which can be related to blunt or penetrating trauma.(1-4) The protective cough reflex has been sporadically associated with the genesis of this entity.(2,5-7) Failing to recognize transdiaphragmatic intercostal hernia can be potentially fatal, because of possible complications, such as strangulation.(8) We report the cases of three patients who developed cough-induced herniation of intestinal loops through the diaphragm and intercostal space, associated with rib fracture, describing the radiographic, ultrasonographic, CT, and magnetic resonance findings obtained in the cases.

Case reports Case 1 A 53-year old man presented to an outpatient clinic reporting bulging of the right inferolateral region of the chest, as well as postprandial gastric fullness and “strange” noises in the region. The patient associated the onset of the condition (more than 1 year prior) with a violent attack of coughing, followed by severe, persistent pain in the right thoracoabdominal junction, worsened by exertion. He reported that, at the time, that episode had been diagnosed as “pneumonia at the right lung base”. Subsequently, an area of ecchymosis was noted along the right lateral thorax and abdomen. The pain and the hematoma resolved over weeks, whereas the progressive bulging of the region,

*Study carried out at the Hospital Israelita Albert Einstein, São Paulo, Brazil. Correspondence to: Ana Carolina Sandoval Macedo. Avenida Albert Einstein, 627, 4º andar, Bloco D, Morumbi, CEP 05652-900, São Paulo, SP, Brasil. Tel. 55 11 2152-2452. Fax: 55 11 2152-2452. E-mail: ana.smacedo@einstein.br Financial support: None. Submitted: 8 October 2012. Accepted, after review: 7 December 2012.

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which worsened with the patient in the orthostatic position, persisted. Physical examination revealed that his abdomen was globular, flaccid, and painless on palpation, and that there was irreducible bulging of the right eighth intercostal space, which became more evident during a Valsalva maneuver. There was an abnormal distance between the ribs of the aforementioned intercostal space, with signs of a previous separation of the costochondral junction. A CT scan of the chest revealed fractures of the anterior portion of the eighth rib, widening of the eighth intercostal space, and diaphragmatic discontinuity, through which loops of small intestine, as well as part of the colon and omentum, protruded into and occupied the subcutaneous tissue of the chest wall. In view of the diagnosis of transdiaphragmatic intercostal hernia, the patient underwent surgery via a right thoracotomy. The hernial sac was identified, the abdominal viscera were returned to the abdominal cavity, the hernial orifice was closed with a double prolene mesh and several interrupted sutures, and the pleural cavity was drained. In closing the thoracotomy, the widened intercostal space was reduced with the use of reinforcement with the same type of mesh, which was fixed to the lower and upper ribs. The patient had a favorable postoperative course, being discharged from hospital on the sixth day, with no evidence of immediate complications (Figure 1).

Case 2 A 71-year-old man reported a 2-year history of bulging of the right thoracoabdominal region, the onset of which occurred after an attack of coughing, associated with severe, stabbing pain in that region, worsened by coughing and relieved with painkillers. In addition, an area of ecchymosis was noted along the lateral region of the abdomen after the onset of pain. The pain gradually resolved, and there was progressive bulging of the region. Physical examination revealed that his abdomen was globular, flaccid, and painless on palpation, and that there was reducible bulging of the eighth intercostal space, which became more evident during a Valsalva maneuver. There was a 4-5 cm distance between the ribs of the aforementioned intercostal space, with signs of a previous separation of the costochondral junction. A chest radiograph showed fractures of the anterior portion of the eighth rib and widening of the eighth intercostal space. Ultrasound examination of the region with a high-frequency transducer demonstrated a formation with echotexture similar to that of the liver, protruding through the aforementioned intercostal space into the subcutaneous region. A noncontrast CT scan confirmed that it was transdiaphragmatic intercostal herniation of part

Figure 1 - In A, posteroanterior chest radiograph. The arrow demonstrates opacification at the base of the right hemithorax, interspersed with some gas images. The arrowhead indicates soft tissue swelling in the periphery of the right lateral chest wall, with some gas images similar to those observed at the base of the right hemithorax. In B, coronal reconstruction of a noncontrast CT scan of the chest showing herniation of abdominal content into the base of the right hemithorax through the diaphragm (arrow), as well as through the eighth intercostal space (asterisk), headed toward the subcutaneous tissue of the chest wall. Note the presence of thin loops in the subcutaneous tissue of the chest wall (arrowhead).

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HERNIA

RIGHT HIPPOCAMPUS

Figure 2 - In A, photograph showing visible bulging of the region of the right eighth intercostal space, on examination of the chest wall. In B, surface ultrasound examination of the region demonstrating a formation with echotexture similar to that of the liver, extending beyond the musculoskeletal boundaries of the chest wall and occupying the subcutaneous region (arrows). In C and D, axial CT slices of the upper abdomen demonstrating that part of hepatic segment V protruded through the area of muscle discontinuity, headed toward the adjacent subcutaneous region.

of hepatic segment V. The patient underwent surgical correction via a thoracotomy, and a diaphragmatic tear was identified near the chest wall. The diaphragm was reattached to the ribs, and the rib borders were approximated with a nonabsorbable suture (Figure 2).

Case 3 A 64-year-old male former smoker (55 packyears) who was being noncompliant with COPD treatment had an episode of uncontrollable coughing that caused acute, intense pain in the right hypochondrium, followed by the onset of ecchymosis, which was visible locally. He sought medical care and received symptomatic treatment only. He experienced progressive worsening of dyspnea, and, after 4 months, dyspnea on minimal exertion became evident. At that point, the patient sought a pulmonologist, who requested a chest

radiograph, which revealed opacification of the right lung base and soft tissue swelling in the right inferolateral chest wall, interspersed with gas images. The patient was tachypneic (RR, 26 breaths/min) and had decreased breath sounds at the right base. In addition, an area of weakness of the ipsilateral chest wall was noted on palpation. A CT scan of the chest demonstrated herniation of abdominal adipose tissue into the right lung base and chest wall, through discontinuities in the diaphragmatic and intercostal muscles, associated with the presence of fractures of the last ribs on the right. Magnetic resonance confirmed the extensive herniation of the abdominal content through the muscle discontinuities. The patient subsequently underwent surgical correction of changes, with the presence of intestinal loops in the subcutaneous and intrathoracic regions being confirmed after a thoracotomy. On examination of the cavity, it was of J Bras Pneumol. 2013;39(4):513-517

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note that there was a rent in the anterolateral portion of the diaphragm, through which the abdominal content protruded. After the structures were returned to their site of origin, the diaphragmatic defect was sutured, and reinforcement with a polypropylene mesh was performed. The patient had a favorable postoperative course, being discharged on the sixth day, with decreased dyspnea (Figure 3).

Discussion Intercostal hernia is mostly caused by blunt or penetrating trauma to the thoracoabdominal region. (9) The occurrence of â&#x20AC;&#x153;spontaneousâ&#x20AC;? diaphragmatic rupture with herniation of abdominal structures is

uncommon.(2,10) Intercostal hernia is mostly associated with factors leading to a sudden increase in abdominal pressure, such as weight lifting, dancing, labor, vomiting, and cough, the last being the most common cause.(10,11) Transdiaphragmatic intercostal hernia can be acute or can progress over time (even years) to be diagnosed.(9) It occurs because of rupture of the diaphragm and intercostal muscles, which is mostly associated with rib fracture. There are two sites that are most susceptible: anteriorly, the costochondral junction to the sternum, because of lack of external intercostal muscles; and, posteriorly, the rib vertebral angle, because of lack of internal intercostal muscles.(9)

Figure 3 - In A, posteroanterior chest radiograph demonstrating opacification at the base of the right hemithorax, superiorly displacing the lung parenchyma (white arrow). Note the widening of the eighth intercostal space and the presence of a structure with gas density, similar to an intestinal loop, occupying the soft tissues of the adjacent chest wall (black arrow). In B, axial CT image of the chest, where it is possible to observe the passage of epiploic fat into the base of the right hemithorax and subcutaneous tissue of the chest wall (asterisk). Note the presence of a fracture of the ninth rib (white arrow). In C, coronal T1-weighted non-fat-saturated magnetic resonance image demonstrating the presence of a large amount of abdominal fat herniated into the base of the right hemithorax. Note the discontinuity of the intercostal muscles (black arrow), through which the content herniates into the subcutaneous tissue of the chest wall. In D, photograph showing the main surgical finding: a rent in the anterolateral portion of the diaphragm.

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Transdiaphragmatic intercostal hernia: imaging aspects in three cases

When intercostal hernia is related to attacks of uncontrollable coughing, it is mostly associated with rib fracture. The cough mechanism involves the opposing forces of the abdominal muscles and chest wall acting on the ribs, leading to fractures and muscle tears.(1,2,9) It presents clinically as reducible bulging of the affected intercostal space.(9) Our three patients reported the development of ecchymosis in the thoracoabdominal region, with progressive bulging. Chest radiograph can demonstrate opacification at the affected lung base, with gas images suggestive of intestinal loops, which extend into the chest wall through the widened intercostal space. The hernial content can be more accurately evaluated by ultrasound, especially when it comes to solid organs, such as the liver. However, this method is not always able to define the hernial content, particularly when the interposition of air-distended loops obstructs the acoustic window, with CT being superior in these cases.(9) To the best of our knowledge, this is the first case report to demonstrate the aspect of an transdiaphragmatic intercostal hernia as seen by magnetic resonance. Treatment in these cases is surgery, which involves reducing the hernia, suturing the diaphragmatic defect, and approximating the ribs. Because of the possibility of recurrence, reinforcement with a prosthetic mesh can be performed.

