Sao Paulo Medical Journal

S達o Paulo Medical Journal/Evidence for Health Care, 2010 January 7; 128(1):1-52.

S達o Paulo

ISSN 1516-3180

Evidence for Health Care January 7, 2010, volume 128, number 1

Randomized controlled trial: Epidural versus intravenous fentanyl for postoperative analgesia following orthopedic surgery

Cross-sectional study: Frequency of subclinical thyroide dysfunction and risk factors for cardiovascular disease among women at a workplace

Systematic review: Specific immunotherapy using Hymenoptera venom

Igreja de Santa Teresinha - Taubat辿 Adriano Aguina

S達o Paulo Medical Journal does not charge authors for publication

Indexed in: Medline, Lilacs, SciELO, Science Citation Index Expanded, Journal Citation Reports/ Sciences Edition (ISI) and EBSCO Publishing

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January 7, 2010, volume 128, number 1

Original articles 5

Current status of transplantation in Brazil

Index

Editorial 3

Paulo Manuel Pêgo-Fernandes, Valter Duro Garcia

Epidural versus intravenous fentanyl for postoperative analgesia following orthopedic surgery: randomized controlled trial Marcelo Soares Privado, Adriana Machado Issy, Vera Lucia Lanchote, João Batista Santos Garcia, Rioko Kimiko Sakata

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Risk factors for cardiovascular disease ten years after preeclampsia

14

Bcl-2 protein frequency in patients with high-risk diffuse large B-cell lymphoma

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Frequency of subclinical thyroid dysfunction and risk factors for cardiovascular disease among women at a workplace

Ivete Cristina Teixeira Canti, Márcia Komlós, Sérgio Hofmeister Martins-Costa, José Geraldo Lopes Ramos, Edison Capp, Helena von Eye Corleta

Abrahão Elias Hallack Neto, Sheila Aparecida Coelho Siqueira, Frederico Luiz Dulley, Alfredo Chauobah, Marcelo Belesso, Rosaura Saboia, Milton Artur Ruiz, Dalton Alencar Fischer Chamone, Juliana Pereira

Rodrigo Diaz-Olmos, Antônio-Carlos Nogueira, Daniele Queirós Fucciolo Penalva, Paulo Andrade Lotufo, Isabela Martins Benseñor

24 Systematic review 30 Case series 38 Case report 42 Letter to the editor 45 Cochrane highlights 47 48 49

Application of Osteorisk to postmenopausal patients with osteoporosis Marcelo Luis Steiner, César Eduardo Fernandes, Rodolfo Strufaldi, Everaldo Cunha Porto, Luciano de Melo Pompei, Sérgio Peixoto

Specific immunotherapy using Hymenoptera venom: systematic review Alexandra Sayuri Watanabe, Luiz Augusto Marcondes Fonseca, Clóvis Eduardo Santos Galvão, Jorge Kalil, Fabio Fernandes Morato Castro

Vulvar melanoma: report on eleven cases and review of the literature Glauco Baiocchi, João Pedreira Duprat, Rogerio Izar Neves, Elza Mieko Fukazawa, Gilles Landman, Gustavo Cardoso Guimarães, Leonardo Jacomo Valadares

Squamous cell carcinoma arising from chronic lymphedema: case report and review of the literature Carlos Augusto Gomes, Camila Beatriz Silva Magalhães, Cleber Soares Junior, Rodrigo de Oliveira Peixoto

Lhermitte’s sign Viroj Wiwanitkit

First-line drugs for hypertension Short versus standard duration antibiotic therapy for acute streptococcal pharyngitis in children

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Organization

Founded in 1932, a bimonthly publication of the Associação Paulista de Medicina e-mail: revistas@apm.org.br

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Scientific Council Abrão Rapoport – Hospital Heliópolis, São Paulo Adriana Costa e Forti – Faculdade de Medicina, Universidade Federal do Ceará Álvaro Nagib Atallah – Escola Paulista de Medicina, Universidade Federal de São Paulo Auro del Giglio – Faculdade de Medicina da Fundação ABC Carlos Alberto Morais Sá – Universidade do Rio de Janeiro - UNIRIO Carmen Cabanelas Pazos de Moura – Instituto Carlos Chagas Filho, Universidade Federal do Rio de Janeiro Cármino Antonio De Souza – Faculdade de Ciências Médicas, Universidade Estadual de Campinas Dario Birolini – Faculdade de Medicina, Universidade de São Paulo Eduardo Katchburian – Escola Paulista de Medicina, Universidade Federal de São Paulo Eduardo Maia Freese de Carvalho – Faculdade de Medicina, Universidade Federal de Pernambuco, Centro de Pesquisas Aggeu Magalhães - CpqAM/FIOCRUZ. Egberto Gaspar de Moura – Instituto de Biologia Roberto Alcantara Gomes, Universidade Estadual do Rio de Janeiro Eliézer Silva – Hosipital Israelita Albert Einstein, São Paulo Emílio Antonio Francischetti - Faculdade de Medicina da Universidade Estadual do Rio de Janeiro Emmanuel de Almeida Burdmann – Faculdade de Medicina de São José do Rio Preto Fabio Bessa Lima – Instituto de Ciências Biomédicas, Universidade de São Paulo Florence Kerr-Corrêa – Faculdade de Medicina de Botucatu, Universidade Estadual de São Paulo Francisco José Penna – Faculdade de Medicina Universidade Federal de Minas Gerais Geraldo Rodrigues de Lima – Escola Paulista de Medicina, Universidade Federal de São Paulo Irineu Tadeu Velasco – Faculdade de Medicina da Universidade de São Paulo João Renato Rebello Pinho – Instituto Adolfo Lutz, Secretaria de Estado da Saúde de São Paulo Joel Spadaro – Faculdade de Ciências Médicas de Botucatu, Universidade Estadual de São Paulo Jorge Pinto Ribeiro – Faculdade de Medicina, Universidade Federal do Rio Grande do Sul Jorge Sabbaga – Hospital Alemão Oswaldo Cruz, São Paulo José Antonio Marin-Neto – Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo José Carlos Nicolau – Instituto do Coração, Universidade de São Paulo José Geraldo Mill – Faculdade de Medicina, Universidade Federal do Espírito Santo

