CLINICS December 2017 by Clinics

Volume 72 Number 12 - December/2017

CLINICS Editor Edmund Chada Baracat

Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil

Area Editors Ana Maria de Ulhoa Escobar Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Anna Sara Shafferman Levin Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Antonio Egidio Nardi Universidade Federal do Rio de Janeiro Rio de Janeiro, RJ, Brazil Anuar Ibrahim Mitre Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Berenice Bilharinho Mendonca Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Bruno Zilberstein Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Carlos Serrano Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Carmen Silvia Valente Barbas Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Claudia Regina Furquim de Andrade Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Claudio Roberto Cernea Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Emilia Inoue Sato Universidade Federal de São Paulo São Paulo, SP, Brazil Flair José Carrilho Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Fulvio Alexandre Scorza Universidade Federal de São Paulo São Paulo, SP, Brazil Geraldo Busatto Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Heitor Franco de Andrade Jr. Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil

Heloisa de Andrade Carvalho Hospital das Clı´nicas da Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Jesus Paula Carvalho Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Joaquim Prado Moraes-Filho Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil José Guilherme Cecatti Universidade Estadual de Campinas Campinas, SP, Brazil José Maria Soares Júnior Hospital das Clı´nicas da Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Luiz Eugenio Garcez-Leme Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Luíz Fernando Onuchic Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Lydia Masako Ferreira Universidade Federal de São Paulo São Paulo, SP, Brazil Marcos Intaglietta University of California, San Diego San Diego, CA, USA Maria José Carvalho Carmona Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Mauricio Etchebehere Universidade Estadual de Campinas Campinas, SP, Brazil Michele Correale University of Foggia Foggia, Italy Naomi Kondo Nakagawa Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Nelson Wolosker Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Newton Kara-Junior Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Olavo Pires de Camargo Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil

Paulo Hoff Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Paulo Pêgo-Fernandes Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Raul Coimbra University of California, San Diego La Jolla, CA, USA Renato Delascio Lopes Duke University Medical Center Durham, NC, USA Ricardo Bassil Lasmar Universidade Federal Fluminense Niterói, RJ, Brazil Ricardo Nitrini Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Rosa Maria Rodrigues Pereira Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Rossana Francisco Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Rubens Belfort Jr. Universidade Federal de São Paulo São Paulo, SP, Brazil Ruth Guinsburg Universidade Federal de São Paulo São Paulo, SP, Brazil Ruy Jorge Cruz Junior University of Pittsburgh Pittsburgh, PA, USA Sandro Esteves ANDROFERT - Andrology & Human Reproduction Clinic Campinas, SP, Brazil Sergio Paulo Bydlowski Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Sigmar de Mello Rode Universidade Estadual Paulista Júlio de Mesquita Filho São José dos Campos, SP, Brazil Simone Appenzeller Universidade Estadual de Campinas Campinas, SP, Brazil Valeria Aoki Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil

Editorial Board Abhijit Chandra King George’s Medical College Lucknow, India Adamastor Humberto Pereira Universidade Federal do Rio Grande do Sul Porto Alegre, RS, Brazil Adauto Castelo Universidade Federal de São Paulo São Paulo, SP, Brazil Ademar Lopes Fundação Antônio Prudente, Hospital do Câncer São Paulo, SP, Brazil Alberto Azoubel Antunes Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Alexandre Roberto Precioso Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Andrea Schmitt University of Goettingen Goettingen, Germany

Arnaldo Valdir Zumiotti Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Artur Brum-Fernandes Université de Sherbrooke Québec, Canadá Carmita Helena Najjar Abdo Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Cesar Gomes Victora Faculdade de Medicina da Universidade Federal de Pelotas Pelotas, RS, Brasil Daniel Romero Muñoz Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Eduardo Ferreira Borba Neto Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Edmund Neugebauer Witten/Herdecke University Witten, North Rhine - Westphalia, Germany

Egberto Gaspar de Moura Jr. Universidade do Estado do Rio de Janeiro Rio de Janeiro, RJ, Brazil Ernest Eugene Moore University of Colorado Denver Denver, CO, USA Euclides Ayres Castilho Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Fábio Biscegli Jatene Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Francisco Laurindo Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Hiroyuki Hirasawa Chiba University School of Medicine Chiba, Japan Irismar Reis de Oliveira Faculdade de Medicina da Universidade Federal da Bahia Salvador, BA, Brasil

Irshad Chaudry University of Alabama Birmingham, AL, USA Ivan Cecconello Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Ke-Seng Zhao Southern Medical University Guangzhou, China Laura Cunha Rodrigues London School of Hygiene and Tropical Medicine - University of London London, UK Marcelo Zugaib Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Marco Martins Amatuzzi Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Maria Aparecida Shikanai Yasuda Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil

Mauro Perretti William Harvey Research Institute London, UK

Noedir Antonio Groppo Stolf Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil

Michael Gregory Sarr Mayo Clinic Rochester, MN, USA

Pedro Puech-Leão Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Peter Libby Brigham and Women’s Hospital Boston, Boston, MA, USA Philip Cohen University of Houston Health Center Houston, Texas, USA Rafael Andrade-Alegre Santo Tomás Hospital Republic of Panamai, Panamá Ricardo Antonio Reﬁnetti Faculdade de Medicina da Universidade Federal do Rio de Janeiro Rio de Janeiro, RJ, Brazil Roberto Chiesa San Raffaele Hospital Milan, Italy

Milton de Arruda Martins Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Mitchell C. Posner The University of Chicago Medical Center Chicago, IL, USA Moyses Szklo Johns Hopkins Bloomberg School of Public Health Baltimore, USA Naomi Kondo Nakagawa Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Navantino Alves Faculdade de Ciências Médicas de Minas Gerais Belo Horizonte, MG, Brazil

Samir Rasslan Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Tarcisio Eloy Pessoa de Barros Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Valentim Gentil Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Wagner Farid Gattaz Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil

Board of Governors Alberto José da Silva Duarte Aluisio Augusto Cotrim Segurado Ana Claudia Latronico Xavier Berenice Bilharinho de Mendonça Carlos Alberto Buchpiquel Carlos Roberto Ribeiro de Carvalho Clarice Tanaka Claudia Regina Furquim de Andrade Cyro Festa Daniel Romero Muñoz Edivaldo Massazo Utiyama Edmund Chada Baracat Eduardo Massad Eloisa Silva Dutra de Oliveira Bonfá Euripedes Constantino Miguel Fábio Biscegli Jatene Flair José Carrilho Geraldo Busatto Gerson Chadi Gilberto Luis Camanho Giovanni Guido Cerri Irene de Lourdes Noronha Irineu Tadeu Velasco

Ivan Cecconello Jorge Elias Kalil José Antonio Franchini Ramires José Antonio Sanches José Eduardo Krieger José Otávio Costa Auler José Ricardo de Carvalho Mesquita Ayres Linamara Rizzo Battistella Luiz Augusto Carneiro D’Albuquerque Luiz Fernando Onuchic Magda Maria Sales Carneiro-Sampaio Manoel Jacobsen Teixeira Marcelo Zugaib Miguel Srougi Milton de Arruda Martins Mirian Nacagami Sotto Nelson de Luccia Olavo Pires de Camargo Paulo Andrade Lotufo Paulo Hilário Nascimento Saldiva Paulo Manuel Pêgo Fernandes Paulo Marcelo Gehm Hoff Paulo Rossi Menezes

Editorial Director

Kavita Kirankumar Patel-Rolim Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil

Pedro Puech-Leão Remo Susanna Ricardo Ferreira Bento Ricardo Nitrini Roberto Kalil Roberto Zatz Roger Chammas Rolf Gemperli Rosa Maria Rodrigues Perreira Sandra Joseﬁna Ferraz Ellero Grisi Selma Lancman Tarcísio Eloy Pessoa de Barros Uenis Tannuri Umbertina Conti Reed Valentim Gentil Vanderson Geraldo Rocha Venâncio Avancini Ferreira Alves Vicente Odone Wagner Farid Gattaz Werther Brunow de Carvalho William Carlos Nahas Wilson Jacob

Editorial Assistants

Nair Gomes Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil Daniela Aquemi Higa Faculdade de Medicina da Universidade de São Paulo São Paulo, SP, Brazil

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ISSN-1807-5932

CLINICS CONTENTS Clinics 2017 72(12)718–790

CLINICAL SCIENCE

Screening protocol for dysphagia in adults: comparison with videoﬂuoroscopic ﬁndings Fernanda C. Sassi, Gisele C. Medeiros, Bruno Zilberstein, Shri Krishna Jayanthi, Claudia R.F. de Andrade. . . . . . . . 718

Serum 25-hydroxyvitamin D levels in patients with Granulomatosis with Polyangiitis: association with respiratory infection Mariana O. Perez, Ricardo M. Oliveira, Mauricio Levy-Neto, Valeria F. Caparbo, Rosa M.R. Pereira . . . . . . . . . . . 723

Effects of periarticular injection on analgesic effects and NSAID use in total knee arthroplasty and total hip arthroplasty Wen-rui Ban, Ery-ang Zhang, Lei-feng Lv, Xiao-qian Dang, Chen Zhang . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729

Depression and adherence to antiretroviral treatment in HIV-positive men in São Paulo, the largest city in South America: Social and psychological implications Ricardo Pereira de Moraes, Jorge Casseb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743

Microcirculation improvement after short-term infusion of vasopressin in septic shock is dependent on noradrenaline Ana Paula Metran Nascente, Flávio Geraldo Rezende Freitas, Jan Bakker, Antônio Tonete Baﬁ, Renata Teixeira Ladeira, Luciano Cesar Pontes Azevedo, Alexandre Lima, Flavia Ribeiro Machado . . . . . . . . . . . . . 750

Pain and quality of life in breast cancer patients Weruska Alcoforado Costa, Michelly Nóbrega Monteiro, Janice Franc¸a Queiroz, Ana Katherine Gonc¸alves . . . . . . . 758

Characteristics and Outcomes of Intensive Care Unit Survivors: Experience of a Multidisciplinary Outpatient Clinic in a Teaching Hospital Péricles A.D. Duarte, Jaquilene Barreto Costa, Silvana Trilo Duarte, Sheila Taba, Claudia Regina Felicetti Lordani, Erica Fernanda Osaku, Claudia Rejane Lima Macedo Costa, Dalas Cristina Miglioranza, Daniela Prochnow Gund, Amaury Cesar Jorge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764

Evaluation of the efﬁcacy and safety of endovascular management for transplant renal artery stenosis Leonardo G.M. Valle, Rafael N. Cavalcante, Joaquim M. Motta-Leal-Filho, Breno B. Affonso, Francisco L. Galastri, Marisa P. Doher, Nadia K. Guimarães-Souza, Ana K.N. Cavalcanti, Rodrigo G. Garcia, Álvaro Pacheco-Silva, Felipe Nasser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773

BASIC RESEARCH

Experimental implantation of an arterial substitute made of silicone reinforced with polyester fabric in rabbits Laila Massad Ribas, Inez Ohashi Torres, Fernanda Appolonio, Karina Paula Domingos Rosa, Fabio Rodrigues Ferreira do Espírito-Santo, Nelson De Luccia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 780

Second hand tobacco smoke adversely affects the bone of immature rats Rodrigo César Rosa, Sângela Cunha Pereira, Fabrizio Antônio Gomide Cardoso, Abadio Gonc¸alves Caetano, Hildemberg Agostinho Rocha de Santiago, José Batista Volpon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785

RETRACTION

Risk factors for the prognosis of pediatric medulloblastoma: a retrospective analysis of 40 cases Jianzhong Yu, Rui Zhao, Wei Shi, Hao Li . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790

CLINICAL SCIENCE

Screening protocol for dysphagia in adults: comparison with videofluoroscopic findings Fernanda C. Sassi,I Gisele C. Medeiros,II Bruno Zilberstein,III Shri Krishna Jayanthi,IV Claudia R.F. de AndradeI,* I

Departamento de Fisioterapia, Fonoaudiologia e Terapia Ocupacional, Faculdade de Medicina (FMUSP), Universidade de Sao Paulo, Sao Paulo, SP, BR. Divisa˜o de Fonoaudiologia, Hospital das Clı´nicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR. III Divisao de Cirurgia Digestiva, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR. IV Instituto de Radiologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR. II

OBJECTIVES: To compare the videofluoroscopic findings of patients with suspected oropharyngeal dysphagia with the results of a clinical screening protocol. METHODS: A retrospective observational cohort study was conducted on all consecutive patients with suspected oropharyngeal dysphagia between March 2015 and February 2016 who were assigned to receive a videofluoroscopic assessment of swallowing. All patients were first submitted to videofluoroscopy and then to the clinical assessment of swallowing. The clinical assessment was performed within the first 24 hours after videofluoroscopy. The videofluoroscopy results were analyzed regarding penetration/aspiration using an 8-point multidimensional perceptual scale. The accuracy of the clinical protocol was analyzed using the sensitivity, specificity, likelihood ratios and predictive values. RESULTS: The selected sample consisted of 50 patients. The clinical protocol presented a sensitivity of 50% and specificity of 95%, with an accuracy of 88%. ‘‘Cough’’ and ‘‘wet-hoarse’’ vocal quality after/during swallowing were clinical indicators that appeared to correctly identify the presence of penetration/aspiration risk. CONCLUSION: The clinical protocol used in the present study is a simple, rapid and reliable clinical assessment. Despite the absence of a completely satisfactory result, especially in terms of the sensitivity and positive predictive values, we suggest that lower rates of pneumonia can be achieved using a formal dysphagia screening method. KEYWORDS: Dysphagia; Screening Test; Modified Barium Swallow; Aspiration; Pneumonia. Sassi FC, Medeiros GC, Zilberstein B, Jayanthi SK, de Andrade CR. Screening protocol for dysphagia in adults: comparison with videofluoroscopic findings. Clinics. 2017;72(12):718-722 Received for publication on March 15, 2017; First review completed on March 27, 2017; Accepted for publication on August 15, 2017 *Corresponding author. E-mail: clauan@usp.br

’ INTRODUCTION

the respiratory tract (8). Thus, underlying clinical conditions may interact with dysphagia to produce aspiration, pneumonia, and/or respiratory compromise (9). Moreover, dysphagia may interfere with nutrition, delay clinical recovery and even lead to death if not diagnosed early and properly (1,10). Therefore, earlier detection of dysphagia leads to earlier selection of an adequate treatment. This not only shortens the reestablishment of the overall health status (i.e., a return to effective swallowing function and nutritional homeostasis) but also reduces the overall rehabilitation costs (11,12). Currently, no consensus exists on a standard method of assessment (13). Screening tools and bedside swallowing assessments are routinely conducted as initial assessments of swallowing, after which an instrumental evaluation may be performed (14). Bedside screening of dysphagia has been shown to effectively reduce the incidence rate of pneumonia, and dysphagia screening has been gradually incorporated into guidelines for the care of specific groups of patients (15,16). These instruments, however, have variable sensitivities and specificities for detecting oropharyngeal dysphagia and aspiration (17-20). To date, the Toronto Bedside Swallowing Screening Test (TOR-BSST) reported in

Dysphagia is defined as difficulty in swallowing foods, liquids or both (1). Neurological, muscular, anatomical, and/ or psychological factors may predispose a person to present difficulty in swallowing (2). The prevalence of functional oropharyngeal dysphagia is very high; it affects more than 37%-78% of acute ischemic and hemorrhagic stroke patients (3,4), 52-82% of patients with neurodegenerative diseases, 42-87% of patients after prolonged orotracheal intubation (5), more than 35% of patients with head and neck diseases (6), and more than 60% of elderly institutionalized patients (7). The movements involved in the act of swallowing are intended not only to obtain nourishment but also to protect

Copyright & 2017 CLINICS – This is an Open Access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/ 4.0/) which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited. No potential conflict of interest was reported. DOI: 10.6061/clinics/2017(12)01

718

Screening protocol for dysphagia Sassi FC et al.

CLINICS 2017;72(12):718-722

Swallowing was analyzed by reviewing the digitalized images of each swallow. Penetration/aspiration (25) was determined using an 8-point multidimensional perceptual scale. Scores were assigned as follows: 1 - material does not enter the airway; 2 - material enters the airway, remains above the vocal folds, and is ejected from the airway; 3 - material enters the airway, remains above the vocal folds and is not ejected from the airway; 4 - material enters the airway, touches the vocal folds and is ejected from the airway; 5 - material enters the airway, touches the vocal folds and is not ejected from the airway; 6 - material enters the airway, passes below the vocal folds and is ejected into the larynx or out of the airway; 7 - material enters the airway, passes below the vocal folds and is not ejected from the trachea despite effort; 8 - material enters the airway, passes below the vocal folds, and no effort is made to eject it. Patients were diagnosed with dysphagia if they received a score of 4 points or above on the perceptual scale. Despite the acceptance of this technique as the gold standard for evaluating swallowing abilities, its reliability among experts remains low (26). Thus, two speech-language pathologists who were not involved in performing the swallowing study, each with more than four years of experience with dysphagia, reviewed each VFS result. The interrater reliability was high, with an intraclass correlation coefficient (ICC) of 0.90.

a study by Martino et al. (21) is the only instrument that has shown high sensitivity and high negative predictive values for the early detection of dysphagia. Unfortunately, this protocol has only been validated for stroke patients. Videofluoroscopy (VFS), also called a modified barium swallow study, is the gold standard method for studying the oral and pharyngeal mechanisms of dysphagia and for evaluating the efficacy and safety of swallowing (7). VFS provides direct visualization of the anatomy and physiology of swallowing, including the motions of the jaws, tongue, palate, pharynx, larynx, and esophagus (22). Although VFS is considered the criterion standard for identifying aspiration/silent aspiration during swallowing, it generally incurs a substantial monetary cost, entails radiation exposure, has limited standardization, and is not feasible for all patients (e.g., moderately ill patients cannot be transported to the radiology department) (23). In addition, VFS requires specialized equipment and personnel who are not readily available in many hospitals (24). This study was specifically designed to compare the videofluoroscopic findings of patients with suspected oropharyngeal dysphagia with the results of a clinical screening protocol.

â&#x20AC;&#x2122; MATERIALS AND METHODS The study was approved by an institutional review board to ensure the ethical conduct of research studies with human subjects (CAPPesq HCFMUSP 1.781.177). Written informed consent was obtained from all participants.

Part 2 â&#x20AC;&#x201C; Clinical assessment of swallowing The clinical assessment of swallowing was performed within the first 24 hours after VFS and involved the application of the Dysphagia Risk Evaluation Protocol (DREP) (9,27). This protocol is routinely used by the Division of Orofacial Myology at our hospital to assess swallowing dysfunction in patients. The protocol includes items previously described as being effective in identifying high-risk patients with suspected dysphagia (28,29). Items were chosen based on several guiding principles, such as ease of administration, ease of interpretation and pre-existing research supporting each itemâ&#x20AC;&#x2122;s relationship with dysphagia. The protocol is divided into two sections, a water swallow test and a puree/solid swallow test, and the results are marked as either pass or fail for each of the observed items. Based on a previous study (27), we only used the results obtained from the water swallow test and analyzed the variables considered as possibly significant high-risk indicators of dysphagia (i.e., multiple swallows, cervical auscultation, vocal quality, cough and choking). As determined by the authors of the protocol, patient swallowing was assessed during the administration of 5 ml of water (via a syringe). The test was repeated, if necessary, up to 3 times to confirm the results. Patients were placed in an upright position so that their sitting position did not interfere with the research results. The assessed items and the criteria used to interpret the results were as follows:

Study Participants We conducted a retrospective observational cohort study. The study population included all consecutive patients with suspected oropharyngeal dysphagia who were referred by the medical team to the Radiology Institute of Hospital das ClÄąÂ´nicas to complete a videofluoroscopic assessment of swallowing between March 2015 and February 2016. Patients were eligible if they met the following criteria: a) older than 18 years; b) X14 points on the Glasgow Coma Scale; c) absence of a tracheostomy tube; d) no medical contraindications to performing a barium swallow due to radiation exposure, allergies or postural limitations; e) no restrictions on liquid intake; and f) completion of the clinical assessment of swallowing within the first 24 hours after VFS.

Measures The swallowing assessment was performed in two parts: Part 1 - Videofluoroscopic assessment of swallowing All patients first completed VFS. The fluoroscopy unit used in this study was the GE Medical Systems ADVANTX (GE Healthcare, Wakeska, Wisconsin, USA). All VFS studies were performed in the lateral plane by a VFS-trained radiographer and two trained speech and language therapists. The participants remained seated, at an angle of 90o, with their heads positioned horizontally during the entire examination. Liquid barium (Opti-bar) at a concentration of 100% w/v was used. The protocol adopted for the swallowing assessment involved the ingestion of food with different consistencies and is routinely used at our hospital to investigate swallowing characteristics, especially the presence of aspiration. In the present study, we only considered the swallowing of 10 ml of the liquid consistency (liquid barium at a concentration of 100% w/v) for analysis. The mixture was measured using a disposable syringe and was offered to the participants in a cup.

Multiple swallows per bolus: Pass - The patient only requires only 1 swallow per bolus. Fail - The patient presents more than one swallow per bolus, presents drooling/ spillage from mouth, or requires cues to complete the task. Cervical auscultation (a stethoscope is placed at the lateral aspects above the cricoid cartilage and in front of the sternocleidomastoid muscle and large vessels): Pass - The patient presents the 3 characteristic sounds (two clicks followed by an expiratory sound), indicating that the bolus has passed through the pharynx. Fail - The patient does

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Figure 1 - Flow diagram for the swallowing study. n â&#x20AC;&#x201C; number of patients, VFS â&#x20AC;&#x201C; videofluoroscopy of swallowing.

Table 2 - Distribution of patients according to the clinical

Table 1 - Distribution of patients according to the multidimensional perceptual scale (videofluoroscopy of swallowing).

protocol. Clinical signs

Score

1 2 3 4* 5 6 7 8

31 4 11 1 1 0 1 1

62 8 22 2 2 0 2 2

Multiple swallows Cervical auscultation Voice quality Cough Choking

n â&#x20AC;&#x201C; number of participants; % â&#x20AC;&#x201C; percentage of participants; * cut-off value for dysphagia.

n (%) Pass Fail Pass Fail Pass Fail Pass Fail Pass Fail

29 (58) 21 (42) 50 (100) 0 49 (98) 1 (2) 45 (90) 5 (10) 50 (100) 0

n â&#x20AC;&#x201C; number of participants; % â&#x20AC;&#x201C; percentage.

â&#x20AC;&#x2122; RESULTS

not present any sound or presents sounds other than those described above. Vocal quality: Pass - The patient does not present any alterations within the first minute after swallowing. Fail The patientâ&#x20AC;&#x2122;s voice becomes gurgly (â&#x20AC;&#x2DC;â&#x20AC;&#x2DC;wetâ&#x20AC;&#x2122;â&#x20AC;&#x2122;) within the first minute after swallowing. Cough: Pass - The patient does not cough within the first minute after swallowing. Fail - The patient coughs (voluntary or not) with or without throat clearing within the first minute after swallowing. Choking: Pass - The patient does not choke after swallowing. Fail - The patient chokes during and/or after swallowing. Patients were considered as being at risk for penetration/ aspiration if they failed at least one of the above items. The only exception was for the item â&#x20AC;&#x2DC;â&#x20AC;&#x2DC;multiple swallowsâ&#x20AC;&#x2122;â&#x20AC;&#x2122;, as reports in the literature have shown that this sign can be related to a physiological adaptation and therefore cannot be interpreted as an alteration in the swallowing mechanism (30).

The selected sample consisted of 50 patients (13 males and 37 females), with ages ranging from 24 to 87 (62.2Âą16.0) years. Patients were diagnosed with the following medical conditions: 20 (40%) had gastroenterological diseases, 15 (30%) had neurological diseases, 8 (16%) had pulmonary diseases, 4 (8%) had cardiologic diseases, 2 (4%) had vascular diseases, and 1 (2%) had rheumatologic disease. Figure 1 shows the results obtained from VFS and the clinical protocol. Tables 1 and 2 display the distribution of patients according to their results on VFS and the clinical protocol, respectively. According to the results of both instruments, most patients presented normal swallowing function. Patients who had altered VFS results exhibited an even distribution among the scores, which was considered as altered on the multidimensional scale. Regarding the clinical signs, most patients who failed presented cough followed by alterations in vocal quality. A comparison of the results obtained for the instruments used to identify dysphagia is presented in Table 3. The clinical protocol had a sensitivity of 50% and a specificity of 91.3% compared to VFS. The negative predictive value was 95%, with an accuracy of 88%. Cohenâ&#x20AC;&#x2122;s kappa coefficient indicated an agreement of 0.336 between the tests, i.e., a fair agreement. For the two participants who had indications of

Data Analysis. Univariate statistics were used to describe the data, including percentages, means and standard deviations. The accuracy of the clinical protocol was tested using the sensitivity, specificity, likelihood ratios, and predictive values. The agreement between the VFS and clinical protocol results was verified using Cohenâ&#x20AC;&#x2122;s kappa coefficient.

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Table 3 - Comparison of the accuracy measures of the clinical and VFS results. VFS

Clinical protocol

Dysphagia (n)

No dysphagia (n)

2 2

4 42

Sensitivity = 50% False negative = 4%

Specificity = 91.3% False positive = 8%

Dysphagia (n) No dysphagia (n)

PPV = 0.33 NPV = 0.95 PLR = 0.57 NLR = 0.55

VFS – videofluoroscopy of swallowing; n – number of patients; PPV – positive predictive value; NPV – negative predictive value; PLR – positive likelihood ratio; NLR – negative likelihood ratio.

In our study, selection bias primarily accounted for the relatively moderate sensitivity and low positive predictive values of the DREP in identifying swallowing dysfunction. According to the criteria adopted by our hospital (i.e., public, high complexity, limited staff with expertise to perform VFS), patients who are suspected of having dysphagia are first referred for complete VFS by the medical team, who in many cases do not have the necessary knowledge to identify swallowing disorders, and then to a speech-language pathologist for a clinical assessment. Consequently, 46 patients were diagnosed as having no dysphagia according to the gold standard parameter. The diagnosis and management of dysphagia requires a multidisciplinary approach (6). As is the case with other pathological conditions, the literature suggests that a diagnostic procedure should start with a screening test (8). Based on the screening results, only highrisk patients who are reasonably suspected of having dysphagia should proceed to a more specific examination (i.e., VFS or video endoscopic examination). This procedure avoids not only radiation exposure, but also unnecessary costs. Notably, one central aim of our study was to determine the specificity and sensitivity of using a clinical protocol to detect penetration/aspiration in a heterogeneous group of patients. Most of the existing screening methods have only been validated in patients with dysphagia caused by stroke (3,16,17,20,21,34), which limits the application of these tests to patients with dysphagia caused by other diseases. Despite the absence of a completely satisfactory result, especially in terms of sensitivity and positive predictive values, we suggest that lower rates of pneumonia can be achieved using a formal dysphagia screening method (15). Our study should be viewed as an effort to standardize care for patients with swallowing disorders across all settings. Given the current trend of having an evidence-based method (9), screening tools validated in different populations with dysphagia will allow for earlier referral to properly diagnose a patient and direct treatment, which will reduce complications, malnutrition and even death. Future studies will involve the application of the DREP prior to VFS in specific populations using different food consistencies and volumes for possible adjustments.

dysphagia on both instruments (true positive results), the most effective predictor was the presence of cough (100%).

’ DISCUSSION Dysphagia screening tools are the most widely used methods of assessing oropharyngeal dysphagia worldwide (8,14). The tests are typically easy to perform and extremely useful for obtaining a rough estimation of the swallowing condition (8). Evidence shows that the implementation of screening tools to identify risks of dysphagia has resulted in substantial reductions in pneumonia rates (15,16). Moreover, the literature suggests that protocols including a water swallow test yield the best patient outcomes (15,31). In this sense, the DREP fits with what has previously been described in the literature as a good bedside swallowing assessment for dysphagia. Although aspiration is not present in all dysphagia patients, it is considered the most important symptom associated with swallowing dysfunction (8). During the assessment of dysphagia, choking is a conspicuous symptom that can be objectively observed. However, a study by Wu et al. (32) reported that choking is a poor indicator of aspiration because it cannot predict silent aspiration. In our study, of 6 patients who failed the DREP, 5 patients presented coughing after the water swallow test, and 1 presented an altered vocal quality (i.e., a wet-hoarse voice). Our findings are consistent with previous studies that have reported both items as being sensitive for detecting penetration/aspiration (17,33). Regarding accuracy, the DREP demonstrated a high specificity and negative predictive value but only a moderate sensitivity: 50% for aspiration/penetration. The specificity of the DREP is at the higher end of the range of that of other dysphagia screening tests, which varies from 49% to 67% (19,31). In the present study, VFS showed penetration/aspiration to be present in 4 patients. A comparison of the ability of the DREP and VFS to detect penetration/aspiration revealed that the DREP correctly identified penetration/aspiration in 2 patients who also presented altered results on VFS. For the remaining 2 patients who presented altered results on VFS, the DREP indicated false negative results. Moreover, the DREP yielded 4 false positive results, indicating that the screening protocol may have a tendency to overidentify penetration/aspiration. Poor sensitivity values (i.e., 47%) (34) and overestimation of the risk for penetration and aspiration have previously been reported in the literature (14,35). The number of false positive results of the DREP does not seem to have a major negative impact on patients, as it may only lead to a VFS referral. However, the necessity for a more specific assessment involves additional costs and is usually time consuming (21).

’ AUTHOR CONTRIBUTIONS Sassi FC organized and conducted the statistical analyses, interpreted the results and wrote a major portion of the manuscript. Medeiros GC collected and analyzed data, interpreted the results and wrote the manuscript. Zilberstein B participated in the data analyses, interpretation of the results and writing of the manuscript. Jayanthi SK participated in the data analyses, interpretation of the results and writing of the manuscript. de Andrade CR was responsible for the research and experimental design, contributed to the data analysis and manuscript preparation.

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CLINICAL SCIENCE

Serum 25-hydroxyvitamin D levels in patients with Granulomatosis with Polyangiitis: association with respiratory infection Mariana O. Perez,I Ricardo M. Oliveira,II Mauricio Levy-Neto,I Valeria F. Caparbo,I Rosa M.R. PereiraI,* I

Divisao de Reumatologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR. II RDO Diagnosticos Medicos, Sao Paulo, SP, BR.

OBJECTIVES: To determine the possible association of serum 25-hydroxyvitamin D (25OHD) levels with disease activity and respiratory infection in granulomatosis with polyangiitis patients during two different periods: winter/spring and summer/autumn. METHODS: Thirty-two granulomatosis with polyangiitis patients were evaluated in the winter/spring, and the same patients (except 5) were evaluated in summer/autumn (n=27). The 25OHD levels were measured by radioimmunoassay. Disease activity was assessed by the Birmingham Vasculitis Activity Score Modified for Wegener’s Granulomatosis (BVAS/WG) and antineutrophil cytoplasmic antibody (ANCA) positivity. Respiratory infection was defined according the Centers for Disease Control and Prevention criteria. RESULTS: 25OHD levels were lower among patients in winter/spring than in summer/autumn (32.31±13.10 vs. 38.98±10.97 ng/mL, p=0.04). Seven patients met the criteria for respiratory infection: 5 in winter/spring and 2 in summer/autumn. Patients with respiratory infection presented lower 25OHD levels than those without infection (25.15±11.70 vs. 36.73±12.08 ng/mL, p=0.02). A higher frequency of low vitamin D levels (25OHDo20 ng/mL) was observed in patients with respiratory infection (37.5% vs. 7.8, p=0.04). Serum 25OHD levels were comparable between patients with (BVAS/WGX1 plus positive ANCA) and without disease activity (BVAS/WG=0 plus negative ANCA) (35.40±11.48 vs. 35.34±13.13 ng/mL, p=0.98). CONCLUSIONS: Lower 25OHD levels were associated with respiratory infection but not disease activity in granulomatosis with polyangiitis patients. Our data suggest that hypovitaminosis D could be an important risk factor for respiratory infection in granulomatosis with polyangiitis patients. KEYWORDS: Granulomatosis with Polyangiitis; Vasculitis; Vitamin D; Respiratory Tract Infections; Disease Activity. Perez MO, Oliveira RM, Levy-Neto M, Caparbo VF, Pereira RM. Serum 25-hydroxyvitamin D levels in patients with Granulomatosis with Polyangiitis: association with respiratory infection. Clinics. 2017;72(12):723-728 Received for publication on April 18, 2017; First review completed on May 16, 2017; Accepted for publication on August 29, 2017 *Corresponding author. E-mail: rosamariarp@yahoo.com

’ INTRODUCTION

tract infection and disease activity in GPA. Airway infection and disease activity involving the respiratory tract are clinically very similar. Moreover, airway infection may elicit disease activity, and disease activity may exacerbate and perpetuate airway infection in GPA patients (4,5). Vitamin D, in addition to acting on bone metabolism, acts as an immunomodulator, participating in innate and adaptive immune responses. 25-hydroxyvitamin D (25OHD) deficiency has been associated with disease activity in some autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis (6-8). 25OHD deficiency has also been associated with infection, particularly by respiratory viruses and mycobacteria (9-16). Therefore, this study aimed to determine the possible association of 25OHD concentrations with disease activity and respiratory infections in patients with GPA during two different periods: winter/spring and summer/autumn. To the best of our knowledge, no studies have evaluated vitamin D serum levels in GPA patients and their association with disease activity or respiratory infection.

Granulomatosis with polyangiitis (GPA, previously known as Wegener’s granulomatosis) describes systemic vasculitis of small vessels that is strongly associated with antineutrophil cytoplasmic antibodies (ANCAs) directed against proteinase-3. GPA has many heterogeneous manifestations, especially in the upper and lower respiratory tracts and kidneys (1). The respiratory tract is frequently affected in GPA, with involvement of the upper airway or the development of pulmonary disease (2). Patients with GPA have higher mortality during the first year of disease due to infection in most cases (3). In clinical practice, it can be very difficult to differentiate respiratory Copyright & 2017 CLINICS – This is an Open Access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/ 4.0/) which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited. No potential conflict of interest was reported. DOI: 10.6061/clinics/2017(12)02

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’ MATERIALS AND METHODS

according to 34 items that are categorized into 9 groups. The BVAS/WG values range from 0 to 63. Disease activity was defined as a BVAS/WG score X1, and remission was defined as a BVAS/WG score of 0 (19). ANCA positivity was assessed using an indirect immunofluorescence method and was also used as a parameter of disease activity (20). The Vasculitis Damage Index (VDI) was used to assess damage in all patients. The VDI is a validated checklist of 64 items divided into 11 organ-based systems and an ‘other’ category corresponding to potential treatment side effects. An item of damage was only recorded if it occurred after the onset of vasculitis and was considered permanent, defined as persistence for more than 3 months. In patients with established comorbidities prior to vasculitis, an item was only recorded if it had deteriorated significantly within at least 3 months since disease onset (21).

Patient selection A total of 61 consecutive patients with GPA who regularly attended the outpatient Vasculitis Clinic of the Clinic Hospital of the University of São Paulo were screened from January 2011 to December 2013. All patients fulfilled the 1990 American College of Rheumatology (ACR) (17) and 2012 Revised International Chapel Hill Consensus criteria for the classification of GPA (18). Twenty-nine of these patients met the exclusion criteria due to the presence of other ANCAassociated diseases, autoimmune diseases, or concomitant non-respiratory infections. Therefore, 32 patients were evaluated (Figure 1). Demographic and clinical data, including race, age, disease duration, clinical manifestations, comorbidities, GPA treatment (glucocorticoid and immunosuppressive treatments) and vitamin D supplementation, were obtained through interviews with the patients and medical chart reviews. GPA was previously divided into clinical subgroups categorized by disease severity (localized, generalized and severe) (17). The study was performed in accordance with the Declaration of Helsinki. All subjects provided written informed consent before inclusion in the study.

Respiratory infection Infection of the upper or lower airways was diagnosed according to the Centers for Disease Control and Prevention (CDC) criteria. Upper respiratory infection (pharyngitis, laryngitis, epiglottitis and sinusitis) and lower respiratory infection (pneumonia, bronchitis, tracheobronchitis, bronchiolitis and tracheitis) were defined based on clinical, laboratory, imaging and microbiological parameters (22).