References 1. Unlu E, Temizoz O, Cagli B. Acquired spontaneous intercostal abdominal hernia: case report and a comprehensive review of the world literature. Australas

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Radiol. 2007;51(2):163-7. http://dx.doi.org/10.1111/j.14401673.2006.01661.x PMid:17419863 2. Daniel R, Naidu B, Khalil-Marzouk J. Cough-induced rib fracture and diaphragmatic rupture resulting in simultaneous abdominal visceral herniation into the left hemithorax and subcutaneously. Eur J Cardiothorac Surg. 2008;34(4):914-5. http://dx.doi.org/10.1016/j. ejcts.2008.06.048 PMid:18715797 3. Fiane AE, Nordstrand K. Intercostal pulmonary hernia after blunt thoracic injury. Eur J Surg. 1993;159(67):379-81. PMid:8104503 4. Llarges CM, Roesler LV, Gomes AF, Barreto CE. Hérnia diafragmática encarcerada com boa evolução após duas intervenções cirúrgicas: relato de caso. J Pneumol. 1998;24(1):43-6. 5. George L, Rehman SU, Khan FA. Diaphragmatic rupture: A complication of violent cough. Chest. 2000;117(4):1200-1. http://dx.doi.org/10.1378/chest.117.4.1200 PMid:10767262 6. Connery A, Mutvalli E. Cough-induced abdominal intercostal hernia. JRSM Short Rep. 2010;1(3):23. http:// dx.doi.org/10.1258/shorts.2010.010029 PMid:21103115 PMCid:PMC2984347 7. Hillenbrand A, Henne-Bruns D, Wurl P. Cough induced rib fracture, rupture of the diaphragm and abdominal herniation. World J Emerg Surg. 2006;1:34. http:// dx.doi.org/10.1186/1749-7922-1-34 PMid:17125506 PMCid:PMC1675993 8. Bendinelli C, Martin A, Nebauer SD, Balogh ZJ. Strangulated intercostal liver herniation subsequent to blunt trauma. First report with review of the world literature. World J Emerg Surg. 2012;7(1):23. http://dx.doi.org/10.1186/17497922-7-23 PMid:22800293 PMCid:PMC3441203 9. Cole FH Jr., Miller MP, Jones CV. Transdiaphragmatic intercostal hernia. Ann Thorac Surg. 1986;41(5):565-6. http://dx.doi.org/10.1016/S0003-4975(10)63045-7 10. Croce EJ, Mehta VA. Intercostal pleuroperitoneal hernia. J Thorac Cardiovasc Surg. 1979;77(6):856-7. PMid:374885 11. Nakanishi H, Iwasaki S, Ohkawa Y, Nakazawa H, Mineta H. Diaphragmatic rupture due to violent cough during tracheostomy. Auris Nasus Larynx. 2010;37(1):121-4. http:// dx.doi.org/10.1016/j.anl.2009.01.015 PMid:19423248

About the authors Ana Carolina Sandoval Macedo

Attending Physician. Hospital Israelita Albert Einstein, São Paulo, Brazil.

Fernando Uliana Kay

Attending Physician. Hospital Israelita Albert Einstein, São Paulo, Brazil.

Ricardo Mingarini Terra

Collaborating Professor. Department of Thoracic Surgery, University of São Paulo School of Medicine, São Paulo, Brazil.

José Ribas Milanez de Campos

Tenured Professor. Department of Thoracic Surgery, University of São Paulo School of Medicine, São Paulo, Brazil.

André Galante Alencar Aranha

Coordinator. Department of Thoracic Surgery, Fundação Lusíada School of Medicine; and Assistant Professor. Respiratory Tract Department, Methodist University at Santos School of Medicine, Santos, Brazil.

Marcelo Buarque de Gusmão Funari

Medical Manager. Imaging Department, Hospital Israelita Albert Einstein, São Paulo, Brazil.

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Letter to the Editor Not all that wheezes is asthma! Nem tudo que sibila é asma!

José Antônio Baddini Martinez

To the Editor: Health professionals working in the field of respiratory diseases are used to finding, in the routine examination of patients, sounds to which we in Brazil give the standardized name of sibilos (wheezing).(1,2) Wheezing is characterized by continuous, musical, adventitious breath sounds that last more than 250 ms and can appear during both inhalation and exhalation. In the English-language literature, the term wheeze is often employed to designate wheezing (higherpitched sounds) and another type of sound that, in Brazil, we prefer to call rhonchi (lower-pitched sounds). It is known that rhonchi and wheezing are produced by the appearance of oscillations in the airways and adjacent tissues because of the presence of severe airflow obstruction. The pitch differences between the two types of sound would depend on different frequencies of oscillation, which are higher in wheezing (approximately 400 Hz) and lower in rhonchi (around 200 Hz). Wheezing is a common finding in patients with bronchospasm and airway obstruction. There is no doubt that one of the most common causes of wheezing complaints, or of auscultation of wheezing on physical examination, is bronchial asthma. Nevertheless, numerous other diseases can present with this sign. Examples of these conditions include tracheal stenosis, central airway tumors, pulmonary edema, and pulmonary aspiration.(2,3) This is certainly the type of knowledge that is expected to be a required component of the basic education of all physicians, even of nonspecialists in respiratory medicine. However, to our surprise, in recent years, we have collected many clinical cases referred to our facility or private health care clinic for evaluation with a diagnosis of “severe asthma” or “difficult-to-control asthma” that are in fact cases involving completely different diseases. Many of these patients report for the appointment after long periods of investigation and unsuccessful treatments. Atopy testing and allergy desensitization therapy are common. Longterm use of high doses of systemic corticosteroids J Bras Pneumol. 2013;39(4):518-520

is the rule. The presence of severe side effects related to the last treatment is a constant, and these side effects contribute substantially to the deterioration of the patient’s overall clinical status. In fact, in some cases, despite the diagnosis of “severe asthma”, we never were able to detect a single episode of wheezing. Asthma is a highly prevalent disease, and chronic recurrent episodes of dry cough, dyspnea, chest tightness, and wheezing are important for characterizing the disease. (4) It should be borne in mind that not always all of these findings are present, which can make it difficult to diagnose asthma. On physical examination, wheezing is in fact the most common finding. Bronchial hyperresponsiveness is a characteristic of individuals with asthma, although it is not always present, depending on the treatment given or the type of definition employed. (4) However, bronchial hyperresponsiveness can also be found in many other conditions, such as allergic rhinitis, COPD, right after respiratory infections, bronchiectasis, cystic fibrosis, heart failure, acute chest syndrome of sickle cell anemia, use of beta blockers, etc. (5-7) All these conditions described can present with wheezing and certainly do not characterize asthma. In these situations, diagnoses of “COPD + asthma”, “bronchiectasis + asthma”, or “heart failure + asthma” are also unacceptable. An early study used methacholine challenge testing in 34 patients complaining of wheezing, the etiology of which remained unclear. (8) Wheezing complaints could only be attributed to asthma in 35% of the cases. In that sample, the most common etiology of wheezing was the presence of secretions in the upper airways, usually after respiratory infection. It is known that the sounds heard by those patients originate from partial occlusion by secretions present at the level of the vocal cords. Similar results were obtained in another study, which included 441 patients with symptoms consistent with asthma, of whom 53.1% had a history of wheezing. (9) In 48.3% of the

Not all that wheezes is asthma!

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Chart 1 - Causes of wheezing other than asthma. Extrathoracic upper airway Intrathoracic upper airway obstruction obstruction Postnasal drip Tracheal stenosis Vocal cord dysfunction Airway tumors Hypertrophied tonsils Foreign body aspiration Upper airway tumors Intrathoracic goiter Retropharyngeal abscess Tracheobronchomegaly Laryngeal edema or stenosis Tracheomalacia Laryngocele Vascular compression Vocal cord paralysis Relapsing polychondritis Cricoarytenoid arthritis Wegener’s granulomatosis

cases, no bronchial hyperresponsiveness was detected, and, in another 40.6%, bronchial hyperresponsiveness was also associated with evidence of extrathoracic airway disorders, such as pharyngitis and sinusitis. Asthma is an important disease because of its high prevalence and, if not diagnosed and treated properly, its high mortality. (4) These facts fully justify the large number of educational campaigns, which have been carried out in recent decades, among the general population and health professionals. In Brazil, everything indicates that a significant portion of individuals with asthma remain misdiagnosed and mistreated. However, it has been reported that, in Canada, up to 41% of patients labeled as having asthma at the level of primary care do not fulfill diagnostic criteria for the disease. (10) In South Africa, much of what is labeled as asthma can be airflow obstruction secondary to tuberculosis, smoking, and occupational exposure. (11) Therefore, clinicians working in various settings should always be careful not to diagnose patients with other diseases that often require very different approaches as having asthma. The approach to patients complaining of wheezing, presenting with physical examination findings of wheezing, or both, requires careful clinical history taking, with an emphasis on triggers, improvement factors, duration of wheezing, and course of wheezing over time. It is essential that, in addition to upper airway symptoms and digestive and cardiac symptoms,

Lower airway obstruction COPD Bronchiectasis Pulmonary edema Gastric aspiration Pulmonary embolism Bronchiolitis Cystic fibrosis Carcinoid syndrome Lymphangitic carcinomatosis Parasitic infections Bronchospasm of various causes (anaphylaxis, toxic gas inhalation, post-viral infection, drug-induced cause, acute chest syndrome, etc.)

all types of respiratory symptoms present be properly assessed. The personal histories should be carefully investigated, especially regarding history of diseases, smoking, and occurrence of environmental exposure. Physical examination must be complete and cannot be limited only to pulmonary auscultation. Routine chest X-rays and spirometry, ideally with printing of the flow-volume curve and evaluation of bronchodilator response, are usually the most useful ancillary tests in this assessment. Chart 1 lists the potential causes of wheezing, all of which should be considered in the differential diagnosis with asthma.(3,12) In summary, wheezing is a complaint or physical examination finding that needs to be properly interpreted within a broad clinical context and within the individual clinical context of the patients who seek medical attention because of their disease. The phrase coined in the 1930s and attributed to the American otolaryngologist Chevalier Jackson will always remain current: “Not all that wheezes is bronchial asthma.”