José Mendes Aldrighi – Faculdade de Saúde Pública, Universidade de São Paulo José Roberto Lapa e Silva – Instituto de Doenças do Tórax, Universidade Federal do Rio de Janeiro Leopoldo Soares Piegas – Instituto Dante Pazzanese de Cardiologia, São Paulo Luiz Jacintho da Silva – Faculdade de Ciências Médicas, Universidade Estadual de Campinas Luiz Paulo Kowalski – Hospital AC Camargo, São Paulo Márcio Abrahão – Escola Paulista de Medicina, Universidade Federal de São Paulo Maria Inês Schmidt – Faculdade de Medicina, Universidade Federal do Rio Grande do Sul Maurício Mota de Avelar Alchorne – Escola Paulista de Medicina, Universidade Federal de São Paulo Mauro Schechter – Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro Milton de Arruda Martins – Faculdade de Medicina, Universidade de São Paulo Moysés Mincis – Faculdade de Ciências Médicas de Santos Nelson Hamerschlak – Hospital Israelita Albert Einstein, São Paulo Noedir Antônio Groppo Stolf – Faculdade de Medicina, Universidade de São Paulo Pérsio Roxo Júnior – Faculdade de Medicina de Ribeirão Preto Raul Cutait – Hospital Sírio-Libanês, São Paulo Raul Negrão Fleury – Instituto Lauro de Souza Lima, Coordenadoria dos Institutos de Pesquisa da Secretaria de Saúde de São Paulo Raul Marino Junior – Faculdade de Medicina, Universidade de São Paulo Ricardo Brandt de Oliveira – Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo Roberto A. Franken – Faculdade de Ciências Médicas da Santa Casa de Misericórdia de São Paulo Ruy Laurenti – Faculdade de Saúde Pública, Universidade de São Paulo Wadih Arap – MD Anderson Cancer Center, University of Texas, Houston, United States Wilson Roberto Catapani – Faculdade de Medicina do ABC, Santo André Wilson Cossermelli – Reclin Reumatologia Clínica, São Paulo Wellington Cardoso – Boston University, Boston, United States

Diretoria executiva da Associação Paulista de Medicina (Triênio 2008-2011) Presidente (Campinas) ........................................................... Jorge Carlos Machado Curi

Diretor social (São Paulo) ....................................................... Nelson Álvares Cruz Filho

1o vice-presidente (São Paulo)................................................. Florisval Meinão

Diretor social adjunto (Santos) ................................................ Antonio Ismar Marçal Menezes

2o vice-presidente (Jaú) .......................................................... Paulo De Conti

Diretora de ações comunitárias (São Paulo) ............................. Yvonne Capuano

3o vice-presidente (Marília) ..................................................... Donaldo Cerci Da Cunha

Diretor de ações comunitárias adjunto (Assis) .......................... Roberto de Mello

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4 vice-presidente (Presidente Prudente).................................. Roberto Lotfi Jr.

Diretor cultural (Marília) ......................................................... Ivan de Melo Araújo

Secretário geral (São Paulo) ................................................... Ruy Yukimatsu Tanigawa

Diretor cultural adjunto (São Paulo) ......................................... Guido Arturo Palomba

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1 Secretário (Jales) ............................................................... Paulo Cezar Mariani

Diretor de serviços aos associados (Piracicaba) ........................ Paulo Tadeu Falanghe

Diretor administrativo (São Paulo) ........................................... Akira Ishida

Diretor de serviços aos associados adjunto (São Paulo) ............ Cristião Fernando Rosas

Diretor administrativo adjunto (Ribeirão Preto) ......................... João Carlos Sanches Anéas 1o diretor de patrimônio e finanças (São Paulo) ........................ Murilo Rezende Melo 2o diretor de patrimônio e finanças (São Paulo) ........................ Clóvis Francisco Constantino Diretor científico (São Paulo) .................................................. Álvaro Nagib Atallah Diretor científico adjunto (São Paulo)....................................... Paulo Manuel Pêgo Fernandes Diretor de defesa profissional (São Bernardo do Campo) ........... Tomás Patrício Smith-Howard Diretor de defesa profissional adjunto (São Paulo) .................... Jarbas Simas Diretor de comunicações (Piracicaba) ...................................... Renato Françoso Filho Diretor de comunicações adjunto (São Paulo) ......................... Leonardo da Silva

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Diretor de economia médica (São Paulo) ................................. José Antonio de Lima Diretor de economia médica adjunto (Araraquara).................... Helder de Rizzo da Matta 1o diretor distrital (São Caetano do Sul) ................................... Delcides Zucon 2o diretor distrital (Santos)...................................................... Arnaldo Duarte Lourenço 3a diretora distrital (São José dos Campos) .............................. Silvana Maria Figueiredo Morandini 4o diretor distrital (Sorocaba) .................................................. João Márcio Garcia 5o diretor distrital (Campinas) ................................................. José Renato dos Santos 6o diretor distrital (Franca) ...................................................... Luis Fernando Peixe

Diretor de marketing (São Paulo) ............................................ Nicolau D’Amico Filho

7o diretor distrital (Botucatu)................................................... Noé Luiz Mendes de Marchi