Seasonal variations Considering that vitamin D concentrations may be influenced by seasonal variations, serum 25OHD levels were measured during two periods of the year in each patient. Samples from 32 patients were evaluated in the winter/ spring, and 27 samples from the same patients were evaluated in the summer/autumn, resulting in a total of 59 samples. Five patients were lost in the summer/autumn season: 1 patient died in another hospital from supposed pulmonary septic shock, 1 patient had a diagnosis of septic arthritis, and 3 patients were lost to follow-up.

Laboratory parameters Serum 25OHD levels were measured by radioimmunoassay (DiaSorin, Stillwater, MN, USA). Vitamin D deficiency was defined as 25OHD levels less than 20 ng/mL (23), with 25OHD concentrations sub-categorized as o20 ng/mL and X20 ng/mL. C-reactive protein (CRP) levels and the erythrocyte sedimentation rate (ESR) were also evaluated because they may be elevated due to infection and/or disease activity. CRP was measured using the immunoturbidimetric method, and levels higher than 5 mg/L were considered abnormal. The ESR was measured by the Westergren test, with normal reference values in the first hour as follows: men o15 mm/ h and women o20 mm/h. The white blood cell count (WBC) was measured in a local laboratory by an automated cell counter, with normal levels ranging from 4,000 to 11,000/mm3.

Disease activity and damage scores GPA disease activity was assessed using the Birmingham Vasculitis Activity Score Modified for Wegener’s Granulomatosis (BVAS/WG), an established tool for clinical use and research that measures disease activity, vasculitis treatment outcomes, and the prognosis. The BVAS/WG measures activity

Figure 1 - Selection of Granulomatosis with Polyangiitis (GPA) patients.

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Statistical analysis

patients in the summer/autumn. At baseline (winter/spring), 24 (75%) patients were using immunosuppressive agents, 24 (75%) were using trimethoprim-sulfamethoxazole, 16 (50%) were using prednisone and 3 (9.4%) were using rituximab. Seven patients met the criteria for infection of the upper or lower airways: 5 in winter/spring and 2 in summer/autumn (Table 1). The same patient exhibited infection in winter/ spring and subsequently in summer/autumn (patient #4 = patient #7). We observed 5 cases of tracheobronchitis, 1 case of pneumonia and 1 case of sinusitis. Table 1 shows the diagnostic criteria for respiratory infection. Two patients fulfilled the criteria for respiratory infection and the BVAS/WG criteria for respiratory activity simultaneously. Table 2 shows the treatments applied in patients with disease activity and respiratory infection. All 7 patients with respiratory infection, except 1, were using immunosuppressive agents, and 5 were using prednisone (15.7±17.89 mg/ day). No differences regarding prednisone, immunosuppressive agents or rituximab use were observed between GPA patients with and without infection. Moreover, no differences were observed relative to treatment in patients with and without disease activity (Table 2). No difference in the frequency of respiratory infection relative to a particular season was observed (data not shown). Of the 59 samples, 39 (66%) were obtained from patients who had received vitamin D supplementation (mean 8007,000 IU/day). No difference was observed in 25OHD concentrations between patients with or without supplementation (34.87±12.51 vs. 36.31±12.81 ng/mL, p=0.68). However, 25OHD concentrations were significantly lower in patients in the winter/spring period than in the summer/autumn period (32.31±13.10 vs. 38.98±10.97 ng/mL, p=0.04).

Statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS for Windows, 21.0, SPSS Inc). The results are presented as the mean ± SD for continuous variables and as percentages for categorical variables. Quantitative variables were analyzed with Student’s T-test (normal distribution) or the Mann-Whitney (non-normal distribution) test. Differences between categorical variables were evaluated using the chi-squared or Fisher’s exact test. Statistical significance was indicated by p values less than 0.05. A receiver operator characteristic (ROC) curve was constructed using continuous serum 25OHD levels to identify a predictive value of 25OHD associated with respiratory infection.

’ RESULTS Fifty-three percent of GPA patients were women (n=17), and 65.6% (n=21) were white, with a mean age of 46.2± 13.1 years. The mean age at diagnosis was 38.5±13.7 years, and the mean disease duration was 8.9±4.2 years. Most GPA patients had the generalized disease form (71.8%), and the localized form was observed in 28.2% of the patients. Regarding the baseline clinical condition (winter/spring), 12 (37.5%) patients exhibited disease activity by the BVAS/ WG criteria (BVAS/WGX1), and the mean BVAS/WG was 1.37±2.49. Of these, 7 patients had upper airway involvement (58.3%), 5 had ocular involvement (41.6%), 4 had lower airway involvement (33.3%), 1 had neurological involvement (8.3%) and 1 had articular involvement (8.3%). The mean VDI was 5.5±2.3. ANCA positivity was observed in 59.4% of the patients in the winter/spring and in 70.4% of the

Table 1 - Respiratory infections in seven patients with Granulomatosis with Polyangiitis (GPA) and their respective BVAS/WG and serum 25OHD levels. Patient

Infection

Infection Criteria

Season

Pneumonia

Sinusitis

Tracheobronchitis

Fever, cough, dyspnoea, leucocitosis, chest X-ray (pulmonary infiltrates), positive pleural fluid culture (Acinetobacter baumanni) Fever, nasal discharge, headache, X-ray with evidence of infection Fever, cough, leucocitosis, chest X-ray without evidence of pneumonia Fever, cough, wheeze, increased pulmonar secretion, chest X-ray without evidence of pneumonia, positive bronchoalveolar lavage fluid culture (Streptococcus viridans) Fever, coagh, leucocitosis, chest X-ray without evidence of pneumonia Fever, cough, wheeze, leucocitosis, chest X-ray without evidence of pneumonia Fever, cough, wheeze, increased pulmonar secretion, chest X-ray without evidence of pneumonia

BVAS

BVAS Criteria

25OHD ng/mL

Vitamin D supplementation

Winter/ spring

18.52

Winter/ spring Winter/ spring Winter/ spring

Nasal crusts

25.19

Yes

Proptosis

Yes

Neuropathy

37.65

Yes

7.48

Yes

Hearing loss Pulmonary

41.55

Yes

26.68

Yes

Winter/ spring Summer/ autumn Summer/ autumn

BVAS/WG: Birmingham Vasculitis Activity Score Modified for Wegener’s Granulomatosis.

Table 2 - Current treatment in patients with Granulomatosis with Polyangiitis (GPA) with activity disease and respiratory infection. Disease Activity

Prednisone, n (%) Immunosuppressive, n (%) Rituximab, n (%)

Respiratory Infection

Activity (n=25)

No Activity (n=34)

p-values

Infection (n=7)

No Infection (n=52)

p-values

15 (60) 21 (84) 2 (8)

11 (32.3) 19 (55.8) 1 (2.9)

0.06 0.09 1.00

5 (71.4) 6 (85.7) 0

20 (38.4) 34 (65.3) 3 (5.7)

0.12 0.41 1.00

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vs. 34.68±13.32 ng/mL, p=0.75), high CRP vs. normal CRP (37.06±13.68 vs. 34.67±12.13 ng/mL, p=0.51) and high ESR vs. normal ESR (35.06±11.63 vs. 35.51±13.10 ng/mL, p=0.89). In contrast, patients with a diagnosed respiratory infection had lower 25OHD concentrations than those without infection (25.15±11.70 vs. 36.73±12.08 ng/mL, p=0.02). Moreover, a higher frequency of low vitamin D levels (25OHD o20 ng/mL) was observed in patients with respiratory infection (37.5% vs. 7.8, p=0.04) (Table 3). ROC curve analysis indicated that a serum 25OHD level less than 27.9 ng/mL was associated with respiratory infection, with a sensitivity of 71.4%, a specificity of 75% and an area under the curve of 0.769 (Figure 2). For 25OHD levels less than 30 ng/mL, the sensitivity was 71.4%, and the specificity was 70.2% or respiratory infection.

Table 3 - Respiratory infection (presence or not), values of white blood cell count, C-reactive protein and erythrocyte sedimentation rate comparing patients with Granulomatosis with Polyangiitis (GPA) with serum levels of 25OHD X 20 ng/mL vs. o 20 ng/mL.

Infection No Yes WBC High Normal CRP High Normal ESR High Normal

25OHD X 20 ng/mL (n=51)

25OHD o 20 ng/mL (n=8)

47 (92.2%) 4 (7.8%)

5 (62.5%) 3 (37.5%)

3 (5.9%) 48 (94.1%)

2 (25%) 6 (75%)

15 (29.4%) 36 (70.6%)

2 (25%) 6 (75%)

18 (35.3%) 33 (64.7%)

2 (25%) 6 (75%)

p-values 0.04

0.13

1.00

0.70

’ DISCUSSION

Respiratory infection by Centers for Disease Control and Prevention (CDC) criteria. WBC: White blood cell count (normal values: 4,000 - 11,000/mm3). CRP: C-reactive protein (high: 45 mg/L). ESR: Erythrocyte sedimentation rate (high: 415mm for men and 420mm for women).

This study evaluated serum 25OHD levels in GPA patients and demonstrated for the first time that lower serum 25OHD levels were associated with respiratory infection in these patients. In fact, vitamin D deficiency has been linked to bacterial and viral infections, such as influenza, parainfluenza and respiratory syncytial virus (9-16,24,25). Our study confirmed and extended previous findings showing that 25OHD values lower than 20 ng/mL could be associated with respiratory infection. Epidemiologic studies have explored the association between seasonal variations in vitamin D levels and infections. In winter, lower serum vitamin D levels were associated with a higher incidence of infections, including septic shock (26), respiratory infection (27) and influenza (27,28). Defense against infectious processes appears to be an extra-skeletal effect of vitamin D. Vitamin D increases the chemotaxis of inflammatory cells, enhances the phagocytosis of these cells, and stimulates the production of reactive oxygen species, leading to the destruction of pathogens. Vitamin D has also been associated with the direct production of cathelicidin, a peptide with bactericidal action (12,15,16,29). Regulation of the vitamin D receptor (VDR) is a mechanism used to defend against pathogens. However, some pathogens can evade the immune system by down-regulating VDR on the surfaces of monocytes and macrophages (30). VDR is present in most cells of the immune system, especially lymphocytes, neutrophils, macrophages and dendritic cells, and suppresses antigen presentation and the activation and recruitment of Th1 lymphocytes (15,31). In our study, ROC curve analysis showed that serum 25OHD levels less than 27.9 ng/mL were associated with respiratory infection. Previous studies have shown that vitamin D status is associated with the risk of respiratory infection, especially in healthy individuals with levels below 20 ng/mL (4,5). Subclinical 25OHD deficiency was associated with severe lower respiratory tract infection in an Indian study (10), and clinical vitamin D deficiency was associated with a 13-fold increased risk of pneumonia in Ethiopian children (32). A Finnish study with young army recruits identified an association of 25OHD serum levels o16 ng/mL with acute respiratory infections and more days of absence from duty (33). In addition, Cannell et al. compiled epidemiological data regarding the association between seasonal variations in vitamin D levels and influenza and concluded that a lack of vitamin D during the winter may correspond to the infectivity of the influenza virus (28).

Figure 2 - ROC curve analysis for serum 25OHD levels and respiratory infection in Granulomatosis with Polyangiitis (GPA) patients. 25OHD concentrations less than 27.9 ng/mL were predictor of respiratory infection with 71.4% sensitivity and 75% specificity.

No differences were observed in the data of GPA patients between the winter/spring season (n=32) and the summer/ autumn (n=27) relative to the BVAS/WG (1.37±2.49 vs. 1.70±1.81, p=0.28), VDI (5.50±2.25 vs. 5.29±2.30, p=0.36), WBC (7,435±2,943 vs. 6,711±2,209/mm3, p=0.14), ESR (13.41± 16.94 vs. 13.41±12.94 mm/h, p=0.49) and CRP level (6.00± 10.72 vs. 10.49±23.71 mg/L, p=0.17). No differences were observed regarding serum 25OHD levels and disease activity parameters relative to a BVAS/WG X1 vs. a BVAS/WG=0 (35.48±12.23 vs. 35.25±12.99 ng/mL, p=0.94), ANCA positivity vs. ANCA negativity (35.73±12.23

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A randomized, double-blind, placebo-controlled trial in schoolchildren demonstrated that vitamin D supplementation (1,200 U/day) significantly decreased the incidence of influenza infection by 42% in the winter (16). Interestingly, in our study, no association between lower vitamin D levels and disease activity was observed, although the association between vitamin D levels and the immune system has been recognized in the literature. Vitamin D acts as an immunomodulator of the innate and acquired immune system, balances proinflammatory and anti-inflammatory cytokines, decreases the maturation of dendritic cells, reduces the proliferation of B lymphocytes, increases Th1 and Th17 responses and stimulates Treg cells (13). Poor vitamin D status is associated with the risk of rheumatologic diseases, including systemic lupus erythematous, rheumatoid arthritis and Behc¸et’s disease (7,34). However, no study has demonstrated an association of disease activity in ANCA-associated vasculitis with vitamin D serum levels and vitamin D supplementation. As expected, our study identified lower serum 25OHD levels among subjects in the winter/spring period than in the summer/autumn period, reflecting the relationship between seasonality and vitamin D serum concentrations (16). Our patients were evaluated during two different periods, winter/ spring and summer/autumn, but no difference between disease activity or infection was observed between seasons. Interestingly, in our study, no associations between infection or disease activity and CRP, ESR or WBC values were observed. Although these markers can be altered by certain conditions, laboratory parameters can also be affected by glucocorticoid and immunosuppressive treatments (35). A limitation of this study is that our findings were restricted to more severe GPA disease because our patients predominantly had the generalized form of GPA with a high VDI, indicating greater severity and a higher risk of mortality (36). Moreover, we applied strict inclusion and exclusion criteria, and all patients, except for 5, were evaluated during two different periods. This study was also very strict in considering the CDC criteria for respiratory infection to avoid presumptive diagnoses of infection. Lower 25OHD levels were associated with respiratory infection but not disease activity in GPA patients. Our data suggest that 25OHD hypovitaminosis could be an important risk factor for respiratory infection in GPA.

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Vitamin D status and its association with quality of life, physical activity, and disease activity in rheumatoid arthritis patients. J Clin Rheumatol. 2015;21(3):126-30, http://dx.doi.org/10.1097/RHU.0000000000000233. 9. Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet. 2000;355(9204):618-21, http://dx.doi.org/10.1016/S01406736(99)02301-6. 10. Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical vitamin D deficiency with severe acute lower respiratory infection in Indian children under 5 y. Eur J Clin Nutr. 2004;58(4):563-7, http://dx.doi. org/10.1038/sj.ejcn.1601845. 11. Fleming DM, Elliot AJ. Epidemic influenza and vitamin D. Epidemiol Infect. 2007;135(7):1091-2. 12. Crowle AJ, Ross EJ, May MH. 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’ AUTHOR CONTRIBUTIONS Perez MO, Oliveira RM and Pereira RM were responsible for the study design. Perez MO and Pereira RM were responsible for the study conduct, data analysis and manuscript drafting. Perez MO, Oliveira RM, Caparbo VF, Levy-Neto M and Pereira RM were responsible for the data and laboratory collection, data interpretation, revision of the manuscript content and approval of the ﬁnal version of the manuscript. Pereira RM takes responsibility for the integrity of the data analysis.

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CLINICAL SCIENCE

Effects of periarticular injection on analgesic effects and NSAID use in total knee arthroplasty and total hip arthroplasty Wen-rui Ban, Ery-ang Zhang, Lei-feng Lv, Xiao-qian Dang, * Chen Zhang * The First Department of Orthopedics, the Second Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an Shaanxi, 710004, P. R China.

OBJECTIVES: This study examined periarticular multimodal drug injection and the use of nonsteroidal antiinflammatory drugs for an early analgesic effect after total knee arthroplasty and total hip arthroplasty. Patient satisfaction and benefits from the treatment were also assessed. METHODS: A total of 110 patients who were scheduled to undergo total knee arthroplasty and 86 patients who were scheduled to undergo total hip arthroplasty were divided into two groups, the study group and the control group. The study group received a periarticular multimodal drug injection during surgery. The control group received an equal volume of normal saline. All patients received an analgesia pump and a moderate dose of nonsteroidal anti-inflammatory drugs. Resting and motion Numeric Rating Scale scores, the Western Ontario and McMaster Universities Arthritis Index, knee or hip joint range of motion, length of postoperative hospital stay, patient satisfaction, total nonsteroidal anti-inflammatory drug consumption and side effects were recorded. RESULTS: Both study groups exhibited significant improvement in pain Numeric Rating Scale scores during rest and exercise several days after the surgery. The range of joint motion was greater in the study group, and the length of postoperative hospital stay was shorter than that in the control group. Patients in the study group consumed fewer nonsteroidal anti-inflammatory drugs and reported greater satisfaction with surgery. CONCLUSION: Intraoperative periarticular multimodal drug injection significantly relieved pain after surgery and reduced nonsteroidal anti-inflammatory drug consumption. These patient had a better postoperative experience, including satisfaction and rehabilitation. KEYWORDS: Arthroplasty; Pain; Knee; Hip; Analgesia; Nonsteroidal Anti-Inflammatory Drugs. Ban WR, Zhang EA, Lv LF, Dang XQ, Zhang C. Effects of periarticular injection on analgesic effects and NSAID use in total knee arthroplasty and total hip arthroplasty. Clinics. 2017;72(12):729-736 Received for publication on June 29, 2017; First review completed on August 24, 2017; Accepted for publication on October 3, 2017 *Corresponding author. E-mail: dangxiaoqian@vip.163.com / osteozhang@163.com

’ INTRODUCTION

process. Moreover, the clinical application of many analgesic methods is limited (5-7). Therefore, identification of effective and safe analgesic treatments is an important challenge. Periarticular injection effectively prevents pain and leads to a lower systemic side effect profile. This randomized, singleblind study aimed to compare the analgesic effects of periarticular injection in TKA and THA postoperative patients and nonsteroidal anti-inflammatory drug (NSAID) use.

Total knee arthroplasty (TKA) and total hip arthroplasty (THA) are important treatments for severe joint disease that can relieve joint pain and improve joint function. Approximately 90% of patients with pain and dysfunction show improvement after TKA, which also improves their quality of life. Most patients (85%) are very satisfied with the curative effect of surgery and postoperative quality of life (1,2). However, postoperative pain has a harmful effect on important organs and directly affects postoperative rehabilitation exercises (3,4). Pain after surgery increases patients’ concerns about rehabilitation exercises, which affects the rehabilitation

’ MATERIALS AND METHODS Patient population Approval was obtained from the Biomedical Ethics group of the medical department of Xi’an Jiaotong University (number 2012-693). From 2012.9.1 - 2015.11.01, we conducted a prospective, randomized single-blinded study of all eligible men and nonpregnant women who were scheduled to undergo primary TKA and THA for osteoarthritis. All patients were at least 20 years old and no more than 80 years old. The following inclusion criteria were used: (1) the American Society of Anesthesiologists (ASA) grade I - III rating; (2)

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weight index of 20 - 35 kg/m2; (3) unilateral TKA and THA; (4) ability to cooperate with the investigation and understand the pain score; and (5) provision of informed consent. The following exclusion criteria were applied: (1) did not meet the above requirements; (2) nervous or mental disorders; (3) known drug allergy or tolerance to study drugs; (4) renal insufficiency or abnormal liver enzymes; (5) acute or chronic knee infection; and (6) serious cardiovascular disease, diabetes, or uncontrolled angina. All patients were randomly divided into two groups. No significant differences in baseline demographics were observed between the two groups (Table 1). Figure 1 shows a detailed flowchart describing our selection criteria and decision-making process in determining study participants.

subcapsular muscles and subcuticular tissues. All patients received patient-controlled analgesia (2 mg/kg sufentanil and 0.2 mg/kg tropisetron mixed with sterile normal saline solution in a total volume of 100 ml), and we limited the drip rate to 2 ml/h. Patients were administered moderate NSAIDs (celecoxib) based on their needs 6 h postoperatively. All patients were asked to perform ankle pump exercises during the 24 h after surgery and active flexion movement 24 h after surgery. Pain scores, Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores, adverse reactions, range of motion and use of NSAIDs were recorded daily. The average of the measurements was calculated. Patient satisfaction was assessed on the seventh day after surgery.

Observation indexes Pain scores were measured using the Numeric Rating Scale score (NRS), where 0 indicated no pain and 10 indicated the worst imaginable pain. We recorded the pain score, range of motion, and NSAID use 12 h, 24 h, 48 h, 72 h, 4 d, 5 d, 6 d, 7 d, and 14 d after surgery. The number of reports of nausea, vomiting and other adverse reactions was recorded during hospitalization. Evaluations of satisfaction, including pain control, hospitalization days, functional recovery and general satisfaction, were recorded on the seventh day after surgery.

Patient grouping A biostatistician who was blinded to the research study generated a random number sequence with a simple random number table. All random number cards were settled in sealed envelopes. Patients were allocated either to the study group or control group based on whether the random number was odd or even when he or she was enrolled. Injections in the study group consisted of 200 mg of ropivacaine, 30 mg of ketorolac, 5 mg of hexadecadrol, and 0.3 ml of epinephrine. These drugs were mixed in a sterile normal saline solution with a combined volume of 50 ml. The control group received an equal volume of normal saline solution. All patients received general anesthesia, and the same surgeon performed all surgeries. All patient implants are from Johnson & Johnson of America. The mixed drugs were injected in the entire length of the wound, especially in the

Statistical analysis Statistical interactions between the two groups and time were assessed to determine the longitudinal effects of group on the outcome of interest. Enumeration data were evaluated using the chi-square test, and measurement data were analyzed using t tests. Our sample size estimate was based

Table 1 - Demographic data for patients in the study.

Age Sex (male: female) BMI HSS score Harris score WOMAC score

TKA study group (n=55)

TKA control group (n=55)

THA study group (n=43)

THA control group (n=43)

63±11 13:42 24.16±2.69 49.45±12.96

65±9 15:40 24.09±3.11 49.02±14.23

58±11 19:24 23.35±2.23

55±13 18:25 22.90±3.56

49.10±13.18

50.63±14.02

46.87±13.29 41.30±12.73

43.42±15.27 38.51±14.92

All data except sex are denoted as the mean±SD. There was no significant difference between the two groups. WOMAC score: Western Ontario and McMaster Universities Arthritis Index.

Figure 1 - Subject inclusion decision tree.

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flexion within 7 days postoperatively (Table 4, Figure 4). These differences were significant (po0.05). The study group was administered a dose of celecoxib that was far lower than that in the control group. The TKA study group received a total of 965 mg of Celebrex, while the control group received 1,325 mg in one week (po0.05). The THA study group was treated with 918 mg of Celebrex, while the control group was treated with 1,238 mg in one week (po0.05) (Table 5, Figure 5). The WOMAC scores of the TKA study group were significantly better than those of the control group at 48 h, 72 h, and 4 d, and the scores of the THA study group were better than those of the control group at 48 h, 72 h, 4 d and 5 d (Table 6, Figure 6). These differences were significant (po0.05). The length of postoperative hospital stay was significantly different between groups. The hospital stay duration in the TKA study group was 9.25±1.99 days, compared to 10.44± 2.62 days in the control group (po0.05), whereas the hospital stay duration in the THA study group was 8.08±2.11 days, compared to 10.06±2.59 days in the control group (po0.05). We found that postoperative pain satisfaction was significantly higher in both study groups than in the control group. We also observed that functional recovery and general satisfaction in the THA study group were significantly higher than in the control group (po0.05). However, no

on the WOMAC score. According to the results of our preexperiment (n=10), we defined an important between-group difference to be approximately 2 points in the TKA group and 3 point in THA group 2 to 4 days post-arthroplasty. The power was set at 0.80 and the overall type I error probability at 0.05. Applying these assumptions yielded an approximate required sample size of 41 subjects in the TKA groups and 36 subjects in the THA groups. Because many of the late eligible patients volunteered to join, we expanded the sample size. All information was processed using SPSS 23.0. Statistical significance was set at po0.05.

’ RESULTS We found that NRS scores with activity within a few days after surgery were lower in the study group than in the control group (Table 2, Figure 2). Patients in the THA study group also reported less pain than those in the TKA study group. The NRS scores at rest also displayed the same trend (Table 3, Figure 3). The TKA study group showed a larger range of knee flexion within 4 days postoperatively than the control group, whereas the THA study group showed a larger range of hip Table 2 - The NRS scores with activity.

12 h 24 h 48 h 72 h 4d 5d 6d 7d 14 d

TKA study group

TKA control group

t-value

p-value

THA study group

THA control group

t-value

p-value

6.83±0.78 6.29±0.73 5.68±0.72 5.11±0.75 4.43±0.65 3.85±0.60 3.31±0.60 2.82±0.60 1.86±0.41

7.25±0.80 6.69±0.88 6.05±0.82 5.43±0.77 4.54±0.82 3.96±0.79 4.47±0.74 2.96±0.76 1.84±0.36

-2.832 -2.567 -2.483 -2.191 -0.757 -0.839 -1.219 -1.092 0.245

0.006 0.012 0.015 0.031 0.451 0.403 0.225 0.277 0.807

6.77±0.88 6.13±0.82 5.42±0.79 4.77±0.78 4.07±0.80 3.61±0.72 2.89±0.66 2.40±0.65 1.26±0.57

7.77±0.90 6.96±1.14 6.25±1.13 5.42±1.21 4.68±1.13 3.90±1.03 3.25±0.93 2.72±0.90 1.33±0.65

-5.185 -3.894 -2.980 -2.071 -2.182 -1.495 -2.067 -1.933 .0.562

o0.001 o0.001 0.004 0.041 0.032 0.139 0.042 0.057 0.576

Figure 2 - The NRS scores with activity. *The average NRS score with activity in the TKA study group was lower than that in the control group at 12 h, 24 h, 48 h, and 72 h; the average NRS score in the THA group was lower than that in the control group at 12 h, 24 h, 48 h, 72 h, 4 d and 6 d.

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Table 3 - The NRS scores at rest.

12 h 24 h 48 h 72 h 4d 5d 6d 7d 14 d

TKA study group

TKA control group

5.10±0.89 4.44±0.84 3.88±0.63 3.48±0.58 3.05±0.54 2.51±0.49 2.12±0.46 1.80±0.43 1.24±0.23

5.58±0.94 5.00±0.88 4.28±0.75 3.72±0.71 3.26±0.60 2.67±0.50 2.23±0.46 1.86±0.41 1.21±0.22

t-value -2.788 -3.423 -3.018 -1.965 -1.893 -1.747 -1.240 -0.797 0.549

p-value

THA study group

THA control group

t-value

p-value

0.006 0.001 0.003 0.052 0.061 0.084 0.218 0.427 0.584

4.88±1.13 4.29±0.93 3.50±1.01 3.03±0.79 2.37±0.67 1.90±0.66 1.48±0.59 1.14±0.56 0.79±0.33

6.14±1.01 5.24±1.10 4.41±1.22 3.65±1.12 2.94±0.96 2.26±0.83 1.72±0.74 1.30±0.63 0.86±0.42

-5.444 -4.301 -3.750 -2.996 -3.247 -2.213 -1.674 -1.227 -0.910

o0.001 o0.001 o0.001 0.004 0.002 0.030 0.098 0.223 0.366

Figure 3 - *The NRS scores at rest. The average score in the TKA study group was lower than that in the control group at 12 h, 24 h, and 48 h, whereas the average score in the THA study group was lower than that in the control group at 12 h, 24 h, 48 h, 72 h, 4 d and 5 d.

Table 4 - Range of motion after the operation.

12 h 24 h 48 h 72 h 4d 5d 6d 7d 14 d

TKA study group (˚)

TKA control group (˚)

t-value

p-value

THA study group (˚)

THA control group (˚)

t-value

p-value

15.33±3.92 22.18±5.59 33.05±7.17 45.16±7.87 56.91±8.42 68.82±9.26 78.80±7.94 86.00±7.72 100.15±10.51

13.04±3.70 17.85±5.13 28.22±7.34 40.05±9.64 52.64±10.74 65.76±10.14 76.91±9.64 86.53±8.70 100.84±10.56

3.253 4.231 3.497 3.045 2.321 1.650 1.123 0.336 0.344

0.002 o0.001 0.001 0.003 0.022 0.102 0.264 0.737 0.732

19.06±5.16 31.08±8.12 50.69±9.27 62.23±9.62 70.56±9.84 80.66±12.96 84.48±12.58 88.01±12.68 91.79±11.96

15.55±4.67 23.54±5.72 35.71±6.49 43.84±7.29 57.66±8.23 61.54±9.20 68.64±8.90 74.52±9.47 87.45±10.59

3.306 4.954 8.644 9.957 6.582 7.858 6.716 5.570 1.780

0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 0.079

analgesia frequently causes complications, such as nausea, hypotension, and urinary retention. TJR patients often receive anticoagulant drugs to prevent DVT, but these agents increase the risk of operative bleeding (9,10). The effect of intravenous analgesia is poor, and patients are prone to respiratory depression, nausea, vomiting, itching, and sleepiness (10,11). We compared resting and motion NRS scores, joint range of motion, WOMAC scores, time of active exercise, length of postoperative hospital stay, patient satisfaction, total NSAID consumption and side effects between the two groups to identify safer and more effective perioperative analgesic methods. Our results demonstrated that periarticular injection for postoperative pain control led to good patient recovery and effectively reduced the use of NSAIDs, which can cause

significant differences in the degree of satisfaction related to hospitalization days were observed.

’ DISCUSSION Adequate postoperative pain control in total joint replacement (TJR) during postoperative functional recovery is very important, and a sufficient analgesic effect can help relieve pain, allow patients to get out of bed earlier to exercise, restore joint function, and prevent the formation of deep vein thrombosis (DVT) (8). Severe pain also leads to prolonged hospital stays and increased opioid use. Many treatment options for joint replacement postoperative analgesia exist, but all these options have limitations. For instance, epidural

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Figure 4 - Range of motion.

Table 5 - NSAID consumption.

24 h 48 h 72 h 4d 5d 6d 7d

TKA study group

TKA control group

t-value

p-value

THA study group

THA control group

t-value

p-value

283.64±83.36 229.09±68.51 185.45±55.84 109.09±84.49 61.82±80.49 60.00±78.41 36.36±64.88

330.91±85.79 283.64±78.80 212.73±47.35 183.64±60.14 145.45±78.92 89.09±83.16 58.18±73.76

-2.931 -3.874 -2.763 -5.331 -5.502 -1.888 -1.647

0.004 o0.001 0.007 o0.001 o0.001 0.062 0.102

265.91±77.59 206.82±92.50 161.36±57.93 111.36±81.32 63.64±80.96 59.09±75.69 34.09±47.95

307.14±83.79 257.14±76.93 204.76±43.91 176.19±57.63 126.19±85.71 85.71±84.31 71.43±63.58

-2.369 -2.736 -3.901 -4.247 -3.481 -1.542 -3.084

0.020 0.008 o0.001 o0.001 0.001 0.127 0.003

Figure 5 - NSAID consumption.

reported similar findings (11-15). Busch et al. (11) found that the combination of ropivacaine and ketorolac tromethamine as a periarticular multimodal drug injection effectively reduced the intake of opioids, and postoperative NRS scores at 6 h, 12 h, and 24 h were significantly lower than those in the control group during the perioperative period of TKA.

serious side effects. The limitations of our study include the short-term follow-up period and that patients may not have effectively evaluated their situation and NSAID drug use. Our study found that NRS scores with activity or rest were lower in the study group than in the control group during the early perioperative period, and previous studies have

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Table 6 - WOMAC scores after the operation.

24 h 48 h 72 h 4d 5d 6d 7d 14 d

TKA study group

TKA control group

82.88±1.39 75.68±2.22 72.05±3.01 66.69±4.29 61.71±6.42 57.23±6.02 52.76±5.44 47.66±5.78

83.29±1.48 79.14±1.79 73.69±3.04 68.48±4.73 63.60±5.31 57.44±5.60 53.88±6.07 46.18±6.95

t-value -1.497 -8.997 -2.834 -2.075 -1.683 -0.187 -1.018 -1.214

p-value

THA study group

THA control group

t-value

p-value

0.137 o0.001 0.005 0.040 0.095 0.852 0.311 0.228

82.14±0.93 78.18±1.94 72.39±3.58 64.91±5.97 60.18±7.03 57.48±5.85 52.68±6.63 41.34±6.17

81.88±2.80 80.02±4.29 75.62±5.54 69.79±6.06 65.21±7.18 59.69±7.46 53.12±5.40 40.86±7.80

0.572 -2.586 -3.228 -3.757 -3.285 -1.535 -0.334 0.334

0.569 0.011 0.002 o0.001 0.001 0.128 0.739 0.739

Figure 6 - WOMAC scores after the operation.

in the control group. Early postoperative exercise is beneficial for postoperative rehabilitation and may prevent some treatment complications (18-22). In fact, similar to the VAS score trend, this difference is not obvious in TKA. In particular, the difference in WOMAC scores between the two groups is subtle because the WOMAC score is divided into three parts; pain is only one part of it, and there were no significant differences between the two groups in many items of the WOMAC score. We focused on the use of NSAIDs after surgery. Celecoxib capsules are a relatively new selective COX-2 inhibitor that primarily inhibit a COX-2 zymoprotein to block the synthesis of prostaglandins and achieve anti-inflammatory effects. Numerous studies have demonstrated that patients who receive celecoxib exhibit a reduced incidence of nausea and vomiting (28%). However, no research has used large samples to assess the side effects of celecoxib (23). Indeed, the side effects of postoperative celecoxib analgesia remain a problem that is difficult to ignore (23,24). Our results demonstrated that the study group ingested much less celecoxib than the control group. Six patients in our study reported nausea and vomiting in the TKA study group compared to 7 patients in the TKA control group, while 8 patients in the THA group reported side effects. No cardiac or central nervous system toxicity was observed. No significant differences were observed between the two groups, although the long-term side effects of drug treatment require further study. Indeed, previous studies have suggested that the longterm use of NSAIDs significantly increases the incidence of

Wei Liu et al. (12) found that the average NRS score of THA study patients was significantly lower than that in the control group. Todd et al. (13) performed a randomized double-blind controlled study and found that the combination of ropivacaine, adrenaline and ketorolac tromethamine exhibited a better effect than the use of ropivacaine and epinephrine alone, and it effectively reduced the amount of morphine for analgesia (16). Dexamethasone as a long-term glucocorticoid exhibits strong anti-inflammatory effects, and ropivacaine or bupivacaine combined with dexamethasone prolongs the effect of local anesthetics (17). Therefore, different drugs and drug delivery methods exhibit different effects, and these differences require further research. In addition, on postoperative days 2 to 3, the experimental group showed a better analgesic effect, and this difference gradually disappeared after 3 days. Although there was still a statistically significant difference between the two groups, the difference is very subtle and soon disappeared. This is because the periarticular multimodal drug injection effect is relatively short. We also noted that the effect of TKA postoperative analgesia between the two groups is subtle, which indicates that intraoperative periarticular multimodal drug injection may not be sufficient to completely control postoperative pain in TKA patients. All patients reported mild pain after 1 week. Patients with better pain relief exhibited improved postoperative motion and WOMAC scores. This study demonstrated that the range of keen flexion of the TKA study group patients within 4 days and that of the THA study group patients within 6 days after surgery were better than that

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’ REFERENCES

adverse reactions (25). Our results showed that periarticular multimodal drug injection significantly reduced the intake of NSAIDs, which may reduce the discomfort caused by NSAIDs. In this study, we recommended that patients take no more than 200 mg daily, unless there is a special need. Therefore, the difference between the two groups was not very large but was sufficient to show that periarticular multimodal drug injection can effectively reduce the intake of NSAIDs. With the development of new technologies, the use of NSAIDs has shown a decreasing trend, but many drug guides still recommend oral NSAIDs, which is why we selected NSAIDs to study. The ultimate goal is elimination of NSAID for pain control in the future We applied a digital classification method for the patients to evaluate all aspects of satisfaction during hospitalization. We found that postoperative pain satisfaction in the study group was significantly higher than that in the control group, and we also found that functional recovery and general satisfaction in the THA study group were significantly higher than in the control group. However, no significant differences existed in the degree of satisfaction with the number of hospitalization days. THA patients showed better pain control and rehabilitation satisfaction than TKA patients. This result may be because TKA patients feel more pain after surgery than THA patients; thus, periarticular injection may be effective in controlling postoperative pain in THA patients but may not be sufficient to completely control postoperative pain in TKA patients. Additionally, this difference between groups may also be related to operation time, bleeding volume, degree of tissue damage, patient expectations, and other relevant issues, although these factors were not analyzed in the current study. Our results suggest that we cannot focus only on pain control after surgery in TJR patients; instead, a variety of measures should be used to improve the prognosis of patients and their comprehensive quality of life. Periarticular multimodal drug injection is a simple, safe surgery that effectively reduced the pain of patients after TKA and THA, and this method effectively advanced the time that patients began joint exercises, improved joint function recovery, and shortened hospital stay. Local dosing in the joint reduced the intake of NSAIDs, which may reduce NSAIDinduced damage to the digestive tract and kidney. We believe that with the development of new technologies, the use NSAID for pain control after TKA and THA will decrease.