José Antônio Baddini Martinez Associate Professor, Department of Clinical Medicine, Faculdade de Medicina

de Ribeirão Preto da Universidade de São Paulo – FMRP-USP, University of São Paulo at Ribeirão Preto School of Medicine – Ribeirão Preto, Brazil

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References 1. Manço JC. Fundamentos da ausculta pulmonar. Medicina (Ribeiräo Preto). 1994;27(1/2):66-82. 2. Meslier N, Charbonneau G, Racineux JL. Wheezes. Eur Respir J. 1995;8(11):1942-8. http://dx.doi.org/10.118 3/09031936.95.08111942 PMid:8620967 3. Smyrnios NA, Irwin RS. Wheeze. In: Irwin RS, Curley FJ, Grossman RF, editors. Diagnosis and Treatment of Symptoms of the Respiratory Tract. Armonk: Futura Pub Co; 1997. p. 117-53. 4. Cruz AA, Fernandes AL, Pizzichini E, Fiterman J, Pereira LF, Pizzichini M, et al. Diretrizes da Sociedade Brasileira de Pneumologia e Tisiologia Para o Manejo da Asma – 2012. J Bras Pneumol. 2012;38(Suppl 1):S1-S46. 5. Sterk PJ, Fabbri LM, Quanjer PH, Cockcroft DW, O’Byrne PM, Anderson SD, et al. Airway responsiveness. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993;16:53-83. PMid:8499055 6. Borges Mde C, Ferraz E, Vianna EO. Bronchial provocation tests in clinical practice. Sao Paulo Med J. 2011;129(4):243-9. http://dx.doi.org/10.1590/S151631802011000400008 PMid:21971900

7. Vendramini EC, Vianna EO, De Lucena Angulo I, De Castro FB, Martinez JA, Terra-Filho J. Lung function and airway hyperresponsiveness in adult patients with sickle cell disease. Am J Med Sci. 2006;332(2):68-72. http://dx.doi.org/10.1097/00000441-200608000-00003 PMid:16909052 8. Pratter MR, Hingston DM, Irwin RS. Diagnosis of bronchial asthma by clinical evaluation. An unreliable method. Chest. 1983;84(1):42-7. http://dx.doi.org/10.1378/ chest.84.1.42 PMid:6861547 9. Bucca C, Rolla G, Brussino L, De Rose V, Bugiani M. Are asthma-like symptoms due to bronchial or extrathoracic airway dysfunction? Lancet. 1995;346(8978):791-5. http://dx.doi.org/10.1016/S0140-6736(95)91617-2 10. LindenSmith J, Morrison D, Deveau C, Hernandez P. Overdiagnosis of asthma in the community. Can Respir J. 2004;11(2):111-6. PMid:15045041 11. Ehrlich RI, White N, Norman R, Laubscher R, Steyn K, Lombard C, et al. Wheeze, asthma diagnosis and medication use: a national adult survey in a developing country. Thorax. 2005;60(11):895-901. http://dx.doi.org/10.1136/ thx.2004.030932 PMid:16263947 PMCid:1747242 12. Irwin RS. Evaluation of wheezing illnesses other than asthma in adults. In: UpToDate, Basow DS, editor. UpToDate. Waltham: UpToDate; 2013.

Submitted: 09 December 2012. Accepted, after review: 17 December 2012.

J Bras Pneumol. 2013;39(4):518-520

Letter to the Editor Visual scale for the quantification of hyperhidrosis Visual scale for the quantification of hyperhidrosis

Roberto de Menezes Lyra

To the Editor: In most cases, patients with hyperhidrosis have unpleasant sensory and emotional experiences in the social sphere, experiences that are difficult to express to physicians in a simple way and to be understood by society. In contrast, assessing and quantifying

hyperhidrosis clinically is not an easy task; therefore, I have read with great enthusiasm the study by Sakiyama et al. describing a quantitative assessment of the intensity of palmar and plantar sweating in patients with primary palmoplantar hyperhidrosis. (1)

Figure 1 - Visual scale for the quantification of hyperhidrosis.

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Lyra RM

A measuring device will certainly add to improving the quantification of hyperhidrosis during clinical assessment. This is because the clinical presentation of hyperhidrosis varies widely from person to person, although there is a certain pattern of presentation in localized hyperhidrosis. It is assumed that this is due in part to the large anatomical variation in the sympathetic chain and also to the fact that the sympathetic nervous system shows a metameric distribution that is not so precise, which makes it difficult to be mapped as dermatomes.(2,3) Formerly, in order to quantify hyperhidrosis, we had no other way but to measure it clinically with a visual scale by means of which the patient was asked to grade the intensity of hyperhidrosis on the basis of drawings in the scale, ranging from being normal to having the worst possible level of hyperhidrosis. Therefore, the intensity of hyperhidrosis at the initial assessment, as well as at each assessment and, if necessary, also in the postoperative period, can be recorded on the medical charts.(4) In addition, we quantify the presentation of hyperhidrosis, whether it is generalized or localized, and the type of body distribution (Figure 1). We use hachures to demarcate the areas of excessive sweating on the drawings of the human body. Subsequently, using the visual scales shown in Figure 1, we determine the amount of sweat produced and the type of localized hyperhidrosis (palmar, axillary, plantar, or any combination of the three) presented by the patient. Physiologically, there is great variability in sweat production, which depends on environmental

heat, seasons, physical exertion, stress, and even circadian cycle. Therefore, it is of the utmost importance that the patient guide us and quantify the areas that should be demarcated, thereby providing a strong foundation for reasoning about the choice of clinical or surgical treatment of hyperhidrosis.(5)

Roberto de Menezes Lyra Thoracic Surgeon, Hospital do Servidor Público Estadual de São Paulo – HSPE/ SP, São Paulo Hospital for State Civil Servants – São Paulo, Brazil

References 1. Sakiyama BY, Monteiro TV, Ishy A, de Campos JR, Kauffman P, Wolosker N. Quantitative assessment of the intensity of palmar and plantar sweating in patients with primary palmoplantar hyperhidrosis. J Bras Pneumol. 2008;38(5):573-8. http://dx.doi.org/10.1590/ S1806-37132012000500006 2. Zhang B, Li Z, Yang X, Li G, Wang Y, Cheng J, Tang X, Wang F. Anatomical variations of the upper thoracic sympathetic chain. Clin Anat. 2009;22(5):595-600. http:// dx.doi.org/10.1002/ca.20803 PMid:19418453 3. Schünnke M, Schulte E, Schumacher U. Dores viscerais. In: Prometheus, atlas de anatomia: cabeça e neuroanatomia. Rio de Janeiro: Guanabara Koogan; 2007. p. 322-3 4. Lyra Rde M, Campos JR, Kang DW, Loureiro Mde P, Furian MB, Costa MG, et al. Guidelines for the prevention, diagnosis and treatment of compensatory hyperhidrosis. J Bras Pneumol. 2008;34(11):967-77. PMid:19099105 5. Boscardim PC, Oliveira RA, Oliveira AA, Souza JM, Carvalho RG. Thoracic sympathectomy at the level of the fourth and fifth ribs for the treatment of axillary hyperhidrosis. J Bras Pneumol. 2011;37(1):6-12. http://dx.doi.org/10.1590/ S1806-37132011000100003 PMid:21390426

Submitted: 13 December 2012. Accepted, after review: 18 December 2012.

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Letter to the Editor Pulmonary histoplasmosis presenting with a halo sign on CT in an immunocompetent patient Histoplasmose pulmonar presente com sinal do halo em TC em um paciente imunocompetente

Graziella Hanna Pereira, Liliane Yuri Almeida, Rosa Shizuda Okubo, Edson Marchiori

To the Editor: Histoplasmosis is a common endemic mycosis. Although most infections in immunocompetent individuals are self-limiting, some patients develop severe pneumonitis or other types of chronic pulmonary infection. Specific imaging findings depend on the organisms involved, the underlying condition of the patient, and his condition after immune depleting procedures. The disease process in immunocompetent patients is usually limited to a solitary nodule on chest X-rays or CT scans, but enlarged hilar or mediastinal lymph nodes can also be observed.(1) We report here the case of an immunocompetent patient with histoplasmosis who presented with a halo sign on CT. A 47-year-old man presented with dry cough, chest pain, fatigue, and fever, having started 15 days prior. He reported neither

comorbidities nor a contact with environments with mold. The patient was negative for HIV by ELISA. Laboratory tests revealed leukocytosis, elevated C-reactive protein levels (33 mg/L), and hypertransaminasemia (three-fold higher than the upper limit of normal). CT scanning revealed a pulmonary nodule with a halo sign in his left lower lobe (Figure 1) and left para-hilar lymph nodes. Histological examination of a pulmonary biopsy sample obtained during bronchoscopy showed nonspecific inflammatory alterations. Cultures for mycobacteria and fungi were negative. Serology by counterimmunoelectrophoresis was positive for histoplasmosis. Treatment was initiated with itraconazole (400 mg/day). After 30 days, a CT scan showed that the size of the nodule was reduced by half. The patient showed progressive improvement of clinical symptoms and a reduction of the para-

Figure 1 - A CT scan at the level of the lower lobes showing a nodule surrounded by ground-glass attenuation (halo sign) in the left lower lobe.