Diretor de marketing adjunto (Sorocaba) ................................. Wilson Olegário Campagnone

8o diretora distrital (São José do Rio Preto) .............................. Regina Maria Volpato Bedone

Diretor de eventos (São Paulo) ................................................ Lacildes Rovella Júnior

9a diretora distrital (Araçatuba) ............................................... Margarete de Assis Lemos

Diretora de eventos adjunta (São Paulo) .................................. Mara Edwirges Rocha Gândara

10o diretor distrital (Presidente Prudente) ................................ Ademar Anzai

Diretor de tecnologia da informação (Lins) ............................... Ronaldo Perches Queiroz

11o diretor distrital (Assis) ...................................................... Carlos Chadi

Diretor de tecnologia de informação adjunto (São Paulo) .......... Ivo Carelli Filho

12o diretor distrital (São Carlos) .............................................. Luís Eduardo Andreossi

Direto de previdência e mutualismo (Araçatuba) ...................... Alfredo de Freitas Santos Filho

13o diretor distrital (Barretos) ................................................. Marco Antônio Teixeira Corrêa

Diretora de previdência e mutualismo adjunta (São Paulo) ........ Maria das Graças Souto

14o diretor distrital (Piracicaba) .............................................. Antonio Amauri Groppo

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Estado atual do transplante no Brasil Paulo Manuel Pêgo-FernandesI, Valter Duro GarciaII

Editorial

Current status of transplantation in Brazil

Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

In 1964, kidney transplantation began in Brazil and, in 1968, heart, liver, intestine and pancreas transplantations were performed. Like elsewhere in the world, the disappointing results led to suspension of the transplant programs in the early 1970s, for all organs except kidneys.1 The discovery of cyclosporine in the 1970s, and its clinical application as immunosuppressive medication in early 1980, provided better results from kidney transplantation. Subsequently, the programs for heart (1984), liver (1985) and pancreas transplantation (1987) were reactivated and an early lung transplantation program was instituted in Brazil (1989).1 Regarding regulation, transplantation can be divided into three phases. The first, in which demand and allocation of organs was the responsibility of the transplantation centers, with no control from the Ministry of Health or other government bodies, extended from 1964 to 1987.1 The second phase started in 1987, with the publication by the Ministry of Health of the Integrated Plan for Chronic Renal Patient treatment (SIRC-TRANS), which was designed to set standards for the accreditation and functioning of kidney transplantation centers, and to determine the amounts for payment by the public health system.2 In the same year, in some states, government agencies and foundations took over responsibility for procurement and/or allocation of organs. The first organizations were the Immunogenetics and Organ Transplantation Program (PITO) in Rio de Janeiro,3 the São Paulo Interior Transplantation (SPIT) system4 and the Rio Grande do Sul Transplant Coordination service (RS-Tx).5 The Constitution of 1988 prohibited the sale of organs, and this was regulated by the transplantation law of 1992.6 In the same year, the Ministry of Health created the Integrated System for High Complexity Procedures (SIPAC), for kidney, liver, heart, lung and bone marrow transplantation. This established quality control mechanisms for transplant centers, accreditation for regulated transplantation services and set the amounts to be paid for these procedures.

The third phase began in 1998 with new legislation on transplantation and the creation of the National Transplant System (SNT) and the Centers for Notification, Procurement and Distribution of Organs (CNCDOs) in the states and Federal District. Controlling and funding all the processes of donation and transplantation became the responsibility of the federal government.1 Overall coordination of the SNT was assisted by Technical Advisory Groups (GTAs) and Technical Councils, with regard to specific organs and tissues, and the SNT was made responsible for transplant policy in this country. The CNCDOs controlled the logistics of donation and allocation in the states.1 In 1999, the National Center for Notification, Procurement and Distribution of Organs (CNNCDO) was created. It was established at the airport of Brasilia and was made responsible for the distribution of organs among all the states.1 In 2000, based on the Spanish model and at the request of the Brazilian Association of Organ Transplantation, the Transplantation Hospital Coordinator was created. This subsequently became known as the Intra-Hospital Committee for the Donation of Organs and Tissues for Transplantation (CIHDOTT), which was used in most states. São Paulo continued with the American model of using Organ Procurement Organizations (OPOs).1 Between 2000 and 2004, dozens of training courses were conducted for hospital transplantation coordinators in 18 states.7 With this organizational system, the donor rate in this country remained stable at around three per million population (pmp) between 1993 and 1998 and increased to 7.4 pmp between 1999 and 2004. However. from 2005 onwards, there was a progressive decrease in the donor rate, reaching 5.4 pmp in June 2007. This was caused I

Associate professor, Department of Cardiopneumonology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.

Director, Department of Kidney and Pancreas Transplantation, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil.

II

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Pêgo-Fernandes PM, Garcia VD by a number of factors, such as changes in the SNT that interrupted the courses. This led to a series of changes and improvements in transplantation policy that reversed this situation. Two years later (September 2009), the donor rate was 8.6 pmp, an increase of 54% over this period, thereby reaching the goal proposed for this year. However, the efforts in this area need to be redoubled in order to achieve the proposed donor rate targets of 10 pmp in 2010, 14 pmp in 2013 and 20 pmp in 2017.