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’ ACKNOWLEDGMENTS Second Afﬁliated Hospital of Xi’an Jiaotong University Research Fund (YJ (QN) 201421). Second Afﬁliated Hospital of Xi’an Jiaotong University Talent Cultivation Research Fund RC (XM) 201501. Shaanxi Provincial Key Research and Development Project (2017SF-141). Wu Jieping Medical Foundation Special Fund for Clinical Research (320.6750.17007).

’ AUTHOR CONTRIBUTIONS Ban WR made substantial contributions to the conception and design of the manuscript, acquisition of the data, analysis and interpretation of the data and manuscript drafting. Lv LF collected the range of motion and the patient satisfaction data. Zhang EA collected the NRS and WOMAC scores. Dang XQ and Zhang C conceived the study and participated in its design and coordination, revised the manuscript critically for important intellectual content and approved the ﬁnal version of the manuscript. All authors read and approved the ﬁnal version of the manuscript.

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24. Mammoto T, Fujie K, Mamizuka N, Taguchi N, Hirano A, Yamazaki M, et al. Effects of postoperative administration of celecoxib on pain management in patients after total knee arthroplasty: study protocol for an open-label randomized controlled trial. Trials. 2016;17:45, http://dx.doi. org/10.1186/s13063-015-1106-2. 25. Laine L. The gastrointestinal effects of nonselective NSAIDs and COX-2selective inhibitors. Semin Arthritis Rheum. 2002;32(3 Suppl 1):25-32, http://dx.doi.org/10.1053/sarh.2002.37217. 26. Ishida K, Shibanuma N, Matsumoto T, Tei K, Kuroda R, Kurosaka M. Periarticular multimodal drug injection improves post-operative pain and functional recovery after total knee arthroplasty. J Orthop Sci. 2016;21(2): 178-83, http://dx.doi.org/10.1016/j.jos.2015.12.004.

21. Joseph AA, Merboldt KD, Voit D, Dahm J, Frahm J. Real-time magnetic resonance imaging of deep venous flow during muscular exercise-preliminary experience. Cardiovasc Diagn Ther. 2016;6(6):473-81, http://dx.doi.org/ 10.21037/cdt.2016.11.02. 22. Sochart DH, Hardinge K. The relationship of foot and ankle movements to venous return in the lower limb. J Bone Joint Surg Br. 1999; 81(4):700-4. 23. Huang YM, Wang CM, Wang CT, Lin WP, Horng LC, Jiang CC. Perioperative celecoxib administration for pain management after total knee arthroplasty â&#x20AC;&#x201C; a randomized, controlled study. BMC Musculoskelet Disord. 2008;9:77, http://dx.doi.org/10.1186/14712474-9-77.

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A new low-cost negative-pressure wound therapy versus a commercially available therapy device widely used to treat complex traumatic injuries: a prospective, randomized, non-inferiority trial Fabio Kamamoto,I,* Ana Lucia Munhoz Lima,II Marcelo Rosa de Rezende,III Rames Mattar-Junior,IV Marcos de Camargo Leonhardt,IV Kodi Edson Kojima,IV Carla Chineze dos SantosV I Pesquisador, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, SP, BR. II Departamento de Controle de Infeccao Hospitalar, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, SP, BR. III Departamento de Microcirurgia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, SP, BR. IV Instituto de Ortopedia e Traumatologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, SP, BR. V Consultor Independente, Sao Paulo, SP, BR.

OBJECTIVES: Negative-pressure wound therapy has been widely adopted to reduce the complexity of treating a broad range of acute and chronic wounds. However, its cost is high. The objective of this study was to evaluate the following two different methods of negative-pressure wound therapy in terms of healing time: a low-cost method of negative-pressure wound therapy (a pressure stabilizer device connected to a hospital wall-vacuum system with a gauze-sealed dressing, USP) and the standard of care (vacuum-assisted closure, VAC). METHODS: This is a randomized, controlled, non-inferiority, unblinded trial. Patients admitted with complex injuries to a trauma center in a public referral hospital who were indicated for orthopedic surgery were randomized to a USP or VAC group. The primary outcome was the time required to achieve a ‘‘ready for surgery condition’’, which was defined as a wound bed with healthy granulation tissue and without necrosis or purulent secretion. Wound bed area contraction, granulation tissue growth and the direct costs of the dressings were secondary outcomes. RESULTS: Variation in area and granulation tissue growth were essentially the same between the systems, and healing time was equal between the groups (p=0.379). In both systems, serial debridement increased wound area (p=0.934), and granulation tissue was also increased (p=0.408). The mean treatment cost was US$ 15.15 in the USP group and US$ 872.59 in the VAC group. CONCLUSIONS: For treating complex traumatic injuries, USP was non-inferior to and less expensive than VAC. KEYWORDS: Negative-Pressure Wound Therapy; Wound Healing; Wounds and Injuries; Cost Savings. Kamamoto F, Lima AL, de Rezende MR, Mattar-Junior R, Leonhardt MC, Kojima KE, et al. A new low-cost negative-pressure wound therapy versus a commercially available therapy device widely used to treat complex traumatic injuries: a prospective, randomized, non-inferiority trial. Clinics. 2017;72(12):737-742 Received for publication on June 7, 2017; First review completed on September 6, 2017; Accepted for publication on October 6, 2017 *Corresponding author. E-mail: fabio.kamamoto@gmail.com

’ INTRODUCTION

simplified the treatment of wounds for doctors, and nurses (2). Some authors have suggested that NPWT could be used in traumatic wounds as a bridge to definitive closure when primary closure is not possible after or between debridement procedures (3-5). The most substantial disadvantage of this procedure is its cost, which remains high and generally unaffordable over prolonged use (2,6). As mentioned by the authors of a University of Chicago Medical Center (UCMC) study: ‘‘this financial burden can limit the use of NPWT in settings and situations where budgets are constrained, particularly in public hospitals and for patients who are underinsured or uninsured (not to mention in developing countries globally). From the health care providers’ standpoint, our interest in coming up with more cost-effective alternatives is

Negative-pressure wound therapy (NPWT) was approved by the FDA (Food and Drug Administration) in 1996 and has since then been widely adopted as a treatment for a broad range of wounds (1). NPWT has many indications, including both acute and chronic injuries (2), and has

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Interventions

obvious; such efforts can ultimately translate to increased availability/accessibility of therapies for patients in various settings. Furthermore, for issues as prevalent as wound care management, they can also have a significant financial impact on hospitals and the health care system as a whole’’ (7). In 2007, the University of São Paulo (USP) developed a low-cost NPWT that used a pressure stabilizer device (Curavac VX 200, Ventrix Health Innovation, Brazil), connected to a hospital wall-vacuum and a gauzed-sealed dressing. This system will henceforth be referred to as ‘‘USP’’. However, so far, no randomized clinical trial has compared USP NPWT with a commercially available vacuum-assisted closure device (VAC system, KCI, San Antonio, TX, USA). We therefore performed the present study. Although different NPWT systems are available, VAC was chosen as the standard of care based on feasibility. The VAC system was the first NPWT to be approved by the FDA since 1996, and it remains the leader in sales worldwide and the only one available in the University of São Paulo Hospital. The primary objective was to determine whether the ‘‘USP’’ method is non-inferior to the standard of care, VAC, with respect for the time required to achieve a ‘‘ready for surgery’’ status in trauma patients. The following were secondary outcomes: changes in wound size, granulation tissue growth and the overall associated costs of the dressings between the two systems.

In the VAC group, GranuFoam sponge (Kinetics Concepts, Inc., San Antonio, TX, USA) was applied to the wounds and sealed using an occlusive plastic dressing. Continuous suction at 120 mmHg was then initiated. In the USP group, a 100% cotton sterile gauze dressing was applied to the wound. Then, an 18-Fr polyvinyl nasogastric tube was placed in the center of the dressing and sealed in place using a transparent adhesive and a sterile, waterproof film (Opsite Drape, Smith & Nephew, Kingston Upon Hill, UK). The dressing was connected to the hospital’s continuous suction equipment that was accessed on the wall of each room via a plastic sterile secretion collector tube. An anti-bacterial filter was used to avoid contamination by the hospital vacuum net (Zammi, Rio de Janeiro, Brazil). Because the pressure in the vacuum net is naturally unstable, a pressure stabilizer device was specifically designed for this purpose (Curavac VX 200, Ventrix Health Innovation, Brazil). The equipment was regulated to provide a continuous pressure of 120 mmHg. This device uses a system of springs to restrain any increase in pressure over the established limit and keep it stable when wall vacuum pressure decreases. The dressing was changed twice per week in all patients while they were under general anesthesia. When necessary, surgical debridement was performed at the same time. During dressing changes, all disposable articles were discarded. The pressure stabilizer device that was used in the study group is composed of a permanent material that can be used for many treatments.

’ METHODS Outcomes

Design, setting and ethics A prospective, randomized, non-inferiority trial was designed to compare two different negative-pressure devices used for wound closure. The trial occurred at the Orthopedics and Traumatology Institute of Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (FMUSP), in São Paulo, Brazil. The study was previously approved by the University of São Paulo Ethics Committee (0371/11), and the protocol is registered in the ClinicalTrials.gov Registry.

The primary outcome used was the time (in days) necessary to achieve a ‘‘ready for the surgery’’ condition, which was defined as a wound bed with healthy granulation tissue and without necrosis or purulent secretion (8). The patient follow-up period started as soon as the first debridement was performed and the NPWT dressings were placed and continued until a surgery achieved definitive wound closure. The following were secondary outcomes:

Participants and sampling

1. Changes in wound bed area over time. The dimensions of each wound were documented using digital photography at each dressing change. The images were uploaded and the wound area calculated using the National Institutes of Health ImageJ software with the scale set using the ruler in the image. 2. Granulation tissue growth: The percentage of the wound bed that was composed of granulation tissue was calculated in wound images by dividing the amount of red tissue area by the total wound area. 3. Costs: The direct costs of each type of dressing were also measured. In both groups, these costs included the cost of supplies (e.g., suction canisters, catheters or drains, tubing, gauze, and adhesive drapes). The following two main cost analyses were performed: the costs associated with each dressing exchange and the average cost of treatment. The direct costs of dressing exchange were recorded (i.e. the cost of inputs) for each of the treatments applied in the USP and VAC groups. In the USP group, the prices paid by the hospital for a 55 x 45 cm sterile adhesive film, a zoobec sterile gauze, a urethral catheter no. 16 and a 500 ml secretion collecting bottle were recorded.

All consecutive patients admitted to one public university hospital (Hospital das Clínicas, University of São Paulo) with acute wounds caused by open fractures inflicted by highenergy trauma between September 2013 and July 2016 were eligible for this study. To be included in this study, the cases had to involve severe wounds that would not close on the first attempt (without surgery). The exclusion criteria were diabetes mellitus, diagnosed peripheral vascular disease, chronic use of steroids, coagulopathies and cancer. The sample size was calculated to allow a comparison of the time required to achieve a wound bed that is ready for surgery. Since we expected USP and VAC to have similar effects on wound bed preparation time, we used a noninferiority testing strategy. The non-inferiority margin was set at 5%, meaning that the data would support the noninferiority of USP if the number of days necessary to be ready for surgery was no more than 5% greater in the USP than in the VAC group. To achieve 80% statistical power and a significance (alpha) level of 5%, the estimated required sample size was 36 treatments in each group.

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and are listed in Table 1. A total of 19 wounds were analyzed in the USP group, and 32 were analyzed in the VAC group. Two patients died in the USP group as a result of multiple organ failure during clinical care for severe trauma. No patient in the VAC group died. It was not possible to maintain vacuum pressure in 2 cases in the USP group and 1 case in the VAC group. The following patients were lost: in the USP group, 17 patients were lost due to: the hospital lacked the supplies required to perform the dressing procedure in the hospital (5 cases), the patient was transferred to another setting and was lost to follow-up (8 cases), and it was impossible to maintain vacuum (2 cases). In the VAC group, 2 cases were lost to follow-up, and in 1 case, it was impossible to maintain vacuum.

In the VAC group, the costs of the sponge kit and the secretory collection bottle were recorded. To determine the average cost of treatment, the cost of each dressing change was multiplied by the number of exchanges performed in each of the groups during the study period. The prices were quoted on October 21, 2016 and obtained from the hospital’s electronic stock control system.

Failure of intervention Failure of therapy was recorded in any of the following situations: 1. A dressing could not be maintained because of persistent fluid or suction leaks. If, after two attempts at dressing reinforcement during a 24-hour period, the seal could not be maintained, the patient was considered a case of intervention failure. 2. If a patient developed bleeding, invasive wound infection or sepsis, or a situation in which the dressing could worsen the patient’s clinical condition, NPWT was discontinued and considered a failure. 3. If the patient died before the achieving a ‘‘ready for surgery’’ condition.

Primary outcome: time to heal There were 19 wounds in the 17 patients in the USP group, in which 15 had 1 wound, and 2 had 2 wounds each. The VAC group consisted of 30 patients with 1 wound and 1 patient with 2 wounds for a total of 32 wounds. All wounds in all patients were included in the analysis. The number of days necessary to achieve a ‘‘ready for surgery’’ condition was similar across the 51 included wounds. In the USP group, the 19 wounds took 9.6±4.5 days to heal, while in the VAC group, the 32 wounds took 12.8±8.6 days to recover (p=0.379) (Figure 2).

Randomization and blinding To allocate the participants, a computer-generated list was obtained using the website www.randomization.com. The patients were randomized by the number sequence to either the USP or VAC group in a 1:1 ratio in four blocks. The allocations were printed and inserted into opaque, sealed, numbered envelopes. A research assistant who was blind to the allocation drew one envelope per consecutive patient and then revealed the allocation to the assistant physician only at the moment the patient was admitted for therapy. The two methods used to perform NPWT were obviously visually different, and it was therefore impossible to blind either the therapists or the patients to the method of treatment. However, the two researchers who used ImageJ to perform the measurements used to evaluate wound closure in each digital image were blinded to patient allocation.

Secondary outcomes 1. Changes in wound bed area: there was an increase in wound surface area in both groups. However, the rate of change was not significantly different between the groups (1.13± 0.80 in the USP group and 1.12±0.80 in the VAC group; p=0.934) (Figure 3). 2. Granulation tissue growth: There was an increase in granulation tissue percentage in both groups. The rate of change was 53.01% for USP and 44.18% for VAC. However, the rate of change between the groups was not significantly different (p=0.408). The percentage of granulation tissue growth per day for the USP and VAC groups were: 5.79±2.93 and 5.06±5.15) (p=0.408; Figure 4). 3. Mean cost of treatment: Cost of each dressing: The mean cost of supplies for each dressing used in VAC therapy was US$ 513.29 (R$ 1,622.00). The mean cost of supplies for each dressing changed performed in USP therapy was US$ 8.22 (R$ 26.00). These prices were quoted on October 21st 2016 by the Purchasing Department of our hospital. The U.S. dollar exchange rate was 3.16 (as of October 21st, 2016). Mean cost of treatment: This metric was calculated as the mean cost of the dressings multiplied by the mean number of dressings applied. The total in the USP group was US$ 15.15 (R$ 47.89), and the total in the VAC group was US$ 872.59 (R$ 2,757.40). Tables 2 and 3 show that the cost was significantly different between the groups.

Statistical methods A per protocol analysis was performed to evaluate the primary and secondary outcomes. Initially, all data were recorded descriptively, as absolute numbers, frequencies, and confidence intervals for categorical data and as the means and standard deviations for continuous data. Pearson’s chi-squared test was used for comparisons of categorical data, and MannWhitney or Student’s t tests were used for comparisons of continuous data between the groups. An alpha error of 0.05 was adopted as indicative of significance. SPSS 23 for Mac software was used for the statistical analysis.

’ RESULTS Participant flow, treatment failures and baseline data

’ DISCUSSION

During the study period, 120 patients were assessed for eligibility. Of these, 38 were excluded (20 who did not meet eligibility criteria and 18 who were unable to consent). Two further patients refused to participate. As shown in the flow diagram presented in Figure 1, a total of 72 patients (36 in each group) were enrolled in the study. Baseline demographics and clinical data were similar between the groups

Negative-pressure wound therapy (NPWT) was first described in 1966 (9). Although various NPWT systems are currently available on the market, their costs have limited their accessibility in many institutions (2,6). More recently, researchers have studied low-cost methods of performing NPWT (2,6,10,11). In 2007, the University of São Paulo developed a low-cost

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Figure 1 - Flow diagram of patient inclusion and exclusion.

Table 1 - Demographics and Clinical Characteristics. Variable

USP (n=19)

VAC (n=32)

Mean age (years) Gender, male (%, n) Trauma by traffic accidents* Anatomical region (inferior limb) Initial area (cm2)

34.7±15.1 84% (16) 94% 93.8% 80±55

33.4±16.1 90% (29) 84% 94.7% 105.7±106.3

0.603 0.659 0.392 0.885 0.711

* Car or motorcycle collision or pedestrian run over.

NPWT based on a pressure stabilizer device. The experience of the authors with this method was published in 2010 as a case series (12). In the present study, we performed a prospective, randomized clinical trial to compare the USP method with another NPWT method that uses the VAC system. We chose to perform a non-inferiority trial based on the expectation that the time necessary for the wound bed to

Figure 2 - Time necessary to achieve a ‘‘ready for the surgery’’ condition (days).

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Table 2 - Cost of dressings (US$/day). Variable

USP (n=18)

VAC (n=32)

Mean cost per dressing Mean treatment cost

US$ 8.22 US$ 15.15

US$ 513.29 US$ 872.59

Table 3 - Comparative cost of dressings (US$/day).

Area Granulation Cost

VAC initial

VAC post

USP initial

USP post

105.71074 38.68743

93.013 82.86846 2757.4000

80.00431 34.03333

73.41 87.03500 47.8947

between the genders (13,14). This higher male prevalence was expected because the patients in this study were recruited in a trauma center, where the majority of victims are males who were involved in traffic accidents. Still, we observed no baseline difference between the groups with regard for gender, and the male prevalence was the same in both groups. Another limitation that could be noted is the lack of blinding, which raises the possibility of investigator bias. Patient allocation could not be blinded because the two devices are clearly different from the point of view of both the researchers and the patients. We minimized this risk by blinding the two evaluators who used ImageJ software to measure the wound area and determine the percentage of area with granulation tissue. The total number of wound treatments analyzed in the study did not reach the estimated sample size, mainly because we had difficulties with the supply of required materials in our public hospital. Additionally, some patients were first admitted in our hospital (a referral center for trauma) but were later transferred to another hospital, resulting in loss to follow-up. However, even if the length of the study had been extended to increase the sample size, it would not have influenced the primary outcome result. The similarity between the two evaluated methods of performing NPWT has also been reported by multiple authors in different countries (2,6,10,11). The USP method of performing NPWT is non-inferior to the VAC System for treating complex traumatic injuries.

Figure 3 - Changes in wound bed area (%).

Figure 4 - Granulation tissue increase (%).

improve (in days) would be longer in patients treated with USP therapy than in those treated with a VAC System (primary outcome). Wound bed area contraction and granulation tissue growth were also assessed as secondary outcomes. The USP group did indeed heal three days faster. Although this was not a statistically significant difference, the USP group presented less variability than the VAC group. In addition, USP and VAC were demonstrated to be equally effective, showing that the USP system is non-inferior to the VAC system, which is significantly more expensive. In a public trauma center such as ours, this difference can result in huge savings in resources that can therefore be used to treat more patients. The cost of treatment in the USP group was approximately 2% of the cost in the VAC system. This study replicates and extends the results of Dorafshar et al. (6) and demonstrates that the two methods of NPWT (USP and VAC) presented here achieved very similar results with regard for increased granulation tissue. The wound area was increased in both groups, probably as a result of the surgical debridement required to prepare the wound bed. However, there was no difference in wound area between the groups. There was a higher prevalence of male patients in our study, and this could be considered a limitation of our study because there may be differences in wound healing

’ ACKNOWLEDGMENTS The study was supported by ﬁnancial assistance from CNPq (Conselho Nacional de Desenvolvimento Cientíﬁco e Tecnológico), grant 400.804/ 2014-0.

’ AUTHOR CONTRIBUTIONS Kamamoto F was responsible for the study design, data collection and interpretation, manuscript drafting, and approval of the final version of the manuscript for publication. Lima AL was responsible for the study design, data collection and interpretation, and approval of the final version of the manuscript for publication. Mattar-Junior R was responsible for the study design, data collection, approval of the final version of the manuscript for publication. de Rezende MR, Leonhardt MC, Kojima KE and dos Santos CC were responsible for the data collection and analysis, and approval of the final version of the manuscript for publication.

’ REFERENCES 1. Krug E, Berg L, Lee C, Hudson D, Birke-Sorensen H, Depoorter M, et al. Evidence-based recommendations for the use of Negative Pressure Wound Therapy in traumatic wounds and reconstructive surgery: steps

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3. 4.

5. 6.

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8. Mouës CM, van den Bemd GJ, Meerding WJ, Hovius SE. An economic evaluation of the use of TNP on full-thickness wounds. J Wound Care. 2005;14(5):224-7, http://dx.doi.org/10.12968/jowc.2005.14.5.26776. 9. Mirazimov BM. [Free skin graft of the foot with vacuum preparation of the wound surface]. Ortop Travmatol Protez. 1966;27(10):19-22. 10. Fenn CH, Butler PE. Abdominoplasty wound-healing complications: assisted closure using foam suction dressing. Br J Plast Surg. 2001; 54(4):348-51, http://dx.doi.org/10.1054/bjps.2000.3552. 11. Mansoor J, Ellahi I, Junaid Z, Habib A, Ilyas U. Clinical evaluation of improvised gauze-based negative pressure wound therapy in military wounds. Int Wound J. 2015;12(5):559-63, http://dx.doi.org/10.1111/iwj.12164. 12. Kamamoto F, Lima Jr JE, Batista BN, Zilli B, Ferreira MC. Experiência do Hospital Universitário da USP com o curativo de pressão negativa tópica para o tratamento de feridas complexas. Rev Bras Cir Plast. 2010;25 (sup1): 74. Available from: http://www.rbcp.org.br/details/684/experiencia-do-hospi taluniversitario-da-usp-com-o-curativo-de-pressao-negativa-topica-para-otrat amento-de-feridas-complexas. Accessed in 2017 (Apr 25). 13. Engeland CG, Sabzehei B, Marucha PT. Sex Hormones and Mucosal Wound Healing. Brain Behav Immun. 2009;23(5):629-35, http://dx.doi. org/10.1016/j.bbi.2008.12.001. 14. Wehrens KM, Arnoldussen CW, Booi DI, van der Hulst RR. Clinical Evaluation of Wound Healing in Split-Skin Graft Donor Sites Using Microscopic Quantification of Reepithelialization. Adv Skin Wound Care. 2016;29(6):254-60, http://dx.doi.org/10.1097/01.ASW.0000481179.88936.d4.

towards an international consensus. Injury. 2011;42 Suppl 1:S1-12, http://dx.doi.org/10.1016/S0020-1383(11)00041-6. Chaput B, Garrido I, Eburdery H, Grolleau JL, Chavoin JP. Low-cost Negative-pressure Wound Therapy Using Wall Vacuum: A 15 Dollars by Day Alternative. Plast Reconstr Surg Glob Open. 2015;3(6):e418, http://dx.doi.org/10.1097/GOX.0000000000000347. Yang CC, Chang DS, Webb LX. Vacuum-assisted closure for fasciotomy wounds following compartment syndrome of the leg. J Surg Orthop Adv. 2006;15(1):19-23. Zannis J, Angobaldo J, Marks M, DeFranzo A, David L, Molnar J, et al. Comparison of fasciotomy wound closures using traditional dressing changes and the vacuum-assisted closure device. Ann Plast Surg. 2009; 62(4):407-9, http://dx.doi.org/10.1097/SAP.0b013e3181881b29. Wong LK, Nesbit RD, Turner LA, Sargent LA. Management of a circumferential lower extremity degloving injury with the use of vacuum-assisted closure. South Med J. 2006;99(6):628-30. Dorafshar AH, Franczyk M, Gottlieb L, Wroblewski KE, Lohman RF. A prospective randomized trial comparing subatmospheric wound therapy with a sealed gauze dressing and the standard vacuum-assisted closure device. Ann Plast Surg. 2012;69(1):79-84, http://dx.doi.org/10.1097/SAP. 0b013e318221286c. Kim JJ, Franczyk M, Gottlieb LJ, Song DH. Cost-effective Alternative for Negative-pressure Wound Therapy. Plast Reconstr Surg Glob Open. 2017;5(2):e1211, http://dx.doi.org/10.1097/GOX.0000000000001211.

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Depression and adherence to antiretroviral treatment in HIV-positive men in Sa˜o Paulo, the largest city in South America: Social and psychological implications Ricardo Pereira de Moraes,I,* Jorge CassebI,II I

Ambulatorio de Imunodeficiencias Secundarias, Departamento de Dermatologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, SP, BR. II Instituto de Medicina Tropical de Sao Paulo, Sao Paulo, SP, BR.

OBJECTIVES: The aim of the present study was to investigate the prevalence of depression and adherence to antiretroviral treatment in two groups of individuals: men who have sex with men (MSM) and men who have sex with women (MSW). METHODS: Two hundred and sixteen participants (MSM=116; MSW=100) who visited the Clinics Hospital of the School of the Medicine of the University of Sa˜o Paulo completed two independent surveys (the BECK Depression Inventory and an adherence self-declared questionnaire) to evaluate their depression status and adherence to antiretroviral treatment, respectively. RESULTS: The study highlighted a positive relationship between depression and low adherence to Highly Active Antiretroviral Therapy in these patients regardless of age and sexual orientation. In addition, MSM subjects were two times more prone than MSW subjects to develop depression symptoms. White or mixed race men showed 7.6 times greater adherence to treatment than black men. The probability of complete adherence to treatment was 3.8 times higher in non-depressed subjects than in depressed subjects regardless of their ethnicity. The chance of developing depression was 4.17 times higher for an individual with non-adherent behavior than for an adherent individual. CONCLUSIONS: Individuals with low adherence rates have proportionally higher depression rates. Depressed men tend to show less adherence to treatment. Black but not mixed race or white men show less adherence to Highly Active Antiretroviral Therapy and have a greater chance of developing depression, which directly interferes with adherence. The chances of developing depression are four times greater for a patient with nonadherent behavior than for a patient with adherent behavior. KEYWORDS: Adherence; Depression; Epidemiology; Ethnicity/Race; Gender. de Moraes RP, Casseb J. Depression and adherence to antiretroviral treatment in HIV-positive men in Sa˜o Paulo, the largest city in South America: Social and psychological implications. Clinics. 2017;72(12):743-749 Received for publication on February 27, 2017; First review completed on July 28, 2017; Accepted for publication on October 11, 2017 *Corresponding author. E-mail: r.moraes@usp.br

’ INTRODUCTION

At present, HIV is considered a chronic condition that requires a continuous and prolonged use of drugs (1). Adherence to treatment and maintaining a relationship with health services are key indicators of the success of the medical management of chronic diseases (2). The degree of adherence to treatment depends on the extent to which the patient understands and agrees with the provided guidelines. In cases with low adherence, the patient may develop opportunistic infections and experience daily discomfort or recurrent episodes of minor viral infections, leading to poor consequences in the individual’s life. An emerging major public health problem is the possibility of transmission of a multidrug-resistant virus (2). Several authors have shown that poor adherence to drug therapy has significantly reduced the well-known clinical benefits for HIV-infected individuals, leading to a complete failure of treatment and the patient’s death. Following 95% of the proposed treatment scheme is the desired level of adherence (3,4,5).

Globally, HIV/AIDS is a serious public health concern. Brazil faces severe social implications due to an estimated HIV-infected population of 700,000. Historically, two important facts underscore the calamity of the AIDS epidemic—in 1995, AIDS was the cause of the highest number of deaths worldwide, and the largest number of new HIV cases was diagnosed in 1997. Due to a great deal of effort by the international community and the availability of advanced medical care for infected patients, the infection rate has largely stabilized.

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’ MATERIALS AND METHODS

Many studies have noted the need to monitor patients’ adherence statuses. The initial phase of treatment is considered the most critical period for successful adherence. Therefore, approaches including individualized care and constant monitoring of the patient by a multidisciplinary team are recommended (6). Currently, 91% of adherence studies have been performed in the United States and Europe, and few studies have reported data from Brazil. Even the sparse Brazilian reports suffer from limitations, because they have not been conducted in accordance with international standards (5,7). Therefore, monitoring adherence to antiretroviral treatment at referral centers is an important method to identify those at high risk for treatment failure and provide an early intervention (6,2). Drug efficacy is also determined by various psychological factors. Depression, which is a common condition that affects more than 350 million people worldwide according to the World Health Organization, is directly associated with nonadherence to HIV treatment (8,9) and is expected to be the third leading cause of disability worldwide by 2020 (10). Depression is a common mental health problem that is associated with a decreased quality of life, productivity loss, and family stress (Reviewed by 11). Depressive symptoms are often managed by primary care physicians unless the severity of the condition requires specialist psychiatric care (Reviewed by 11). Some common features of depression include the presence of an irritable mood accompanied by somatic and cognitive changes that significantly affect the individual’s capacity to function (12). Depression is characterized by general feelings of sadness, anhedonia, avolition, worthlessness, and hopelessness. Cognitive and neurovegetative symptoms, such as difficulty concentrating, memory alterations, anorexia, and sleep disturbances, have also been reported (12). The high level of correlation between depression/suicide and depression/non-adherence to treatment is disturbing for care providers. Studies have suggested that depression is the most common psychological disorder affecting HIV-infected individuals (13). Moreover, depression and anxiety affect a patient’s behaviors and consequently their adherence to treatment due to apathy, hopelessness, self-neglect, and forgetfulness, which aggravates the scenario (14,15,16). Failure to adopt the treatment in a proper manner has been identified in HIV-positive individuals reporting at least one episode of depression, which increases their chances of developing further health problems (17) and risky behaviors (13,18). Globally, people living with HIV/AIDS are affected by depression two times as often as the general population (9,19,20). In addition, the frequency of depressive episodes has a direct correlation with the chances of non-adherence to antiretroviral therapy (21). Changes in an individual’s behaviors due to depression can also disrupt interpersonal relationships and social networks, which negatively influences the immune status and productive lifestyle and considerably increase welfare-related problems (8,22). Due to the scarce data available on the relationship between depression and adherence to antiretroviral treatment in Brazil, the present study aimed to investigate the prevalence of depression among male HIV/AIDS patients classified as men who have sex with men (MSM) and men who have sex with women (MSW) in São Paulo city, which is the most developed region of Brazil.

Participants A total of 216 men with HIV attending the Clinics Hospital of the School of Medicine of the University of São Paulo participated in the study. All participants were referred for follow-up treatment by the local blood bank (Fundac¸ão Pró-Sangue Hemocentro de São Paulo) after a positive serology test for HIV. The data collection period was between March 2014 and December 2015.

Procedure A cohort of 304 HIV-positive men in active follow-up at the Clinics Hospital of the Medical School of the University of São Paulo was invited to participate in this study. Two hundred and sixteen participants (71.05%) agreed to participate after meeting the following inclusion criteria: HIV status; minimum age of 18 years; and use of antiretroviral drugs. The participants were divided into two groups (MSM and MSW).

Ethics Committee The study was approved by the Ethics Committee of the Clinics Hospital of the School of Medicine of the University of São Paulo (CAPPesq, number 473.230). The participants consented to the use of survey data in the present analysis.

Questionnaires The Beck Depression Inventory was applied to identify possible depression symptoms among all subjects. The Beck inventory is a self-administered questionnaire that consists of 21 groups of statements. The inventory, which was previously validated for use among the Brazilian public, enables the construction of a depression score for each participant based on a self-report (23,17,18). To evaluate adherence, one inventory was applied with functions similar to the inventories adopted for the START (‘‘The Strategic Timing of Antiretroviral Treatment Study’’) and SMART (19,20) studies (24).

Statistical analysis Descriptive statistics with means and standard deviations (SDs) were reported for continuous variables, and frequencies were reported for categorical variables. A two-way contingency analysis (w2) was performed to assess whether a categorical variable significantly differed between the two groups (MSM and MSW), and Student’s t-test was performed to compare continuous variables between the groups. The statistical analysis was performed using logistic regression for adherence and analysis of categorical data for depression. The following variables were collected from each participant and tested for both models: age group (40 years or younger and 41 years or older); schooling (in years); ethnicity (white, mixed, or black); viral load; CD4+ T lymphocyte count; marital status (married, single, separated, or divorced); sexual orientation (MSM or MSW); and mode of transmission of disease (sexual contact with a person of the same sex or with a person of the opposite sex, blood products, or others). A model of the linear log class was used within the categorized data analysis to estimate the probability of depression. Initially, one linear log model was built to check which variables were associated with the depression level. Subsequently, the most parsimonious model was achieved using adherence and age as variables. The model’s goodness of fit (and that of the intermediate models resulting from models

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(School of Medicine, University of São Paulo) web server. This tool allowed validation, auditing, and export of the study data(25).

with feature removal) was measured using statistical ward continuity. Regarding the adherence model, logistic regression was used to analyze the association between adherence to treatment and other variables. All features were initially included in the model, and the final and most parsimonious model was achieved using stepwise selection with depression and ethnicity as its variables. The quality of adjustment of the model was checked using a residual envelope graph. After quality adjustment for both models using a statistical ward (categorical data) and envelope graph (logistic regression), the final analysis was performed using the R Studio software. The results of both models were expressed and interpreted through odds ratios (ORs) and 95% confidence intervals (CIs) for all features whether or not they were statistically significant. The level of significance for all statistical tests was set at 0.05.