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Pereira GH, Almeida LY, Okubo RS, Marchiori E.

aortic adenopathy. Treatment was maintained for one year, during which the patient remained asymptomatic, the nodule completely disappeared, and the lymphadenopathy resolved. However, histoplasmosis by counterimmunoelectrophoresis remained positive. We reported the case of an immunocompetent patient who presented with a halo sign and lymphadenopathy caused by histoplasmosis, showing a good clinical response after one year of treatment with itraconazole (400 mg/day). Histoplasma capsulatum is a major endemic human fungal pathogen that can cause a broad variety of clinical presentations, ranging from mild, focal pulmonary disease to life-threatening systemic infections.(1) In one study, open lung biopsies of 155 patients with undiagnosed lung lesions showed that infectious etiologies were responsible for 19% of the lesions, the most common diagnosis in this group being histoplasmosis (41%).(2) The halo sign is characterized by a ground-glass opacity surrounding a nodule, mass, or round area of consolidation.(3) This sign is frequently an early indicator of invasive pulmonary aspergillosis in immunocompromised patients,(4) but it might also indicate other invasive fungal diseases. Our patient required treatment with high doses of itraconazole for one year. Azoles, such as itraconazole and voriconazole, and amphotericin B have significant activity against H. capsulatum. However, approximately 10% of the patients hospitalized due to histoplasmosis die,(5) despite the lack of antifungal resistance among recovered isolates.(6) In conclusion, a halo sign on CT might indicate active histoplasmosis, which may require long-term treatment, even in immunocompetent patients.

Graziella Hanna Pereira Infectious Disease Specialist, Hospital Nipo-Brasileiro de São Paulo, São Paulo, Brazil

Liliane Yuri Almeida Pulmonologist, Hospital Nipo-Brasileiro de São Paulo, São Paulo, Brazil Rosa Shizuda Okubo Radiologist, Hospital Nipo-Brasileiro de São Paulo, São Paulo, Brazil Edson Marchiori Radiologist, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

References 1. Chong S, Lee KS, Yi CA, Chung MJ, Kim TS, Han J. Pulmonary fungal infection: imaging findings in immunocompetent and immunocompromised patients. Eur J Radiol. 2006;59(3):371-83. http://dx.doi.org/10.1016/j. ejrad.2006.04.017 PMid:16725293 2. Georgiadou SP, Sampsonas FL, Rice D, Granger JM, Swisher S, Kontoyiannis DP. Open-lung biopsy in patients with undiagnosed lung lesions referred at a tertiary cancer center is safe and reveals noncancerous, noninfectious entities as the most common diagnoses. Eur J Clin Microbiol Infect Dis. 2013;32(1):101-5. http://dx.doi. org/10.1007/s10096-012-1720-9 PMid:22895891 3. Silva CI, Marchiori E, Souza Júnior AS, Müller NL; Comissão de Imagem da Sociedade Brasileira de Pneumologia e Tisiologia. Illustrated Brazilian consensus of terms and fundamental patterns in chest CT scans. J Bras Pneumol. 2010;36(1):99-123. http://dx.doi.org/10.1590/S180637132010000100016 PMid:20209314 4. Greene RE, Schlamm HT, Oestmann JW, Stark P, Durand C, Lortholary O, et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis. 2007;44(3):373-9. http://dx.doi. org/10.1086/509917 PMid:17205443 5. Nosanchuk JD, Zancopé-Oliveira RM, Hamilton AJ, Guimarães AJ. Antibody therapy for histoplasmosis. Front Microbiol. 2012;3:21. http://dx.doi.org/10.3389/ fmicb.2012.00021 PMid:22347215 PMCid:3270318 6. Brilhante RS, Fechine MA, Mesquita JR, Cordeiro RA, Rocha MF, Monteiro AJ, et al. Histoplasmosis in HIV-positive patients in Ceará, Brazil: clinical-laboratory aspects and in vitro antifungal susceptibility of Histoplasma capsulatum isolates. Trans R Soc Trop Med Hyg. 2012;106(8):484-8. http://dx.doi.org/10.1016/j. trstmh.2012.05.003 PMid:22703696

Submitted: 22 December 2012. Accepted, after review: 07 January 2013

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Letter to the Editor Stress cardiomyopathy following acute ischemic stroke during flexible bronchoscopy: a rare sequence of complications Cardiomiopatia induzida por stress após acidente vascular cerebral isquêmico agudo durante broncoscopia flexível: uma rara sequência de complicações

Sonja Badovinac, Marta Korsic, Branka Cucevic, Valentina Slivnjak, Andrea Vukic Dugac, Marko Jakopovic

To the Editor: Flexible bronchoscopy is a routine procedure used in a wide spectrum of airway pathologies, with a rare incidence of severe complications. We would like to present a case of a rare and odd sequence of complications in a patient treated in our clinic. A 74-year-old woman who had metastatic angiosarcoma in the thoracic wall, with known multiple pulmonary metastases, previously treated with chemotherapy, and without medical history of vascular diseases was admitted to our clinic due to hemoptysis and fever. At admission, the neurological status of the patient was unremarkable, and the patient showed no signs of chest pain. Baseline electrocardiogram (ECG) revealed no significant findings (Figure 1A). Laboratory tests revealed normocytic anemia (hemoglobin, 97 g/L; hematocrit, 0.295 g/L), leukocytosis (10.9 × 109 cells/L), and elevated C-reactive protein (219.4 mg/L). Signs of renal or hepatic impairment were not registered. Fiberoptic bronchoscopy was indicated, and a blood clot was found in the left lower lobe bronchus. After the aspiration of the clot, there were no signs of active bleeding. During the procedure, the patient became unresponsive, presented with mydriasis, and stopped breathing but showed no alterations in heart rhythm. The patient was intubated, being initially manually ventilated, and started breathing spontaneously but remained unconscious for the next six hours. At admission in the ICU, her arterial blood pressure was 95/70 mmHg, and her oxygen saturation was 93%. The patient received oxygen support, which was discontinued when oxygen saturation was above 96% and her arterial blood pressure was normal. Initially, the patient was treated with dextrose saline intravenous infusion, aspirin, systemic corticosteroids, and diazepam. Right bulbar deviation, tonic spasm of the right arm, and flaccid

paralysis on the left side were found. There was a negative Babinski sign on the left. Brain magnetic resonance imaging demonstrated ischemic brain lesions in the right frontal cortex without signs of hemorrhage or cerebral metastases. Subsequently, ECG showed deep negative T waves in anterolateral leads (Figure 1B) with mildly increased troponin levels (troponin T, 0.270 µg/L). Transthoracic echocardiography revealed characteristic findings: ejection fraction of 45%, hypokinesis of apical and mid segments, and hiperkinesis of basal segments of the left ventricle—apical ballooning syndrome (Figure 2). Follow-up laboratory tests showed no pathological findings indicating secondary hepatic or renal impairment. Supportive treatment with an angiotensin-converting enzyme inhibitor, a betablocker, aspirin, and a diuretic resulted in a decrease in troponin levels within 24 h (0.130 µg/L) and clinical improvement. The patient stayed 4 days in the ICU followed by 27 days of hospital stay. The patient suffered serious neurological damage with left-sided hemiplegia, but subsequent tests revealed normalization of cardiologic findings and normal ECG (Figure 1C). During hospitalization, no recurrence of hemoptysis was found. Neurological rehabilitation of the patient was conducted after discharge. Flexible bronchoscopy is a diagnostic and interventional technique, widely used for various pulmonary pathologies. Introduced in the late 1960s, flexible bronchoscopy was recognized as one of the diagnostic and therapeutic cornerstones of pulmonary medicine. It is a safe procedure. In one recent retrospective study, the overall rate of serious complications was 0.5%.(1) The most common complications were related to local anesthesia (0.3-0.5%); hypoxemia (0.2-21.0%); arrhythmias (1-10%); bleeding following biopsy (0.12-7.50%); pneumothorax/pneumomediastinum (1-6%); and J Bras Pneumol. 2013;39(4):525-528

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Figure 1 - Electrocardiograms. In A, normal sinus rhythm with one supraventricular ectopic beat and nonspecific ST-T segment abnormalities in precordial leads. In B, deep negative T waves in anterolateral leads. In C, slight sinus arrhythmia with no significant ST-T segment abnormalities.

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Stress cardiomyopathy following acute ischemic stroke during flexible bronchoscopy: a rare sequence of complications

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Figure 2 - Echocardiogram (four-chamber view) showing apical ballooning of the left ventricle (blue arrow) and hyperkinesis of basal segments in the left ventricle (red arrow). LA: left atrium; LV: left ventricle; RA: right atrium; and RV: right ventricle.

fever (0.9-2.5%). Death occurs in 0.1-0.2% of the cases.(2) One of the few serious complications that exceptionally might occur during the procedure is the development of ischemic cerebrovascular stroke secondary to disordered heart rhythm, hypoxemia, or air embolism.(1,2) Stress cardiomyopathy, which is recognized as a unique form of transient cardiomyopathy and was first described in 1990,(3,4) is a reversible cardiac impairment that mimics an acute ischemic cardiac event without significant pathomorphological changes in the coronary arteries.(3) Stress cardiomyopathy has the following characteristics: new ST-segment abnormalities on ECG (elevation and/or T-wave inversion), modest elevation in myocardial lesion biomarkers (troponin I, troponin T, and creatine kinase MB), transient left ventricular dysfunction, echocardiographic signs of hypokinesia/akinesia, and ballooning of the apical part of the left ventricle with reduced left ventricular ejection fraction.(4,5) Stress cardiomyopathy can occur after acute mental or physical stress, subarachnoid hemorrhage, ischemic stroke, major head trauma, acute medical illness, pheochromocytoma exacerbation, and as a result of exogenous catecholamine administration.(6-9) The pathophysiological mechanisms for the development of these disorders are not fully

understood, but there is evidence of elevated levels of catecholamines, which indicates a connection with previously experienced extreme stress.(10) All of the changes are reversible, supportive care is usually sufficient, and normalization of the left ventricle function can be expected within 1-3 months.(8) Our patient experienced a rare sequence of complications during and after fiberoptic bronchoscopy. It is known that cerebrovascular and cardiovascular complications are more common in oncology patients, but this particular order of complications deserves attention. Since the patient presented with hemoptysis, it was extremely important that the correct diagnosis of transient cardiomyopathy was made because of the potential risk of recurrent bleeding in case the stress cardiomyopathy had been mistaken for acute coronary syndrome and anticoagulant therapy had been introduced. Therefore, familiarity with and awareness of potential complications, appropriate diagnostic tools, and management knowledge are paramount to successful treatment of such events. To our knowledge, this is the first reported case of such a sequence of bronchoscopy-related complications in one patient. J Bras Pneumol. 2013;39(4):525-528