The forecast for 2009, from the data obtained up to September, is that 4,130 kidney transplants (21.8 pmp) will be performed in Brazil, i.e. 31% of the 13,300 cases that enter the waiting list each year (70 pmp); 1,301 liver transplantations (6.9 pmp): 31% of the 4,160 needed (25 pmp); 193 heart transplantations (1.0 pmp): 18% of the 1,104 needed (6 pmp); 169 pancreas transplantations (0.9 pmp): 30% of the 570 needed (3 pmp); and 63 lung transplantations (0.3 pmp): about 4% of the 1,472 needed (8 pmp). The use of organs in Brazil is highly variable: exceeding 70% for kidneys and livers, around 15% for hearts and only 5% for lungs.8-10 Regarding the transplantation of corneas, which can also come from donors up to six hours after death, 13,052 transplants (71 pmp) are expected to be performed, i.e. 79% of the 16,560 needed (90 pmp). Some states, like São Paulo and Paraíba, have already been able to bring down the waiting list for corneas to zero.8,9 For organ transplantation to increase in Brazil, it is essential to improve the four pillars that support the donation process for transplantation: legislation, financing, organization and education. The legal measures include the implementation of a registration system for voluntary donors, and the prevention of any form of trade through greater control over transplants from unrelated living donors and prohibition of transplantation involving deceased donors who were non-resident aliens in the country. With regard to financial measures, adjustments to the funding available for organ procurement and transplantation need to be made, in order to include new medications like belatacept, rituximab and bortezomib as medicines supplied by the public system for transplantation patients, and to include payment by the public healthcare system for new diagnostic procedures such as C4d in biopsies, antigenemia or polymerase chain reaction (PCR) tests for diagnosing cytomegalovirus and quantitative measurement of viral load in cases of Epstein-Barr virus (EBV) and BK virus (BKV). Among the organizational measures deemed vital are training and motivation for intensive care physicians and neurologists, for diagnosing brain death and maintaining potential donors. Hospitals also need to be equipped through purchasing equipment to document brain death, training the hospital

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transplantation coordinators and having teams for organ procurement and transplantation available 24 hours a day in all states. Finally, educational policies are still needed, both for professionals and students in the healthcare field and for the population.

REFERENCES 1.

Garcia VD, Pestana JOM, Ianhez LE. História dos transplantes no Brasil. In: Garcia VD, Abbud-Filho M, Neumann J, Pestana JOM, editors. Transplante de órgãos e tecidos. 2a ed. São Paulo: Segmento Pharma; 2006. p. 27-42.

2. Garcia VD, Abbud-Filho M, Keitel E, Neumann J. Situação atual do processo doação – transplante. In: Garcia VD, editor. Por uma política de transplantes no Brasil. São Paulo: Office Editora e Publicidade Ltda; 2000. p. 19-35.

3. Vasconcelos MSF, Menezes PA, Menezes JAV, et al. O transplante renal no Hospital dos Servidores do Estado – Rio de Janeiro. Revisão de 380 transplantes. JBT Jornal Brasileiro de Transplantes. 1998;1:71-83.

4. Ferraz AS, Santos CM, Wen LY, Voltarelli JC. The experience of the “São Paulo Interior Transplant” with a multifactorial system for selection of cadaver kidney recipients. Transplant Proc. 1991;23(5):2676-7.

5. Garcia VD, Hoelfmann N, Bittar AE, Goldani JC. Transplant coordinators in Rio Grande do Sul, Brazil: initial analysis. Transplant Proc. 1991;23(5):2519-20.

6. Brasil. Lei no 8.489, de 18 de novembro de 1992. Dispõe sobre a retirada e transplante de tecidos, órgãos e partes do corpo humano, com fins terapêuticos e científicos e dá outras providências. Available from: http://www.prosangue.sp.gov.br/pdf/Lei%20n.8489%20 de%2018.11.92%20conf.pdf. Accessed in 2009 (Dec 14).

7. Garcia VD, Miranda T, Luca L, Nothen R, Teixeira Pinto JB. Training hospital transplantation coordinators in Brazil. Transplant Proc. 2007;39(2):336-8.

8. Garcia VD. Editorial. RBT Registro Brasileiro de Transplantes. 2009;15(3):3. Available from: http:// www.abto.org.br/abtov02/portugues/populacao/rbt/anoXV_n3/index.aspx?idCategoria=2. Accessed in 2009 (Dec 18).

9. Associação Brasileira de Transplantes de Órgãos. Dados gerais. RBT Registro Brasileiro de Transplantes. 2009;15(3):5-20. Available from: http://www.abto.org.br/abtov02/portugues/populacao/rbt/anoXV_n3/index.aspx?idCategoria=2. Accessed in 2009 (Dec 18).

10. Fernandes PM, Samano MN, Junqueira JJ, Waisberg DR, Noleto GS, Jatene FB. Perfil do doador de pulmão disponibilizado no estado de São Paulo, Brazil, em 2006 [Lung donor profile in the State of São Paulo, Brazil, in 2006]. J Bras Pneumol. 2008;34(7):497-505.

Sources of funding: Not declared Conflict of interest: None Date of first submission: November 18, 2009 Last received: December 14, 2009 Accepted: December 18, 2009

Address for correspondence: Paulo Manuel Pêgo-Fernandes Av. Dr. Enéas de Carvalho Aguiar, 44 Instituto do Coração (InCor) Secretaria do Serviço de Cirurgia Torácica, 2o andar — Bl. 2 — Sl. 9 São Paulo (SP) — Brasil CEP 05403-000 Tel. (+55 11) 3069-5248 E-mail: paulo.fernandes@incor.usp.br E-mail: vdurogarcia@terra.com.br

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Fentanil peridural versus venoso na analgesia pós-operatória de cirurgia ortopédica: ensaio clínico aleatório Marcelo Soares PrivadoI, Adriana Machado IssyII, Vera Lucia LanchoteIII, João Batista Santos GarciaIV, Rioko Kimiko SakataV

Original article

Epidural versus intravenous fentanyl for postoperative analgesia following orthopedic surgery: randomized controlled trial

Universidade Federal de São Paulo — Escola Paulista de Medicina (Unifesp-EPM), São Paulo, Brazil

KEY WORDS: Analgesia.