’ RESULTS Demographic and clinical laboratory data Among the 216 HIV-infected men, 116 (53.7%) were MSM and 100 (46.3%) were MSW (Table 1). The ethnicities of the subjects were as follows: 70.4% white; 17.6% mixed; 8.8% black; and 3.2% unknown (Table 1). The majority of the participants in both groups were over 40 years of age. No significant differences in ethnicity and age were observed between the MSM and MSW. Similarly, schooling was identical for both groups. However, significant differences were found in the marital status (po0.001), with 86.2% of the MSM and 38.0% of MSW single and 5.1% of the MSM and 50.0% of the MSW married (Table 1). The transmission of infection occurred chiefly through sexual intercourse with persons of the same sex (43.6%, with rates of 73.3% and 9% for MSM and MSW, respectively),

Electronic data management The database was developed using the Research Electronic Data Capture (REDCap) tool hosted in our institution’s Table 1 - Demographic data from 216 patients infected by HIV. Variables Mean age Age in years p40 X41 Ethinicity White Mixed Black W/information Marital Status Single Married Separated Divorced W/information *Education in years until 05 until 09 more than 10 W/information Transmission *S.C.W.S.S.P. *S.C.W.O.S.P. Blood Others Unknown W/information Lymphocytes T CD4+ o200 200 - 350 350 - 500 4500 Viral load HIV 0 - 10.000 10.000 - 100.000 41000.000

MSW

Total

44.6±11.98

48±10.39

46.2±11.37

0.026

[-6.38; -0.42]

39 (33.6%) 77 (66.4%)

19 (19%) 81 (81%)

58 (26.9%) 158 (73.1%)

0.024 0.024

[2.2%; 27.1%] [-27.1%; -2.2%]

85 20 11 0

(73.3%) (17.2%) (9.5%) (0%)

67 18 8 7

(67%) (18%) (8%) (7%)

152 38 19 7

(70.4%) (17.6%) (8.8%) (3.2%)

0.39 1 0.87 0.004

[-7.0%; 19.4%] [-11.7%; 10.2%] [-6.9%; 9.9%] [-12.9%; -1.1%]

100 6 1 8 1

(86.2%) (5.1%) (0.9%) (6.9%) (0.9%)

38 50 5 3 4

(38%) (50%) (5%) (3%) (4%)

138 56 6 11 5

(63.9%) (25.9%) (2.8%) (5.1%) (2.3%)

o0.001 o0.001 0.09 0.32 0.18

8 36 62 10

(6.9%) (31.1%) (53.4%) (8.6%)

9 40 41 10

(9%) (40%) (41%) (10%)

17 76 103 20

(7.9%) (35.2%) (47.7%) (9.2%)

0.75 0.22 0.09 0.91

85 4 0 1 18 8

(73.3%) (3.4%) (0%) (0.9%) (15.5%) (6.9%)

9 37 3 4 32 15

(9%) (37%) (3%) (4%) (32%) (15%)

94 41 3 5 50 23

(43.6%) (19%) (1.4%) (2.3%) (23.1%) (10.6%)

o0.001 o0.001 0.10 0.18 0.007 0.09

[53.5%; 75.0%] [-44.5%; -22.6%] [-7.3%; 12.7%] [-8.3%; 2.0%] [-28.6%; -4.3%] [-17.4%; 1.2%]

19 7 30 60

(16.4%) (6%) (25.9%) (51.7%)

20 6 20 54

(20%) (6%) (20%) (54%)

39 13 50 114

(18.1%) (6%) (23.1%) (52.8%)

0.60 1 0.39 0.84

[-14.9%; 7.6%] [-6.4%; 6.4%] [-6.3%; 18.0%] [-16.6%; 12.0%]

206 (95.4%) 8 (3.7%) 2 (0.9%)

0.52 0.48 1

[-4.1%; 9.2%] [-8.5%; 3.7%] [-2.9%; 2.6%]

112 (96.6%) 3 (2.6%) 1 (0.8%)

94 (94%) 5 (5%) 1 (1%)

*p-value

CI 95% (msm – msw)

MSM

[35.9%; 60.5%] [-56.4%; -33.3%] [-9.7%; 1.4%] [-2.7%; 10.5%] [-8.3%; 2.0%] [-10,3%; 6,1%] [-22,7%; 4,7%] [-1,7%; 26,6%] [-10,0%; 7,3%]

* The p-values (Fisher Exact test) indicated here indicate whether HSM / MSM populations are different in age, ethnicity, marital status, education, transmission, lymphocytes T CD4+ and viral load. There is no relation to the response variables (adherence and depression). * in education item in this table, divided by educational cycles practiced in Brazil. * MSM = Men who have sex with men * MSW= Men who have sex with women * S.C.W.S.S P.= Sexual contact with same sex partner * S.C.W.O.S.P. = Sexual contact with opposite sex partner.

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Table 2 - Absolute numbers and respective percent of depression by Beck depression inventory (BDI) and adherence data by START questionnaire. B.D.I. 0 - 13 14 - 19 20 - 28 29 - 63 Adherence All Majority Half Few None

MSM 73/ 22/ 12/ 9/

MSW

All

*p-value

CI 95% (msm â&#x20AC;&#x201C; msw)

(62.9%) (18.9%) (10.3%) (7.7%)

73/ 13/ 5/ 9/

(73%) (13%) (5%) (9%)

146/ 35/ 17/ 18/

(67.5%) (16.2%) (7.9%) (8.4%)

0.15 0.32 0.23 0.93

[-23.3%; 3.2%] [-4.7%; 16.6%] [-2.5%; 13.3%] [-9.5%; 7.1%]

106/ (91.4%) 7/ (6.0%) 2/ (1.7%) 0 1/ (0.9%)

90/ 6/ 1/ 2/ 1/

(90%) (6.0%) (1.0%) (2.0%) (1.0%)

196/ 13/ 3/ 2/ 2/

(90.8%) (6.0%) (1.4%) (0.9%) (0.9%)

0.91 1 1 0.21 1

[-7.3%; [-6.4%; [-3.1%; [-5.6%; [-2.8%;

10.1%] 6.4%] 4.5%] 1.7%] 2.6%]

B.D.I. 0 - 13 - Minimum depression 14 - 19 - Mild depression 20 - 28 - Moderate depression 29 - 63 - Severe depression. ADHERENCE All - Ingestion of all prescribed doses Majority - Ingestion of most prescribed doses Half - half doses intake Few - Ingestion of a few doses None - Do not eat the doses indicated.

o200 mm3 (Table 1). The viral load was undetectable or o10,000 copies in 95.4% of the participants (Table 1).

Table 3 - Demonstration of the Log-linear class for categorized data analysis regarding depression as a response variable related to the other variables. Variable Age

Viral Load

Lymphocytes T CD4+

Marital status

Education

Transmission

Orientation

Ethinicity

Adherence

Depression level Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe

Depression and adherence p-value

0.96 0.042 0.27 0.77 0.73 0.68 0.07 0.50 0.68 0.46 0.98 0.88 0.91 0.15 0.99 0.72 0.60 0.076 1.00 0.11 0.17 0.76 0.22 0.25 0.53 0.046 0.43

0.97 0.34 0.64 1.38 1.46 1.42 2.56 0.70 0.85 0.69 1.01 1.06 0.94 2.16 0.99 0.84 0.76 0.51 1.00 0.42 0.59 0.78 0.42 3.32 0.60 0.26 0.61

The Beck questionnaire revealed that 32.5% of the participants in both groups had some level of depression (Table 2). Importantly, 8.4% of the participants presented severe symptoms of depression (Table 2). Almost all participants (90.8%) declared adherence to the antiretroviral therapy (Table 2).

95% CI [0.32; [0.12; [0.29; [0.16; [0.17; [0.27; [0.92; [0.25; [0.40; [0.26; [0.35; [0.48; [0.35; [0.76; [0.47; [0.31; [0.27; [0.24; [0.38; [0.14; [0.28; [0.16; [0.11; [0.42; [0.12; [0.07; [0.18;

2.91] 0.96] 1.40] 12.13] 12.88] 7.36] 7.09] 1.97] 1.79] 1.84] 2.91] 2.33] 2.51] 6.10] 2.09] 2.25] 2.13] 1.07] 2.61] 1.23] 1.28] 3.74] 1.67] 26.00] 2.99] 0.97] 2.09]

Depression as a variable response After dividing the variable response (depression) into four categories (minimum or none, mild, moderate, and severe), the probability of each category was estimated based on the explanatory variables (see Table 3). Table 3 shows the results of the final log-linear class model from the categorized data analysis. The category of depression used as a reference was minimum or none. Variables such as adherence (p=0.046), age (p=0.042), and transmission (p=0.076) showed a greater correlation with depression in the multivariate analysis. Since the sample size might not be representative of all categories of depression, considering p=0.07 statistically significant was acceptable. The results showed that men younger than 40 years had a 2.9-fold higher chance of developing moderate depression than older men. Men who acquired the disease due to sexual contact with persons of the same sex had a 2.0-fold greater chance of developing severe depression than men who acquired the disease through sexual contact with the opposite sex. Those reporting poor adherence to treatment had a 3.8-fold higher chance of suffering from moderate depression than those reporting complete adherence. The results are summarized in Tables 3 and 4. The goodness of fit of the model was validated using statistical ward continuity (p=0.73). This test verified our hypotheses and proved that the model was adequate, with a high p-value indicating that the residues followed a normal distribution with a mean of 0 and variance of 1 (Figure 1).

whereas 19.0% of the infections were acquired via sexual intercourse with persons of the opposite sex (3.4% and 37% for MSM and MSW, respectively) (Table 1). A higher percentage of individuals in the MSW group than in the MSM group did not know how they acquired the infection (Table 1). Clinical data indicate that 52.8% of all participants had CD4+ lymphocyte counts 4500 mm3, and 18.1% had counts

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Table 4 - Chances of individual develop depression in the studied group. Observed distribution of depression per transmission and adhrence. Depression Transmission

Adherence

Same Sex

Minimum

Yes No Yes No

Oposite Sex/Others

54 4 82 6

Mild

(64.3%) (40%) (73.2%) (60%)

17 3 14 1

Moderate

(20.2%) (30%) (12.5%) (10%)

7 1 6 3

Severe

(8.3%) (10%) (5.4%) (30%)

6 2 10 0

Total

(7.1%) (20%) (8.9%) (0%)

84 10 112 10

Table 6 - Observed distribution of adherence per ethnicity and depression. Variable Ethinicity

Depression

Adherence

White/Mixed

w/o depression w depression w/o depression w depression

125 58 11 2

Black

Table 5 - Demonstration of the multivariate analysis regarding adherence as a response variable related to the other variables studied. p-value

Odds Ratio

Age Ethnicity Marital status Education Transmission Sexual Orientation Lymphocytes T CD4+ Viral load HIV Depression

0.33 0.0008 0.47 0.53 0.28 0.37 0.5 0.26 0.0134

1.85 7.68 1.6 0.98 2.18 0.5 1.45 0.35 3.81

95% CI [0.61; [2.34; [0.44; [0.93; [0.53; [0.11; [0.53; [0.06; [1.32;

(94%) (90.6%) (84.6%) (33.3%)

non adherence 8 6 2 4

(6%) (9.4%) (15.4%) (66.7%)

Total 133 64 13 6

likelihood ratio (with p=0.05). The results of the model showed that ethnicity (p=0.0008) and depression (p=0.0134) were significantly related to adherence, whereas the relationships of the other variables were not significant [age (p=0.33), viral load (p=0.26), CD4+ T lymphocyte count (p=0.5), marital status (p=0.47), education (p=0.53), transmission (p=0.28), and sexual orientation (p=0.37)] (Table 5). The distribution of adherence based on ethnicity and depression is shown in Table 6. Accordingly, white or mixed race men with depression reported 90.6% adherence to antiretroviral therapy, whereas black men with depression reported 33.3% adherence to treatment. Our statistical analysis showed that white or mixed race men were 7.7 times more likely to adhere to treatment than black men. The probability of a non-depressed subject adhering completely to the treatment was 3.8 times higher than the probability of depressed subjects adhering to treatment regardless of ethnicity.

Figure 1 - The diagnosis of the logistic regression model. Since all residues are within the confidence band of the expected distribution, the model is well adjusted.

Variable

Adherence

5.60] 25.21] 5.78] 1.04] 8.94] 2.26] 8.94] 2.17] 11.02]

â&#x20AC;&#x2122; DISCUSSION The goal of our study was to evaluate the prevalence of depression in men with HIV/AIDS who had sex with men (MSM) or women (MSW) and its relationship with treatment adherence. Our results showed that adherence did not depend on age or sexual orientation; the overall adherence rate in this study was 90.74%. Ninety-five percent of non-depressed men adhered to treatment, whereas 86% of depressed individuals showed adherence. Black men showed less adherence (68%) than white (93%) and mixed race men (97%). Regardless of sexual orientation, the non-adherents were 2.84 times more likely to develop depression. Thus, depression has a direct negative action on adherence. Depression was the most commonly reported psychological disorder among our participants. In addition, being in a constant state of depression might influence immune responses (9,21,26). Notably, this disorder is largely underdiagnosed in this population (27). Depression in an HIVinfected individual has been reported to largely hinder the patientâ&#x20AC;&#x2122;s life. In a study with 55 individuals, Porche and Willis (2006) found that 64% of the participants were diagnosed with depression, although only 42% reported symptoms (28).

For the regression model for a variable adherence, the above results for all variables tested. Among them, only ethnicity and depression are statistically significant (po0.05). The results can be interpreted through odds ratios and their respective confidence intervals. The interpretation of the odds ratios indicates that, from the statistical model, it is considered that black men have a 7.7 times greater chance of not being adherent in relation to men of the other ethnicities. Men who have any level of depression have a 3.8 times greater chance of not being adherent compared to those without depression.

Adherence as a variable response The adherence and non-adherence parameters were analyzed by logistic regression. The probabilities were estimated for each category by considering other variables (age, viral load, CD4+ T lymphocyte count, marital status, education, HIV transmission, and sexual orientation). The parameters were shortened and validated through successive tests of the

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addressed the psychological symptoms of depression in patients. Regarding the ethnicities of the patients, we found that black men were less adherent to treatment than white and mixed race men. The probability of non-depressed white or mixed race men adhering to treatment was 96.7%; however, the probability of adherence decreased to 88.5% in depressed individuals. Conversely, the probability of adherence in nondepressed black men was 79.2%, whereas the probability decreased to 49.9% in depressed black men. These results corroborate those of other studies showing black men have lower adherence (44,45) and less of a propensity toward adherence with antiretroviral therapy (46). Studies on African-American men have indicated that stigma, poor reliability on medical assistance, poor social conditions, and psychosocial issues negatively impact the care inherent for those with HIV-positive conditions (47,4). Unfortunately, our study data did not consider the economic statuses of the patients for analysis. Consideration of the economic statuses would have allowed a better interpretation of our findings on the population of African Brazilian men living with HIV/AIDS. The relationship between age, adherence, and moderate depression was significant in our patient groups. To the best of our knowledge, our study is the first to report the prevalence of depression and adherence to antiretroviral treatment in HIV-positive men in São Paulo, which is the largest city in South America. Our report showed evidence that black men living with HIV/AIDS who had same-sex partners needed more attention from a multidisciplinary team regarding their depression statuses and reduced adherence to antiretroviral treatment.

The most common symptoms of depression reported in our survey were in agreement with studies from different countries (29,30). Investigations worldwide have revealed that the prevalence of depression is two to three times higher in HIVpositive individuals than in the general population (31,33). The depression rates in our sample were comparable to those reported in other studies. However, no significant differences were found between the groups regarding sexual orientation, although the MSM group showed a higher tendency for depression since they predominantly contracted the disease by sexual contact with people of the same sex. One main novel element in this study was that although previous studies compared the state of depression between groups of patients with HIV and those without (34), this study performed a comparison between two subgroups of HIV-infected individuals. Our results suggested that sexual orientation had no significant influence on depression, whereas age and adherence had detrimental effects on moderate depression symptoms. Married men showed a lower rate of depression than the other men. In line with this finding, the group with the highest prevalence of depression was divorced individuals. Importantly, single men who were infected through intercourse with same-sex partners showed two times more severe depression symptoms than men who were infected through intercourse with partners of the opposite sex. Previous studies have shown that HIV-infected women have higher levels of depression than HIV-infected men (15,22,35,36). A survey in Brazil reported by Mello et al. (2006) indicated that the prevalence of depression in HIV-infected women ranged from 25% to 45%. Interestingly, the percentage of depression observed in the MSM group in our study was comparable to that reported for HIV-positive women in other studies (35,33,29). Depression is widely thought to reduce the degree of adherence to antiretroviral therapy (37,38). In contrast, our results indicated that even depressed patients showed adequate adherence to antiretroviral treatment. Studies have confirmed that good adherence rates are directly related to medical assertiveness, which encourages the patient to establish a good relationship with health professionals (24,39,40). Different cohorts of HIV-infected patients reported an average of 65.6% adherence to Highly Active Antiretroviral Therapy (41,42). Similarly, in the present study, we observed a high rate of adherence to antiretroviral treatment. We noted that depression and adherence did not show any correlation with sexual orientation. Another study reported that no significant relationship existed between depression and nonadherence to antiretroviral treatment (37). The high rates of adherence among both groups can be attributed to the excellent services offered by health professionals in our care setting. Most patients in our cohort were under follow-up care for a long time, which suggested that a consistent relationship was a decisive factor for the success of antiretroviral treatment. Many other studies have reached a similar conclusion (43,31). The likelihood of adherence to antiretroviral treatment is 83% higher if symptoms of depression are identified and care is provided. The risk of non-adherence increases by 35% among those who do not receive any treatment for depression (30). We observed a significant relationship between depression and adherence. Most of the non-adherent patients presented only milder forms of depression, because the multidisciplinary treatment approach in our institution quickly and appropriately

’ AUTHOR CONTRIBUTIONS de Moraes RP was responsible for the research procedures and manuscript writing. Casseb J was the research supervisor.

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Immune Defic Syndr. 2011;58(2):181-7, http://dx.doi.org/10.1097/QAI. 0B013E31822D490A. World Health Organization. The Global Burden of Disease: 2004 update. 2004 Update. 2008;146, http://dx.doi.org/10.1590/1516-4446-2016-2107. Petrosyan Y, Sahakyan Y, Barnsley JM, Kuluski K, Liu B, Wodchis WP. Quality indicators for care of depression in primary care settings: a systematic review. Syst Rev. 2017;6(1):126, http://dx.doi.org/10.1186/s13643-017-0530-7. Ribeiro A, Ribeiro JP, von Doellinger O. Revista Brasileira de Psiquiatria Depression and psychodynamic psychotherapy. Rev Bras Psiquiatr. 2017. Salomon EA, Mimiaga MJ, Husnik MJ, Welles SL, Manseau MW, Montenegro AB, et al. Depressive symptoms, utilization of mental health care, substance use and sexual risk among young men who have sex with men in EXPLORE: implications for age-specific interventions. AIDS Behav. 2009;13(4):811-21, http://dx.doi.org/10.1007/s10461-008-9439-4. Penzak SR, Reddy YS, Grimsley SR. Depression in patients with HIV infection. Am J Health Syst Pharm. 2000;57(4):376-86. Nogueira Campos L, De Fátima Bonolo P, Crosland Guimarães MD. Anxiety and depression assessment prior to initiating antiretroviral treatment in Brazil. AIDS Care. 2006;18(6):529-36, http://dx.doi.org/10.1080/ 09540120500221704. Ibor EL, Pagán EM, Lapuerta CL, Laderas LB, Díaz JM, Rodrigo EA. +Es importante valorar los síntomas de Ansiedad y Depresión en población VIH? Rev Multidiscip del Sida. 2015;1(4):52-5. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561-71, http:// dx.doi.org/10.1001/archpsyc.1961.01710120031004. Beck AT, Steer RA, Carbin MG. Psychometric properties of the Beck Depression Inventory: Twenty-five years of evaluation. Clin Psychol Rev. 1988;8:77-100, http://dx.doi.org/10.1016/0272-7358(88)90050-5. www.soropositivo.org [cited 2016 Sep 2]. O’Connor JL, Gardner EM, Esser S, Mannheimer SB, Lifson AR, Telzak EE, et al. A simple self-reported adherence tool as a predictor of viral rebound in people with viral suppression on antiretroviral therapy. HIV Med. 2016;17(2):124-32, http://dx.doi.org/10.1111/hiv.12284. Uthman OA, Magidson JF, Safren SA, Nachega JB. Depression and adherence to antiretroviral therapy in low-, middle- and high-income countries: a systematic review and meta-analysis. Curr HIV/AIDS Rep. 2014;11(3):291-307, http://dx.doi.org/10.1007/s11904-014-0220-1. Reis RK, Haas VJ, Santos CB Dos, Teles SA, Galvão MTG, Gir E. Symptoms of depression and quality of life of people living with HIV/AIDS. Rev Lat Am Enfermagem. 2011;19(4):874-81, http://dx.doi.org/10.1590/ S0104-11692011000400004. Gomes-Oliveira MH, Gorenstein C, Lotufo Neto FL, Andrade LH, Wang YP. Validation of the Brazilian Portuguese Version of the Beck Depression Inventory-II in a community sample. Rev Bras Psiquiatr. 2012;34(4): 389-94, http://dx.doi.org/10.1016/j.rbp.2012.03.005. O’Connor JL, Gardner EM, Mannheimer SB, Lifson AR, Esser S, Telzak EE, et al. Factors associated with adherence amongst 5295 people receiving antiretroviral therapy as part of an international trial. J Infect Dis. 2013;208(1):40-9, http://dx.doi.org/10.1093/infdis/jis731. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) - A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377-81, http://dx.doi.org/10.1016/j.jbi. 2008.08.010. Fasce Cayo N. Depresión en personas que viven con VIH. Revista de Psicolología de la PUCP. 2002;20(1):73-91. Olatunji BO, Mimiaga MJ, O’Cleirigh C, Safren SA. Review of treatment studies of depression in HIV. Top HIV Med. 2006;14(3):112-24. Porche DJ, Willis DG. Depression in HIV-infected men. Issues Ment Health Nurs. 2006;27(4):391-401, http://dx.doi.org/10.1080/0161284060 0569658. Primeau MM, Avellaneda V, Musselman D, St. Jean G, Illa L. Treatment of depression in individuals living with HIV/AIDS. Psychosomatics. 2013;54(4):336-44, http://dx.doi.org/10.1016/j.psym.2012.12.001.

749

CLINICAL SCIENCE

Microcirculation improvement after short-term infusion of vasopressin in septic shock is dependent on noradrenaline Ana Paula Metran Nascente,I Fla´vio Geraldo Rezende Freitas,I Jan Bakker,II,III Antoˆnio Tonete Bafi,I Renata Teixeira Ladeira,I Luciano Cesar Pontes Azevedo,I Alexandre Lima,II Flavia Ribeiro MachadoI,* I Departamento de Anestesiologia, Dor e Terapia Intensiva, Universidade Federal de Sao Paulo, Sao Paulo, SP, BR. II Department of Intensive Care Adults, Erasmus MC - University Hospital Rotterdam, the Netherlands. III Division of Pulmonary, Allergy and Critical Care, Department of Medicine. College of Physicians & Surgeons of Columbia, University of New York, USA.

OBJECTIVES: To assess the impact of vasopressin on the microcirculation and to develop a predictive model to estimate the probability of microcirculatory recruitment in patients with septic shock. METHODS: This prospective interventional study included patients with septic shock receiving noradrenaline for less than 48 hours. We infused vasopressin at 0.04 U/min for one hour. Hemodynamic measurements, including sidestream dark-field imaging, were obtained immediately before vasopressin infusion, 1 hour after vasopressin infusion and 1 hour after vasopressin withdrawal. We defined patients with more than a 10% increase in total vascular density and perfused vascular density as responders. ClinicalTrials.gov: NCT02053675. RESULTS: Eighteen patients were included, and nine (50%) showed improved microcirculation after infusion of vasopressin. The noradrenaline dose was significantly reduced after vasopressin (p=0.001) and was higher both at baseline and during vasopressin infusion in the responders than in the non-responders. The strongest predictor for a favorable microcirculatory response was the dose of noradrenaline at baseline (OR=4.5; 95% CI: 1.2-17.0; p=0.027). For patients using a noradrenaline dose higher than 0.38 mcg/kg/min, the probability that microcirculatory perfusion would be improved with vasopressin was 53% (sensitivity 78%, specificity 77%). CONCLUSIONS: In patients with septic shock for no longer than 48 h, administration of vasopressin is likely to result in an improvement in microcirculation when the baseline noradrenaline dose is higher than 0.38 mcg/kg/min. KEYWORDS: Septic Shock; Vasopressin; Microcirculation; Vasopressors; Hemodynamic. Nascente AP, Freitas FG, Bakker J, Bafi AT, Ladeira RT, Azevedo LC, et al. Microcirculation improvement after short-term infusion of vasopressin in septic shock is dependent on noradrenaline. Clinics. 2017;72(12):750-757 Received for publication on May 31, 2017; First review completed on July 17, 2017; Accepted for publication on October 11, 2017 *Corresponding author. E-mail: frmachado@unifesp.br

’ INTRODUCTION

aiming to sparingly use catecholamines in critically ill patients is strong. Vasopressin has been used as an adjunct to noradrenaline for severe hypotension. A previous meta-analysis of randomized trials suggested improved survival in patients with septic shock who received vasopressin (8-10), although a recent study failed to show improvement in renal dysfunction (11). In addition, several studies have demonstrated that adding vasopressin to a noradrenaline infusion decreases catecholamine requirements (12-17). Microcirculatory alterations are a hallmark of sepsis, are associated with outcomes (18-20) and are stronger predictors than global hemodynamic variables (21). The effects of vasopressin on the microcirculation have not been adequately studied. The strong vasoconstrictive action, which might hamper microcirculatory flow, of vasopressin is a focus of concern (22). However, the effects of vasopressin on V1 receptors in combination with the reduced dose of adrenergic vasopressors could potentially lead to improved perfusion at the microcirculatory level despite potential negative effects on macrocirculatory parameters such as cardiac output (23-26).

In patients with septic shock, noradrenaline is usually administered to achieve an adequate mean arterial pressure (MAP) to maintain sufficient organ perfusion. However, adrenergic receptors are hyposensitive during the advanced stages of septic shock (1,2), and the use of a high noradrenaline dose in these circumstances is associated with adverse events (3-6). Excessive use of adrenergic drugs is associated with not only undesirable hemodynamic effects but also enhanced coagulation, reduced innate and adaptive immunity and increased bacterial replication and virulence (7). Thus, the rationale for developing strategies

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the images was blinded to the patients and details associated with the images.

Based on these observations, we carried out a prospective study to evaluate the effects of vasopressin on microcirculatory parameters. In addition, we assessed potential predictive factors related to microcirculation recruitment by vasopressin in septic patients using noradrenaline to sustain MAP.

Study protocol Immediately before vasopressin infusion, each patient was evaluated for adequate intravascular volume as evidenced by pulse pressure variation assessment (DX 2020, Dixtal, São Paulo, Brazil) after adequate continuous sedation to control spontaneous ventilatory efforts. Patients with a pulse pressure variation 413% received repeated Ringer’s lactate challenges until the pulse pressure variation was below this value. Patients with pulse pressure variations that could not be measured received fluid challenges until no increase in cardiac output greater than 10% was evident. Vasopressors were used to maintain MAP above 65 mmHg. The oxygen inspiratory fraction was adjusted to maintain peripheral oxygen saturation above 92%. Thirty minutes after the initial stabilization, we obtained the baseline hemodynamic, respiratory, and sublingual microcirculatory measurements (T0). After the baseline measurements, vasopressin was administered at a fixed dose of 0.04 U/min. One hour after vasopressin infusion, we collected the data from the same variables (T1). Vasopressin was stopped, and new measurements were recorded after 1 hour (T2). If clinically required, the vasopressor infusion was adjusted during the study period to maintain a target MAP level 465 mmHg. If the patients received dobutamine, the doses were kept constant during the study procedure. Patients were excluded from the study if there was a clinical indication of tapering of the ventilator parameters or additional sedation during the intended study period.

’ MATERIALS AND METHODS Study population This prospective study was conducted in a 35-bed intensive care unit of a teaching hospital. Between June 2010 and August 2012, we included patients with septic shock who received adrenergic vasopressors for less than 48 hours and were monitored with an arterial catheter and a pulmonary artery catheter because we required the monitoring of the cardiac index (CI). According to the unit protocol, in the absence of contraindications, patients with septic shock using noradrenaline above 0.3 mcg/kg/min during the first 24 hours of shock were monitored with a pulmonary artery catheter. Sepsis was defined according to the Society of Critical Care MedicineAmerican College of Chest Physicians Consensus Conference (27). Septic shock was defined as fluid-refractory hypotension requiring vasopressors with no requirement of elevated lactate levels because the study was conducted before the new definition of septic shock (28). Exclusion criteria included the following: use of vasopressin; acute coronary disease; suspected or confirmed acute mesenteric ischemia; severe hyponatremia (Na+ o130 mmol/L); Raynaud’s phenomenon; systemic sclerosis; pregnancy; or a technical difficulty preventing sublingual video microscopy. The study was conducted according to the Helsinki Declaration, which was revised in 1983, and according to the Resolution 196/96 of the Conselho Nacional de Saude. The Research and Ethics Committee of the institution approved study number 2081/08, and all patients or their legal representatives provided informed consent. ClinicalTrials.gov: NCT02053675.

Statistical analysis

Data are expressed as the mean±standard deviation, median [interquartile range], or frequency (n, %), as appropriate. The time points of the study were defined as T0 (baseline before vasopressin infusion), T1 (one hour after vasopressin infusion), and T2 (one hour after cessation of vasopressin infusion). The Shapiro-Wilk test and stratified distribution plots were used to verify the normality of the distribution of continuous variables. All quantitative data were normally distributed except for the doses of noradrenaline and lactate. Data that were not normally distributed underwent log transformation to achieve close to normal distribution and were then qualified for longitudinal testing. We categorized patients as responders and non-responders based on changes to sublingual vascular density. Because visible obstructed capillaries do not change TVD but have effects on PVD, we defined responders as those who presented a more than a 10% increase in TVD or PVD after vasopressin infusion. This cut-off was based on a previous study showing that slight changes in the microcirculation are associated with the degree of organ dysfunction (30). Factors associated with the microcirculation response were analyzed using a multivariate regression analysis to develop the predictive model for improvement in microcirculation. Relevant candidate predictor variables at baseline were selected for possible inclusion in the model, including TVD, noradrenaline dose, MAP, HR, CVP, lactate and CI. A backward-elimination approach was tested with all variables, and hypothesis tests were sequentially applied to determine which variables would be removed from the final model. (Predictors were removed if the significance level was more than 0.10.)

Measurements The demographic and sepsis characteristics and the severity scores from the APACHE II and SOFA were recorded. Hemodynamic measurements included semi-continuous thermodilution CI (Vigilance, Edwards LifeSciences, Irvine, CA, USA), heart rate (HR), MAP, central venous pressure (CVP), pulmonary arterial pressure (PAP), and pulmonary arterial occlusion pressure (PAOP). Ventilator settings were recorded and arterial and mixed venous blood were collected for blood gases analysis, oxygen venous saturation (SvO2) and serum lactate. We assessed sublingual microcirculation using sidestream dark-field (SDF) imaging (Microscan, MicroVision Medical, Amsterdam, Netherlands). To ensure image quality, a skilled physician using the recommended techniques obtained all of the images (29). Three high-quality steady images of at least 20 seconds on both sides of the tongue were obtained while avoiding pressure artifacts. All images were captured using a portable computer and an analog/digital video converter. Microcirculatory parameters, including the microcirculatory flow index (MFI), total vascular density (TVD), proportion of perfused vessels (PPV), perfused vascular density (PVD) and heterogeneity index (HI) (29), were analyzed using AVA 3.0s software (MicroVision Medical, Amsterdam, Netherlands). We obtained only images that were related to vessels with diameters less than 20 mm. We assigned a random number to each image, and the investigator (A.P.M.N.) who analyzed

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Table 1 - Demographic data and sepsis characteristics. Variable Age (years) Males APACHE II Admission SOFA

All patients (n=18)

Responders (n=9)

62.3±17.8 11 (61.1) 13.4±4.6 11 (8, 13)

Non-responders (n=9)

63.9±17.4 6 (66.7) 14.1±6.1 10 (7, 12.5)

60.2±19.8 5 (55.6) 12.9±3.1 11 (9.5,13)

Admission category Ward Surgery Emergency department

7 (38.9) 9 (50) 2 (11.1)

4 (44.4) 4 (44.4) 1 (11.1)

3 (33.3) 5 (55.6) 1 (11.1)

Patient category Medical Elective surgical Emergency surgical

9 (50) 3 (16.7) 6 (33.4)

5 (55.6) 2 (22.2) 2 (22.2)

4 (44.4) 1 (11.1) 4 (44.4)

Type of infection Community Nosocomial - ward Nosocomial - ICU

5 (27.8) 8 (44.4) 5 (27.8)

1 (11.1) 5 (55.6) 3 (33.3)

4 (44.4) 3 (33.3) 2 (22.2)

Site of infection Lung Abdominal Urinary Catheter Bloodstream Unknown

5 6 2 1 2 2

2 2 0 1 2 2

3 4 2 0 0 0

Organ dysfunctions (number) Duration of organ dysfunction (hours) Duration of vasopressor use (hours) ICU mortality Hospital mortality

p value 0.601 0.629 0.630 0.881

0.774

0.287

0.164 (27.8) (33.3) (11.1) (5.6) (11.1) (11.1)

4.17±1.61 36.54 (30.0, 51.8) 27.2±12.2 11 (61.1) 13 (72.2)

(22.2) (22.2) (0) (11.1) (22.2) (22.2)

3.78 ±1.4 39.9 (29.7, 56.5) 24.7±13.8 6 (66.7) 6 (66.7)

(33.3) (44.4) (22.2) (0) (0) (0)

4.56±1.8 34.7 (27.7, 45.4) 29.3±10.9 5 (55.6) 7 (77.8)

0.322 0.606 0.457 0.629 0.599

APACHE, Acute Physiological Chronic Health Evaluation; SOFA, Sequential Organ Failure Assessment; ICU, intensive care unit. The results are expressed as the number (%), mean±standard deviation or median (25%, 75%).

study. Their characteristics at baseline are listed in Table 1. The patients received adrenergic vasopressors for a mean of 27.2±12.2 hours, and the hospital mortality rate was 72%. All patients received 0.04 U/min of vasopressin for one hour, except for one patient who received a dose of 0.02 U/min. At baseline, only four patients received epinephrine (mean dose, 0.28±0.08 mcg/kg/min), and five patients received dobutamine (mean dose, 5.6±2.9 mcg/kg/min). For most patients, we did not change these medication doses; however, for one patient we reduced the epinephrine dose from 0.26 mg/kg/min to 0.13 mg/kg/min instead of reducing the noradrenaline dose because an increase in MAP and excessive tachycardia were evident. In 3 patients, an assessment of the T2 measurement was not possible because there was a clinical indication of tapering of the ventilator parameters or additional sedation. After vasopressin infusion, the absolute mean reduction in the norepinephrine infusion rate was 32.2±27.4%; p=0.001. Nine patients showed improvements in microvascular density after 1 hour of vasopressin infusion. Tables 2 and 3 show the hemodynamic and sublingual microcirculation parameters, respectively, which are stratified by responders and non-responders. Both responders and non-responders had a significant decrease in the noradrenaline dose during the infusion of vasopressin, whereas the noradrenaline dose was significantly higher in the responders than the nonresponders both at baseline and during vasopressin infusion (Table 2). Only 5 patients were using dobutamine at baseline; 2 were responders, and 3 were non-responders. After discontinuation of the vasopressin infusion, the noradrenaline dose increased significantly in the non-responder group only,

Discriminative ability was determined with the c-statistic, which is equivalent to the area under the receiver operator characteristic (ROC) curve. The results were then summarized in a graphical assessment of the expected probability for a microcirculatory response based on the final model. The statistical comparisons at each time point of the study were performed using a generalized mixed-model analysis to estimate the mean response differences and significance of the covariates (global hemodynamic variables and sublingual microcirculation parameters) within the time points (factor) between responders and non-responders (dependent variable). The interaction was tested for each time point to investigate the relationship between changes in hemodynamic variables (MAP, CVP and CI) and microcirculatory parameters. SPSS (version 23.0, SPSS, Chicago, IL, USA) was used for statistical analyses. A p-valueo0.05 was considered to be statistically significant.