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Badovinac S, Korsic M, Cucevic B, Slivnjak V, Vukic Dugac A, Jakopovic M

Sonja Badovinac Physician, Department of Respiratory Diseases, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia Marta Korsic Physician, Department of Respiratory Diseases, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia Branka Cucevic Head, Department of Pulmonary Oncology, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia Valentina Slivnjak Physician, Department of Cardiology, Hospital for Medical Rehabilitation Krapinske Toplice, Krapinske Toplice, Croatia Andrea Vukic Dugac Physician, Department of Respiratory Diseases, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia Marko Jakopovic Head, Department of Pulmonary Circulation, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia

References 1. Pue CA, Pacht ER. Complications of fiberoptic bronchoscopy at a university hospital. Chest. 1995;107(2):430-2. http:// dx.doi.org/10.1378/chest.107.2.430 2. Geraci G, Pisello F, SciumĂ¨ C, Li Volsi F, Romeo M, Modica G. Complication of flexible fiberoptic bronchoscopy. Literature review [Article in Italian]. Ann Ital Chir. 2007;78(3):18392. PMid:17722491 3. Akashi YJ, Nakazawa K, Sakakibara M, Miyake F, Koike H, Sasaka K. The clinical features of takotsubo cardiomyopathy. QJM. 2003;96(8):563-73. http://dx.doi.org/10.1093/ qjmed/hcg096 PMid:12897341 4. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J. 2008;155(3):408-17. http://dx.doi.org/10.1016/j.ahj.2007.11.008 PMid:18294473 5. Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J. 2006;27(13):1523-9. http://dx.doi.org/10.1093/eurheartj/ehl032 PMid:16720686 6. Ako J, Sudhir K, Farouque HM, Honda Y, Fitzgerald PJ. Transient left ventricular dysfunction under severe stress: brain-heart relationship revisited. Am J Med. 2006;119(1):10-7. http:// dx.doi.org/10.1016/j.amjmed.2005.08.022 PMid:16431176 7. Lee VH, Oh JK, Mulvagh SL, Wijdicks EF. Mechanisms in neurogenic stress cardiomyopathy after aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2006;5(3):243-9. http://dx.doi.org/10.1385/NCC:5:3:243 8. Bybee KA, Prasad A. Stress-related cardiomyopathy syndromes. Circulation. 2008;118(4):397-409. http:// dx.doi.org/10.1161/CIRCULATIONAHA.106.677625 PMid:18645066 9. Yoshimura S, Toyoda K, Ohara T, Nagasawa H, Ohtani N, Kuwashiro T, et al. Takotsubo cardiomyopathy in acute ischemic stroke. Ann Neurol. 2008;64(5):547-54. http:// dx.doi.org/10.1002/ana.21459 PMid:18688801 10. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352(6):539-48. http://dx.doi.org/10.1056/ NEJMoa043046 PMid:15703419

Submitted: 16 November 2012. Accepted, after review: 16 January 2013.

J Bras Pneumol. 2013;39(4):525-528

Instructions for Authors The Jornal Brasileiro de Pneumologia (J Bras Pneumol, Brazilian Journal of Pulmonology) ISSN1806-3713, published once every two months, is the official organ of the Sociedade Brasileira de Pneumologia e Tisiologia (Brazilian Thoracic Society) for the publication of scientific papers regarding Pulmonology and related areas. After being approved by the Editorial Board, all articles will be evaluated by qualified reviewers, and anonymity will be preserved throughout the review process. Articles that fail to present merit, have significant errors in methodology or are not in accordance with the editorial policy of the journal will be directly rejected by the Editorial Board, with no recourse. Articles may be written in Portuguese, Spanish or English. In the online version of the Journal (www.jornaldepneumologia.com.br, ISSN1806-3756), all articles will be made available in Spanish or Portuguese, as well as in English. Authors may submit color figures. However, the cost of printing figures in color, as well as any related costs, will be borne by the authors. For further clarification, please contact the Journal Secretary by e-mail or by telephone. The Jornal Brasileiro de Pneumologia upholds the World Health Organization (WHO) and International Committee of Medical Journal Editors (ICMJE) policies regarding the registration of clinical trials, recognizing the importance of these initiatives for the registration and international, open-access dissemination of information on clinical trials. Therefore, as of 2007, the Journal only accepts clinical trials that have been given an identification number by one of the clinical trials registries meeting the criteria established by the WHO and the ICMJE. This identification number must be included at the end of the abstract. Within this context, the Jornal Brasileiro de Pneumologia adheres to the definition of a clinical trial as described by the WHO, which can be summarized as “any study that prospectively assigns human beings to be submitted to one or more interventions with the objective of evaluation the effects that those interventions have on health-related outcomes. Such interventions include the administration of drugs, cells and other biological products, as well as surgical procedures, radiological techniques, the use of devices, behavioral therapy, changes in treatment processes, preventive care, etc

are available at: www.jornaldepneumologia.com.br/sgp. Although all manuscripts are submitted online, they must be accompanied by a Copyright Transfer Statement and Conflict of Interest Statement signed by all the authors based on the models available at: www.jornaldepneumologia.com.br. It is requested that the authors strictly follow the editorial guidelines of the journal, particularly those regarding the maximum number of words, tables and figures permitted, as well as the rules for producing the bibliography. Failure to comply with the author instructions will result in the manuscript being returned to the authors so that the pertinent corrections can be made before it is submitted to the reviewers. Special instructions apply to the preparation of Special Supplements and Guidelines, and authors should consult the instructions in advance by visiting the homepage of the journal. The journal reserves the right to make stylistic, grammatical and other alterations to the manuscript. With the exception of units of measure, abbreviations should be used sparingly and should be limited only to those that are widely accepted. These terms are defined in the List of Abbreviations and Acronyms accepted without definition in the Journal. Click here (List of Abbreviations and Acronyms). All other abbreviations should be defined at their first use. For example, use “C-reactive protein (CRP)”, and use “CRP” thereafter. After the definition of an abbreviation, the full term should not appear again. Other than those accepted without definition, abbreviations should not be used in titles, and their use in the abstracts of manuscripts should be avoided if possible. Whenever the authors mention any substance or uncommon piece of equipment they must include the catalogue model/number, name of manufacturer, city and country of origin. For example: “. . . ergometric treadmill (model ESD-01; FUNBEC, São Paulo, Brazil) . . .” In the case of products from the USA or Canada, the name of the state or province should also be cited. For example: “. . . guinea pig liver tTg (T5398; Sigma, St. Louis, MO, USA) . . .”

Authorship criteria

Title Page: The title page should include the title (in Portuguese and in English); the full names, highest academic degrees and institutional affiliations of all authors; complete address, including telephone number, fax number and e-mail address, of the principal author; and a declaration of any and all sources of funding. Abstract: The abstract should present the information in such a way that the reader can easily understand without referring to the main text. Abstracts should not exceed 250 words. Abstracts should be structured as follows: Objective, Methods, Results and Conclusion. Abstracts for review articles and case reports may be unstructured. Abstracts for brief communications should not exceed 100 words. Summary: An abstract in English, corresponding in content to the abstract in Portuguese, should be included. Keywords: Three to six keywords in Portuguese defining the subject of the study should be included as well as the corresponding keywords in English. Keywords in Portuguese must be based on the Descritores em Ciência da Saúde (DeCS, Health and Science Keywords), published by Bireme and available at: http://decs.bvs.br, whereas keywords in English should be based on the National Library of Medicine Medical Subject Headings (MeSH), available at: http://www.nlm.nih.gov/mesh/MBrowser.html.

An individual may be considered an author of an article submitted for publication only if having made a significant intellectual contribution to its execution. It is implicit that the author has participated in at least one of the following phases: 1) conception and planning of the study, as well as the interpretation of the findings; 2) writing or revision of all preliminary drafts, or both, as well as the final revision; and 3) approval of the final version. Simple data collection or cataloging does not constitute authorship. Likewise, authorship should not be conferred upon technicians performing routine tasks, referring physicians, doctors who interpret routine exams or department heads who are not directly involved in the research. The contributions made by such individuals may be recognized in the acknowledgements. The accuracy of all concepts presented in the manuscript is the exclusive responsibility of the authors. The number of authors should be limited to six, although exceptions will be made for manuscripts that are considered exceptionally complex. For manuscripts with more than six authors, a letter should be sent to the Journal describing the participation of each.

Presentation and submission of manuscripts All manuscripts must be submitted online from the home-page of the journal. The instructions for submission

Manuscript preparation

Text:

Original articles: For original articles, the text (excluding the title page, abstracts, references, tables, figures and figure legends) should consist of 2000 to 3000 words.