ABSTRACT

Analgesia, epidural.

CONTEXT AND OBJECTIVE: Controversy exists regarding the site of action of fentanyl after epidural injection. The objective of this investigation was to

Fentanyl.

compare the efficacy of epidural and intravenous fentanyl for orthopedic surgery.

Pharmacology.

DESIGN AND SETTING: A randomized double-blind study was performed in Hospital São Paulo.

Orthopedics.

METHODS: During the postoperative period, in the presence of pain, 29 patients were divided into two groups: group 1 (n = 14) received 100 μg of fentanyl epidurally and 2 ml of saline intravenously; group 2 (n = 15) received 5 ml of saline epidurally and 100 μg of fentanyl intravenously. The analgesic supplementation consisted of 40 mg of tenoxicam intravenously and, if necessary, 5 ml of 0.25% bupivacaine epidurally. Pain intensity was evaluated on a numerical scale and plasma concentrations of fentanyl were measured simultaneously.

RESULTS: The percentage of patients who required supplementary analgesia with tenoxicam was lower in group 1 (71.4%) than in group 2 (100%): 95% confidence interval (CI) = 0.001-0.4360 (P = 0.001, Fisher’s exact test; relative risk, RR = 0.07). Epidural bupivacaine supplementation was also lower in group 1 (14.3%) than in group 2 (53.3%): 95% CI = 0.06-1.05 (P = 0.03, Fisher’s exact test; RR = 0.26). There was no difference in pain intensity on the numerical scale. Mean fentanyl plasma concentrations were similar in the two groups.

CONCLUSION: Intravenous and epidural fentanyl appear to have similar efficacy for reducing pain according to the numerical scale, but supplementary analgesia was needed less frequently when epidural fentanyl was used.

CLINICAL TRIAL REGISTRATION NUMBER: NCT00635986

PALAVRAS-CHAVE: Analgesia.

Analgesia epidural.

Fentanila.

Farmacologia.

Ortopedia.

RESUMO CONTEXTO E OBJETIVO: Existem controvérsias sobre o local de ação do fentanil injetado por via peridural. O objetivo foi comparar a eficácia do fentanil peridural e do venoso em cirurgias ortopédicas.

TIPO DE ESTUDO E LOCAL: Estudo aleatório, duplo-cego, realizado no Hospital São Paulo.

MÉTODO: No pós-operatório, na presença de dor, 29 pacientes foram divididos em dois grupos: grupo 1 (n = 14) recebeu solução de 100 mcg de fentanil por via peridural e 2 ml de solução salina venosa; grupo 2 (n = 15), 5 ml de solução salina peridural e 100 μg de fentanil venoso. A complementação analgésica foi com 40 mg de tenoxicam venoso e, se necessário, 5 ml de bupivacaína 0.25%. A intensidade da dor foi avaliada pela escala numérica e a concentração plasmática do fentanil foi medida simultaneamente.

RESULTADOS: A percentagem de pacientes que necessitaram de complementação analgésica com tenoxicam foi menor no grupo 1 (71.4% versus 100.0% grupo 2): intervalo de confiança, IC 95% = 0.001-0.4360 (P = 0.001, teste exato de Fisher; risco relativo, RR = 0.07). A complementação com bupivacaína peridural também foi menor no grupo 1 (14.3% versus 53.3% grupo 2): IC 95% = 0.06-1.05 (P = 0.03, teste exato de Fisher; RR = 0.26).

Não houve diferença na intensidade da dor avaliada pela escala numérica. As concentrações plasmáticas do fentanil foram semelhantes nos dois grupos.

CONCLUSÃO: A eficácia do fentanil venoso e peridural parece ser semelhante na redução da dor de acordo com a escala numérica, porém a frequência de analgesia suplementar foi menor com o uso do fentanil peridural.

REGISTRO DE ENSAIO CLÍNICO: NCT00635986

I

MD, PhD. Anesthetist, Department of Anesthesia, Universidade Federal do Maranhão (UFMA), São Luis, Maranhão, Brazil.

PhD. Assistant professor and pharmacologist, Department of Anesthesia, Universidade Federal de São Paulo — Escola Paulista de Medicina (Unifesp-EPM), São Paulo, Brazil.

III PhD. Titular professor and toxicologist, Department of Toxicology, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.

IV MD, PhD. Assistant professor and anesthetist, Department of Anesthesia, Universidade Federal do Maranhão (UFMA), São Luís, Maranhão, Brazil.

V MD, PhD. Associate professor, anesthetist and coordinator of the Pain Clinic, Department of Anesthesia, Universidade Federal de São Paulo — Escola Paulista de Medicina (UnifespEPM), São Paulo, Brazil II

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INTRODUCTION The discovery that opioids act by activating receptors located in the dorsal horn of the spinal cord, and reports of intense and long-lasting pain relief after intrathecal injection of morphine1 have been important steps for postoperative analgesia.

Fentanyl is one of the most widely used opioids administered epidurally. The risk of respiratory depression is low and the incidence of side effects (itching, nausea, vomiting and urine retention) is lower than that observed with morphine.2 Controversy exists regarding the site of action of fentanyl after epidural injection. Some authors have suggested that its effect is directly mediated in the spinal cord, while others have believed that the main site of action is the supraspinal region, in view of its high liposolubility, with consequent absorption into the systemic circulation and distribution to the brain.3 Other investigators have suggested a combination of these two mechanisms to explain the action of epidural fentanyl.4 Thus, further studies are necessary to explain the sites of action of this drug when administered epidurally and also to determine whether there is any difference in the analgesic effect between applying the drug intravenously and epidurally.