’ RESULTS We screened 116 patients with septic shock who were admitted to the intensive care unit. Fifty-one patients were not included because SDF or the study team were not available. Other reasons for non-eligibility included the following: absence of a Swan-Ganz catheter (n=27), reversal of shock before the baseline assessment (n=10), lack of informed consent (n=3), acute coronary disease (n=2), use of norepinephrine longer than 48 hours (n=2), previous use of vasopressin (n=1), pregnancy (n=1) and death before inclusion (n=1). Eighteen consecutive patients with septic shock were included in the

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Table 2 - Global hemodynamic parameters and noradrenaline dose recorded at the three different time points during the study protocol and categorized according to responders and non-responders. Variables

Subgroup

T0 (n=18)

T1 (n=18)

T2 (n=15)

Noradrenaline (mg/K/min)

Non-responder Responder p value

0.28 (0.17-0.41) 0.68 (0.40-1.04) 0.008

0.15 (0.09-0.24)* 0.49 (0.38-0.88)* 0.010

0.39 (0.23-0.56)* 0.59 (0.42-0.88) 0.320

HR (bpm)

Non-responder Responder p value

101 (12) 113 (25) 0.220

96 (14)* 109 (23) 0.150

101 (11)* 116 (20)* 0.060

MAP (mmHg)

Non-responder Responder p value

74.6 (8) 70.4 (3) 0.152

74.4 (5) 70.8 (3) 0.089

70.1 (5) 70.5 (4) 0.370

CI (L/min.m2)

Non-responder Responder p value

4.5 (1.28) 4.2 (1.20) 0.560

SI (mL/m2)

Non-responder Responder p value

45.2 (15.2) 36.4 (7.1) 0.146

38.8 (12.9) 34.6 (7.2) 0.405

40.5 (11.5) 34.7 (7.9) 0.262

Lactate (mg/dL)

Non-responder Responder p value

21.3 (14.0-32.0) 30.8 (24.0-43.8) 0.22

18.9 (12.9-27.1) 28.7 (21.9-46.0) 0.15

25.0 (12.9-43.8) 27.1 (23.1-32.1) 0.23

SvO2 (%)

Non-responder Responder p value

71.4 (6.9) 75.7 (5.7) 0.170

69.1 (9.5) 72.5 (5.4) 0.360

73.3 (8.8) 71.7 (5.4)* 0.450

a-vCO2

Non-responder Responder p value

3.0 (1.3) 4.1 (2.2) 0.28

4.8 (1.6) 5.5 (3.9) 0.44

4.6 (2.0) 4.8 (1.3) 0.85

DO2 (mL/min)

Non-responder Responder p value

791 (673-1435) 836 (678-1080) 0.51

739 (568-986)* 738 (613-955) 0.89

731 (542-1231) 740 (673-1116) 0.70

VO2 (mL/min)

Non-responder Responder p value

188 (152-370) 197 (145-243) 0.19

171 (132-292)* 199 (145-206) 0.42

188 (156-278)* 196 (173-221) 0.29

Extraction rate (%)

Non-responder Responder p value

25.6 (21-26) 22.0 (18-31) 0.49

23.1 (19-34) 22.6 (18-28) 0.29

23.3 (21-35) 23.7 (17-29) 0.39

3.6 (1.04)* 3.7 (0.91) 0.900

4.0 (0.96)* 3.9 (0.82) 0.510

Time points are defined as before (T0), during (T1) and after (T2) vasopressin infusion. There were 9 responders and 9 non-responders. HR, heart rate; MAP, mean arterial pressure; CI, cardiac index; SI, systolic index; SvO2, oxygen mixed venous saturation. Data are expressed as the mean (standard deviation) or median (25%, 75%). * po0.05 vs. previous time point within the same group.

Table 3 - Sublingual microcirculation parameters recorded at the three different time points during the study protocol and categorized according to responders and non-responders. Variable

Subgroup 2

TVD (mm/mm )

Non-responder Responder p value

15.9 (2.5) 14.3 (1.7) 0.13

14.4 (1.8)* 16.3 (1.6)* 0.03

14.8 (0.58) 15.2 (1.57)* 0.35

PVD (mm/mm2)

Non-responder Responder p value

13.9 (2.7) 12.1 (1.9) 0.11

12.4 (1.8)* 14.4 (1.4)* 0.02

12.6 (1.3) 13.0 (1.9)* 0.47

PPV (%)

Non-responder Responder p value

87.3 (7.6) 83.5 (6.0) 0.26

86.5 (6.4) 89.0 (4.8)* 0.36

85.0 (7.8) 86.6 (7.0) 0.62

MFI

Non-responder Responder p value

2.7 (0.2) 2.7 (0.1) 0.69

2.8 (0.2) 2.6 (0.3) 0.15

2.7 (0.2) 2.7 (0.2) 0.89

Time points are defined as before (T0), during (T1) and after (T2) vasopressin infusion. There were 9 responders and 9 non-responders. TVD, total vascular density; PPV, proportion of perfused vessels; PVD, perfused vascular density; MFI, microcirculatory flow index; Data are expressed as the mean (standard deviation) or median (25%, 75%). * po0.05 vs. previous time points within the same group.

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Figure 1 - Probability of microcirculatory response based on a dose of noradrenaline at T0 (logarithmic scale). The dotted line shows the threshold value of the predicted probability of 53% for patients receiving a noradrenaline dose higher than 0.38 mcg/kg/min (78% sensitivity and 77% specificity).

Table 4 - Predicted probability of the different doses of noradrenaline for microcirculatory responses with their corresponding sensitivity and specificity.

and both responders and non-responders received similar noradrenaline doses at that time. According to our interaction analysis in the generalized mixed-model, the changes in CI, MAP and CVP had no significant effects on TVD or PVD. Interestingly, the decrease in noradrenaline dosing in the non-responder group was associated with a decrease in CI, oxygen delivery (DO 2 ) and oxygen consumption (VO2), whereas CI was restored to baseline levels after discontinuation of the vasopressin and the subsequent increase in noradrenaline dosing to maintain MAP (Table 2). The hemodynamic parameters, laboratory variables and microcirculatory measurements in the whole population obtained before and after the vasopressin infusion are listed in the electronic supplementary material (Table S1 and S2). In a multivariate regression model (Table S3), the strongest predictor for an improvement in the microcirculation was the baseline dose of noradrenaline (OR=4.5; 95% CI: 1.2-17.0; p=0.027). Figure 1 shows the probability of a microcirculatory response based on the noradrenaline dose. The model showed adequate calibration, good discrimination and an area under the ROC curve of 0.85 (95% CI: 0.66-0.99). The probability for 78% sensitivity is indicated, which corresponds to a predicted probability of more than 50% for patients receiving a noradrenaline dose higher than 0.38 mcg/kg/min (log scale 4-0.97 in the graph). Table 4 shows the final model with predicted probabilities for a microcirculatory response to vasopressin according to different

Noradrenaline dose (mcg/kg/min)

Predicted probability for the microcirculatory response to vasopressin

Sensitivity*

Specificity*

27.8% 53.0% 77.6%

89% 78% 67%

56% 77% 99%

40.17 40.38 40.68

* ROC curve, AUC = 85%, p=0.013.

infusion doses of noradrenaline to facilitate practical application.

â&#x20AC;&#x2122; DISCUSSION The primary finding of this study was that the improvement in the microcirculatory parameters after vasopressin infusion in the septic shock patients was highly associated with the level of noradrenaline dependency and was independent of systemic hemodynamic parameters (CI, MAP, and CVP). This finding suggests that the patientâ&#x20AC;&#x2122;s noradrenaline dose is directly proportional to the likelihood that the patient will respond to vasopressin infusion. For clinical decision making, patients receiving a noradrenaline dose above 0.38 mcg/kg/min (independent of hemodynamic conditions)

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Although our study was not designed to assess causality, we can provide several hypotheses. Vasopressin led to a reduction in the noradrenaline dose in all patients. This result suggests that the use of receptors other than adrenergic receptors will lead to a better response in vasopressor tone and, consequently, to a reduction in the need for vasopressors. Reducing the excessive vasopressor effect of noradrenaline may have led to an increase in microcirculatory density and perfusion in the responders. Non-responders were using a smaller dose of noradrenaline, which suggests less severe disease and vasodilation. In this context, vasopressin might have caused excessive vasoconstriction, as suggested by the finding of a decrease in PVD. Moreover, the potential negative effects of vasopressin in cardiac output may have played a role. Patients who had a smaller reduction in CI after vasopressin infusion would be likely to show improvements in microcirculation. The differences between the responders and non-responders regarding the impact of vasopressin on CI, DO2 and VO2 were interesting. For the non-responders, the CI reduction did not compromise the microcirculation but was associated with a decrease in VO2 that was reversed when vasopressin was suspended. This finding hypothetically suggests that if vasopressin is used, a decrease in noradrenaline requirements may occur if the microcirculation does not improve the overall effect of vasopressin, which might be harmful. However, these notions are speculations because distinguishing the effects of vasopressin on contractility from its vasoconstrictive effects on microcirculation is difficult. Although this study provides novel observations, a fixed dose of vasopressin was used, which could be considered insufficient to show any beneficial or harmful effects. A previous study suggested that a higher dose of vasopressin (0.067 U/min) would restore hemodynamics more effectively and that the dose was not associated with a high incidence of adverse effects (38). Another limitation of the present study is the absence of a control group. However, this study was designed to allow every patient to serve as his or her own control, which minimizes bias. Therefore, the significant improvement or decrease in the sublingual microcirculation parameters during and after vasopressin infusion strengthens our findings. An additional limitation is the short observation period of our study as a longer AVP infusion period might have a different impact on the microcirculatory response. Notably, the high severity of illness in our population is another limitation worth considering. These patients had a mean organ dysfunction incidence of 4.2 and a high mortality rate. Thus, the effects of vasopressin may be different in patients with a less severe shock. In conclusion, the clinical monitoring of the sublingual microcirculation can help identify patients with septic shock that might benefit from the association of vasopressin. Our results suggest that a noradrenaline dose above 0.38 mcg/ kg/min might be a good predictor for the microcirculatory response to the vasopressin infusion. Additional research that explores different microcirculatory beds and uses different measurement tools for assessing microcirculation will improve our knowledge concerning the role of vasopressin in septic shock resuscitation.

are candidates for vasopressin use with a 53% probability of recruiting the microcirculation. These findings, which were not previously reported, may help with selecting patients who may benefit from the association of vasopressin according to their noradrenaline dependency status. The effects of vasopressin in the microcirculation have already been demonstrated by Morelliâ&#x20AC;&#x2122;s group, which showed that continuous infusions of low-dose vasopressin and terlipressin improved the MFI after 6 hours. However, the authors found similar results in the control group, which suggests that these changes may not have been related to vasopressin use (31). In our study, we assessed only the short-term effects of vasopressin. Although a subgroup analysis of the VASST study has suggested that patients with less severe septic shock, who require 5 to 14 mcg of noradrenaline per minute, would have better clinical outcomes with the use of vasopressin (32) at the microcirculatory level; however, our results point in the opposite direction. Our multivariate model showed that the most clinically useful predictor for a microcirculatory response was the noradrenaline dose required to maintain a MAP above 65 mmHg. Vasopressin infusion also reduced norepinephrine requirements without any significant adverse effect during this short period of infusion. Microcirculatory alterations can be observed even when systemic hemodynamics are within satisfactory goals. The independence of the microcirculation parameters has been previously reported (18) (33) (34,35). However, microcirculatory perfusion can be affected by cardiac output and arterial pressure when these variables are critically altered. We found that non-responders had a significant reduction in their cardiac output, DO2 and VO2 during vasopressin infusion, which suggests that changes in the systemic hemodynamics may lead to microcirculatory alterations. However, the reduction in DO2 was not followed by an increase in arterial lactate or differences in other tissue perfusion parameters, suggesting that these macrohemodynamic alterations were not clinically relevant. However, changes in the CI were not associated with improvement in the microcirculation in our multivariate model. This result highlights the relevance of measuring CI in studies aiming to assess microcirculation even if the enrollment rate is compromised. In fact, one of the major reasons for not enrolling patients in our study was the absence of CI measurements. Additionally, the reduction in CI may have been related to the reduction in the noradrenaline dose and, consequently, to its inotropic and chronotropic effects or its effect on venous return. A non-significant reduction in the SI was evident during vasopressin infusion. The reduction in noradrenaline dose might be considered a beneficial effect as increasing evidence indicates that the excessive use of catecholamines is associated with potential iatrogenic complications. These potential harmful effects are not exclusively related to wellknown hemodynamic effects, namely, increased energy expenditure; excessive vasoconstriction; and splanchnic hypoperfusion with altered gut motility, function and potential bacterial translocation. Convincing evidence exists showing that the phagocytic capacity of macrophages and neutrophils is inhibited (36), together with lymphopenia and a shift toward a Th2 pattern (37). Bacterial virulence and proliferation is also enhanced (7). Metabolic changes include hyperglycemia, hypertriglyceridemia and thyroid hormone alterations. Coagulation disorders with enhanced clot formation and a reduction in fibrinolysis have also been reported (7). Thus, the use of vasopressin is part of the decatecholaminization strategy that has gained increased support in critical care.

â&#x20AC;&#x2122; ACKNOWLEDGMENTS We express our gratitude to Dr. Arnaldo Dubin and Vanina Kanoore Edul from the Universidad Nacional de La Plata, Argentina for enabling A.P.M.N. to receive training in sidestream dark-ďŹ eld analysis. We also thank

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Dr. Ivan Koh for assisting us in using the SDF device. Financial support: Fundac¸ão de Amparo a Pesquisa do Estado de São Paulo (FAPESP), Grant 2009/50096-6. The funding organization played no role in the design of the study, data collection, analysis, interpretation of data or writing of the manuscript.

18. De Backer D, Ortiz JA, Salgado D. Coupling microcirculation to systemic hemodynamics. Curr Opin Crit Care. 2010;16(3):250-4, http://dx.doi.org/ 10.1097/MCC.0b013e3283383621. 19. De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med. 2002;166(1):98-104, http://dx.doi.org/10.1164/rccm.200109-016OC. 20. Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med. 2004;32(9):1825-31, http://dx. doi.org/10.1097/01.CCM.0000138558.16257.3F. 21. De Backer D, Donadello K, Sakr Y, Ospina-Tascon G, Salgado D, Scolletta S, et al. Microcirculatory Alterations in Patients With Severe Sepsis: Impact of Time of Assessment and Relationship With Outcome. Crit Care Med. 2013;41(3):791-9, http://dx.doi.org/10.1097/CCM.0b013e3182742e8b. 22. Dunser MW, Mayr AJ, Tur A, Pajk W, Barbara F, Knotzer H, et al. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med. 2003;31(5):1394-8, http://dx.doi.org/10.1097/01.CCM.0000059722. 94182.79. 23. Luckner G, Dunser MW, Stadlbauer KH, Mayr VD, Jochberger S, Wenzel V, et al. Cutaneous vascular reactivity and flow motion response to vasopressin in advanced vasodilatory shock and severe postoperative multiple organ dysfunction syndrome. Crit Care. 2006;10(2):R40, http:// dx.doi.org/10.1186/cc4845. 24. Dunser MW, Mayr AJ, Stallinger A, Ulmer H, Ritsch N, Knotzer H, et al. Cardiac performance during vasopressin infusion in postcardiotomy shock. Intensive Care Med. 2002;28(6):746-51, http://dx.doi.org/10.1007/ s00134-002-1265-y. 25. Gordon AC, Russell JA, Walley KR, Singer J, Ayers D, Storms MM, et al. The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med. 2010;36(1):83-91, http://dx.doi.org/10.1007/s00134-009-1687-x. 26. Ertmer C, Rehberg S, Westphal M. Vasopressin analogues in the treatment of shock states: potential pitfalls. Best Pract Res Clin Anaesthesiol. 2008; 22(2):393-406, http://dx.doi.org/10.1016/j.bpa.2008.02.007. 27. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644-55, http://dx.doi.org/10.1378/chest.101.6.1644. 28. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10, http://dx.doi.org/ 10.1001/jama.2016.0287. 29. De Backer D, Hollenberg S, Boerma C, Goedhart P, Buchele G, OspinaTascon G, et al. How to evaluate the microcirculation: report of a round table conference. Crit Care. 2007;11(5):R101, http://dx.doi.org/10.1186/cc6118. 30. Trzeciak S, McCoy JV, Phillip Dellinger R, Arnold RC, Rizzuto M, Abate NL, et al. Early increases in microcirculatory perfusion during protocoldirected resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med. 2008;34(12):2210-7, http://dx.doi.org/10.1007/s00134-008-1193-6. 31. Morelli A, Donati A, Ertmer C, Rehberg S, Kampmeier T, Orecchioni A, et al. Effects of vasopressinergic receptor agonists on sublingual microcirculation in norepinephrine-dependent septic shock. Crit Care. 2011;15 (5):R217, http://dx.doi.org/10.1186/cc10453. 32. Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-87, http://dx.doi.org/10.1056/NEJMoa067373. 33. De Backer D, Creteur J, Dubois MJ, Sakr Y, Koch M, Verdant C, et al. The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. Crit Care Med. 2006;34(2):403-8, http://dx.doi.org/10.1097/01.CCM.0000198107. 61493.5A. 34. Jhanji S, Stirling S, Patel N, Hinds CJ, Pearse RM. The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock. Crit Care Med. 2009;37(6):1961-6, http://dx. doi.org/10.1097/CCM.0b013e3181a00a1c. 35. Dubin A, Pozo MO, Casabella CA, Palizas F Jr, Murias G, Moseinco MC, et al. Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study. Crit Care. 2009;13(3):R92, http://dx.doi.org/10.1186/cc7922. 36. Wenisch C, Parschalk B, Weiss A, Zedwitz-Liebenstein K, Hahsler B, Wenisch H, et al. High-dose catecholamine treatment decreases polymorphonuclear leukocyte phagocytic capacity and reactive oxygen production. Clin Diagn Lab Immunol. 1996;3(4):423-8. 37. Kohm AP, Sanders VM. Norepinephrine and beta 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo. Pharmacol Rev. 2001;53(4):487-525. 38. Torgersen C, Dunser MW, Wenzel V, Jochberger S, Mayr V, Schmittinger CA, et al. Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial. Intensive Care Med. 2010;36(1):57-65, http://dx.doi.org/10.1007/s00134009-1630-1.

’ AUTHOR CONTRIBUTIONS Nascente AP and Machado FR are the guarantors of the entire manuscript. Nascente AP, Machado FR and Freitas FG designed the study. Nascente AP collected all of the data. All authors helped with the data interpretation and drafting of the manuscript. All authors revised and approved the ﬁnal version of the manuscript.

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’ APPENDIX Table S1 - Changes in hemodynamic, respiratory and metabolic variables after vasopressin infusion – global analysis. Variables

Norepinephrine (mg/kg/min) Heart rate (bpm) MAP (mmHg) CVP (mmHg) PAOP (mmHg) mPAP (mmHg) CO (L/min) CI (L/min.m2) SI (ml/beat/m2) PPV (%) DO2 (ml/min) VO2 (mL/min) Extraction rate (%) PEEP (cmH2O) FiO2 (%) pO2/FiO2 ratio Lactate (mg/dL) a-vCO2 (mmHg) Urine output (ml/kg/h) SvO2 (%) Haemoglobin (g/dL)

T0 (n=18)

T1 (n=18)

T2 (n=15)

0.41 (0.23, 0.90) 107.4±19.7 72.56±6.2 11.6±5.0 9.6±4.5 27.6±8.0 7.8±2.9 4.4±1.2 40.8±12.4 5.0 (3.0, 10.5) 813.5 (676.2, 1153.0) 188.0 (142.0, 246.0) 24.6±7.1 9.6±3.6 0.40 (0.40, 0.50) 231.2 (169.4, 263.5) 30.3±17.3 3.7 (2.5, 4.7) 0.2 (0.0, 1.4) 73.6±6.5 9.0±1.4

0.31 (0.09, 0.76)* 102.7±19.9* 72.7±4.4 11.8±4.6 10.6±3.7 26.9±7.4 6.7±2.4* 3.7±0.9* 36.9±10.6 4.0 (2.1, 8.7) 738.5 (595.5, 939.5)* 171.0 (140.0, 203.0)* 25.6±7.9 9.6±3.6 0.40 (0.40, 0.50) 222.5 (187.6, 255.7) 27.6±15.8 4.6 (3.2, 6.5) 0.1 (0.0, 0.4) 70.9±7.7 8.8±1.4

0.56 (0.23, 0.85)* 110.53±18.9* 70.4±4,0 11.5±4.5 9.0±4.2 26.7±7.5 7.1±2.2* 4.0±0.8* 37.0±9.6 4.7 (4.0, 5.7) 740.0 (643.0, 1048.0) 196.0 (164.0, 225.0)* 25.0±7.1 9.5±3.9 0.4 (0.4, 0.5) 203.0 (185.0, 231.0) 29.6±15.4 4.7 (4.0, 5.7) 0.0 (0.0, 0.5) 72.4±6.7 8.8±1.5

Time points are defined as before (T0), during (T1) and after (T2) vasopressin infusion. MAP, mean arterial pressure; CVP, central venous pressure; PAOP, pulmonary artery occluded pressure; PAP, pulmonary artery pressure; CO, cardiac output; CI, cardiac index; SI, systolic index; PPV, pulse pressure variation; DO2, oxygen delivery; PEEP, positive end expiratory pressure; FiO2, fraction of inspired oxygen; pO2, oxygen partial pressure; DCO2, venous-arterial CO2 gradient; SvO2, oxygen mixed venous saturation. Data are expressed as number (%), mean±standard deviation or median (25%, 75%). * po0.05 vs. previous time point.

Table S2 - Changes in the microcirculatory variables after vasopressin infusion – global analysis. Variable TVD (mm/mm2) PVD (mm/mm2) PPV (%) MFI

15.1± 2.2 13.0±2.4 87.1 (83.0, 90.5) 2.7 (2.6, 2.9)

15.2±1.8 13.4±1.8 88.6 (84.1, 90.5) 2.9 (2.5, 3.0)

15.2±1.5 12.9±1.7 85.8 (83.4, 90.5) 2.7 (2.5, 3.0)

Time points are defined as before (T0), during (T1) and after (T2) vasopressin infusion. TVD, total vascular density; PPV, proportion of perfused vessels; PVD, perfused vascular density; MFI, microcirculatory flow index; HI, heterogeneity index. Data are expressed as mean±standard deviation or median (25%, 75%). * po0.05 vs. previous time point.

Table S3 - Multivariable regression model to changes in microcirculatory response. Independent variable

b coefficient±SE

TVD HR MAP CVP Lactate CI Noradrenaline dose*

-0.73±0.4 0.013±0.07 -0.15±0.31 0.09±0.34 -0.07±0.068 -0.83±0.81 4.8±2.3

OR 95% CI 0.479 1.013 0.855 1.104 0.925 0.433 5.611

(0.180 (0.877 (0.463 (0.566 (0.811 (0.088 (1.130

– – – – – – –

1.272) 1.172) 1.579) 2.154) 1.056) 2.128) 27.861)

p-value 0.14 0.85 0.61 0.77 0.25 0.30 0.03

* Noradrenaline dose was used as a categorized variable. Backward-elimination approach was tested and predictors were removed if significance level were more than 0.10. Independent variables at baseline were included: Total Vascular Density (TVD), hear rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), lactate, cardiac index (CI) and noradrenaline dose.

757

CLINICAL SCIENCE

Pain and quality of life in breast cancer patients Weruska Alcoforado Costa, Michelly No´brega Monteiro, Janice Franc¸a Queiroz, Ana Katherine Gonc¸alves* Universidade Federal do Rio Grande do Norte, Natal, RN, BR.

OBJECTIVE: To evaluate the influence of pain on quality of life in breast cancer patients. METHODS: A cross-sectional study of 400 patients, including 118 without metastasis, 160 with loco-regional metastasis and 122 with distant metastasis. The instruments used were the European Organization for Research and Treatment for Cancer Quality of Life Questionnaire-Core 30 and the Breast Cancer-specific 23 and short McGill Pain Questionnaire. RESULTS: In total, 71.7% of patients reported pain. The most frequent sensory descriptor used by patients was ‘jumping.’ In the evaluative dimension, the main descriptor chosen was troublesome. The Global Health self-assessment showed pain to be inversely correlated with quality of life: the group without metastasis had a mean score of 55.3 (SD=24.8) for those in pain, which rose to 69.7 (SD=19.2) for those without pain (p=0.001). Subjects with loco-regional metastasis had score of 59.1 (SD=21.3) when in pain, and those without pain had a significantly higher score of 72.4 (SD=18.6) (po0.001). Patients from the distant metastasis group showed similar results with a mean score of 48.6 (SD=23.1) for those in pain and 67.6 (SD=20.4) for those without pain (p=0.002). Regarding the association of pain intensity and quality of life, patients with distant metastasis and intense pain had the worst scores for quality of life with a functional scale mean of 49.9 (SD=17.3) (po0.009), a Symptom Scale score of 50.0 (SD=20.1) (po0.001) and a Global Health Scale score of 39.7 (SD=24.7) (po0.006). CONCLUSIONS: Pain compromises the quality of life of patients with breast cancer, particularly those with advanced stages of the disease. KEYWORDS: Breast Cancer; Quality of Life; Health-Related Quality of Life; Pain; Short McGill Pain Questionnaire. Costa WA, Monteiro MN, Queiroz JF, Gonc¸alves AK. Pain and quality of life in breast cancer patients. Clinics. 2017;72(12):758-763 Received for publication on May 20, 2017; First review completed on July 23, 2017; Accepted for publication on October 11, 2017 *Corresponding author. E-mail: anakatherine_ufrnet@yahoo.com.br

’ INTRODUCTION Breast cancer (BC) is often associated with long-term psychological distress, chronic pain, fatigue and impaired quality of life (QoL) (1-5). Approximately 20% to 50% of patients complain about pain, a number which rises to 90% for patients in metastatic or terminal stages (6-10). Pain is one of the most frequently reported adverse effects that occurs as part of the disease process or as a side-effect of treatment. It is a problem for a majority of BC patients and has an unfavorable effect on QoL (11-15). More recent epidemiological data obtained from a metaanalysis suggest that pain is prevalent in 39.3% of cases after curative treatment, 55.0% during cancer treatment, and in 66.4% in advanced or terminal stages of the disease (10). The frequency of pain increases as the disease progresses, causing physical, emotional, spiritual and functional discomfort. This impedes performance of daily activities and disturbs sleeping and eating habits. As a result, cognitive function is impaired

and affective, sexual and family relationships are strained, and work and leisure activities are difficult. This leads to greatly decreased QoL for these women (9). Pain is understood as a complex multidimensional experience that must be evaluated in its affective and cognitive dimension. Emotional and cognitive factors have a strong influence on pain perception (16-18); however, untreated pain affects physical, psychological, social and spiritual wellbeing (19,20). Pain is a stressful, individual and subjective human experience and has been associated with feelings of social isolation (21); thus, evaluating pain is one of the most challenging areas of care for this type of patient. The ability to accurately measure and interpret pain through valid and reliable tools or instruments may be clinically important in determining medical protocol and non-pharmaceutical interventions (22). The purpose of this study was to evaluate the influence of pain on the QoL of women with BC. A detailed evaluation of pain enables caretakers to create a strategy to reduce pain and prevent any secondary symptoms, which improves patient QoL.

’ MATERIALS AND METHODS This prospective study was conducted with 400 women diagnosed with BC undergoing chemotherapy, radiotherapy, surgery, hormone therapy, or exclusively in palliative care.

No potential conflict of interest was reported. DOI: 10.6061/clinics/2017(12)07

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A second questionnaire associated with the EORTC QLQC30, also translated and validated for use in Portuguese, was used to evaluate QoL. This instrument, EORTC BR23, is specifically used for BC patients and consists of 23 questions answered on a 4-point scale (from 1 to 4). It is composed of two scales: the Functional Scale composed of 4 sub-items (body image, sexual function, sexual pleasure and future perspectives) and the Symptom Scale consisting of 4 subitems (side effects of systemic therapy, breast symptoms, arm symptoms and hair loss) (26). The use of these questionnaires was authorized both by Ferreira et al. (24) and the EORTC group. All procedures required by the organization were conducted. Additionally, the Karnofsky Performance Status (KPS) was used to evaluate functional capacity. A descriptive analysis of the qualitative variables was performed through the absolute and relative frequency distribution. The T-test for independent samples was used to compare the mean total scores of the EORTC QLQ-C30 and BR23 variables for pain in the three groups of cancer patients. An analysis of variance (ANOVA) was performed to identify any existing correlations between all collected variables. Then, the Tukey test was applied to evaluate the magnitude of the latter. A significance level of 5% was used, and all calculations were performed using SPSS.V.13.

The study occurred in the oncology center at a referral hospital in a medium-sized city in the northeast of Brazil from July 2014 to April 2015. Patients were selected through non-probability sampling, and patient interviews were conducted during appointments or in the chemotherapy infusion room. A patient was considered eligible for the study if they were diagnosed with BC, undergoing treatment for the disease or exclusively in palliative care, and were over 18. Women without cognitive ability and/or verbalization, patients who had not started treatment, and those who had been previously diagnosed with depression were excluded. Three study groups were created within the sample: 1-118 patients without metastasis (MTX), 2- 160 patients with locoregional MTX and 3- 122 patients with distant MTX. Ethical issues were considered, and the Local Research Ethics Committee approved the present study (no. CAAE 17956113.9.0000.5293) in compliance with the Declaration of Helsinki and Resolution 466/12 of the Brazilian National Health Council, which addresses research on human beings. Before starting the interview, the study objectives were explained, and the patients participating in the study were asked to sign a free and informed consent form. This ensured that participation was voluntary and that answers would be kept anonymous and confidential. Pain was evaluated using the Short-Form McGill Pain Questionnaire (SF-MPQ) proposed by Melzack (23) and validated in Portuguese by Ferreira et al. (24). This version consists of 15 pain descriptors belonging to its three dimensions: Sensory (throbbing, jumping, flashing, sharp-pricking, tugging, burning, spreading, sore/aching), Affective (tiringexhausting, sickening, suffocating, frightful-blinding, nagging) and Evaluative (troublesome, unbearable). These descriptors were classified as ‘‘present’’ or ‘‘absent.’’ In addition to these descriptors, the instrument also integrates a Numeric Pain Rating Scale. The level of pain intensity was classified as mild, moderate and severe. These levels were based on the intensity with which each patient classified their pain on the Numerical Scale. Thus, 1 to 3 represents mild pain, whereas 4 to 6 represents moderate pain and 7 to 10 intense pain. The questionnaire also includes a Body Diagram to determine the location of the pain referred to by the subjects. To assess QoL, the European Organization device for Research and Treatment for Cancer Questionnaire-Core 30 (EORTC QLQ-C30) was used. This questionnaire is a valid and reliable evaluation of cancer patient QoL and has been considered useful in many clinical trials and studies. The EORTC QLQ-C30 (version 3.0) is composed of 30 items, embedded in three scales, corresponding to the patient’s condition in the past week. The first scale, the Functional Scale, consists of five domains: physical, emotional, social, cognitive, and role functioning. The second scale, the Scale of Symptoms, consists of three sub-scales (pain, fatigue, nausea and vomiting) and six single items (dyspnea, sleep disorders, loss of appetite, constipation, diarrhea, and financial difficulties) and finally, the Global health scale. Questions 1-28 are answered on a four-point scale, with each item classified from none (score value=1) to very much (score value=4). Questions 29 and 30 are answered on a seven-point scale going from bad (score value=1) to good (score value=7). All items were then linearly transposed onto a scale from 0 to 100. For the five functional scales and global health scale, a higher score indicates a higher level of functioning or overall QoL. Conversely, for the symptom scale and single items, a higher score implies a higher level of symptoms or problems (25).

’ RESULTS Evaluating the sociodemographic profile of the 400 women, we see that most women were between 51 to 60 years of age (28.8%) or 41 to 50 (28%), and 60% were from the countryside. Other sociodemographic characteristics show that more than half, or 54.8%, had only received an elementary school education, 51% were married, only 39.3% were on sick leave, and Catholicism predominated in 63.3% of the patients. Concerning clinical variables, 87% of the women had a tumor with the histological appearance of invasive ductal carcinoma, 40% had loco-regional MTX, 76.5% had undergone some prior treatment [surgery (68.5%), chemotherapy (52.5%), radiation (22.3%), hormonal therapy (29.3%) and/or therapy with bisphosphonates (12.8%)], and 99% were undergoing some type of treatment [(surgery--late post-surgery (4%), chemotherapy (70%), radiotherapy (4%), hormonal therapy (25.3%), and/or therapy with bisphosphonates (19,8%)] at the time of the interview. Table 1 describes the characteristics of pain, a common complaint among the women (71.7%). Pain was generally reported as diffuse in the three groups of patients. Those who reported pain in more than one site had some form of MTX (36.5% with loco-regional MTX and 45.7% with distant MTX). Interestingly, pain in the upper limbs was more prevalent in patients without MTX. Table 1 also addresses the nature of pain, classifying it according to the frequency of sensory descriptors. For the group without MTX, words such as jumping (70.1%), sore/ aching (65.7%) and sharp-pricking (61.2%) were most common. For loco-regional MTX, the subjects described the pain as jumping (80.9%), sore/aching (67.0%) and sharp-pricking (63.5%), whereas patients with distant MTX described it as sore/aching (74.3%), jumping (73.3%) and spreading (66.7%). Within the affective dimension, the most common descriptors for the group without MTX were sickening (61.2%) and nagging (59.7%). The loco-regional MTX group described it as tiring-exhausting (62.6%) and nagging (60.0%); likewise, the distant MTX group preferred words such as tiringexhausting (80.0%) and nagging (75.2%). In the evaluative

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Table 1 - Intensity and dimension of Pain in breast cancer

Table 2 - Correlation between the presence of Pain and Quality of Life (EORTC QLQC30/BR 23).

patients. Pain

Presence

Yes No Total Location Upper limb Chest Column In two locations Diffuse Total Dimension* Sensory Throbbing Jumping Flashing Sharp-pricking Tugging Burning Spreading Sore/aching Affective Tiring-exhausting Sickening Suffocating Frightful-blinding Nagging Evaluative Troublesome Unbearable

Presence of pain

Breast Cancer Patients Without MTX N (%)

Loco-regional MTX N (%)

Distant MTX N (%)

Total N (%)

67 (56.8) 51 (43.2) 118 (100.0)

115 (71.9) 45 (28.1) 160 (100.0)

105 (86.1) 17 (13.9) 122 (100.0)

287 (71.7) 113 (28.3) 400 (100.0)

19 12 00 24 12 67

(28.4) (17.9) (0.0) (35.8) (17.9) (100.0)

27 20 03 42 23 115

(23.5) (17.4) (2.6) (36.5) (20.0) (100.0)

05 07 09 48 36 105

(4.8) (6.7) (8.6) (45.7) (34.3) (100.0)

51 (17.8) 39 (13.6) 12 (4.2) 114 (39.7) 71 (24.7) 287(100.0)

34 47 22 41 36 26 27 44

(50.7) (70.1) (32.8) (61.2) (53.7) (38.8) (40.3) (65.7)

63 93 34 73 67 44 50 77

(54.8) (80.9) (29.6) (63.5) (58.3) (38.3) (43.5) (67.0)

54 77 48 57 53 44 70 78

(51.4) (73.3) (45.7) (54.3) (50.5) (41.9) (66.7) (74.3)

151 217 104 171 156 114 147 199

(52.6) (75.6) (29.8) (59.6) (54.3) (39.7) (51.2) (69.3)

37 41 14 14 40

(55.2) (61.2) (20.9) (20.9) (59.7)

72 68 10 14 69

(62.6) (59.1) (8.7) (12.2) (60.0)

84 68 29 27 79

(80.0) (64.8) (27.6) (25.7) (75.2)

187 177 53 55 188

(65.1) (61.7) (18.5) (19.2) (65.5)

47 (70.1) 06 (9.0)

96 (83.5) 14 (12.2)

95 (90.5) 25 (23.8)

Yes

EORTC QLQC30

Mean

238 (82.9) 45 (15.7)

Functional Scales Physical functioning Role functioning Cognitive functioning Emotional functioning Social functioning Symptom Scales Global Health Scales

59.8 69.9 37.1 65.9 47.0 77.1 29.0 55.3

Functional Scales Physical functioning Role functioning Cognitive functioning Emotional functioning Social functioning Symptom Scales Global Health Scales

63.9 69.7 38.8 75.5 55.6 79.8 29.0 59.1

Functional Scales Physical functioning Role functioning Cognitive functioning Emotional functioning Social functioning Symptom Scales Global Health Scales

54.1 54.0 27.1 70.5 47.9 77.1 39.6 48.6

Metastasis = MTX * Counted only for patients with pain.