Tables and figures should be limited to a total of five. The number of references should not exceed 30. Original articles should be divided into the following sections: Introduction, Methods, Results, Discussion, Acknowledgments, and References. The Methods section should include a statement attesting to the fact the study has been approved by the ethics in human research committee or the ethics in animal research committee of the governing institution. There should also be a section describing the statistical analysis employed, with the respective references. In the Methods and Results sections, subheadings may be used, provided that they are limited to a reasonable number. Subheadings may not be used in the Introduction or Discussion. Review and Update articles: Review and Update articles are written at the request of the Editorial Board, which may occasionally accept unsolicited manuscripts that are deemed to be of great interest. The text should not exceed 5000 words, excluding references and illustrations (figures or tables). The total number of illustrations should not exceed eight. The number of references should not exceed 60. Pictorial essays: Pictorial essays are also submitted only at the request of the Editors or after the authors have consulted and been granted permission by the Editorial Board. The text accompanying such essays should not exceed 3000 words, excluding the references and tables. No more than 12 illustrations (figures and tables) may be used, and the number of references may not exceed 30. Case Reports: Case Reports should not exceed 1500 words, excluding title page, abstract, references and illustrations. The text should be composed of: Introduction, Case Report, Discussion and References. It is recommended that any and all information that might identify the patient be withheld, and that only those laboratory exams that are important for the diagnosis and discussion be presented. The total number of illustrations (figures or tables) should not exceed three, and the number of references should be limited to 20. When the number of cases presented exceeds three, the manuscript will be classified as a Case Series, and the same rules applicable to an original article will be applied. Brief Communications: Brief communications should not exceed 1500 words, excluding references and tables. The total number of tables and figures should not exceed two, and the references should be limited to 20. The text should be unstructured. Letters to the Editor: Letters to the Editor should be succinct original contributions, not exceeding 800 words and containing a maximum of 6 references. Comments and suggestions related to previously published materials or to any medical theme of interest will be considered for publication. Tables and Figures: All tables and figures should be in black and white, on separate pages, with legends and captions appearing at the foot of each. All tables and figures should be submitted as files in their original format. Tables should be submitted as Microsoft Word files, whereas figures should be submitted as Microsoft Excel, TIFF or JPG files. Photographs depicting surgical procedures, as well as those showing the results of exams or biopsies, in which staining and special techniques were used will be considered for publication in color, at no additional cost to the authors. Dimensions, units and symbols should be based on the corresponding guidelines set forth by the Associação Brasileira de Normas Técnicas (ABNT, Brazilian Association for the Establishment of Technical Norms), available at: http://www.abnt.org.br. Legends: Legends should accompany the respective figures (graphs, photographs and illustrations) and tables. Each legend should be numbered with an Arabic numeral corresponding to its citation in the text. In addition, all abbreviations, acronyms, and symbols should be defined below each table or figure in which they appear.

References: References should be listed in order of their appearance in the text and should be numbered consecutively with Arabic numerals. The presentation should follow the Vancouver style, updated in October of 2004, according to the examples below. The titles of the journals listed should be abbreviated according to the style presented by the List of Journals Indexed in the Index Medicus of the National Library of Medicine, available at: http:// www.ncbi.nlm.nih.gov/entrez/journals/loftext.noprov.html. A total of six authors may be listed. For works with more than six authors, list the first six, followed by ‘et al.’

Examples: Journal Articles

1. Neder JA, Nery LE, Castelo A, Andreoni S, Lerario MC, Sachs AC et al. Prediction of metabolic and cardiopulmonary responses to maximum cycle ergometry: a randomized study. Eur Respir J. 1999;14(6):1204-13.

Abstracts

2. Singer M, Lefort J, Lapa e Silva JR, Vargaftig BB. Failure of granulocyte depletion to suppress mucin production in a murine model of allergy [abstract]. Am J Respir Crit Care Med. 2000;161:A863.

Chapter in a Book

3. Queluz T, Andres G. Goodpasture’s syndrome. In: Roitt IM, Delves PJ, editors. Encyclopedia of Immunology. 1st ed. London: Academic Press; 1992. p. 621-3.

Official Publications

4. World Health Organization. Guidelines for surveillance of drug resistance in tuberculosis. WHO/Tb, 1994;178:1-24.

Theses

5. Martinez TY. Impacto da dispnéia e parâmetros funcionais respiratórios em medidas de qualidade de vida relacionada a saúde de pacientes com fibrose pulmonar idiopática [thesis]. São Paulo: Universidade Federal de São Paulo; 1998.

Electronic publications

6. Abood S. Quality improvement initiative in nursing homes: the ANA acts in an advisory role. Am J Nurs [serial on the Internet]. 2002 Jun [cited 2002 Aug 12]; 102(6): [about 3 p.]. Available from: http://www. nursingworld.org/AJN/2002/june/Wawatch.htm

Homepages/URLs

7. Cancer-Pain.org [homepage on the Internet]. New York: Association of Cancer Online Resources, Inc.; c2000-01 [updated 2002 May 16; cited 2002 Jul 9]. Available from: http://www.cancer-pain.org/

Other situations:

In other situations not mentioned in these author instructions, authors should follow the recommendations given by the International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. Updated October 2004. Available at http://www.icmje.org/.

All correspondence to the Jornal Brasileiro de Pneumologia should be addressed to: Prof. Dr. Carlos Roberto Ribeiro de Carvalho Editor-Chefe do Jornal Brasileiro de Pneumologia SCS Quadra 01, Bloco K, Salas 203/204 - Ed. Denasa. CEP: 70.398-900 - Brasília - DF, Brazil Telefones/Fax: 0xx61-3245-1030, 0xx61-3245-6218 Jornal Brasileiro de Pneumologia e-mail address: jpneumo@jornaldepneumologia.com.br (Editorial assistant: Luana Campos) Online submission of articles: www.jornaldepneumologia.com.br

Próximos Eventos 2013 NACIONAIS

INTERNACIONAIS

Pneumo in Rio - XIV Congresso de Pneumologia e Tisiologia do Estado do Rio de Janeiro Data: 27 a 29 de setembro de 2013 Local: Hotel Atlântico Búzios - Armação de Búzios - RJ Informações: Método Eventos – (21)2548-5141 Email: pneumo2013@metodorio.com.br

ERS 2013 Data: 7 a 11 de setembro de 2013 Local: Barcelona/Espanha Informações: www.ersnet.org CHEST 2013 Data: 26 a 31 de outubro de 2013 Local: Chicago/EUA Informações: www.chestnet.org

15º Congresso Paulista de Pneumologia e Tisiologia Data: 14 a 17 de novembro de 2013 Local: Centro Fecomércio de Eventos Rua Dr. Plínio Barreto, 285 – Bela Vista – São Paulo - SP Informações: SPPT - 0800171618 Email: sppt@sppt.org

2014 NACIONAIS

INTERNACIONAIS

VI Curso Nacional de Ventilação Mecânica III Curso Nacional de Sono Data: 27 a 29 de março de 2014 Local: Hotel Novotel, São Paulo/SP Informações: Secretaria da SBPT Portal: www.sbpt.org.br / Telefone: 0800616218

CHEST World Congress Data: 21 a 24 de março de 2014 Local: Madrid/Espanha Informações: www.chestnet.org

XV Curso Nacional de Atualização em Pneumologia 2014 Data: 24 a 26 de abril de 2014 Local: Hotel Atlântico Búzios, Búzios/RJ. Informações: Secretaria da SBPT Portal: www.sbpt.org.br / Telefone: 0800616218 XXXVI Congresso Brasileiro de Pneumologia e Tisiologia Data: 07 a 11 de outubro de 2014 Local: Expogramado, Gramado/RS Informações: Secretaria da SBPT Portal: www.sbpt.org.br / Telefone: 0800616218

ATS 2014 Data: 16 a 21/05/2014 Local: San Diego/CA Informações: www.thoracic.org ALAT 2014 Local: Plaza Mayor, Medellin, Colombia Data: 31/07 a 02/08/2014 Informações: http://www.congresosalat.org/ ERS 2014 Data: 06 a 10 de setembro de 2014 Local: Munique/Alemanha Informações: www.ersnet.org CHEST 2014 Data: 25 a 30 de outubro de 2014 Local: Austin/Texas Informações: www.chestnet.org XXX Congresso Português de Pneumologia VIII Congresso Luso-Brasileiro de Pneumologia Data: 06 a 09 de novembro Local: Lisboa/Portugal Informações: www.sppneumologia.pt