OBJECTIVE To evaluate the efficacy of fentanyl (100 μg) administered by the epidural or intravenous routes after lower-limb orthopedic surgery, taking the primary outcome to be pain and the secondary outcome to be the requirement for supplementary analgesia during the postoperative period.

METHODS Twenty-nine consecutive patients admitted during a one-year period (from February 2005 to January 2006), of both genders and ranging in age from 18 to 65 years, were studied. They were all classified as presenting American Society of Anesthesiologists (ASA) physical status 1 or 2 and had been scheduled for orthopedic bone surgery on the lower limbs. The study was approved by the Ethics Committee of Hospital São Paulo, Medical School, Universidade Federal de São Paulo — Escola Paulista de Medicina (Unifesp-EPM), and written informed consent was obtained from all patients.

Patients with infection in the puncture area, those with coagulation disorders, pregnant patients, and patients using opioids were excluded from the study.

The study was conducted in a double-blind manner and each patient was randomly assigned to one of two groups. The process of randomization consisted of drawing lots for the procedures, which were kept in sealed envelopes. The draw was performed by a single physician who prepared the medication. Another physician was responsible for injection of the epidural and venous medication, while the researcher was responsible for evaluation of the patients. Both physicians and the patients were unaware of the group chosen by lot until the end of the study.

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The medications were prepared in the same volumes and solution colors for the two groups. Thus, both the physician responsible for the procedure and the researcher were unaware of the group to which the patient belonged.

The epidural anesthesia consisted of 20 ml of 0.5% bupivacaine together with epinephrine (1:200,000), injected between L3-L4 and L4L5 and supplemented with 5 ml of bupivacaine when necessary. After injection, an epidural catheter was inserted for postoperative analgesia.

Sedation was achieved using 2-5 mg of midazolam.

During the postoperative period, when the patient complained of pain, the group 1 patients (n = 14) received 5 ml of a solution containing 100 μg of fentanyl diluted in saline epidurally and 2 ml of saline intravenously. The group 2 patients (n = 15) received 5 ml of saline epidurally and 2 ml of fentanyl (100 μg) intravenously. Thus, the patients of both groups received both an intravenous and an epidural solution, thus ensuring double-blind study conditions, i.e. group 1: epidural fentanyl + intravenous saline (placebo); group 2: epidural saline (placebo) + intravenous fentanyl.

If supplementation was necessary, 40 mg of tenoxicam was administered intravenously, and if the patient continued to complain of pain, 5 ml of 0.25% bupivacaine was injected.

The pain intensity was evaluated 30 minutes, two hours and four hours after injection of fentanyl, on a scale ranging from 0 (no pain) to ten (very intense pain).5,6 On the same occasions, venous blood samples were collected for measurement of plasma fentanyl concentrations.

The blood samples were immediately centrifuged and the plasma was separated and stored at -70 °C until the time for spectrochromatography analysis. The quantification limit of the method was 0.05 ng/ml of plasma.

Thirty patients were originally selected (15 per group), but one patient in group 1 was excluded from the study because blood entered the epidural catheter.

For statistical analysis, the distribution of frequency data was analyzed by means of the chi-square test using the GraphPad InStat software. Two-way repeated-measurement analysis of variance (ANOVA) was used to compare the samples, repeated over time. Student’s t test, Fisher’s exact test, and Mann Whitney test were also applied.

Our hypothesis was that intravenous fentanyl was associated with a response rate of 30%. Assuming that epidural fentanyl would have a response rate of 80% improvement in pain response (primary outcome) and considering a power of 95% (beta) and P = 0.05% (alpha), the sample size would be 15.54.

RESULTS There were no significant differences between the groups with regard to gender, age, weight, height or body mass index (Table 1). In addition, no significant difference in the duration of surgery was observed between the groups (137 minutes for group 1 and 135 minutes for group 2). The interval between the beginning of anesthesia and the administration of epidural fentanyl (group 1) was 380 ± 101 minutes, and the interval between the beginning of anesthesia and the adminis-

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Epidural versus intravenous fentanyl for postoperative analgesia following orthopedic surgery: randomized controlled trial tration of intravenous fentanyl (group 2) was 331 ± 83 minutes, with no significant difference between the groups (Student’s t test, P = 0.17).

The percentage of patients who required supplementary analgesia with tenoxicam was lower in group 1 (71.4%) than in group 2 (100.0%): 95% confidence interval (CI) = 0.001-0.4360 (Fisher’s exact test, P = 0.04; risk relative, RR = 0.07). Epidural bupivacaine supplementation was also lower in group 1 (14.3%) than in group 2 (53.3%): 95% CI = 0.06-1.05 (Fisher’s exact test, P = 0.05; RR = 0.26). The first analgesic supplementation was necessary after 125.7 ± 57.6 minutes in group 1 and after 98.3 ± 49.5 minutes in group 2, without any significant difference (Mann-Whitney test, P = 0.267). No significant difference in pain intensity evaluated on the numerical scale was observed between the groups (Table 2).

The mean plasma fentanyl concentrations (ng/ml) were similar in the two groups (ANOVA, P = 0.67; Table 3). Tables 4, 5 and 6 show the cumulative numbers and percentages of patients who had required supplementary analgesics up to the time of each evaluation (T0, T30, T120 and T240), as well as the mean pain intensity and plasma fentanyl concentrations at these times.