EORTC BR23

dimension, the main descriptor chosen by BC patients was ‘‘troublesome’’ for those without MTX (70.1%), loco-regional MTX (83.5%) and distant MTX (90.5%). Table 2 displays the correlations found between the presence of pain and the different QoL domains (EORTC QLQ-C30 questionnaire): Women who reported pain obtained significantly different scores from those who had no complaints of pain. In the MTX-free group, the mean symptom scores for patients with pain and without pain were 29.0 (SD=15.3) and 13.4 (SD=10.8), respectively (po0.001). The mean Global Health score for patients with pain was 55.3 (SD=24.8), whereas it was 69.7 (SD=19.2) for those without pain (p=0.001). For the locoregional MTX group, the mean symptom score for patients with pain was 29.0 (SD=15.3), whereas those without pain had an average score of 13.4 (SD=10.8) (po0.001). On the Global Health Scale, patients in pain scored 59.1 (SD=21.3), and those without pain scored 72.4 (SD=18.6) (po0.001). For the group with distant MTX, the mean symptom scores for patients with pain and without pain were 39.6 (SD=19.5) and 17.5 (SD=10.0), respectively (po0.001). On the Global Health Scale, the mean score for those reporting pain was 48.6 (SD=23.1), whereas the mean score for those without pain was 67.6 (SD=20.4) (p=0.002). It is important to highlight that the higher the score on the symptom scale, the more symptoms were listed by the patient, thus compromising their QoL. Table 2 also shows us that the presence of pain significantly influences QoL in BC patients when evaluated by EORTC BR23. For patients with distant MTX, those who reported pain had a mean of 56.4 (SD=19.4), whereas those without pain had a mean of 68.4 (SD=13.9) (p=0.016). Patients without pain had a better score on self-image evaluation, thus

Functional Scales Body image Sexual functioning Sexual enjoyment Future perspective Symptom Scales

56.6 68.8 26.1 51.0 31.3 30.9

Functional Scales Body image Sexual functioning Sexual enjoyment Future perspective Symptom Scales

61.1 73.5 29.1 59.0 39.7 29.0

Functional Scales Body image Sexual functioning Sexual enjoyment Future perspective Symptom Scales

56.4 68.2 23.8 47.9 36.2 26.9

No SD

Mean

p-value SD

Without MTX 19.8 76.9 14.7 21.4 84.4 16.0 32.0 60.4 32.3 31.8 81.7 20.1 29.3 65.7 25.6 32.8 91.8 19.2 15.3 13.4 10.8 24.8 69.7 19.2 Loco-regional MTX 17.5 74.7 15.4 21.4 78.5 22.4 30.1 53.7 34.2 26.1 83.0 19.9 29.1 68.5 25.4 28.7 89.2 18.8 15.3 13.4 10.8 21.3 72.4 18.6 Distant MTX 17.4 73.1 17.5 27.4 74.5 23.9 31.3 53.9 36.1 30.2 79.4 23.9 27.7 70.1 29.0 29.6 88.2 20.2 19.5 17.5 10.0 23.1 67.6 20.4

Without MTX 20.2 67.8 15.7 30.9 84.3 22.1 27.9 27.8 28.8 32.8 58.7 31.4 37.1 47.1 39.5 18.5 13.0 13.0 Loco-regional MTX 17.4 71.0 12.0 27.5 87.0 17.4 29.5 21.8 28.6 35.4 56.4 28.5 39.5 65.2 41.0 15.3 13.4 10.8 Distant MTX 19.4 68.4 13.9 32.7 86.3 18.8 26.0 26.5 27.0 30.6 62.5 21.4 39.3 49.0 33.6 14.2 16.5 13.8

o0.001* o0.001* o0.001* 0.001* o0.001* 0.003* o0.001* 0.001* o0.001* 0.023* 0.008* 0.055 0.010* 0.017* o0.001* o0.001* o0.001* 0.004* 0.002* 0.249 0.003* 0.061 o0.001* 0.002*

0.001* 0.002* 0.753 0.400 0.029* o0.001* o0.001* o0.001* 0.159 0.812 o0.001* o0.001* 0.016* 0.003* 0.697 0.203 0.205 0.006*

Metastasis = MTX * T-test.

demonstrating how pain can influence self-esteem and how the limbic system influences pain. On the Symptom Scale, the same group of patients obtained a mean of 26.9 (SD=14.2) for those who were in pain and an average of 16.5 (SD=13.8) for those without pain (p=0.006). Table 3 not only displays the relationship between pain and QoL but also a possible association between pain intensity and better or worse QoL. Patients with distant MTX who rate their pain as ‘‘intense’’ are those with the worst scores on the QoL assessment, with a mean functional score of 49.9 (SD=17.3) (po0.009), a mean symptom score of

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Table 3 - Correlation between the level of Pain, Quality of Life and Functional capacity. Intensity of pain Mild

EORTC QLQ30/KPS

Moderate

Mean

Functional Scales Physical functioning Role functioning Cognitive functioning Emotional functioning Social functioning Symptom Scales Global Health Scales KPS

69.3a 81.2a 43.8 73.2 58.9a 83.3 22.1a 60.1 92.9a

16.6 13.7 29.3 30.9 31.2 29.0 15.2 21.8 6.6

54.0b 64.0b 32.1 58.9 40.2b 73.8 30.3ab 51.8 86.1b

Functional Scales Physical functioning Role functioning Cognitive functioning Emotional functioning Social functioning Symptom Scales Global Health Scales KPS

24.1 73.6 40.2 74.0 57.9 80.5 27.5a 59.3 88.5a

13.3 22.1 30.3 27.4 28.9 27.9 13.9 20.8 7.3

73.6 67.5 41.7 80.1 58.3 75.7 33.6ab 60.1 87.4a

Functional Scales Physical functioning Role functioning Cognitive functioning Emotional functioning Social functioning Symptom Scales Global Health Scales KPS

61.7a 65.6a 39.5 76.3 53.5 76.3 23.6a 50.0a 78.9a

15.4 22.7 33.9 25.0 31.2 30.1 10.5 20.2 8.7

56.1ab 56.3ab 56.3 65.6 52.8 80.1 37.5b 55.5ab 75.5a

Intense SD

Without MTX 18.6 23.4 32.7 31.2 25.7 35.3 16.8 24.1 10.7 Loco-regional MTX 14.5 21.1 32.5 23.7 28.2 31.0 14.3 21.9 9.7 Distant MTX 16.8 26.1 26.1 32.7 25.5 24.7 16.8 20.6 69.0

p-value

Mean

50.3b 56.4b 33.3 65.1 34.1b 69.7 39.4b 52.3 80.0b

22.0 19.8 36.5 34.5 23.7 35.6 15.1 32.9 13.4

0.003* o0.001* 0.370 0.246 0.014* 0.402 0.009* 0.416 0.001*

38.2 66.7 30.3 70.2 47.3 85.7 23.5b 55.9 82.5b

14.8 21.1 21.8 27.7 29.7 25.9 16.8 20.3 8.8

0.321 0.295 0.249 0.264 0.228 0.347 0.015* 0.698 0.013*

47.9b 45.6b 19.2 73.5 39.3 73.9 50.0c 39.7b 69.0b

17.3 29.0 28.0 29.3 26.9 34.8 20.1 24.7 13.9

0.009* 0.024* 0.061 0.317 0.048 0.625 o0.001* 0.006* 0.040*

Metastasis = MTX * ANOVA - test. a,ab,b: Tukey test - the means of the different letters are statistically significant.

The occurrence of pain may be due to the disease process itself or as treatment aftermath, such as post-mastectomy pain, chemotherapy-induced neuropathy or brachial plexus neuropathy from radiation therapy (28-30). This makes pain a significant problem for most women with BC, causing a negative effect on QoL. Despite cancer pain having been very prevalent in this study (71.7% of all groups), even in the non-metastatic group (56.8), the heterogeneity of sociodemographic and clinical characteristics of the subjects did not allow a specific statistical additional comparison between groups. This result was similar to that found by Tamai et al. (31), Nabila et al. (19), and Starkweather et al. (13). Most patients in the sample had distant MTX, which agrees with the literature wherein bone, along with the lungs, is one of the major sites affected by metastatic BC (32,33). In a recent cohort study (34), bone was found to be the first site for metastatic development in 41% of the women. Bone MTX are considered the main cause of cancer pain, impairing functional capacity and limiting QoL (28,32,35). The use of descriptors in the evaluation of pain has been increasingly considered pertinent to research and everyday clinical practice. These words help professionals determine type of pain and appropriate therapy to provide patients with the most pain relief and QoL possible (36). The SF-MPQ showed us that the descriptors most used by the studied population were sore/aching, nagging and troublesome. In agreement with our findings, in a study of 453 Norwegian cancer patients, the most commonly used descriptor for pain

50.0 (SD=20.1) (po0.001) and a Global Health Scale mean of 39.7 (SD=24.7) (po0.006). Functional capacity assessed by the KPS also showed a significant correlation between increased pain intensity and decreased QoL. The latter was observed in all three groups of patients. Women with distant MTX who reported intense pain obtained a mean KPS of 69.0 (SD=13.9) whereas mild pain reports reached a mean KPS of 78.9 (SD=8.7) (po0.040). Pain intensity was also evaluated by EORTC BR23, as shown in Table 4. Patients with distant MTX who defined their pain as ‘‘intense’’ scored worse on the Symptom Scale when evaluating QOL, with a mean of 32.1 (SD=14.8) (p=0.012). This same association was also observed in the sub-item related to ‘‘symptoms of the arm’’ with a mean of 40.7 (SD=29.4) (p=0.001).

’ DISCUSSION Pain is one of the most common and distressing symptoms experienced by cancer patients. Cancer pain involves physical, social, psychological and spiritual components, all of which belong to the term ‘‘total pain’’, which is used to refer to the multidimensional nature of pain (Cicely Saunders). The contribution of each component varies based on both individual factors and circumstances faced by the patient. Therefore, the perception of pain is affected by several variables such as fatigue, insomnia, fear, anxiety, anger, sadness, depression, social isolation, altered perception of self-image and impairment of functional capacity (27).

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Table 4 - Correlation between the level of Pain and Quality of Life in breast cancer women. Intensity of pain Mild

EORTC BR23

Moderate

Mean

Symptom Scales Systemic therapy side effects Breast symptoms Arm symptoms Upset by hair loss

26.1 30.3 32.4 14.7a 5.9

17.7 24.1 18.3 18.4 43.6

33.2 35.9 34.8 31.7a 11.9

Symptom Scales Systemic therapy side effects Breast symptoms Arm symptoms Upset by hair loss

30.7 31.0 39.0 27.0 12.2

14.8 18.4 20.2 20.0 22.1

32.3 38.0 30.8 26.1 12.3

Symptom Scales Systemic therapy side effects Breast symptoms Arm symptoms Upset by hair loss

22.6a 24.8 27.2 22.2a 10.5

10.8 14.5 14.4 22.2 31.5

24.3b 27.9 27.7 21.7b 7.1

Intense SD

Without MTX 17.8 25.9 20.8 25.4 53.4 Loco-regional MTX 15.0 23.4 19.5 19.8 25.7 Distant MTX 13.8 19.9 19.2 17.9 42.2

p-value

Mean

37.6 39.8 32.6 45.5b 18.2

20.6 21.8 29.9 21.3 58.4

0.154 0.495 0.908 o0.001* 0.779

26.3 26.5 32.1 26.0 7.1

13.5 21.0 19.2 19.6 18.9

0.225 0.073 0.145 0.974 0.591

32.1b 36.1 29.1 40.7b 10.3

14.8 18.5 27.4 29.4 42.7

0.012* 0.046 0.939 0.001* 0.920

Metastasis = MTX * ANOVA -test. Tukey test - the means of the different letters are statistically significant.

a,ab,b:

between QoL and pain seems to be inversely proportional because the higher the pain, the lower the QoL. In accordance with our results, the study by Nesvold et al. (40) identified a significant relationship between the related arm and shoulder problems of women with BC and QoL. It is interesting to note that among those without MTX, those with pain had lower means than those without pain for the Future Perspectives item. We believe that this reflects the fact that pain is one of the most feared symptoms, and its presence causes patients worry about its possible cause. This may lead to further worrying about the possibility of MTX and disease progression and consequently one’s mortality. Despite these interesting findings, the present study should be interpreted with caution in light of its limitations. Pain was evaluated based on self-assessment and included estimates in relation to length of time, without the use of physical parameters. We recognize that some treatments by themselves can highly influence pain and QoL of these patients, and the correlation of these parameters with the results would be desirable; however, the heterogeneity of the used protocols made that impossible. Therefore, the results do not take into account the influence of confounding factors and the sample homogeneity. Further studies using different approaches with longitudinal design may provide better explanations of the complex manifestation of breast cancer. BC is the most frequent cancer in women worldwide, and pain is one of the most common symptoms, compromising QoL. In this study, pain was highly prevalent and was detected in 71% of the patients. These findings are significant and justify more attention in the management of these patients in daily practice to minimize this unpleasant symptom that damages functional capacity and haunts the patients emotionally.

was aching (36). Data obtained from another study found that the most common descriptors were throbbing and tiringexhausting (19,31,35). When analyzing the association between the presence of pain and the EORTC domains, it was determined that pain negatively influenced QoL. This was true for the patients with and without MTX. The Global Health scale showed that women in pain considered themselves less healthy overall compared to those without pain (p=0.002). The effect of pain on QoL is not only related to the intensity of pain experienced by patients but also to how pain is perceived in its multidimensional aspect (16,17,37). Our findings identified that patients who classified their pain as intense and suffered from MTX had lower mean values on the Global Health Scale. The results clearly show that the group of patients with distant MTX with acute pain was strongly associated with a decrease in QoL. Pain seemed to impact QoL primarily in patients with distant MTX. These patients not only deal with acute pain but also have significant impairment of the Functional and Symptom Scales. They also suffer from poor body image and are emotionally scarred by the process of treatment and lack of functional capacity. The latter may be because the patient is often disfigured by the palliative treatments made necessary by advanced disease (38). In addition, the perception of pain may contribute to a warped self-image due to the limbic system’s influence on the complexity of pain behavior. Corroborating our findings, a survey of 1965 women with BC conducted in Australia found sexual function to be reduced due to pain and negative body image (39). Interestingly, among those without MTX, those with pain had lower means than those without for the Future Perspectives item. We believe that this reflects the fact that pain is one of the most feared symptoms, and its presence causes patients worry about its possible cause. This may lead to further worrying about the possibility of MTX and disease progression and consequently one’s mortality. The Relationship

’ AUTHOR CONTRIBUTIONS Costa WA was responsible for planning the research, collecting the quantitative data, discussing the results and writing the manuscript.

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Monteiro MN was responsible for analyzing the qualitative data and discussing the results. Queiroz JF was responsible for analyzing the qualitative data, discussing the results and writing the manuscript. Gonc¸alves AK was responsible for planning and supervising the research, analyzing the data, discussing the results, producing the ﬁnal revisions and submitting the manuscript.

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The relationship between malignant wound status and pain in breast cancer patients. Eur J Oncol Nurs. 2016;24:8-12, http://dx.doi.org/10.1016/j.ejon.2016.05.004. 32. Fontanella C, Fanotto V, Rihawi K, Aprile G, Puglisi F. Skeletal metastases from breast cancer: pathogenesis of bone tropism and treatment strategy. Clin Exp Metastasis. 2015;32(8):819-33, http://dx.doi.org/10.1007/s10585015-9743-0. 33. Piccioli A, Maccauro G, Spinelli MS, Biagini R, Rossi B. Bone metastases of unknown origin: epidemiology and principles of management. J Orthop Traumatol. 2015;16(2):81-6, http://dx.doi.org/10.1007/s10195015-0344-0. 34. Berman AT, Thukral AD, Hwang WT, Solin LJ, Vapiwala N. Incidence and patterns of distant metastases for patients with early-stage breast cancer after breast conservation treatment. Clin. Breast Cancer. 2013;13(2):88-94, http://dx.doi.org/10.1016/j.clbc.2012.11.001. 35. Shibata H, Kato S, Sekine I, Abe K, Iguchi H, Izumi T, et al. Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology. ESMO Open. 2016;1(2):e000037, http://dx.doi.org/10.1136/esmoopen-2016000037. 36. Holtan A, Kongsgaard UE. The use of pain descriptors in cancer patients. J Pain Symptom Manage. 2009;38(2):208-15, http://dx.doi.org/10.1016/ j.jpainsymman.2008.08.008. 37. Lamé IE, Peters ML, Vlaeyen JW, Kleef Mv, Patijn J. Quality of life in chronic pain is more associated with beliefs about pain, than with pain intensity. Eur J Pain. 2005;9(1):15-24, http://dx.doi.org/10.1016/j.ejpain. 2004.02.006. 38. Chen CL, Liao MN, Chen SC, Chan PL, Chen SC. Body image and its predictors in breast cancer patients receiving surgery. Cancer Nurs. 2012;35(5):E10-6, http://dx.doi.org/10.1097/NCC.0b013e3182336f8b. 39. Ussher JM, Perz J, Gilbert E. 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CLINICAL SCIENCE

Characteristics and Outcomes of Intensive Care Unit Survivors: Experience of a Multidisciplinary Outpatient Clinic in a Teaching Hospital Pe´ricles A.D. Duarte,I,* Jaquilene Barreto Costa,II Silvana Trilo Duarte,III Sheila Taba,II Claudia Regina Felicetti Lordani,IV Erica Fernanda Osaku,I,V Claudia Rejane Lima Macedo Costa,I,V Dalas Cristina Miglioranza,VI Daniela Prochnow Gund,VI Amaury Cesar JorgeI I

Unidade de Terapia Intensiva Geral, Hospital Universitario do Oeste do Parana, Cascavel, PR, BR. II Departamento de Psicologia, Hospital Universitario do Oeste do Parana, Cascavel, PR, BR. III Departamento de Fonoaudiologia, Hospital Universitario do Oeste do Parana, Cascavel, PR, BR. IV Departamento de Nutricao Clinica, Hospital Universitario do Oeste do Parana, Cascavel, PR, BR. V Departamento de Fisioterapia, Hospital Universitario do Oeste do Parana, Cascavel, PR, BR. VI Departamento de Servico Social, Hospital Universitario do Oeste do Parana, Cascavel, PR, BR.

OBJECTIVES: To describe the experience of an outpatient clinic with the multidisciplinary evaluation of intensive care unit survivors and to analyze their social, psychological, and physical characteristics in a low-income population and a developing country. METHODS: Retrospective cohort study. Adult survivors from a general intensive care unit were evaluated three months after discharge in a post-intensive care unit outpatient multidisciplinary clinic over a period of 6 years (2008-2014) in a University Hospital in southern Brazil. RESULTS: A total of 688 out of 1945 intensive care unit survivors received care at the clinic. Of these, 45.2% had psychological disorders (particularly depression), 49.0% had respiratory impairments (abnormal spirometry), and 24.6% had moderate to intense dyspnea during daily life activities. Patients experienced weight loss during hospitalization (mean=11.7%) but good recovery after discharge (mean gain=9.1%), and 94.6% were receiving nutrition orally. One-third of patients showed a reduction of peripheral muscular strength, and 5.7% had moderate to severe tetraparesis or tetraplegia. There was a significant impairment in quality of life (SF-36), particularly in the physical and emotional aspects and in functional capacity. The economic impacts on the affected families, which were mostly low-income families, were considerable. Most patients did not have full access to rehabilitation services, even though half of the families were receiving financial support from the government. CONCLUSIONS: A significant number of intensive care unit survivors evaluated 3 months after discharge had psychological, respiratory, motor, and socioeconomic problems; these findings highlight that strategies aimed to assist critically ill patients should be extended to the post-hospitalization period and that this problem is particularly important in low-income populations. KEYWORDS: Critical Care; Epidemiology; Rehabilitation; Quality of Life. Duarte PA, Costa JB, Duarte ST, Taba S, Lordani CR, Osaku EF, et al. Characteristics and Outcomes of Intensive Care Unit Survivors: Experience of a Multidisciplinary Outpatient Clinic in a Teaching Hospital. Clinics. 2017;72(12):764-772 Received for publication on June 9, 2017; First review completed on August 8, 2017; Accepted for publication on October 16, 2017 *Corresponding author. E-mail: pericles.duarte@unioeste.br

’ INTRODUCTION

during hospitalization and after discharge from the ICU (1,2). In post-ICU follow-ups, psychological complications (such as depression and post-traumatic stress disorder [PTSD]), as well as motor (i.e., post-critical illness tetraparesis) and respiratory complications (i.e., restrictive and obstructive disorders) have been reported (3-5). Still, the number of studies that have focused on the social and economic impacts of acute illness or on admission to an ICU is low (6). These topics are particularly important when considering the high intrinsic costs of an ICU admission and the wide variety of locations and countries that face the problem of post-ICU complications. Specifically, despite recent studies that have evaluated different characteristics of post-ICU patients (7-9), the economic and social impacts

As the survival rates of patients admitted to intensive care units (ICUs) improve, concerns have arisen regarding mid- to long-term morbidity in this population. Patients who survive a critical illness and hospitalization in an ICU (ICU survivors) may develop physical and/or psychological complications Copyright & 2017 CLINICS – This is an Open Access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/ 4.0/) which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited. No potential conflict of interest was reported. DOI: 10.6061/clinics/2017(12)08

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already discharged (and were therefore at home), and attended the outpatient evaluation. Once the patient attended the consultation at the clinic, no exclusion criteria were applied. However, in practice, not all evaluations could be conducted for each patient depended on the patient’s condition. For example, the psychological interview could not be performed with nonverbal patients or patients who had significant post-ICU neurological sequelae (detected during the outpatient consultation). For this reason, the number of patients per evaluation varies in the descriptions of the results.

have been poorly assessed and described in low-income and developing countries, and the data are scarce. Most of the data used by the field was published by services in countries with higher economic development. Therefore, dissemination of an ICU survivor follow-up policy for low-income countries is extremely important in order to manage the quality of hospital assistance, monitor health rehabilitation, and plan costs and healthcare programs in these places. This study aimed to describe the experience of an outpatient clinic that performed follow-up assessments of a general adult population of ICU survivors in a teaching hospital in a southern Brazilian city, analyzing the patients’ demographic, clinical, and socioeconomic profiles, together with the current clinical conditions of these survivors.

Protocols, criteria, and instruments During the ICU stay, the patients were treated according to the protocols of the ICU regarding mechanical ventilation and weaning, sedation, nutrition and management of specific conditions such as sepsis and trauma. Acute respiratory distress syndrome (ARDS) was identified retrospectively in accordance with the Berlin Definition (10). Sepsis was defined according to the ACCP/SCCM Consensus (11) (available at the time of the study). Trauma was defined as any acute condition caused by an external agent and included traffic accidents, violence (e.g., beatings, injuries from firearms or non-firearm weapons), falls, and workplace accidents, among others. The diagnostic definition of each acute or chronic disease (e.g., Chronic Obstructive Pulmonary Disease [COPD], Chronic Heart Failure [CHF]) was in accordance with the clinical diagnosis of the assisting medical team. The Hospital Anxiety and Depression Scale (HADS) (12) was used to assess psychological complications in the outpatient evaluation, and the Impact of Event Scale-Revised (IES-R) was used to assess PTSD symptoms (13); the cut-off scores were X9 and 420, respectively. The nutritional evaluation was performed by measuring the weight and height of the patient and reviewing the measurements or estimates of the weight made during hospitalization and discharge. The current form of nutrition (i.e., oral, enteral or gastrostomy) was recorded. The physiotherapeutic evaluation comprised an analysis of respiratory and motor functions. Participants completed a questionnaire regarding dyspnea during different activities of daily living using a modified Borg scale (14). To assess respiratory muscle strength, a manovacuometer was used to measure the maximum inspiratory pressure (MaxIP) and maximum expiratory pressure (MaxEP). Muscle strength was evaluated by clinical examination using the Medical Research Council scale (15). Spirometry tests were performed using a One Flow Soft 1.2s device (Essex, UK). When possible (because many patients were wheelchair-bound or bedridden), patients underwent a 6-minute walk test, and dyspnea evaluations and pulse oximetry were subsequently performed. Social and economic conditions were assessed by the social worker using a questionnaire that assessed family income, the number of residents in the home, labor status, and financial support from the government. The psychologist evaluated the quality of life with a questionnaire using the Short-Form Health survey (SF-36) scale (16). The mean value for each dimension was considered.

’ METHODS This cohort observational study investigated general adult ICU survivors in a teaching hospital in the western region of the state of Paraná (southern Brazil) from December 2007 to December 2014. Western Paraná University Hospital has 190 beds and is the tertiary reference center for 26 nearby municipalities (approximately 1.5 million inhabitants). The general ICU is a mixed unit (medical, surgical, and trauma). The ICU had 9 beds until 2012, when it was expanded to 14 beds. Both the hospital and outpatient clinical records were analyzed to include patients admitted to the general adult ICU from December 2007 to December 2014 who were discharged alive from the hospital and evaluated at the Post-ICU Outpatient Clinic 3 months later. (Thus, the patients were evaluated at the Post-ICU Outpatient clinic between February 2008 and February 2015). The data were tabulated in a Microsoft Excel spreadsheet containing data from the hospital and ICU stay, social and demographic characteristics, and from the consultations with the different professionals in the Post-ICU Outpatient Clinic.

Post-ICU Outpatient Clinic The Post-ICU Outpatient Clinic has a multidisciplinary team comprising a physician, nurse, physiotherapist, nutritionist, psychologist, speech therapist, and social worker. All professionals who work in the outpatient clinic are also members of the general ICU team. Three months after discharge from the ICU, the patients were invited by telephone to come to the outpatient clinic, where they were seen by each professional on the team in a single session. Questionnaires and tests from each specialty were administered and lasted approximately 30 minutes for each professional. Patients who failed to attend were actively followed up by telephone, and a new date was scheduled. Patients who failed to appear after two attempts were excluded. Each patient was evaluated only once at the clinic, with no follow-up after this consultation. When necessary, the patient was referred to medical follow-up. The Post-ICU Outpatient clinic routines described herein were implemented and followed at the outpatient clinic independently of the current study. In this article, we only describe the results found during the study period.

Inclusion and exclusion criteria Statistical analysis

All patients hospitalized during the study period were included if they met the following criteria: stayed more than 24 hours in the ICU, were 18 years of age or older, were

Descriptive statistical analysis was performed, and the percentages were compared using the chi-square test.

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hospital mortality than non-medical patients), admission Acute Physiology and Chronic Health Evaluation (APACHE) II score, comorbid conditions (particularly COPD), and the use of invasive mechanical ventilation (MV) (see Appendix; data are not related to post-ICU patients and only related to ICU patients). In contrast, when comparing the survivors and patients seen at the outpatient clinic, only differences in the presence of comorbid conditions were observed (Table 1). At the outpatient evaluation, 45.2% of the patients exhibited a psychological alteration, including depression, anxiety, and PTSD symptoms. More than one problem was detected in nearly half (46.8%) of these patients. Most patients (84.4%) described having some memory of the events in the ICU. Of this group, 39.1% recalled memories of real events, and 45.3% had illusion memories (alone or in combination with real facts), such as dreams (13.3%), nightmares (7.0%), and hallucinations (25.0%). Regarding the nutritional evaluation, nearly all participants (94.6%) (Table 3) were eating by mouth at the time of the outpatient evaluation, even though most received enteral nutrition during their hospital stay. The group had an 11.7% mean weight loss during the hospitalization period, with a 9.1% gain between hospital discharge and the outpatient consultation. Motor impairment was common: 31.8% of the patients (Table 2) had a moderate or intense reduction in the strength of their extremities, and 5.7% had moderate or severe tetraparesis or tetraplegia. Respiratory impairment was even more common than the motor impairment (Table 2). Half of the patients (49.0%) had abnormal spirometry tests. The most common finding was obstructive impairment. However, diaphragm muscle strength (estimated by MaxIP) was adequate: the median result was

The occurrence of baseline characteristics was expressed as the frequency, mean, and standard deviation. The analyses of the baseline and epidemiological data and outcome was conducted using Student’s t-test, analysis of variance, and the Tukey test, assuming a significance level of po0.05. This study was conducted in accordance with the recommendations of Resolution 466/2012 of the Brazilian National Health Council. The project was approved by Western Paraná State University’s Permanent Committee on Ethics and Research involving human beings. Accordingly, postinformed consent was waived since the current study only describes the results of a population that had already previously been treated.

’ RESULTS During the study period, 2617 patients were admitted to the general ICU, and 1945 (74.3%) survived. Patients who were discharged alive from the ICU were transferred to the hospital ward. Of these patients, 688 were evaluated in the Post-ICU Outpatient Clinic (Figure 1). The most common reasons given for not attending the scheduled consultation (non-tabulated data) were a) transportation difficulties since a considerable number of patients lived in other municipalities; b) difficulty arranging for a family member to transport the patient to the consultation, especially in cases of elderly patients; and c) the patient’s clinical condition and limitations (e.g., a bedridden status or difficulty walking). The clinical and epidemiological characteristics of the patients admitted to the ICU, the survivors, and the patients seen at the Outpatient Clinic are presented in Table 1. As expected, differences were detected between the patients admitted to the ICU and the survivors regarding the following: age, reason for hospitalization (medical patients had higher

Figure 1 - Patient flow. ICU: Intensive Care Unit.

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Table 1 - Patient demographic and clinical characteristics.

n Male (%) Age, years, n (%) o40 41-60 61-75 475 Reason for hospitalization, n (%) Trauma Medical Elective surgery Non-traumatic urgent surgery APACHE II, n (%) o5 6-10 11-20 21-30 430 Comorbid conditions, n (%) One or more comorbid condition AIDS Recent/current cancer DM Illicit drugs COPD Alcoholism SH CHF CRF Moderate/severe obesity Use of MV, n (%) Time on MV, days, n (%) 0 1-5 6-10 410 ICU mortality, n (%) Hospital mortality, n (%)

ICU Total

ICU Survivors

Not attending the Outpatient Clinic

Attending the Outpatient Clinic

2617 1639 (62.6%) ---1081 (41.3%) 803 (30.7%) 524 (20.0%) 209 (8.0%) --963 (36.8%) 916 (35.0%) 429 (16.4%) 309 (11.8%) ---39 (1.5%) 188 (7.2%) 882 (33.7%) 1055 (40.3%) 453 (17.3%) --1633 (62.4%) 49 (1.9%) 248 (10.7%) 237 (9.1%) 64 (2.4%) 175 (6.7%) 243 (9.3%) 589 (22.5%) 162 (6.2%) 61 (2.3%) 170 (6.5%) 2269 (86.7%) --348 (13.3%) 1112 (42.5%) 487 (18.6%) 670 (25.6%) 672 (25.7%) 759 (29.0%)

1945 1227 (63.1%) ---897 (46.1%) 567 (29.2%) 350 (18.0%) 131 (6.7%) --761 (39.1%) 570 (29.3%) 393 (20.2%) 221 (11.4%) ---38 (2.0%) 174 (8.9%) 788 (40.5%) 760 (39.1%) 185 (9.5%) --1157 (59.5%) 32 (1.6%) 225 (11.6%) 175 (9.0%) 54 (2.8%) 87 (4.5%) 210 (10.8%) 486 (25.0%) 126 (6.5%) 41 (2.1%) 103 (5.3%) 1610 (82.8%) --335 (17.2%) 811 (41.7%) 335 (17.2%) 464 (23.9%) --121 (6.2%)

1257 801 (63,7%)

688 433 (62.9%) ---335 (48.7%) 212 (30.8%) 109 (15.8%) 32 (4.7%) --290 (42.1%) 180 (26.2%) 136 (19.8%) 82 (11.9%) ---14 (1.9%) 65 (9.5%) 260 (37.8%) 292 (42.5%) 57 (8.3%) --456 (66.3%) 07 (1.0%) 76 (11.0%) 78 (11.3%) 26 (3.8%) 33 (4.8%) 118 (17.1%) 204 (29.6%) 38 (5.5%) 07 (1.0%) 47 (6.8%) 573 (83.3%) --115 (16.7%) 298 (43.3%) 117 (17.0%) 158 (23.0%) -----

563 347 249 98

(44.8%) (27.6%) (19.8%) (7.8%)

478 386 257 136

(38.1%) (30.7%) (20.4%) (10.8%)

24 115 525 465 128

(1.9%) (9.1%) (41.8%) (37.0%) (10.2%)

701 24 149 97 28 54 92 282 88 34 56 1037

(55.8%) (1.9%) (11.8%) (7.7%) (2.2%) (4.3%) (7.3%) (22.4%) (7.0%) (2.7%) (4.4%) (82.5%)

220 513 218 306

(17.5%) (40.8%) (17.3%) (24.4%) -----

p-value Survivors (attending vs. not attending the Outpatient Clinic) ---0.962 ---0.075

---0.134

---0.129

---0.002 0.343 0.722 0.092 0.238 0.828 o0.001 0.021 0.401 0.091 0.173 0.810 --0.493

-----

AIDS: Acquired Immunodeficiency Syndrome; APACHE: Acute Physiology and Chronic Health Evaluation; CHF: Congestive Heart Failure; COPD: Chronic Obstructive Pulmonary Disease; CRF: Chronic Renal Failure; DM: Diabetes Mellitus; ICU: Intensive Care Unit; MV: Mechanical Ventilation; SH: Systemic Hypertension.

â&#x20AC;&#x2122; DISCUSSION

70.0 mmHg, and only 14.1% exhibited MaxIPo40 mmHg. Dyspnea while performing routine daily activities (such as walking, cooking, or showering) was either mild or absent for 58.5% of the participants, and only 9.3% had intense dyspnea during physical activities. Most patients were in precarious financial and social situations: over half had a total family income that was less than US$550.00 per month (Figure 2). Furthermore, half of the families (53.4%) were receiving some kind of financial support from the government (either at the federal, state, or municipal level) at the time of the outpatient evaluation. Among the 211 patients evaluated, 44 (20.8%) were retired or pensioners, 16 (7.6%) were unemployed, 13 (6.2%) were students, and 138 (65.4%) were formal or informal workers (13.8% of whom had returned to work). The SF-36 questionnaire evaluation (Figure 3) showed a significant impairment in quality of life related to health; the mean score was low in all evaluated domains. The most affected items were physical functioning, physical role limitation, pain, and emotional role limitation.

Despite the variety of factors associated with admission to an ICU (particularly the different kinds of diseases and conditions that affect this patient population), multiple mid- and long-term complications can clearly occur among ICU survivors. Such complications are proportional to the severity of the critical illness (e.g., organ failure), comorbidities and factors related to treatment in the ICU (17-19). Mental disorders such as anxiety, depression, and PTSD may appear after hospitalization in an ICU. In our study, one of these disorders was detected in nearly half of the patients, and more importantly, almost 25% of the patients had more than one disorder. Previous studies have reported a prevalence of post-discharge anxiety ranging from 11.9% (20) to 44% (21), and the rates of post-discharge depression vary from 9.7% (20) to 30% (22). These studies also show that 14% to 27% of patients may develop PTSD (22-24). In patients admitted to an ICU, the highest rates of psychological complications (anxiety and depression) were associated with

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Table 2 - Physiotherapeutic and nutritional evaluation at the post-ICU outpatient clinic. Physiotherapeutic evaluation n=591 (with exception of spirometry) MaxIP, mmHg o{-20} {-20} to {-40} 4{-40} Muscular strength (MRC scale) All limbs 4 or 5 (‘‘normal’’) Hemiparesis/hemiplegia Severe paraparesis or paraplegia Moderate tetraparesis Severe tetraparesis or tetraplegia Spirometry, n=427 Normal Restrictive Obstructive Dyspnea on physical exertion, Borg scale 0-1 2-4 5-8 9-10

Nutritional evaluation n=542 Current feeding route Oral Enteral/gastric tube Gastrostomy/Jejunostomy Oral + Enteral

94.6% 2.6% 2.2% 0.6%

68.2% 4.9% 1.6% 4.7% 1.0%

% Weight loss during hospitalization 0 0.1-5% 5.1-10% 10.1-20% 20.1-30%

23.5% 7.5% 17.7% 31.4% 12.8%

51.0% 11.2% 37.8%

430% % Weight gain between discharge from hospital and outpatient consultation 0 0.1-5% 5.1-10% 10.1-20% 20.1-30% 430%

5.4% 8.7% 85.9%

58.5% 16.9% 15.3% 9.3%

7.1%

34.4% 11.4% 18.5% 22.5% 9.2% 4.0%

ICU: Intensive Care Unit; mmHg: Millimeters of mercury; MaxIP: Maximum Inspiratory Pressure; MRC: Medical Research Council; BMI: Body Mass Index.