Estaduais da Sociedade Brasileira de Pneumologia e Tisiologia ASSOCIAÇÃO CATARINENSE DE PNEUMOLOGIA E TISIOLOGIA Presidente: Emílio Pizzichini Secretário: Israel Silva Maia Endereço: Hospital Universitário da UFSC - NUPAIVA - térreo. Campus Trindade, 88.040 - 970 - Florianópolis - SC Tel: (48) 3234-7711/ 3233-0747 E-mail: pizzichi@matrix.com.br ASSOCIAÇÃO MARANHENSE DE PNEUMOLOGIA E CIRURGIA TORÁCICA Presidente: Maria do Rosario da Silva Ramos Costa Secretária: Denise Maria Costa Haidar Endereço: Travessa do Pimenta, 46 65.065-340 - Olho D‘Água - São Luís - MA Tel: (98) 3226-4074 Fax: (98) 3231-1161 E-mail: rrcosta29@hotmail.com SOCIEDADE ALAGOANA DE PNEUMOLOGIA Presidente: Anatercia Passos Cavalcanti Secretária: Seli Almeida Endereço: Rua Walfrido Rocha 225, Jatiuca 57.036-800 - Maceió - AL Tel: (82) 33266618 Fax: (82)3235-3647 E-mail: sociedadealagoana.dt@gmail.com SOCIEDADE AMAZONENSE DE PNEUMOLOGIA E CIRURGIA TORÁCICA Presidente: Edson de Oliveira Andrade Secretária: Mário Sérgio Monteiro Fonseca Endereço: Rua PARAIBA CONJ. ABÍLIO NERY ,2 quadra H ADRIANOPOLIS - CEP: 69057-021- Manaus – AM Tel: (92) 3234-6334 Fax: 32348346 E-mail: f.l.westphal@uol.com.br SOCIEDADE BRASILIENSE DE DOENÇAS TORÁCICAS Presidente: Ricardo Brito Campos Secretário: Bianca Rodrigues Silva Endereço: Setor de Clubes Sul, Trecho 3, Conj. 6 70.200-003 - Brasília - DF Tel/fax: (61) 3245-8001 E-mail: sbdt@ambr.org.br SOCIEDADE CEARENSE DE PNEUMOLOGIA E TISIOLOGIA Presidente: Filadélfia Passos Rodrigues Martins Secretária: Micheline Aquino de Paiva Endereço: Av. Dom Luis, 300, sala 1122, Aldeota 60160-230 - Fortaleza - CE Tel: (85) 3087-6261 3092-0401 E-mail: pneumoceara@gmail.com SOCIEDADE DE PNEUMOLOGIA DA BAHIA Presidente: Margarida Célia Lima Costa Neves Secretária: Nélia Claudia Araújo Endereço: Av. Oceânica, 551 - Ed. Barra Center - sala 112 40.160-010 - Barra - Salvador - BA Tel/fax: (71) 3264-2427 E-mail: spba@terra.com.br / site: www.pneumobahia.com.br SOCIEDADE DE PNEUMOLOGIA DO ESPÍRITO SANTO Presidente: Firmino Braga Neto Secretária: Cilea Aparecida Victória Martins Endereço: Rua Eurico de Aguiar, 130, Sala 514 - Ed. Blue Chip Praia do Campo, 29.055-280 - Vitória - ES Tel: (27) 3345-0564 Fax: (27) 3345-1948 E-mail: firminobn@yahoo.com.br SOCIEDADE DE PNEUMOLOGIA E TISIOLOGIA DO MATO GROSSO Presidente: Keyla Medeiros Maia da Silva Secretária: Wandoircy da Silva Costa Endereço: Rua Prof Juscelino Reiners, Quadra 07, casa 04 78.070-030 - Cuiabá - MT Tel: (65) 3051-2116 E-mail: keyla_m@terra.com.br SOCIEDADE DE PNEUMOLOGIA E TISIOLOGIA DO MATO GROSSO DO SUL Presidente: Angela Maria Dias de Queiroz Secretário: Lilian Andries Endereço: Rua Dr. Arthur Jorge n° 2117 - 902, Bairro São Francisco Campo Grande - MS - CEP: 79010-210 Tel: (67) 33252955 / (67) 99853782 E-mail: diasqueiroz@hotmail.com SOCIEDADE DE PNEUMOLOGIA E TISIOLOGIA DO RIO DE JANEIRO Presidente: Luiz Paulo Pinheiro Loivos Secretária: Patrícia Canto Ribeiro Endereço: Rua da Lapa, 120 - 3° andar - salas 301/302 20.021-180 - Lapa - Rio de Janeiro - RJ Tel/fax: (21) 3852-3677 E-mail: sopterj@sopterj.com.br

SOCIEDADE DE PNEUMOLOGIA E TISIOLOGIA DO RIO GRANDE DO SUL Presidente:

Marcelo Tadday Rodrigues

Vice:

Simone Chaves Fagondes

Endereço:

Av. Ipiranga, 5.311, sala 403 90.610-001 - Porto Alegre - RS

Tel:

(51) 3384-2889

E-mail:

sptrs@sptrs.org.br

Fax: (51) 3339-2998

SOCIEDADE GOIANA DE PNEUMOLOGIA E TISIOLOGIA Presidente:

Paulo Menzel Galvão

Secretária:

Adriana Resplande

Endereço:

Av. T 12, Quadra 123, Lote 19, nº 65 - Setor Bueno

(62) 3087-5844

sgpt2007@gmail.com

74.223-040 - Goiânia - GO SOCIEDADE MINEIRA DE PNEUMOLOGIA E CIRURGIA TORÁCICA Presidente:

Mauricio Meireles Góes

Secretária:

Luciana Macedo Guedes de Oliveira

Endereço:

Av. João Pinheiro, 161 - sala 203 - Centro 30.130-180 - Belo Horizonte - MG

Tel/fax:

(31) 3213-3197

smpct@smpct.org.br

ASSOCIAÇÃO DE PNEUMOLOGIA E CIRUGIA TORÁCICA DO ESTADO DO RIO GRANDE DO NORTE Presidente:

Sérvulo Azevedo Dias Junior

Secretário:

Felipe Costa de Andrade Marinho

Endereço:

Rua Coronel Auris Coelho, 235 - 2º ANDAR

CEP:

59.020-090 - Natal – RN sopern.sbpt@gmail.com

Telefone:

(84)4009-2030 - (84) 9196-4800

ASSOCIAÇÃO PARAENSE DE PNEUMOLOGIA E TISIOLOGIA Presidente:

Carlos Augusto Abreu Alberio

Secretária:

Márcia Cristina Corrêa Vasconcelos

Endereço:

Faculdade de Medicina - Praça Camilo Salgado, 1 Umarizal, 66050-060 - Belém - PA

(91)8115-5048

ca.alberio@uol.com.br

SOCIEDADE PARAIBANA DE PNEUMOLOGIA E TISIOLOGIA Presidente:

Geraldo Antônio de Medeiros

Secretário:

Paulo Roberto de Farias Braga

Endereço:

Av. Senador Rui Carneiro, 423, Miramar 58.015-010 - João Pessoa - PB

(83) 3244-8444

alfredofagundes@gmail.com

SOCIEDADE PARANAENSE DE TISIOLOGIA E DOENÇAS TORÁCICAS Presidente:

Carlos Eduardo do Valle Ribeiro

Secretário:

Mariane Gonçalves Martynychen Canan

Endereço:

Av. Sete de Setembro, 5402 - Conj. 105, 10ª andar Batel - CEP: 80240-000 - Curitiba - PR

(41) 3342-8889

contato@pneumopr.org.b

SOCIEDADE PAULISTA DE PNEUMOLOGIA E TISIOLOGIA Presidente:

Mônica Corso Pereira

Secretária:

Maria Raquel Soares

Endereço:

Rua Machado Bittencourt, 205, 8° andar, conj. 83 04.044-000 Vila Clementino - São Paulo - SP

0800 17 1618 sppt@sppt.org.br

site: www.sppt.org.br

SOCIEDADE PERNAMBUCANA DE PNEUMOLOGIA E TISIOLOGIA Presidente:

Alina Farias França de Oliveira

Secretária:

Adriana Velozo Gonçalves

Endereço:

Rua João Eugênio de Lima , 235 Boa Viagem 51030-360 - Recife - PE

Tel/fax:

(81) 3326-7098 pneumopernambuco@gmail.co

SOCIEDADE PIAUIENSE DE PNEUMOLOGIA E TISIOLOGIA Presidente:

Antonio de Deus Filho

Secretária:

Tatiana Santos Malheiros Nunes

Endereço:

R. Areolino de Abreu, 1674. Centro 64000-180 - Teresina - PI

Tel:

(86) 3226-1054 j.barreto@uol.com.b

SOCIEDADE SERGIPANA DE PNEUMOLOGIA E TISIOLOGIA Presidente:

José Barreto Neto

Secretário:

Almiro Oliva Sobrinho

Endereço:

Av. Gonçalo Prado Rollemberg, 211, Sala 206 Bairro São José, 49010-410 - Aracaju - SE

Tel:

(79) 3213-7352 j. barreto@uol.com.br

Exclusivo

DAXAS diminui as exacerbações e melhora a qualidade de vida1,2 ®

modo de ação anti-inflamatória3,4

Reduz a taxa de exacerbação em pacientes exacerbadores frequentes e não frequentes 5

Melhora a função pulmonar em + 80 mL em estudo com broncodilatador de longa ação6

É indicado para DAXAS® ESTÁ DISPONÍVEL EM CAIXAS COM 30 COMPRIMIDOS 7

1 comprimido ao dia

adultos com doença pulmonar obstrutiva crônica (DPOC) grave (VEF1 pós-broncodilatador < 50% do predito) associada com bronquite crônica que apresentam histórico de exacerbações frequentes, em complementação ao tratamento com broncodilatadores.7

Associado ao tratamento de manutenção7

® 1

Referências bibliográficas: 1. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011;163(1):53-67. 2. Calverley PM et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374(9691):685-94. 3. Hatzelmann A et al. The preclinical pharmacology of roflumilast – A selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2010; 23(4):235-56. 4. Sanz MJ, Cortijo J, Morcillo EJ. PDE4 inhibitors as new anti-inflammatory drugs: effects on cell trafficking and cell adhesion molecules expression. Pharmacol Ther 2005; 106(3):269-297. 5. Wedzicha JA et al. Efficacy of roflumilast in the chronic obstructivepulmonary disease frequent exacerbator phenotype.Chest. 2012. doi:10.1378/chest.12-1489. 6. Fabbri LM et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long acting bronchodilators: two randomised clinical trials. Lancet. 2009;374(9691):695-703. 7. Daxas® [Bula]. São Paulo: Nycomed Pharma.