In group 1, at T30, the mean pain intensity among the patients who did not require supplementary analgesics (n = 13; 93%) was 0.2 and the plasma fentanyl concentration was 0.20 ng/ml. The single patient (7%) who received tenoxicam had a pain intensity score of 3 and a plasma fentanyl concentration of 0.27 ng/ml. At T120, the mean pain intensity among the patients who still had not required analgesic supplements (n = 7; 50%) was 0.3 and the plasma fentanyl concentration was 0.23 ng/ml. For the patients who received tenoxicam (n = 7; 50%), the pain intensity score was 3.9 and the mean plasma fentanyl concentration was 0.23 ng/ml. The single patient (7%) who received bupivacaine presented a pain intensity score of 10 and a plasma fentanyl concentration of 0.26 ng/ml. At T240, the mean pain intensity among the patients who had not required analgesic supplements until that time (n = 4; 29%) was 2.2 and the plasma fentanyl concentration was 0.55 ng/ml. The pain intensity score of the patients who received tenoxicam (n = 10; 71%) was

2.4 and the plasma fentanyl concentration was 0.19 ng/ml. For the patients who received bupivacaine (n = 2; 14%), the pain intensity score was 2.5 and the plasma fentanyl concentration was 0.16 ng/ml.

In group 2, at T30, the mean pain intensity among the patients who did not require tenoxicam supplementation (n = 15; 100%) was 0.9 and the plasma fentanyl concentration was 0.31 ng/ml. At T120, the pain intensity among the patients who did not require analgesic supplements (n = 3; 20%) was 3.4 and the plasma fentanyl concentration was 0.21 ng/ml. The pain intensity among the patients who received tenoxicam (n = 12; 80%) was 4 and the plasma fentanyl concentration was 0.20 ng/ml. For the patients who received bupivacaine (n = 3; 20%), the pain intensity score was 2 and the plasma fentanyl concentration was 0.24 ng/ml. At T240, all the patients had received tenoxicam supplementation, and these patients (n = 15; 100%) presented a pain intensity score of 2.5 and a plasma fentanyl concentration of 0.16 ng/ml. The pain intensity among the patients who had received bupivacaine up to that time (n = 8; 54%) was 0.6 and the plasma fentanyl concentration was 0.19 ng/ml.

The side effects observed were nausea (group 1: one patient; group 2: one patient), vomiting (group 2: one patient), and urine retention (group 2: two patients).

DISCUSSION Several investigators7-20 have evaluated the mechanism of action of fentanyl administered epidurally. Although many studies3,9-12,15,17 have concluded that the mechanism of action is associated with systemic absorption of the opioid into the circulation, followed by a supraspinal effect, many investigators continue to use fentanyl as a continuous infusion. According to the literature,2,9 with continuous infusion, the higher plasma concentration of fentanyl promotes supraspinal action.

In these studies, the plasma fentanyl concentrations were around 0.63 ng/ml for patients to maintain pain relief. We used a single bolus of epidural fentanyl.

Table 1. Demographic data on the patients Gender (F, M) 3F; 11 M 5F; 10 M 0.6817

Group 1 (n = 14) Group 2 (n = 15) P

Age (years) 35.28 ± 15.68 41.26 ± 13.24 0.27621

Weight (kg) 71.14 ± 11.79 74.73 ± 9.25 0.36321

Height (cm) 170.93 ± 8.27 167.87 ± 8.32 0.50151

BMI (kg/m2) 24.42 ± 4.12 26.52 ± 2.46 0.16281

Group 1 = epidural fentanyl; Group 2 = intravenous fentanyl; P = statistical significance, ≤ 0.05; M = male; F = female; BMI = body mass index; p = Fisher’s exact test; P1 = Student’s t test; values expressed as mean ± standard deviation.

Table 2. Pain intensity at each evaluation time (mean ± standard error of the mean)

Group 1 (n = 14) 95% CI Group 2 (n = 15) 95% CI P2

T30 0.35 ± 0.22 - 0.13 - 0.84 0.86 ± 0.43 - 0.06 - 1.80 0.7013

Time (minutes) T120 2.07 ± 0.86 0.21 - 3.93 3.60 ± 0.70 2.09 - 5.10 0.0843

T240 2.35 ± 0.65 0.95 - 3.76 2.46 ± 0.80 0.73 - 4.20 0.8794

P

Table 3. Fentanyl plasma concentrations (ng/ml)

1

0.0112 0.0101

Group 1 = epidural fentanyl; Group 2 = intravenous fentanyl; T30; T120; T240 = times (min) after the administration of fentanyl; 95% CI = 95% confidence interval; P1 = analysis of variance (ANOVA); P2 = Student’s t test.

Group 1 (n = 14) 95% CI Group 2 (n = 15) 95% CI P2

T30 0.21 ± 0.06 0.17 - 0.24 0.31 ± 0.16 0.22 - 0.39 0.0734

Time (min) T120 0.23 ± 0.15 0.15 - 0.32 0.21 ± 0.10 0.15 - 0.26 0.9304

T240 0.29 ± 0.41 0.06 - 0.53 0.16 ± 0.08 0.11 - 0.21 0.3480

0.6642 0.0008

Group 1 = epidural fentanyl; Group 2 = intravenous fentanyl; T30; T120; T240: times (min) after the administration of fentanyl; 95% CI = 95% confidence interval; P1 = analysis of variance (ANOVA); P2 = Student’s t test.

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Privado MS, Issy AM, Lanchote VL, Garcia JBS, Sakata RK Although methods for measuring plasma fentanyl concentrations are available, they do not reflect the degree of activation of opioid receptors by the drug.10 Studies evaluating the site of action of epidural fentanyl have usually focused on the plasma concentration of the drug, its analgesic effect and the need for supplementary analgesia.

However, a greater challenge would be to study the binding of this drug to its receptor.