Table 3 - Psychological evaluation at the Post-ICU Outpatient Clinic (n=628). Psychological problems (%) No: 56.9% Yes: 43.1% HADS Anxiety Depression IES-R PTSD Memories of events in the ICU, % No Yes Real events Illusion memories Combination (illusions and real events)

Mean ± SD 5.4 ± 4.83 4.7 ± 4.83

0-9 70.8% 77.4%

10-20 29.2% 22.6%

420 -----

9.2 ± 11.81

69.9%

13.9%

16.2%

15.6% 84.4% 39.1% 5.5% 39.8%

ICU: Intensive Care Unit; HADS: Hospital Anxiety and Depression Scale; IES-R: Impact of Event Scale-Revised; PTSD: Post-Traumatic Stress Disorder. The incidence of psychological problems also includes patients with more than one condition (e.g., anxiety + depression).

confirms the need for follow-up outpatient clinics; however, few services follow their patients after discharge from the ICU, and the number of rehabilitation services that focus on patient recovery is small. A Brazilian study has shown that up to 40% of ICU survivors require rehospitalization during the first year post-ICU (18). Consequently, the concept of critical patient care expands to a more encompassing care perspective, and intensive care is considered a continuum that should also include patient follow-up after discharge. Our respiratory evaluation results indicate that most of the patients did not present a significant gas exchange compromise and had adequate respiratory muscle strength. In addition, only a minority of the patients had moderate/severe dyspnea. The literature shows that the degree of respiratory impairment in survivors depends on the primary etiology of respiratory failure in the ICU. Despite the functional impairment, dyspnea and diminished quality of life of surviving patients with ARDS, most studies have shown that the residual impairment of gas exchange in these patients is small and that few survivors still exhibit hypoxemia or a need for

unfavorable socioeconomic conditions (25) or serious complications during ICU, such as ARF requiring dialysis (7). An important consideration is that, in our study, we have evaluated the presence of PTSD symptoms, which may have led to an overestimation of the incidence of this disorder (24). Another important finding was the report of memory illusions (including hallucinations) by the surviving patients. The incidence of memory illusions may be correlated with psychological disorders and a reduction in quality of life among ICU survivors (26). Even among the ‘‘real’’ memories, 67.2% of the patients mentioned memories of confusion, agitation, physical restraint (53.7%), thirst (51.2%), and procedures (24.7%), such as the presence of a tracheal tube, tracheal aspiration, and extubation. Therefore, strategies for humanizing ICU care will have both short-term and longterm impacts on survivors. In our experience of the follow-up outpatient clinic with a multidisciplinary team, we observed psychological and physical complications 3 months after discharge as well as the need to refer patients to other specialties. This finding

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Figure 2 - Monthly family income (US$).

Figure 3 - Quality-of-Life scores, according to SF-36 (scored from 0 to 100; the higher the value, the lower the disability; n = 322). SF-36: Medical Outcomes Study 36-Item Short-Form Health Survey.

Due to various factors, including serious injury, metabolic stress, inflammatory polyneuropathy, and nutritional disorders, critical patients suffer rapid deteriorations in adipose and muscular tissue mass (30-32). As a result, persistent muscular weakness is common during the first months after a critical illness, having a profound impact on respiratory and motor function and on quality of life (3,19,33). The relatively low incidence of severe tetraparesis/motor sequelae in our population may be due to the lower incidence of sepsis upon admission (which is the main factor related to residual

domiciliary oxygen (4,28). In contrast, up to 70% of patients admitted to the ICU due to decompensated COPD required home oxygen therapy after discharge from the hospital (27), and the MaxIP of hospitalization survivors in this group is correlated with functional recovery and pulmonary rehabilitation (29). The authors believe that the relatively reduced respiratory impairment of our population can be justified mainly by the low prevalence of chronic respiratory diseases and the high incidence of young people with trauma (with adequate respiratory recovery).

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so the long-term consequences in this population remain unknown. Currently, our Post-ICU Outpatient clinic is expanding the follow-up to 6 months after discharge. (Therefore, patients will be seen 2 times after leaving the ICU). In the future, we hope to describe this improved follow-up evaluation. Because this study was an observational study (applied to an already existing reality in ICU and post-ICU outpatient care), some relevant data could not be adequately analyzed or collected (e.g., correlations between post-ICU psychological disorders and the sedation time or type, motor characteristics with curare use, or nutritional status variables during the ICU stay) due to difficulties in accessing these data from the patients’ charts. However, the execution of this study has provided the staff with several elements that can be used toward improving the collection of these data for possible future analyses. The patient population in our study also had specific characteristics, including a high incidence of trauma, young age, and low-income status, and may not correspond to the populations of other ICUs or social realities. A significant percentage of ICU survivors seen 3 months after discharge presented with psychological, respiratory, motor, and socioeconomic complications, emphasizing that strategies for the care of critically ill patients must be extended to the post-hospitalization period.

muscle weakness) (3,19). However, another factor may be that patients with higher impairment (bedridden) did not attend the clinic, resulting in a bias in the incidence of severe tetraparesis/motor sequelae. Nutritional conditions and weight variations are among the major immediate and late consequences of critical illness (34). Several related factors include dysphagia (1), loss of appetite (34), metabolic consumption of muscle mass, and loss of muscle mass due to inactivity (3). In the present study, significant weight loss was detected during hospitalization. However, considerable weight gain was also detected in the studied group during the post-hospitalization period. These findings highlight the importance of nutritional and speech therapeutic interventions in the rehabilitation of critical patients, particularly those with neurological impairments, since recovering the ability to eat by mouth is a goal that should be quickly attained. Since this population is affected by psychological and physical disorders, the quality of life is compromised, particularly regarding physical components. A marked reduction in the quality of life has been demonstrated in post-ICU patients, particularly in the first months after discharge, with variable improvement after 6–12 months (35). A limitation of our quality-of-life analysis is our lack of pre-ICU data, which would further support the results of this study. However, since a significant percentage of patients (e.g., trauma patients) had no previous illnesses, the numbers are notable. Even though our University Hospital is located in a city within Brazil’s wealthiest region (the south), our study population comprised low-income patients (treated in a public hospital) in a country with notorious shortcomings in its public healthcare system (despite important improvements in recent years, such as the creation of the Unified Health System, or SUS) (36). Very few hospitals in Brazil are focused on rehabilitation, and few cities have public home care services (37). Therefore, the vast majority of patients, even those with serious functional sequelae, must remain in their own homes, with either precarious specialized care (physiotherapy, nursing, nutrition, speech therapy) or none at all. This scene becomes even more problematic when considering that most patients in this study were victims of trauma, were young, and could therefore potentially return to their usual living conditions if only the treatment received at the hospital had been maintained during their post-hospital rehabilitation. Consequently, we must emphasize the social roles that the ICU teams play in learning about the realities of the population they serve and about the impacts of critical illness and hospitalization, particularly in low-income countries. This study has several limitations, some of which are inherent to its nature. First, this was a single-center observational study. Therefore, any generalization of the described findings may be inadequate. Another limitation refers to the number of patients attended in the outpatient clinic compared to the total number of patients discharged alive from the hospital. Social and medical factors may have prevented many families from transporting patients to the outpatient clinic. Thus, the data for the treated patients may not accurately reflect the clinical severity and precarious socioeconomic conditions of our population. However, the results obtained in our clinic have assisted efforts by our institution to improve post-hospital care (including social assistance). Additionally, our outpatient clinic conducted only a single evaluation of the ICU survivors 3 months after discharge,

’ ACKNOWLEDGMENTS The authors would like to thank the physicians, healthcare professionals, residents, and students working at the general ICU and at the Multidisciplinary Post-ICU Outpatient Clinic for adult patients at the Western Paraná State University Hospital, Cascavel, Brazil.

’ AUTHOR CONTRIBUTIONS Duarte PA designed the study, analyzed the data and wrote the manuscript. Costa JB, Duarte ST, Taba S, Lordani CR, Osaku EF, Costa CR, Miglioranza DC, Gund DP and Jorge AC collected the data, analyzed the data, and wrote the manuscript. All authors have read and approved the ﬁnal version of the manuscript.

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’ APPENDIX Supplementary Table - Comparison of admitted ICU patients to ICU surviving patients.

n Male, % Age, years, median ± SD Age, years, n (%) o40 41-60 61-75 475 Reason for hospitalization, n (%) Trauma Clinical Elective surgical Non-traumatic urgency surgical APACHE II, median ± SD APACHE II, n (%) 1-5 6-10 11-20 21-30 430 Comorbid conditions, n (%) Any None AIDS Recent/current cancer DM Illegal drugs COPD Alcoholism SH CHF CRF Moderate/severe obesity MV use, n (%) Time on MV, days, n (%) 0 1-5 6-10 410 ICU mortality, % Hospital mortality, n (%)

ICU Total

ICU Survivors

2617 1639 (62.6%) 46.0 ± 19.83 --1081 (41.3%) 803 (30.7%) 524 (20.0%) 209 (8.0%) --963 (36.8%) 916 (35.0%) 429 (16.4%) 309 (11.8%) 22.0 ± 8.66 --39 (1.5%) 188 (7.2%) 882 (33.7%) 1055 (40.3%) 453 (17.3%) --1633 (62.4%) 984 (37.6%) 49 (1.9%) 248 (10.7%) 237 (9.1%) 64 (2.4%) 175 (6.7%) 243 (9.3%) 589 (22.5%) 162 (6.2%) 61 (2.3%) 170 (6.5%) 2269 (86.7%) --348 (13.3%) 1112 (42.5%) 487 (18.6%) 670 (25.6%) 672 (25.7%) 759 (29.0%)

1945 1227 (63.1%) 44.0 ± 19.63 --897 (46.1%) 567 (29.2%) 350 (18.0%) 131 (6.7%) --761 (39.1%) 570 (29.3%) 393 (20.2%) 221 (11.4%) 20.0 ± 7.77 --38 (2.0%) 174 (8.9%) 788 (40.5%) 760 (39.1%) 185 (9.5%) --1157 (59.5%) 788 (40.5%) 32 (1.6%) 225 (11.6%) 175 (9.0%) 54 (2.8%) 87 (4.5%) 210 (10.8%) 486 (25.0%) 126 (6.5%) 41 (2.1%) 103 (5.3%) 1610 (82.8%) --335 (17.2%) 811 (41.7%) 335 (17.2%) 464 (23.9%) --121 (6.2%)

p-value Total vs. Survivors --o0.001

--0.120 o0.001 0.001 0.711 o0.001

--0.05 0.518 0.363 0.949 0.453 0.002 0.104 0.053 0.726 0.725 0.104 o0.001 --o0.001

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772

CLINICAL SCIENCE

Evaluation of the efficacy and safety of endovascular management for transplant renal artery stenosis Leonardo G.M. Valle,I,* Rafael N. Cavalcante,I Joaquim M. Motta-Leal-Filho,I Breno B. Affonso,I Francisco L. Galastri,I ´ lvaro Pacheco-Silva,II Marisa P. Doher,II Nadia K. Guimara˜es-Souza,II Ana K.N. Cavalcanti,II Rodrigo G. Garcia,I A I Felipe Nasser I Departamento de Radiologia Intervencionista, Hospital Israelita Albert Einstein, Sao Paulo, SP, BR. Albert Einstein, Sao Paulo, SP, BR.

Departamento de Nefrologia, Hospital Israelita

OBJECTIVES: To evaluate the safety and efficacy of endovascular intervention with angioplasty and stent placement in patients with transplant renal artery stenosis. METHODS: All patients diagnosed with transplant renal artery stenosis and graft dysfunction or resistant systemic hypertension who underwent endovascular treatment with stenting from February 2011 to April 2016 were included in this study. The primary endpoint was clinical success, and the secondary endpoints were technical success, complication rate and stent patency. RESULTS: Twenty-four patients with transplant renal artery stenosis underwent endovascular treatment, and three of them required reinterventions, resulting in a total of 27 procedures. The clinical success rate was 100%. All graft dysfunction patients showed decreased serum creatinine levels and improved estimated glomerular filtration rates and creatinine levels. Patients with high blood pressure also showed improved control of systemic blood pressure and decreased use of antihypertensive drugs. The technical success rate of the procedure was 97%. Primary patency and assisted primary patency rates at one year were 90.5% and 100%, respectively. The mean follow-up time of patients was 794.04 days after angioplasty. CONCLUSION: Angioplasty with stent placement for the treatment of transplant renal artery stenosis is a safe and effective technique with good results in both the short and long term. KEYWORDS: Transplant Renal Artery Stenosis; Endovascular Treatment; Stenting; Renal Transplantation. Valle LG, Cavalcante RN, Motta-Leal-Filho JM, Affonso BB, Galastri FL, Doher MP, et al. Evaluation of the efficacy and safety of endovascular management for transplant renal artery stenosis. Clinics. 2017;72(12):773-779 Received for publication on June 6, 2017; First review completed on September 12, 2017; Accepted for publication on October 17, 2017 *Corresponding author. E-mail: dr.lgmvalle@gmail.com

’ INTRODUCTION Renal transplantation is an important therapeutic option for patients with end-stage chronic kidney disease, and it is associated with increased rates of survival and a better quality of life in these patients (1). However, certain complications following transplantation may affect the graft and patient survival. With advances in immunosuppressive drugs, graft loss due to rejection has decreased to rates of 20-30%. Additionally, other complications have also gained major importance (2). Transplant renal artery stenosis (TRAS) is the most common vascular complication that may occur after transplantation, affecting 1-23% of patients (3).

Vascular alterations in the renal artery of the transplanted kidney may be either asymptomatic and/or associated with cases of refractory hypertension during clinical treatment and/or graft dysfunction (6), and they are typically related to decreases in overall survival rates of patients who undergo renal transplantation (4-7). The benefits of endovascular intervention for the correction of TRAS remain under debate, however, and few results are currently available in the literature. It is believed that this technique may aid in the control of high blood pressure and may improve renal function, contributing substantially to better graft and patient survival (3,8-10). This study aimed to evaluate the safety and efficacy of endovascular intervention with angioplasty and stent placement in patients with TRAS.

’ MATERIALS AND METHODS Study design

No potential conflict of interest was reported.

This was a retrospective study carried out in the Department of Interventional Radiology and Nephrology, and it

DOI: 10.6061/clinics/2017(12)09

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was approved by the Ethics and Research Committee of the institution.

antihypertensive drugs, in patients with arterial hypertension secondary to TRAS.

Patients and eligibility

Statistical analysis The quantitative characteristics evaluated in the patients are described using summary measures (i.e., mean, standard deviation, median and quartiles), and the qualitative variables are described using absolute and relative frequencies. The creatinine levels were compared preoperatively using the lowest value at follow-up via the paired Wilcoxon test. Blood pressure controls, measured mainly by the total number of medications used, were also compared between the preoperative and follow-up periods using the paired Wilcoxon test. A Kaplan-Meier analysis was used to determine the graft survival curve and to evaluate patency rates and the probability of occurrence of events. A p-value p0.05 was considered significant.

All patients diagnosed with TRAS who underwent endovascular treatment from February 2011 to April 2016 were included in this study. The diagnosis of TRAS was confirmed via Doppler ultrasonography (peak systolic velocity 4200-250 cm/s, resistance index 40.8, pulsatility index 41.5, stenosis/prestenotic velocity gradient 42:1, tardus parvus in systolic acceleration 40.1 seconds, or acceleration in renal hilum 4100 cm/s). All patients included in the study had either graft dysfunction or resistant systemic hypertension. Graft dysfunction was defined as delayed graft function in kidney transplants assessed by measuring the creatinine level and estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, while resistant systemic hypertension was defined as blood pressure 4140/ 90 mmHg, despite treatment with antihypertensive drugs.

â&#x20AC;&#x2122; RESULTS From February 2011 to April 2016, 29 patients who were diagnosed with TRAS using Doppler ultrasonography underwent angiography. Twenty-four of these cases underwent endovascular treatment, and three required reinterventions, resulting in a total of 27 procedures. Five patients underwent only diagnostic angiography without intervention and, therefore, were excluded from the final analysis. In four of these cases, angiography showed only mild stenosis with no flow change, while the remaining patient demonstrated severe stenosis and thrombosis of segmental branches, with changes in the parenchymal phase of the angiographic study. No treatment approach was indicated for this patient.

Endovascular procedure Patients with stenosis diagnosed using Doppler ultrasonography underwent an angiographic study. The access route for the procedures was either the ipsilateral or contralateral common femoral artery. Pelvic and transplanted renal artery angiograms were performed for anatomical evaluation and lesion quantification. Following angiographic confirmation of stenosis, systemic heparinization was performed with unfractionated heparin, followed by transposition of the lesion with a 0.014 guidewire. All cases were treated with stent implantation: in one case, a self-expanding stent was used, and in the other cases, expandable balloon stents, such as Visions Cobalt Chromium (Abbott Laboratories, Chicago, IL, USA), TAXUSt LibertĂŠt (Boston Scientific Corporation, Natick, MA, USA), Expresst Vascular Stent (Boston Scientific Corporation), Dynamic Stent (BIOTRONIK, Berlin, Germany), and/or Direct-Stents (InSitu Technologies, St. Paul, MN, USA), were used. The materials were used without standardization at the discretion of the interventional physician. At the end of the procedure, hemostatic devices, such as the Perclose Proglide (Abbott) and/or the StarClose (Abbott) devices, were used at the puncture site.

Patient profile The profile of the study population and the data concerning the renal grafts, as well as the surgical procedures used, are described in Table 1 and Table 2. Table 1 - Demographic Profile of Patients. Variable Sex Male Female Hypertension No Yes DM No Yes CVD No Yes Smoking* No Yes Dyslipidemia No Yes Death No Yes Total

Clinical variables and outcomes Information such as sex, age, risk factors, technical data related to transplantation (i.e., from both the donor and recipient), laboratory tests, diagnostic methods, anatomical pattern of stenosis, and technical details related to treatment (e.g., contrast volume, tomographic imaging, material used, treatment methods, postoperative assessment with arterial patency, blood pressure control, renal function, and survival) was collected. Renal function was determined using serum creatinine levels, and the eGFR was obtained in the preoperative and postoperative periods (i.e., 48 hours prior and 30, 60, and 90 days after) via the CKD-EPI equation. Technical success was defined as revascularization with stent implantation without complications and/or with complete absence of or o30% residual stenosis. Clinical success was defined as improved renal function (both creatinine levels and eGFR) in cases of renal dysfunction or improved blood pressure control, with a reduction in the use of

15 7

68.2 31.8

2 20

9.1 90.9

16 6

72.7 27.3

18 4

81.8 18.2

17 4

81.0 19.0

13 9

59.1 40.9

20 2 22

90.9 9.1 100

* Information was not available for all patients. DM: Diabetes mellitus. CVD: Cardiovascular disease.

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Table 2 - Data Analysis Associated with the Renal Graft and Surgical Procedure. Variable

Mean

Median

Minimum

Maximum

Age Days until TRAS Donor age Graft survival rate Radioscopy time (min) Contrast volume (ml)

49.9 169.1 42.6 689.5 20.4 185.1

14.3 165.8 13.9 462.9 11.8 52.0

51.5 132.5 43.5 575.5 16.1 180.0

20.0 13.0 19.0 115 7.2 100

75.0 706.0 69.0 2069 56 300

22 22 22 22 18 17

Table 3 - Evaluation of the Stenosis Site. Stenosis site

Anastomosis Distal Total

Days until TRAS Mean

Median

Minimum

Maximum

190.23 138.56 169.09

212.82 49.81 165.84

135 130 132.5

13 86 13

706 246 706

13 9 22

0.794

Mann-Whitney U test.

Figure 1 - Preoperative and postoperative mean serum creatinine levels (in days).

Figure 2 - Preoperative and postoperative mean creatinine clearance rates (CKD-EPI) (in days).

Of the 24 patients who were diagnosed with TRAS and underwent endovascular treatment, 21 had graft dysfunction and 3 had resistant systemic hypertension. Three of these patients underwent re-stenosis due to graft dysfunction. All arterial anastomoses were performed on the iliac arteries. In one case, anastomosis was performed on the internal iliac artery (4.5% of cases), while anastomosis was performed on the external iliac artery in the remaining cases. Of the 24 grafts used in the study, six (25%) grafts were from living donors. Furthermore, only one graft used during a reintervention was from a living donor (33% for reintervention).

and decreased use of antihypertensive drugs (po0.008) (Table 5).

Procedures and patency The median diameter and length of the stents used were 5 and 12 mm, respectively (Table 6). Intraoperative tomographic imaging was performed in 37% of the cases, with no significant increase in contrast volume or radioscopy time noted (Table 7). The primary patency and assisted primary patency rates in one year were 90.5% and 100%, respectively. Both rates were maintained until the end of the study, considering the mean follow-up time of patients of 794.04 days after angioplasty (Figure 3). During the evaluation period, two patients died due to non-renal causes; their grafts were patent and functioned properly for 587 days and 1,023 days, respectively.

Technical and clinical success The technical success rate of the procedure was 97%. The mean pretreatment and post-treatment stenosis rates were 79.40% and 2.40%, respectively. No relationship between the postoperative period and the stenosis site was found (Table 3). The clinical success rate was 100%. All patients showed decreased serum creatinine levels (Figure 1) and improved eGFR and creatinine levels (Figure 2), with a statistically significant improvement noted following 30 days of treatment (po0.001), which was further maintained after 60 and 90 days (Table 4). Patients with high blood pressure also showed improved control of systemic blood pressure

Re-interventions Of the three cases requiring re-intervention, one was due to in-stent re-stenosis after two months of treatment (Dynamic Stent 5 12, BIOTRONIK, Berlin, Germany). In this case, the patientâ&#x20AC;&#x2122;s renal dysfunction remained after stent placement. A new Doppler ultrasonography exam showed increased resistance in the renal artery. Angioplasty

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Table 4 - Variation in Serum Creatinine Levels and Creatinine Clearance Rates (CKD-EPI) throughout the Study. Variable

Time

Mean

Median

Minimum

Maximum

Creatinine

Preoperative period Immediate postoperative period 30 days 60 days 90 days End of follow-up Preoperative period Immediate postoperative period 30 days 60 days 90 days End of follow-up

3.05 2.56 1.73 1.78 1.62 1.67 28.39 33.49 44.92 46.71 51.41 51.91

1.61 1.49 0.47 0.59 0.53 0.68 17.18 15.64 15.06 20.78 23.38 21.71

2.76 2.01 1.78 1.68 1.68 1.68 23.26 31.84 40.85 42.41 41.11 45.50

1.34 1.27 0.89 0.67 0.65 0.80 7.48 6.93 21.47 23.62 21.47 18.00

6.88 7.59 3.03 2.94 3.03 3.49 68.15 63.00 76.57 103.90 107.78 100.00

22 22 21 20 21 22 22 22 21 20 21 22

o0.001

CKD-EPI

o0.001

Bonferroni correction.

Table 5 - Preoperative and Postoperative Quantitative Analysis of Antihypertensive Drugs used by Patients. Variable Preoperative antihypertensive drugs Postoperative antihypertensive drugs

Mean

Median

Minimum

Maximum

2.09 1.59

1.15 1.05

2 1.5

0 0

4 4

22 22

0.008

Wilcoxon signed-rank test.

Table 6 - Evaluation of Patency Times and Stent Sizes. Variable

Mean

Median

Minimum

Maximum

Patency time (days) Mean diameter of stents Mean length of stents

488.91 4.89 12.68

450.09 1.46 7.14

345 5 12

21 2 0

1830 8 28

22 19 22

Table 7 - Evaluation of Contrast Volume in Milliliters and Scoping Time Related to Cone-beam CT. Variable

CBCT

Mean

Median

Minimum

Maximum

Contrast volume (ml)

No Yes Total No Yes Total

195.11 173.75 185.06 21.536 19.08 20.444

58.01 45.336 51.986 13.3556 10.2365 11.7964

200 175 180 17.765 16.06 16.125

130 100 100 10.5 7.2 7.2

300 250 300 56 34.5 56

9 8 17 10 8 18

0.481

Radioscopy time (min)

0.762

Mann-Whitney U test.

using an IntraStents balloon catheter (Covidien, Dublin, Ireland) was subsequently performed. The second case of re-intervention was due to graft dysfunction. Three renal arteries were transplanted, with one branch initially treated with a stent (Visions Cobalt Chromium 3.0 15, Abbott Laboratories) and two branches treated with a pharmacological balloon catheter (FALCON 3 40). During the follow-up, five months after angioplasty, the patientâ&#x20AC;&#x2122;s serum creatinine levels were found to have increased, and a stent was placed in the two branches initially treated with a balloon (Visions Cobalt Chromium 2.0 28, Abbott Laboratories), with progression occurring favorably. The third case underwent re-intervention initially due to graft dysfunction. The patient underwent endovascular treatment with stent placement (Dynamic Renal Stent, BIOTRONIK, Berlin, Germany) and, after an initial improvement of symptoms, exhibited further worsening of renal function. A second intervention was performed in which renal stent patency was observed, although with dissection of the left

Figure 3 - Patency probability following the procedure (in days).

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Figure 4 - A 51-year-old female patient with acute graft dysfunction. (A) Angiographic study showing severe renal artery stenosis (arrow) in the segment distal to the anastomosis. (B) Control angiography after stenting, showing adequate positioning of an Expresst Vascular Stent 6 18 (Boston Scientific Corporation, Natick, MA, USA) with successful lesion treatment.

or the surgical procedure and was found to present early after transplantation (14,15). The stenosis that occur later, sometimes several years after transplantation, usually reflect atherosclerotic disease and are also associated with rejection and/or cytomegalovirus infection (4,5,16,17). In our study, no relationship was found between the anastomosis site and time of onset. A review of the medical records showed that no vascular lesion was reported during organ recruitment or the surgical procedure, although other changes not described during the procedure, such as hyperflexion of blood vessels and endothelial injury during graft perfusion, are related to this type of stenosis. The treatment of TRAS is crucial, as the presence of graft dysfunction and/or high blood pressure may alter the renal graft and compromise patient survival (10,18-20). Concerning therapeutic options, clinical and medical care is limited to patients with TRAS, stable renal function, and non-significant lesions, while surgical intervention should be reserved as a salvage option in cases in which angioplasty is unsuccessful (9). Endovascular intervention, despite risks such as renal artery disease, re-stenosis, thromboembolism and complications related to the puncture site, may be considered a first-line therapy for TRAS (9,21,22). Our results are similar to those in the literature, which describe a technical success rate ranging from 89 to 100% (4,16,21,23). In our study, the technical success rate was 97% and the clinical success rate was 100%. Ngo et al. systematically reviewed 32 studies of TRAS and found a clinical success rate between 65.5 and 94% (24). Among the 28 studies that evaluated renal function, the mean creatinine level reduced 0.45 mg/dL after 30 days and 0.82 mg/dL after six months. Estimated GFR was evaluated in 11 studies, which showed an average gain of 8.6 mL/min/ 1.73 m2 three months after endovascular intervention. Our review showed that renal function significantly improved following intervention, with values higher than those found in these studies. The mean creatinine level decreased by 1.32 mg/dL and the eGFR increased by 16.53 mL/min/ 1.73 m2 after 30 days. These values were maintained after 90 days, and a short-term improvement in renal function was

iliac artery, which was deemed to be a possible complication related to the first procedure. The patient underwent placement of a self-expanding stent (Everflext, Covidien, Dublin, Ireland) in the iliac artery, and renal function improved.

Complications No immediate complications were observed after the procedure. A case of dissection of the common iliac artery with extension to the external iliac artery was diagnosed 30 days after the initial procedure but was resolved with a selfexpanding stent.

â&#x20AC;&#x2122; DISCUSSION This retrospective study was carried out to evaluate the impact of endovascular treatment in patients diagnosed with TRAS, which was proven to be an effective and safe procedure. The prevalence of TRAS observed in our study was 5.6%, similar to that found in other studies (3,5,6,11). Our analysis revealed renal dysfunction, associated with abnormalities in Doppler ultrasonography, to be a major clinical presentation and to be present in 90% of cases, a finding similar to that in other reviews (4,5). A higher peak systolic velocity and velocity gradient between the transplanted renal artery and the iliac artery is a criterion of higher sensitivity in Doppler ultrasonography for TRAS (6). Although some authors cited the presence of a peak systolic pressure gradient 410% or stenosis 450% in angiography as an indication for intervention, no consensus has been established in the literature regarding stenosis ranges and/or standards for intervention (12). In this study, Doppler ultrasonography was used as a screening method in patients with a clinical presentation of TRAS. The anastomosis site and onset may be related to different risk factors. The mean onset of TRAS in our study was 169 days, and the most common site of stenosis was the anastomosis, which is similar to findings described in other studies, and was present in more than half of the cases in this study (4,6,13). This stenosis may be associated with mechanical lesions of the blood vessels during organ recruitment

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the analysis and interpretation, critical revision of the manuscript, final approval of the manuscript and overall responsibility. Cavalcanti AK was responsible for the data collection, manuscript writing, final approval of the manuscript and overall responsibility. Garcia RG conceived and designed the study and was responsible for the critical revision of the manuscript, final approval of the manuscript and overall responsibility. Pacheco-Silva A was responsible for the critical revision of the manuscript, final approval of the manuscript and overall responsibility. Nasser F Conceived and designed the study and was responsible for the critical revision of the manuscript, final approval of the manuscript and overall responsibility.

predictive in the long run. The mean follow-up of patients was 794 days, and all of them maintained stable renal function until the end of the follow-up period. The maintenance of satisfactory kidney function after transplantation is directly related to the graft and patient survival rates, and we expect that these factors may have an effect on our patients (18,19). Among the patients undergoing treatment because of graft dysfunction, three underwent intervention due to delayed graft function (DGF), as they remained on dialysis even after renal transplantation. All of them left dialysis and maintained adequate renal function after correction of TRAS, which had an important effect on graft and patient survival rate, as DGF is associated with poor outcomes (19,25). Despite the heterogeneous results found following endovascular treatment of TRAS with balloon catheters, studies with stent placement showed that high blood pressure was improved following this treatment, with a reduction of antihypertensive drugs, which was also found in our study (24,26). Adequate blood pressure control is very important, as high blood pressure can result in a decreased graft survival rate and left ventricular hypertrophy, the latter of which is an independent risk factor for heart failure and death in both the general population and renal transplant recipients (20,27). During follow-up, patency levels ranging from 63 to 82% were described one year after endovascular treatment, with a re-stenosis rate ranging from 10 to 36% (28). In our study, a primary patency of 90.5% was reached after three months, and assisted primary patency of 100% was achieved after two years following angioplasty with a balloon-expandable stent. In the literature, early complications are noted, including bleeding, pseudoaneurysm formation, thrombosis, arterial dissection, hematoma, and intimal flap, in approximately 10% of cases (6,29). In our experience, no cases of early complications were reported; however, it was observed that late complications occurred in 4% of patients, represented by one cases of iliac artery dissection. No randomized trials comparing multiple treatment techniques for TRAS were found in the literature. This study is limited mainly because it is not a multicenter retrospective study, although our population was larger than that in many studies found in the literature. Based on our experience, we conclude that angioplasty with stent placement for the treatment of TRAS is a safe and effective technique for improving eGFR, serum creatinine levels, high blood pressure control and graft survival rate, with excellent results in both the short and long term.

’ REFERENCES 1. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341(23):1725-30, http://dx.doi.org/10.1056/NEJM 199912023412303. 2. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000;342(9):605-12, http://dx. doi.org/10.1056/NEJM200003023420901. 3. Bruno S, Remuzzi G, Ruggenenti P. Transplant renal artery stenosis. J Am Soc Nephrol. 2004;15(1):134-41, http://dx.doi.org/10.1097/01.ASN.0000 099379.61001.F8. 4. Audard V, Matignon M, Hemery F, Snanoudj R, Desgranges P, Anglade MC, et al. Risk factors and long-term outcome of transplant renal artery stenosis in adult recipients after treatment by percutaneous transluminal angioplasty. Am J Transplant. 2006;6(1):95-9, http://dx.doi.org/10.1111/ j.1600-6143.2005.01136.x. 5. Ghirardo G, De Franceschi M, Vidal E, Vidoni A, Ramondo G, Benetti E, et al. Transplant renal artery stenosis in children: risk factors and outcome after endovascular treatment. Pediatr Nephrol. 2014;29(3):461-7. 6. Braga AF, Catto RC, Dalio MB, Tenório EJ, Ribeiro MS, Piccinato CE, et al. Endovascular approach to transplant renal artery stenosis. Ann Transplant. 2015;20:698-706. 7. Glebova NO, Brooke BS, Desai NM, Lum YW. Endovascular interventions for managing vascular complication of renal transplantation. Semin Vasc Surg. 2013;26(4):205-12, http://dx.doi.org/10.1053/j.semvascsurg.2014. 06.013. 8. Biederman DM, Fischman AM, Titano JJ, Kim E, Patel RS, Nowakowski FS, et al. Tailoring the endovascular management of transplant renal artery stenosis. Am J Transplant. 2015;15(4):1039-49, http://dx.doi.org/ 10.1111/ajt.13105. 9. Chen W, Kayler LK, Zand MS, Muttana R, Chernyak V, DeBoccardo GO. Transplant renal artery stenosis: clinical manifestations. diagnosis and therapy. Clin Kidney J. 2015;8(1):71-8. 10. Feldman HI, Gayner R, Berlin JA, Roth DA, Silibovsky R, Kushner S, et al. Delayed function reduces renal allograft survival independent of acute rejection. Nephrol Dial Transplant. 1996;11(7):1306-13, http://dx.doi.org/ 10.1093/ndt/11.7.1306. 11. Nasserala JC, Oliveira CM, Cerqueira JB, Souza S, Silva SL, Santos LC, et al. Artery Stenosis of the Renal Graft: Experience of a Center of Northeastern Brazil. Transplant Proc. 2016;48(1):74-80, http://dx.doi.org/ 10.1016/j.transproceed.2015.11.004. 12. Beecroft JR, Rajan DK, Clark TW, Robinette M, Stavropoulos SW. Transplant renal artery stenosis: outcome after percutaneous intervention. J Vasc Interv Radiol. 2004;15(12):1407-13, http://dx.doi.org/10.1097/01. RVI.0000141338.62574.F4. 13. Taylan Ozgur Sezer and Cuneyt Hoscoskun. Vascular Complications After Renal Transplantation, Vascular Surgery, Dr. Dai Yamanouchi [Internet], InTech 2012 [cited 09 June 2017]. Available from: https://www. intechopen.com/books/vascular-surgery/vascular-complications-afterrenal-transplantation. 14. Fervenza FC, Lafayette RA, Alfrey EJ, Petersen J. Renal artery stenosis in kidney transplants. Am J Kidney Dis. 1998;31(1):142-8, http://dx.doi. org/10.1053/ajkd.1998.v31.pm9428466. 15. Roberts JP, Ascher NL, Fryd DS, Hunter DW, Dunn DL, Payne WD, et al. Transplant renal artery stenosis. Transplantation. 1989;48(4):580-3. 16. Becker BN, Odorico JS, Becker YT, Leveson G, McDermott JC, Grist T, et al. Peripheral vascular disease and renal transplant artery stenosis: a reappraisal of transplant renovascular disease. Clin Transplant. 1999; 13(4):349-55, http://dx.doi.org/10.1034/j.1399-0012.1999.130412.x. 17. Rengel M, Gomes-Da-Silva G, Incháustegui L, Lampreave JL, Robledo R, Echenagusia A, et al. Renal artery stenosis after kidney transplantation: diagnostic and therapeutic approach. Kidney Int Suppl. 1998;68:S99-106, http://dx.doi.org/10.1038/sj.ki.4490573. 18. Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP. Post-transplant renal function in the first year predicts

’ AUTHOR CONTRIBUTIONS Valle LG conceived and designed the study and was responsible for the analysis and interpretation, data collection, manuscript writing, critical revision of the manuscript, statistical analysis, final approval of the manuscript and overall responsibility. Cavalcante RN and Motta-LealFilho JM were responsible for the analysis and interpretation, manuscript writing, critical revision of the manuscript, statistical analysis, final approval of the manuscript and overall responsibility. Affonso BB conceived and designed the study and was responsible for the critical revision of the manuscript, final approval of the manuscript and overall responsibility. Galastri FL conceived and designed the study and was responsible for the analysis and interpretation, manuscript writing, final approval of the manuscript and overall responsibility. Doher MP was responsible for the analysis and interpretation, data collection, manuscript writing, critical revision of the manuscript, statistical analysis, final approval of the manuscript and overall responsibility. Guimarães-Souza NK was responsible for

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19. 20.