DAXAS® roflumilaste. USO ORAL. USO ADULTO. Apresentações e composição: Comprimidos revestidos com 500 mcg de roflumilaste. Embalagens com 30 unidades. Indicações: para o tratamento de manutenção de pacientes com doença pulmonar obstrutiva crônica (DPOC) grave (VEF1 pós-broncodilatador < 50% do predito) associada com bronquite crônica (tosse e expectoração crônicas) que apresentam histórico de exacerbações (crises) freqüentes, em complementação ao tratamento com broncodilatadores. Contraindicações: Este medicamento não deve ser usado por pacientes com hipersensibilidade ao roflumilaste ou a qualquer dos componentes da formulação. Este medicamento é contraindicado para pacientes com insuficiência hepática moderada e grave (classes ‘B’ e ‘C’ de Child-Pugh), pois não existem estudos sobre o uso do roflumilaste nestes pacientes. Precauções e advertências: DAXAS® deve ser administrado exclusivamente pela via oral. DAXAS® não está indicado para melhora de broncoespasmos agudos. Cada comprimido de DAXAS® contém 199 mg de lactose. Perda de peso: nos estudos de 1 ano (M-124, M-125), uma diminuição no peso corporal ocorreu mais freqüentemente em pacientes tratados com DAXAS® comparativamente aos pacientes que receberam placebo. Depois da descontinuação do DAXAS®, a maioria dos pacientes recuperou o peso corporal após 3 meses. Na ocorrência de uma inexplicada e pronunciada perda de peso, a administração de DAXAS® deve ser descontinuada, se julgado necessário. Intolerância persistente: apesar das reações adversas como diarréia, náusea, dor abdominal e cefaléia serem transitórios e resolverem espontaneamente com a manutenção do tratamento, o tratamento com DAXAS® deve ser revisto em caso de intolerância persistente. Gravidez e Lactação: as informações disponíveis sobre o uso de DAXAS® em gestantes são limitadas, mas não indicaram eventos adversos do roflumilaste sobre a gestação ou sobre a saúde do feto/recém-nato. Não são conhecidos outros dados epidemiológicos relevantes. Estudos em animais demonstraram toxicidade reprodutiva. O risco potencial para humanos ainda não está estabelecido. DAXAS® não deve ser administrado durante o período gestacional. É possível que roflumilaste e/ou seus metabólitos sejam excretados no leite materno durante a amamentação; estudos em animais (ratos) em fase de amamentação detectaram pequenas quantidades do produto e dos seus derivados no leite dos animais. Categoria B de risco na gravidez – Este medicamento não deve ser utilizado por mulheres grávidas ou que estejam amamentando sem orientação médica ou do cirurgião-dentista. Pacientes idosos: os cuidados de uso de DAXAS® por pacientes idosos devem ser os mesmos para os demais pacientes; não são recomendados ajustes na dosagem da medicação. Pacientes pediátricos (crianças e adolescentes menores de 18 anos de idade): o produto não é recomendado para uso neste grupo de pacientes, pois não são disponíveis dados sobre a eficácia e a segurança da administração oral de DAXAS® nesta faixa etária. Pacientes com insuficiência hepática: não é necessário ajuste da dosagem em pacientes com insuficiência hepática leve (classe ‘A’ de Child-Pugh). No entanto, para pacientes com insuficiência hepática moderada ou grave (classes ‘B’ e ‘C’ de Child-Pugh), o uso deste medicamento não é recomendado pois não existem estudos sobre o seu uso nestes pacientes. Pacientes com insuficiência renal: não é necessário ajuste da dose em pacientes com insuficiência renal crônica. Pacientes fumantes com DPOC: não é necessário ajuste da dose. Efeitos na habilidade de dirigir e operar máquinas: É improvável que o uso deste medicamento tenha qualquer efeito na capacidade de dirigir veículos ou de usar máquinas. Pacientes portadores de doenças imunológicas graves, infecciosas graves, câncer (exceto carcinoma basocelular) ou tratados com imunossupressores: o tratamento com DAXAS® não deve ser iniciado ou deve ser suspenso nestes casos. Pacientes portadores de insuficiência cardíaca classes III e IV (NYHA): não existem estudos nesta população de pacientes, portanto o uso neste grupo não é recomendado. Pacientes portadores de doenças psiquiátricas: DAXAS® não está recomendado em pacientes com histórico de depressão associada com ideação ou comportamento suicida. Os pacientes devem ser orientados a comunicar seu médico caso apresentem alguma ideação suicida. Interações medicamentosas: Estudos clínicos de interações medicamentosas com inibidores do CYP3A4 (eritromicina e cetoconazol) não resultaram em aumentos da atividade inibitória total de PDE4 (exposição total ao roflumilaste e ao N-óxido roflumilaste). Estudos de interações medicamentosas com o inibidor do CYP1A2 fluvoxamina e com os inibidores duplos CYP3A4/1A2 enoxacina e cimetidina resultaram em aumentos na atividade inibitória total de PDE4. Desta forma, deve ser esperado um aumento de 20% a 60% na inibição total de PDE4 quando o roflumilaste for administrado concomitantemente com potentes inibidores do CYP1A2, como a fluvoxamina, enquanto não são esperadas interações com os inibidores do CYP3A4 como o cetoconazol. Não são esperadas interações medicamentosas clinicamente relevantes. A administração de rifampicina (um indutor enzimático de CYP450) resultou em uma redução na atividade inibitória total de PDE4 de cerca de 60% e o uso de indutores potentes do citocromo P450 (como fenobarbital, carbamazepina, fenitoína) pode reduzir a eficácia terapêutica do roflumilaste. Não foram observadas interações clinicamente relevantes com os seguintes fármacos: salbutamol inalado, formoterol, budesonida, montelucaste, digoxina, varfarina, sildenafil, midazolam. A co-administração com antiácido e não altera a absorção nem as características farmacológicas do produto. A co-administração com teofilina aumento em 8% a atividade inibitória sobre a fosfodiesterase 4. Quando utilizado com contraceptivo oral contendo gestodeno e etinilestradiol a atividade inibitória sobre a fosfodiesterase 4 aumentou em 17%. Não existem estudos clínicos que avaliaram o tratamento concomitante com xantinas, portanto seu uso em associação não está recomendado. Reações adversas: DAXAS® foi bem avaliado em estudos clínicos, e cerca de 16% experimentaram reações adversas com o roflumilaste em comparação com 5,7% com o placebo. As reações adversas relatadas com mais frequência foram diarreia (5,9%), perda de peso (3,4%), nausea (2,9%), dor abdominal (1,9%) e cefaleia (1,7%). A maior parte destas reações foram leves ou moderadas e desapareceram com a continuidade do tratamento. Os eventos adversos classificados por frequência foram: Reação comum (> 1/100 e < 1/10): Perda de peso, distúrbios do apetite, insônia, cefaléia, diarreia, náusea, dor abdominal. Reação incomum (> 1/1.000 e < 1/100): Hipersensibilidade, ansiedade, tremor, vertigem, tontura, palpitações, gastrite, vômitos, refluxo gastro-esofágico, dispepsia, rash, espasmos musculares, fraqueza muscular, mal-estar, astenia, fadiga, dor muscular, lombalgia. Reação rara (> 1/10.000 e < 1/1.000): Depressão e distúrbios do humor, ginecomastia, disgeusia, hematoquesia, obstipação intestinal, aumento de Gama – GT, aumento de transaminases, urticária, infecções respiratórias (exceto pneumonia), aumento de CPK. Em estudos clínicos, raros casos de pensamento e comportamento suicida (incluindo suicídio completo) foram reportados. Pacientes devem ser instruídos a informar o prescritor sobre qualquer ideação suicida. Posologia e modo de usar: A dose recomendada de DAXAS® é de um comprimido uma vez ao dia. Não é necessário ajuste posológico para pacientes idosos, com insuficiência renal ou com insuficiência hepática leve (classes ‘A’ de Child-Pugh). DAXAS® não deve ser administrado à pacientes com insuficiência hepática moderada ou grave (classe ‘B’ou ‘C’ de Child-Pugh). Os comprimidos de DAXAS® devem ser administrados com uma quantidade de água necessária para facilitar a deglutição. Podem ser administrados antes, durante ou após as refeições. Recomenda-se que o medicamento seja administrado sempre no mesmo horário do dia, durante todo o tratamento. Este medicamento não deve ser partido ou mastigado. MS – 1.0639.0257. DX_0710_0512_VPS

CONTRAINDICAÇÃO: ALERGIA AOS COMPONENTES DA FÓRMULA E PACIENTES COM INSUFICIÊNCIA HEPÁTICA MODERADA A GRAVE. INTERAÇÃO MEDICAMENTOSA: A ADMINISTRAÇÃO DE INDUTORES ENZIMÁTICOS DO CITOCROMO P450, COMO RIFAMPICINA E ANTICONVULSIVANTES, PODE REDUZIR A EFICÁCIA TERAPÊUTICA DO ROFLUMILASTE. NÃO EXISTEM ESTUDOS CLÍNICOS QUE AVALIARAM O TRATAMENTO CONCOMITANTE COM METILXANTINAS, PORTANTO, SEU USO EM ASSOCIAÇÃO NÃO ESTÁ RECOMENDADO. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO.

Medicamento sob prescrição.

Takeda Pharma LTDA. Rua do Estilo Barroco, 721 - 04709-011 - São Paulo - SP. Mais informações poderão ser obtidas diretamente com o nosso Departamento Médico ou por meio de nossos representantes. MATERIAL EXCLUSIVO À CLASSE MÉDICA. MATERIAL PRODUZIDO EM JUNHO/2013

O novo módulo do Ventpro já está no ar!

O Ventpro, em parceira com a Philips oferece a melhor plataforma online para Profissionais de Saúde que buscam formação em Ventilação Não Invasiva.

Módulo 2

“Ventilação Mecânica Não Invasiva no paciente agudo/crítico”

nscreva-se no www.ventpro.eu e assista a primeira aula na íntegra!

APOIO

VOCÊ PODE OFERECER AOS SEUS PACIENTES UMA NOVA MANEIRA DE PREVENIR 1,2 A DOENÇA PNEUMOCÓCICA

Internacionalmente comercializada como

vacina pneumocócica 13-valente (conjugada)

Aprovada - VACINA PNEUMOCÓCICA CONJUGADA 13-VALENTE: A PRIMEIRA E ÚNICA VACINA PNEUMOCÓCICA CONJUGADA INDICADA PARA ADULTOS COM1,2 ...PARA A PREVENÇÃO DE PNEUMONIA E DOENÇA PNEUMOCÓCICA INVASIVA Referências bibliográficas: 1. Bula do produto 2. Centers for Disease Control and Prevention. Licensure of 13-Valent Pneumococcal Conjugate Vaccine for Adults Aged 50 Years and Older. MMWR 2012;61(21):394-5

SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO.

Wyeth Indústria Farmacêutica Ltda Rua Alexandre Dumas, 1860 - 3º andar Chácara Santo Antonio - São Paulo – SP CEP 04717-904

Anúncio destinado à classe médica. Aprovado em Maio/2013.