The need for supplementary analgesia was greater in group 2 than in group 1. This finding suggests that epidural fentanyl is more efficient than intravenous administration of the drug, as also reported in another study.12 Although the statistical analysis did not show any difference in the length of time before the first request for supplementary analgesia, analgesic supplementation occurred earlier in patients who had received intravenous fentanyl, thus suggesting that epidural fentanyl has a longer-lasting effect. Another interesting point was that only two patients needed both types of analgesic supplements after epidural fentanyl while, after intravenous fentanyl, eight patients required both supplements.

The intensity of pain was similar in the two groups, and this has also been reported in other studies.11,13,21 This finding shows that both intravenous and epidural fentanyl promoted good pain relief within the first 30 minutes. However, after this period, part of the analgesic effect was mediated by supplementation. Other investigators also observed that, after the first hour, the pain was less intense after epidural fentanyl than after intravenous administration, despite the similar or even lower plasma concentrations.

A correlation between plasma opioid concentration and pain relief has been reported.22-24 The minimum plasma fentanyl concentration for postoperative pain relief was 0.63 ng/ml.2

The plasma fentanyl concentrations observed at different times were similar to those reported in other studies.3,11,15,21 Some investigators found that the plasma concentration of fentanyl was much lower after epidural injection than after intravenous administration.12,16 In the present study, only two patients in group 1 and one patient in group 2 presented a fentanyl concentration of 0.63 ng/ml during the period analyzed.

Another important point was that, in group 1, most patients presented good pain relief at T30, with plasma fentanyl concentrations lower than 0.63 ng/ml in the absence of any supplementary analgesia. In addition, many group 2 patients showed good pain relief despite a plasma fentanyl concentration below the minimum required for analgesia, although the number of patients was smaller than in group 1. At T120, many group 1 patients still presented good pain relief with plasma fentanyl levels less than 0.63 ng/ml and did not require supplementary analgesics. In group 2, few patients presented adequate pain relief and all of them requested supplementary analgesia. After four hours, some group 1 patients continued to present good pain relief, although they did not receive any analgesic supplement, and their plasma fentanyl concentration was less than 0.63 ng/ml. Four hours after epidural injection, the plasma fentanyl concentration was higher than after two hours, probably because it was spreading out from the distribution sites of the drug.

The better analgesic effect of epidural fentanyl observed in the present study, despite the lower plasma concentration of the drug, suggests that there is an effect caused by spinal action, in addition to the systemic action.

The side effects associated with fentanyl were nausea and vomiting.

Urine retention, an adverse effect more frequently observed after epidu-

Table 4. Cumulative number of applications of supplementary analgesic, pain intensity and plasma fentanyl concentrations among the patients, 30 minutes after administration of epidural or intravenous fentanyl (T30)

N (%) NS C (ng/ml)

G1 13 (93) 0.2 0.4

None G2 15 (100) 0.5 0.3

P 0.4828* 0.5186† 0.6530†

G1 1 (7) 3.0 0.3

Tenoxicam G2 0 (0) -

P 0.4828 -

G1 0 (0) -

Bupivacaine G2 0 (0) -

P -

NS = numerical scale; C = plasma fentanyl concentration; T30 = 30 minutes after administration of epidural or intravenous fentanyl; *Fisher’s exact test; †Mann-Whitney test

Table 5. Cumulative number of applications of supplementary analgesic, pain intensity and plasma fentanyl concentrations among the patients, 120 minutes after administration of epidural or intravenous fentanyl (T120)

N (%) NS C (ng/ml)

G1 8 (57) 1.5 0.2

None G2 3 (20) 2.6 0.2

P 0.0704* 0.5196† 0.3727†

G1 6 (43) 3.0 0.2

Tenoxicam G2 12 (80) 4.0 0.2

P 0.0604* 0.9999† 0.4936†

G1 1 (7) 10 0.26

Bupivacaine G2 3 (20) 0.5 0.3

P 0.5977* -

NS = numerical scale; C = plasma fentanyl concentration; T120 = 120 minutes after administration of epidural or intravenous fentanyl; *Fisher’s exact test; †Mann-Whitney test

Table 6. Cumulative number of applications of supplementary analgesic, pain intensity and plasma fentanyl concentrations among the patients, 240 minutes after administration of epidural or intravenous fentanyl (T240)

N (%) NS C (ng/ml)

G1 10 (71) 2.4 0.3

None G2 8 (53) 3.8 0.2

P 0.4497* 0.6965† 0.1728†

G1 3 (21) 1.3 0.2

Tenoxicam G2 3 (20) 4.0 0.1

P 1.0000* 0.7000† 1.0000†

G1 1 (7) 2.5 0.2

Bupivacaine G2 5 (33) 0.5 0.3

P 0.1686* -

NS = numerical scale; C = plasma fentanyl concentration; T240 = 240 minutes after administration of epidural or intravenous fentanyl; *Fisher’s exact test; †Mann-Whitney test

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Epidural versus intravenous fentanyl for postoperative analgesia following orthopedic surgery: randomized controlled trial ral opioids, was observed in the intravenous group. This effect was probably associated with the epidural bupivacaine used for anesthesia.

CONCLUSION Among patients undergoing lower-limb orthopedic surgery, intravenous and epidural fentanyl appear to have similar efficacy for reducing pain according to the numerical scale, but supplementary analgesia was needed less frequently when epidural fentanyl was used.

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Source of funding: Not declared Conflict of interest: Not declared Date of first submission: November 23, 2007 Last received: January 18, 2010 Accepted: January 18, 2010

Address for correspondence: Adriana Machado Issy Rua Nova York, 539 — apto. 81 Brooklin — São Paulo (SP) — Brasil CEP 04560-001 Tel. (+55 11) 5576-4069 Fax. (+55 11) 5576-4092 E-mail: issyam.dcir@epm.br

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