21.

22. 23.

24.

long-term kidney transplant survival. Kidney Int. 2002;62(1):311-8, http://dx.doi.org/10.1046/j.1523-1755.2002.00424.x. Harada KM, Sampaio EL, Freitas TV, Felipe CR, Park SI, Machado PG. Fatores de risco associados à perda do enxerto e óbito após o transplante renal. J Bras Nefrol. 2008;30(3):213-20. Mange KC, Feldman HI, Joffe MM, Fa K, Bloom RD. Blood pressure and the survival of renal allografts from living donors. J Am Soc Nephrol. 2004;15(1):187-93, http://dx.doi.org/10.1097/01.ASN.000010 4574.04006.08. Salsamendi J, Pereira K, Baker R, Bhatia SS, Narayana G. Successful technical and clinical outcome using a second generation balloon expandable coronary stent for transplant renal artery stenosis: our experience. J Radiol Case Rep. 2015;9(10):9-17, http://dx.doi.org/ 10.3941/jrcr.v9i10.2535. Seratnahaei A, Shah A, Bodiwala K, Mukherjee D. Management of transplant renal artery stenosis. Angiology. 2011;62(3):219-24, http://dx. doi.org/10.1177/0003319710377076. Sankari BR, Geisinger M, Zelch M, Brouhard B, Cunningham R, Novick AC. Post-transplant renal artery stenosis: impact of therapy on long-term kidney function and blood pressure control. J Urol. 1996;155(6):1860-4, http://dx.doi.org/10.1016/S0022-5347(01)66030-0. Ngo AT, Markar SR, Lijster MS, Duncan N, Taube D, Hamady MS. A systematic review of outcomes following percutaneous transluminal

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angioplasty and stenting in the treatment of transplant renal artery stenosis. Cardiovasc Intervent Radiol. 2015;38(6):1573-88, http://dx.doi. org/10.1007/s00270-015-1134-z. Sandes-Freitas TV, Felipe CR, Aguiar WF, Cristelli MP, Tedesco-Silva H, Medina-Pestana JO. Prolonged delayed graft function is associated with inferior patient and kidney allograft survivals. PLoS One. 2015;10(12): e0144188, http://dx.doi.org/10.1371/journal.pone.0144188. Abate MT, Kaur J, Suh H, Darras F, Mani A, Nord EP. The use of drug-eluting stents in management of transplant renal artery stenosis. Am J Transplant. 2011;11(10):2235-41, http://dx.doi.org/10.1111/j.1600-6143. 2011.03652.x. Fernández-Fresnedo G, Escallada R, Martin de Francisco AL, Ruiz JC, Rodrigo E, Castro SS, et al. Association between pulse pressure and cardiovascular disease in renal transplant patients. Am J Transplant. 2005; 5(2):394-8, http://dx.doi.org/10.1111/j.1600-6143.2004.00694.x. Bruno S, Ferrari S, Remuzzi G, Ruggenenti P. Doppler ultrasonography in post-transplant renal artery stenosis: a reliable tool for assessing effectiveness of revascularization? Transplantation. 2003;76(1):147-53, http://dx.doi.org/10.1097/01.TP.0000071849.78031.13. Tian L, He Y, Zhang H, Wu Z, Li D, Chen S. Diabetes insipidus-like state complicating percutaneous transluminal renal stenting for transplant renal artery stenosis. Ann Vasc Surg. 2014;28(5):1271-4, http://dx.doi. org/10.1016/j.avsg.2013.12.023.

BASIC RESEARCH

Experimental implantation of an arterial substitute made of silicone reinforced with polyester fabric in rabbits Laila Massad Ribas,* Inez Ohashi Torres, Fernanda Appolonio, Karina Paula Domingos Rosa, Fabio Rodrigues Ferreira do Espı´rito-Santo, Nelson De Luccia Departamento de Cirurgia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR.

OBJECTIVES: The aim of this study was to analyze silicone tubes with an internal diameter of 4 mm as a possible material for vascular prostheses. METHODS: Grafts were implanted into the infrarenal aortas of 33 rabbits. Fluoroscopic examinations were performed within 150 days after surgical implantation. Sample grafts were analyzed via electron microscopy to evaluate the eventual endothelialization of the prostheses. RESULTS: The patency rates of the prostheses were 87% (±6.7%) after 30 days, 73% (±9.3%) after 60 days and 48% (±12%) after 120 days. The material presented characteristics that support surgical implantation: good tolerance promoted by polyester tear reinforcement, ease of postoperative removal and a lack of pseudoaneurysms. However, intimal hyperplasia was a limiting factor for the patency rate. CONCLUSIONS: We concluded that polydimethylsiloxane has limited potential as an alternative material for small vascular prostheses. KEYWORDS: Vascular Grafting; Polydimethylsiloxane; Polyesters; Silicon; Aorta; Blood Vessel Prosthesis. Ribas LM, Torres IO, Appolonio F, Rosa KP, Espirito Santo FR, De Luccia N. Experimental implantation of an arterial substitute made of silicone reinforced with polyester fabric in rabbits. Clinics. 2017;72(12):780-784 Received for publication on May 15, 2017; First review completed on July 6, 2017; Accepted for publication on August 4, 2017 *Corresponding author. E-mail: lailamassad@gmail.com

’ INTRODUCTION

reconstruction (23). The use of PDMS in the form of various types of catheters for the intravenous administration of substances is also widespread and universally accepted (24,25). The characteristics that make this material attractive for these uses are its excellent thermal stability, good wetting properties, physiological inertness, excellent long-term biostability and low thrombogenicity (26-28). Given that the search for an ideal vascular prosthesis continues and that silicone is a material that promotes few tissue reactions, this study aims to propose an experimental model and test the hypothesis that PDMS is a suitable substitute for small vessels.

Graft replacement of large vessels, such as the aorta and the iliac and femoral arteries, is reasonably achieved using currently available synthetic tubes, such as those composed of polytetrafluoroethylene (PTFE) and Dacron (1-5). However, in small vessels, none of these materials have proved to be superior or equal to the saphenous vein (6-10), which is regarded as the conduit of choice for peripheral revascularization (11-14). A challenge that can arise is the lack of an available vein for arterial replacement. A substantial amount of research has been performed in this field, and there are several options for solving this problem. Cryopreserved donor veins (15,16) and biosynthetic materials are examples of alternatives described in vascular surgery studies (17,18). However, the search for an effective alternative for the replacement of small vessels remains open (19,20). Polydimethylsiloxane (PDMS), or silicone, has been used in medicine since the 1960s (21,22). Due to its characteristics, silicone has become one of the most frequently used materials for prosthetic replacement in various contexts, such as breast

’ MATERIALS AND METHODS All surgical procedures were performed in domestic rabbits (Oryctolagus cuniculus) in the Department of Surgery in the Faculty of Medicine of the University of São Paulo. The animals were provided by that institution’s animal house and were cared for in accordance with principles established by the Animal Welfare Act and the NIH Guide for Care and Use of Laboratory Animals. This study was conducted with the approval of the ethics committee of the Faculty of Medicine of the University of São Paulo. A tubular prosthesis made ??of PDMS (silicone) reinforced with polyester fabric was implanted into the infrarenal aorta of each animal.

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Figure 1 - PDMS prosthesis with a tubular wall of 0.4 mm and an internal diameter of 4 mm.

Synthetic prosthesis

At the end of the experimental procedures, the animals were euthanized while they remained anesthetized with 19.1% potassium chloride (Isofarma, Eusébio, CE, Brazil), and their bodies were disposed of in accordance with the surgical department’s routine procedures. The prostheses were removed after euthanasia, and samples were sent for scanning electron microscopy; images were obtained using a Philips XL30 system (FEI, Hillsboro, Oregon, USA).

The prostheses were prepared in accordance with a patentregistered design (29). Medical-grade silicone in liquid form was mixed with a curing agent and applied over a metal mandrel covered with a polyester fabric to increase the silicone’s tear resistance. To achieve uniform curing, rotational movement of the mandrel was maintained, initially at room temperature and then in an oven to achieve a post-cure temperature of 110oC for 30 minutes. The PDMS prosthesis exhibited a tubular wall of 0.4 mm and an internal diameter of 4 mm (Figure 1). Despite attempts to create a porous tube, the final product was nonporous, and the internal and external surfaces were composed of silicone. The fabric material remained inside the wall simply to provide reinforcement.

Statistical analysis The Kaplan-Meier method was used to analyze risk of occlusion and patent condition. Statistical analyses were performed using SPSS 18.0 software.

’ RESULTS

Anesthetic procedures Animals were anesthetized with a mixture of ketamine hydrochloride (35 mg/kg i.m. Ketalar 10%; Cristalia, São Paulo, Brazil) and xylazine hydrochloride (5 mg/kg i.m. Rompum 2%; Bayer AG, Leverkusen, Germany). During the surgical procedures, the animals received saline solution (0.9% sodium chloride) through a 22G catheter cannulated in the marginal ear vein.

Surgical procedures were performed in 64 animals. Thirty animals (46.9%) survived until late evaluations. Early mortality was observed in 23 animals (35.9%). Eleven animals (17.2%) developed paraplegia in the immediate postoperative period, and these animals were not considered for longterm follow-up. All 30 surviving animals were submitted to angiographic control at the end of the observational period. In three paraplegic animals that were not considered for late follow-up, angiography was performed to diagnose the status of the graft. Another three animals were excluded from late followup because early occlusion (at less than 7 days) of the graft was detected. The remaining 27 animals were analyzed using Kaplan-Meier survival/patency curves.

Surgical technique An anterior laparotomy was performed, and a transperitoneal approach allowed for the dissection of 3 to 4 cm of the infrarenal aorta. A specifically developed self-static retractor was used to avoid evisceration during this exposure. The lumbar arteries were carefully preserved. Before the aorta was clamped with microsurgical clamps, sodium heparin (200 U/kg i.v.; Hepamax, Blausiegel, São Paulo, Brazil) was administered. Anastomoses of the PDMS in the aorta were completed using an end-to-side technique and a continuous 7-0 polypropylene suture. At the end of the proximal anastomosis, blood flow was released for a few minutes for ischemic conditioning. At the end of the vascular anastomosis, pulses were checked, and the aorta was ligated with 4-0 cotton and cut between the anastomotic sites. The animals were evaluated for up to 150 days. All surviving animals were subjected to fluoroscopic examination via retrograde femoral contrast injection.

Surgical characteristics The walls of the prostheses had characteristics of flexibility and hardness that allowed for easy passage of the needle and retention and containment of the suture lines. Thus, satisfactory hemostasis was achieved at the end of the experiments, and the presence of a pulse distal to the anastomoses attested to the immediate patency of the prostheses in all animals.

Prosthesis evaluations

The patency rates of the prosthesis were 87% (±6.7%) after thirty days, 73% (±9.3%) after sixty days, 57% (±11%) after ninety days and 48% (±12%) after one hundred twenty days (Figure 2). The risk of occlusion is indicated in Figure 3.

Prosthesis evaluations Macroscopic analysis

The prostheses were evaluated using aortic fluoroscopy. Images were acquired on a Diasonics OECs 9000 fluoroscopy scanner (Salt Lake City, Utah, USA). Dissection of the femoral artery was performed via unilateral inguinal incision to perfuse the contrast agent diatrizoate meglumine (Reliev 60%; BerliMed S.A., São Paulo, Brazil).

Peri-implant fibrous tissue was easy to identify, and a cleavage plane between the periprosthetic tissue reaction and the tube was observed. Neither aneurysmal dilatation of the implant nor pseudoaneurysm formation in the suture lines was observed. Inside the occluded grafts, whitish thrombi

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Figure 2 - Proportion of "survivors" in the patent condition. The patency rates of the prosthesis were 87% (±6.7%) after thirty days, 73% (±9.3%) after sixty days, 57% (±11%) after ninety days and 48% (±12%) after one hundred twenty days.

Figure 4 - Electron microscopy image showing endothelial growth from the native vessel toward the PDMS graft, which is consistent with intimal hyperplasia.

large vessels, the use of these prostheses is greatly limited in vessels with a diameter of less than four millimeters (9). This study demonstrated that the patency rate for PDMS prostheses after ninety days was 57% (±11%). Nordestgaard et al. (30) performed a similar study but used ePTFE prostheses with a diameter of three millimeters that were also implanted into rabbit aortas. Those authors reported a patency rate of 82% after ninety days. In 2012, Zheng et al. (31) tested polycaprolactone prostheses coated with arginine-glycineaspartic acid in the carotid arteries of ten rabbits, and the patency rate after four weeks was 100%. However, the authors discussed their short observation period and acknowledged that one month is not sufficient for vascular regeneration. If we considered only thirty days of follow-up, then we would have observed 87% patency (±6.7%) in our experiments. Intimal hyperplasia is the result of natural cicatrization after vascular injuries, especially in anastomotic regions, and is a major cause of vascular stenosis and occlusions (32). Anastomotic intimal hyperplasia is more likely to develop for synthetic prostheses than for vein grafts. Given that the endothelium is responsible for preservation of the intravascular structure (33,34), it is natural to search for graft endothelialization. One method for achieving endothelial growth relates to graft porosity. The porosity concept for vascular grafts and the growth of endothelial cells that could pave the inner surface of such grafts remain controversial in medical science. Theoretically, pores are scaffolds for the passage and habitation of vascular cells through the graft lumen. Thus, it was thought that larger spaces between graft nodes would correspond to greater cell housing (35). However, intermediate porosity is considered to be more suitable for preventing intimal hyperplasia (36). In contrast, Lumsden et al. (37) achieved satisfactory results from coating PTFE prostheses with non-porous silicone to promote a smooth and uniform surface and limit internal tissue growth beyond the transanastomotic region. Based on that study, we developed an

Figure 3 - Risk of occlusion of the prosthesis.

vwere observed that were likely caused by intimal hyperplasia, which was subsequently confirmed via scanning electron microscopy.

Scanning electron microscopy Electron microscopy was used to provide additional information in this study. It was possible to observe endothelial growth from the native vessel toward the PDMS graft, a finding consistent with intimal hyperplasia (Figure 4).

’ DISCUSSION Vascular prostheses have been used for several decades to restore blood flow at many sites. However, although the functions of such prostheses have been well established for

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experimental model to test the hypothesis that non-porous silicone could be a suitable prosthesis material for small vessels. We believe that our patency results are consistent with the development of intimal hyperplasia in the anastomotic region. Electron microscopy generated images compatible with endothelial growth from the anastomotic region. Further studies with porous silicone could demonstrate the difference between porous and non-porous grafts and elucidate the cause of intimal cell growth in synthetic prostheses. In evaluations of prostheses, patency has always been demonstrated via contrast injection into the aorta (using arteriography performed via retrograde catheterization) and long-term monitoring. Occlusions that occur in less than thirty days are related to surgical failures, such as technical failures with respect to anastomosis, prosthesis placement, prosthesis folding or insufficient blood flow (38). In our study, we performed prosthesis evaluation for up to 150 days. Within this period, we aimed to perform arteriography as late as possible. The use of polyester as reinforcement for the PDMS was intended to prevent tears during prosthesis suturing because PDMS has a low tear tolerance. This coating appeared to be useful because these events did not occur during any surgical procedure. Moreover, pseudoaneurysms were not observed. Although the silicone graft did not show satisfactory results with respect to long-term patency, the use of this material in other forms, such as sheets, has already been tested. An experimental study that used the same animal model produced extremely good results for patches in the aortas of rabbits (39). The tested material exhibited characteristics that support surgical implantation: good tolerance promoted by polyester tear reinforcement, ease of postoperative removal and lack of pseudoaneurysms. However, intimal hyperplasia was a limiting factor for the patency rate. We concluded that PDMS has limited potential as an alternative small vascular prosthesis material.

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’ ACKNOWLEDGMENTS

19.

We would like to thank Professor Eduardo Massad (LIM 01) and the team in the Department of Surgery in the Faculty of Medicine at the University of São Paulo for supporting this study and treating the study animals respectfully.

20.

’ AUTHOR CONTRIBUTIONS

22.

All of the co-authors participated in the surgical procedures. De Luccia N also contributed to the statistical analysis and supervised the entire study.

23.

21.

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PDMS content affects in vitro hemocompatibility of synthetic vascular grafts. J Mater Sci Mater Med. 2007;18(6):1097-104, http://dx.doi.org/10.1007/ s10856-006-0067-0. Simmons A, Padsalgikar AD, Ferris LM, Poole-Warren LA. Biostability and biological performance of a PDMS-based polyurethane for controlled drug release. Biomaterials. 2008;29(20):2987-95, http://dx.doi.org/10.1016/ j.biomaterials.2008.04.007.

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29. De Luccia N, De Luccia TPB. Prótese vascular feita em silicone. Patent PI 0704867-0, Instituto Nacional de Propriedade Industrial, BR, 2007. 30. Nordestgaard AG, Buckels JA, Wilson SE. Platelet antagonists eliminate thromboembolic complications of small-diameter arterial prostheses. J Vasc Surg. 1987;5(1):110-7, http://dx.doi.org/10.1016/0741-5214(87) 90201-1. 31. Zheng W, Wang Z, Song L, Zhao Q, Zhang J, Li D, et al. Endothelialization and patency of RGD-functionalized vascular grafts in a rabbit carotid artery model. Biomaterials. 2012;33(10):2880-91, http://dx.doi. org/10.1016/j.biomaterials.2011.12.047. 32. Fulton GJ, Davies MG, Barber L, Gray JL, Svendsen E, Hagen PO. Local effects of nitric oxide supplementation and suppression in the development of intimal hyperplasia in experimental vein grafts. Eur J Vasc Endovasc Surg. 1998;15(4):279-89, http://dx.doi.org/10.1016/S10785884(98)80030-0. 33. Rotmans JI, Heyligers JM, Verhagen HJ, Velema E, Nagtegaal MM, de Kleijn DP, et al. In vivo cell seeding with anti-CD34 antibodies successfully accelerates endothelialization but stimulates intimal hyperplasia in porcine arteriovenous expanded polytetrafluoroethylene grafts. Circulation. 2005;112(1): 12-8, http://dx.doi.org/10.1161/CIRCULATIONAHA.104.504407. 34. Jobst BJ, Riegger GA, Griese DP. Endothelial cell seeding fails to prevent intimal hyperplasia following arterial injury in the rat carotid model.

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BASIC RESEARCH

Second hand tobacco smoke adversely affects the bone of immature rats Rodrigo Ce´sar Rosa,I,* Saˆngela Cunha Pereira,II Fabrizio Antoˆnio Gomide Cardoso,I Abadio Gonc¸alves Caetano,I Hildemberg Agostinho Rocha de Santiago,III Jose´ Batista VolponIII I Departamento de Biologia Estrutural, Universidade Federal do Triangulo Mineiro, Uberaba, MG, BR. II Graduacao, Faculdade de Medicina, Universidade de Uberaba, Uberaba, MG, BR. III Departamento de Biomecanica, Medicina e Reabilitacao do Aparelho Locomotor, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, BR.

OBJECTIVES: To evaluate the influence of secondhand cigarette smoke exposure on longitudinal growth of the tibia of growing rats and some parameters of bone quality. METHODS: Forty female rats were randomly divided into four groups: control: rats were sham exposed; 30 days: rats were exposed to tobacco smoke for 30 days; 45 days: rats were exposed to tobacco smoke for 45 days; and 60 days: rats were exposed to tobacco smoke for 60 days. Blood samples were collected to evaluate the levels of cotinine and alkaline phosphatase. Both tibias were dissected and weighed; the lengths were measured, and the bones were then stored in a freezer for analysis of bone mineral content and mechanical resistance (maximal load and stiffness). RESULTS: Exposure of rats to tobacco smoke significantly compromised bone health, suggesting that the harmful effects may be time dependent. Harmful effects on bone growth were detected and were more pronounced at 60-day follow-ups with a 41.8% reduction in alkaline phosphatase levels (po0.01) and a decrease of 11.25% in tibia length (po0.001). Furthermore, a 41.5% decrease in bone mineral density was observed (po0.001), leading to a 42.8% reduction in maximum strength (po0.001) and a 56.7% reduction in stiffness (po0.001). CONCLUSION: Second hand cigarette smoke exposure in rats affected bones that were weaker, deforming them and making them osteopenic. Additionally, the long bone was shorter, suggesting interference with growth. Such events seem to be related to time of exposure. KEYWORDS: Smoking; Bone Development; Bone Density; Tibia; Rats. Rosa RC, Pereira SC, Cardoso FA, Caetano AG, de Santiago HA, Volpon JB. Second hand tobacco smoke adversely affects the bone of immature rats. Clinics. 2017;72(12):785-789 Received for publication on June 15, 2017; First review completed on September 21, 2017; Accepted for publication on October 17, 2017 *Corresponding author. E-mail: rodrigocesarosa@gmail.com

’ INTRODUCTION

The first component results from burning the tobacco at high temperatures (above 950o C) and the passage of smoke through the tobacco column and filter followed by active inhalation by the smokers (3). The second component, sidestream cigarette smoke, is generated at lower temperatures (approximately 350o C) during the slow and spontaneous smoldering of a cigarette, cigar, pipe or fire in a closed environment. Importantly, this type of smoke contains four times more harmful compounds than the main strain smoke, (4) and non-smokers may be exposed to an environment contaminated by so-called second hand smoke (result of expelled smoke and smoke from smoldering burning). It has been demonstrated both clinically and experimentally that tobacco smoke alters bone quality (5) and bone healing (6-8), and in some cases, it is associated with a disturbance in fracture healing (9-11). Additionally, there are some reports that suggest that nicotine causes a decrease in weight and body mass index (12). Children, during the growth period, undergo important physiological events that may be hazardously affected by tobacco smoke. Therefore, the present study aims to evaluate the influence of second

Chronic tobacco smoke inhalation has an important impact on different organs and systems and is strongly associated with an increased incidence of certain types of cancer (1). Tobacco smoke can reach the respiratory system by active inhalation or passively when non-smoking people are exposed to a polluted environment (second hand smoke). In both types of exposure, the smoke travels into the lungs, and then, via the blood circulation, the smoke reaches different organs, disturbing metabolic routes and compromising the individual’s health (2). Tobacco cigarette smoke consists of two components: central or mainstream smoke and peripheral or sidestream smoke.

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Santa Cruz do Sul, RS, Brazil), with each unit containing the following according to the product label: 0.8 mg of nicotine, 10 mg of tar and 10 mg of carbon monoxide.

hand cigarette smoke exposure on longitudinal growth of the tibia in growing rats and on some bone quality parameters.

’ METHODS Analysis of alkaline phosphatase activity in blood plasma

The experimental protocol was carried out according to the Guide for the Care and Use of Laboratory Animals (National Research Council - USA, 2011) and approved by the Ethics Committee on Animal Experimentation of the School of Medicine of Ribeirão Preto, the University of São Paulo, Brazil (Protocol n. 139/2013). Forty female rats (Rattus norvegicus albinus var. Wistar) were obtained from the vivarium of the university and housed under standard laboratory conditions (room temperature 22±2o C, humidity 55±5%, 12 h light-dark cycles) with free access to tap water and chow (Nuvilab CR-1, Colombo, PR, Brazil). The rats weighed 300 to 350 g (80–100 days old), were kept in the laboratory environment for one week for acclimatization and then were randomly distributed into four groups: control: rats were sham exposed; 30 days: rats were exposed to tobacco smoke for 30 days; 45 days: rats were exposed to tobacco smoke for 45 days; and 60 days: rats were exposed to tobacco smoke for 60 days. All animals were housed in standard laboratory cages, with the same number of animals per box, allowing similar gait activities. The animals were inspected daily and weighed weekly. Euthanasia was performed with an overdose of thiopental sodium, injected intraperitoneally. Blood samples were immediately collected by cardiac puncture to evaluate the levels of cotinine and alkaline phosphatase. Both tibias were dissected and weighed; the lengths were measured, and the bones were stored in a freezer for future analysis (bone mineral content and mechanical resistance).

Following euthanasia, blood samples were collected in heparinized tubes that were centrifuged at 1831 g for 10 minutes. Alkaline phosphatase levels were obtained in the plasma fraction using a commercial kit (Roche, Jacarepaguá, RJ, Brazil). The absorbance was read at 410 nm in a spectrophotometer (COBAS Integra, Jacarepaguá, RJ, Brazil). The results were expressed in UI, corresponding to 0.01667 mkat/L.

Level of cotinine in the serum Cotinine in the serum was obtained by heart puncture and processed according to previously described methods (16-19), using a method with a specificity of 97.4% and a sensitivity of 96.3%. A cotinine serum concentration ranging from 2.1 to 17.5 ng/mL was accepted as the cut-off level to characterize the animal exposure as secondhand smoke, similar to levels found in human passive smokers (20,21). Cotinine is a metabolic product of nicotine, with a low rate of metabolism and renal excretion, so that its half-life is ten times longer than that of nicotine. In addition, cotinine remains constant if smoking persists (22), so it is a useful marker for assessing tobacco addiction.

Bone length The lengths of the tibias were obtained with a digital caliper by three consecutive measurements and an average calculation.

Exposure to Tobacco Smoke

Bone mineral density

To expose the rats to cigarette smoke, a special device was constructed based on previous publications (13-15). Details of the equipment that we used can be found in the paper by Santiago et al. (11). In summary, there were four cylindrical compartments to accommodate one rat in each compartment. One end of the cylinder was open and used to manipulate the animal. The other end was funnel-shaped and used to fit the animal muzzle and to introduce and clear the smoke. From a burning cigarette, a peristaltic pump (Provitec AWG 5,000 AX-D, São Paulo, SP, Brazil) aspirated the smoke and transferred it to a distribution chamber and then to the animals’ compartments. A timer controlled the introduction of smoke for 15 s and its substitution with clean air for 30 s, thus completing one cycle. After the exposure, the smoke was exhausted to the outside. The first seven days were used to adapt the rat to smoke exposure and consisted of burning a cigarette twice a day (morning and afternoon), with a six-hour interval between exposures. The following week, the rats were exposed to the smoke of two cigarettes in the morning and two cigarettes in the afternoon, with a six-hour interval. The period of exposure to tobacco was established according to the experimental groups: 30 days, 45 days and 60 days. Every seven days, the percentage of carbon monoxide within each cylindrical chamber was measured with a portable carbon monoxide meter (Instrupemp, ITMCO-1500, São Paulo, SP, Brazil). The four chambers presented similar levels of carbon monoxide (338.79±1.16 ppm). The source of the smoke was Marlboro cigarettes (Phillips Morris,

Bone mineral density was determined by dual-energy X-ray absorptiometry (DXA) using a Lunar DPX-IQ densitometer (Lunar; software version 4.7e, GE Healthcare, Chalfont St. Giles, United Kingdom) with software for small samples. The tibias were immersed in ethanolin a small container, and scanning of the entire bone was carried out. Then, the region of interest was delimited by a square measuring 0.90 cm2, taking the tibial tuberosity as an anatomical landmark.

Mechanical Testing The entire bone was tested in a 3-point flexion. The bone extremities were rested on two metallic supports that were 25 mm apart, and a progressive load was vertically applied at the center of the posterior surface of the bone at a constant displacement rate of 1 mm/min until failure. The testing device (EMIC, São José dos Pinhais, PR, Brazil) was equipped with a 500 N load cell, and the load-deflection curve was obtained in real time. The maximal load and stiffness were calculated using software (TESC software, version 13.4, São José dos Pinhais, PR, Brazil).

Statistical Analysis The SPSS program (SPSS for Windows - Version 11.0 - SPSS Inc.) was used for statistical analysis. Data were initially submitted to descriptive analysis, with a calculation of means and standard deviations. After checking for normality (ANOVA), the level of significance was determined by Tukey’s test, with a significance level of 5% (po0.05).

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’ RESULTS

60-day exposure groups (po0.05), but no difference between the 45- and 60-day exposure groups (p40.05) (Figure 2). The mean maximal load of the tibias from animals exposed to tobacco smoke for 60 days was statistically reduced by 42.8% in comparison with the control animals (po0.001). There was also a significant difference between the 30-day and 60-day exposure groups as well as between the 45-day and 60-day exposure groups (po0.05) (Figure 2). The mean stiffness of the tibias from the 60-day exposure groups was significantly decreased by 56.7% in comparison with the control animals (po0.001). There was also a significant difference between the 30-day and 60-day exposure groups, as well as between the 45-day and 60-day exposure groups (po0.05) (Figure 2).

The levels of cotinine in the blood plasma were significantly lower (po0.001) in the control group (0.0006±0.008 ng/mL) compared to the groups with30 (9.5±0.8 ng/mL), 45 (8.2± 0.85 ng/mL) and 60 days (13.2±1.2 ng/mL) of exposure to tobacco smoke (Figure 1). The alkaline phosphatase activity in blood plasma after 60days of exposure was reduced by 41.8% in relation to the control group (po0.01), but with no significant difference among the exposed groups (p40.05) (Figure 1). The mean tibia length from animals with 60days of exposure was 11.25% shorter than in the control group (po0.001). Additionally, the comparison of the 30 days (1.21%) and 45 days (1.28%) of exposure groups with the 60days of exposure group showed significant differences (po0.001) (Figure 2). The mass of the tibias showed a significant difference between the control and the 60-day group (po0.05), but not among the exposed groups (p40.05) (Figure 2). The mean bone mineral density of the tibias after 60 days of exposure was statistically reduced by 41.5% in comparison with the control animal group. There was also a significant difference between the 30-day exposure and the 45- and

’ DISCUSSION It has been fully demonstrated that addiction to tobacco products compromises general health because it affects the function of many organs and systems and is closely associated with the incidence of cancer and cardiovascular diseases. In the skeletal system, bone quality and fracture

Figure 1 - Biochemical data. A. Levels of cotinine in blood plasm; B. Average of alkaline phosphatase activity in blood plasma. The asterisks indicate comparisons with significant differences.

Figure 2 - Analysis of skeletal development, bone mineral content and mechanical resistance. A. Tibia lengths; B. bone mass; C. bone mineral density; D. maximal load; E. stiffness. The asterisks indicate comparisons with significant differences.

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The second device is based on individual chambers in which the muzzle is exposed, and the effects of fur impregnation do not occur. However, both models present drawbacks because they are not true models of secondhand smoke exposure. Lastly, the smoke in the cameras is characterized as mainstream smoke, which is different than the mixed sidestream and mainstream smoke that is usually found indoors and inhaled by second hand smokers. In summary, our results suggest that exposure of rats to secondhand smoke adversely affects bone structure. Such results are in accordance with those of Santiago et al. (11). Most importantly, smoke also affects bone growth. To the best of our knowledge, this finding was not specifically reported before, but it calls for further basic investigation and clinical studies. However, our results are strong enough to alert health authorities to pass and enforce laws against smoking in indoor environments. Second hand cigarette smoke exposure to rats affected bones that were weaker, deforming them and making them osteopenic. Additionally, the long bone was shorter, suggesting interference with growth. Such events seem to be related to the duration of exposure.

healing are compromised (11,23-25). However, even nonsmokers may be affected by chronic exposure to indoor smoke expelled by active smokers (mainstream smoke) and by smoldering cigarettes (sidestream smoke). The second hand smokers correspond to those individuals who do not smoke but breathe air polluted with tobacco smoke. In addition, the environmental tobacco smoke may impregnate surfaces of furniture, floor, animal fur, towels and bed linens. The toxicity of cigarette smoke increases with aging and length of exposure (26). Moreover, children undergo important physiological changes that are unique during the growth period and that may be hazardously affected by the tobacco smoke. Our results showed that exposure of rats to secondhand tobacco smoke significantly compromised bone health, as demonstrated by the negative repercussions in all of the studied parameters. Further, our results suggest that the harmful effects may be time dependent. However, because the follow up time in our research was 60 days, it was not possible to establish the long-term effects of such exposure. Further, we used immature animals, making it possible to detect the detrimental effects on bone growth. These effects were more pronounced at 60-day follow-ups with a reduction of 11.25% in tibia lengths and may be related to the fact that nicotine interferes with the formation of signaling molecules, leading to changes in metabolism and bone growth (27). However, tobacco smoke contains many other potentially hazardous substances that may affect bone metabolism, thus reinforcing the deleterious effects of nicotine on bone. As expected, the aforementioned characteristics are confirmed by the results of mechanical tests. Thus, tibias from exposed animals were weaker and less rigid. Stiffness is a parameter that represents how the bone deforms under load, and the maximal load refers to bone resistance to deformation. These results are consistent with a study that demonstrated a reduction in the mechanical resistance of bones in rats that underwent subcutaneous injections of nicotine (28). Our current results show a reduction of 41.8% in bone mineral density and 56.7% in stiffness, due to metabolic changes caused by tobacco exposure. The metabolic changes were expressed by a reduction of 41.8% in plasma concentrations of alkaline phosphatase for the 60-day group. Because the majority of serum alkaline phosphatase in the growing period is of skeletal origin (29), these findings may also reflect a depression in bone metabolism. Additionally, previous studies showed the effects of cigarette smoke on cellular and gene expression. Such studies point to a delay in the chondrogenesis of fracture callus (30), osteoblastic gene expression (31) and modulation of osteoprogenitor cells (32). Finally, there are some limitations in our experimental design that may warn against a strict translation of our conclusions to human cases. Our model of second-hand exposure has not been confirmed to mimic what occurs in humans. We chose the interval ranging from 2.1 to 17.5 ng/mL as the cut-off range of cotinine levels to characterize animal exposure to second hand smoke. However, these data were validated in human second-hand smokers, and there is no available information for the rat. Additionally, we were unable to find an ideal environment in which to expose the animals. Two main models are available. In one, the animals are exposed in a collective chamber that is successively filled and exhausted with tobacco smoke (13,14). In this model, the rat fur is impregnated with smoke substances that are ingested when the animals self-clean. Eye irritation also occurs in this model.

’ ACKNOWLEDGMENTS We appreciate the support of the Laboratory Technicians: Rui Marcos da Silva, Jonas Tadeu da Silva, Julio César Abdanur, Kaio Raffael Valotta Bezerra and Rogério Lelis Rocha.

’ AUTHOR CONTRIBUTIONS Rosa RC was responsible for the design, and intellectual and scientific content of the study, technical procedures, acquisition and interpretation of data, manuscript writing, critical revision, and approval of the final version of the manuscript. Pereira SC was responsible for the technical procedures, acquisition and interpretation of data. Cardoso FA was responsible for the acquisition and interpretation of data, statistical analysis, and manuscript revision. Caetano AG was responsible for the acquisition and interpretation of data, and technical procedures. de Santiago HA was responsible for the technical procedures and acquisition of data. Volpon JB was responsible for the design, and intellectual and scientific content of the study, manuscript writing, critical revision and final approval of the manuscript, and securing funding.

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NOTICE OF RETRACTION

Risk factors for the prognosis of pediatric medulloblastoma: a retrospective analysis of 40 cases Jianzhong Yu, Rui Zhao, Wei Shi, Hao Li CLINICS 2017;72(5):294-304 Retraction requested by the Editor of CLINICS in agreement with the authors Retraction type: Redundant publication Comments: The same article was published almost simultaneously in the journal TRANSLATIONAL NEUROSCIENCE AND CLINICS with a different title: ‘‘Factors affecting the prognosis of children with medulloblastoma: A single institution retrospective analysis of 40 cases’’ (http://www.tncjournal.com/EN/10.18679/CN11-6030/R.2017.003). All articles submitted to CLINICS undergo strict quality control and are checked using iThenticate software before being submitted for peer review and before acceptance. The retracted article was checked on September 26, 2016, and February 24, 2017. Unfortunately, the article was published in TRANSLATIONAL NEUROSCIENCE AND CLINICS in May 2017, so there was no way of acknowledging the publication during the evaluation process. The authors submitted all required copyright transfer documents stating that the manuscript had not been submitted to any other journal. The authors stated the following: ‘‘It was an unintentional mistake caused by carelessness. After acceptance of our article in CLINICS, we attended a seminar. TRANSLATIONAL NEUROSCIENCE AND CLINICS indexed our paper after the seminar, and we knew nothing about this at that time. We misunderstood and thought that this would not influence the publication of our paper in CLINICS as TRANSLATIONAL NEUROSCIENCE AND CLINICS is a non-SCI journal, and the paper was indexed only internally.’’

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