Efeitos do tratamento com Hidrogel na cicatrização de
Transcription
Efeitos do tratamento com Hidrogel na cicatrização de
UNIVERSIDADE FEDERAL DO RIO GRANDE DO NORTE CENTRO DE CIÊNCIAS DA SAÚDE PROGRAMA DE PÓS-GRADUAÇÃO EM FISIOTERAPIA Efeitos do tratamento com Hidrogel na cicatrização de úlceras venosas de membros inferiores: Revisão Sistemática Cibele Teresinha Dias Ribeiro Natal 2014 UNIVERSIDADE FEDERAL DO RIO GRANDE DO NORTE CENTRO DE CIÊNCIAS DA SAÚDE PROGRAMA DE PÓS-GRADUAÇÃO EM FISIOTERAPIA Efeitos do tratamento com Hidrogel na cicatrização de úlceras venosas de membros inferiores: Revisão Sistemática Cibele Teresinha Dias Ribeiro Dissertação apresentada à Universidade Federal do Rio Grande do Norte – Programa de pós-graduação em Fisioterapia, para a obtenção do título de Mestre em Fisioterapia. Orientador: Guilherme A. F. Fregonezi Natal 2014 Universidade Federal do Paraná Sistema de Bibliotecas Ribeiro, Cibele Teresinha Dias Efeitos do tratamento com Hidrogel na cicatrização de úlceras venosas de membros inferiores: revisão sistemática. / Cibele Teresinha Dias Ribeiro. – Natal, 2014. 96f: il.; 30cm. Orientador: Guilherme Augusto de Freitas Fregonezi Dissertação (Mestrado) – Programa de Pós-Graduação em Fisioterapia. Centro de Ciências da Saúde. Universidade Federal do Rio Grande do Norte. 1. Úlcera venosa. 2. Insuficiência venosa. 3. Hidrogel. I. Título II. Fregonezi, Guilherme Augusto de Freitas. III Universidade Federal do Rio Grande do Norte. Centro de Ciências da Saúde. Programa de PósGraduação em Fisioterapia. CDU 616-002.44 UNIVERSIDADE FEDERAL DO RIO GRANDE DO NORTE CENTRO DE CIÊNCIAS DA SAÚDE PROGRAMA DE PÓS-GRADUAÇÃO EM FISIOTERAPIA Coordenador do Programa de Pós-Graduação em Fisioterapia: Jamilson Simões Brasileiro iii UNIVERSIDADE FEDERAL DO RIO GRANDE DO NORTE CENTRO DE CIÊNCIAS DA SAÚDE PROGRAMA DE PÓS-GRADUAÇÃO EM FISIOTERAPIA Efeitos do tratamento com Hidrogel na cicatrização de úlceras venosas de membros inferiores: Revisão Sistemática BANCA EXAMINADORA Prof. Dr. Guilherme Augusto Freitas Fregonezi Presidente - UFRN Prof. Drª Selma Sousa Bruno UFRN – Membro Interno Prof. Drª Andrea Lemos Bezerra de Oliveira UFPE – Membro externo Aprovada em 04/02/2014 iv Dedicatória Ao meu esposo, Fernando e a minha filha Bianca. v Agradecimentos Inicialmente quero agradecer a Deus e a minha família por me amparar nos momentos difíceis, me dar força interior para superar as dificuldades, me mostrar o caminho certo nas horas incertas e me suprir em todas as minhas necessidades. Aos meus pais, pela educação, pelos valores, pelo que sou hoje. Ao meu pai, que tenho certeza estar comemorando comigo mais esta vitória. De onde você estiver, pai, agradeço tudo o que fez por mim e por ter mostrado a todos que viver vale a pena e temos que lutar até os últimos segundos de nossas vidas pelo e por quem mais amamos!! A minha mãe, amor incondicional, por sempre me apoiar, ajudar em todos os momentos e estar presente nos momentos mais especiais e importantes da minha vida. A todos os familiares, em especial a minhas irmãs, Danielle e Franciele, as quais sempre estiveram ao meu lado, me apoiando e que, apesar da distância, nossa união e cumplicidade sempre estiveram presentes. A minha tia Solange, que teve uma participação especial na minha educação como minha professora também. Ao meu professor mais especial, esposo, companheiro, amigo, meu “porto seguro”, Fernando Dias, obrigada por tudo! Agradeço por toda a sua paciência em sempre estar pronto a passar o seu conhecimento de maneira clara e com entusiasmo. Você é um exemplo de professor e pesquisador. São admiráveis a sua dedicação ao ensino e a forma como contagia a todos a também querer aprender cada vez mais. E a minha filha Bianca, que é a razão da minha vida. Agradeço ao Professor Guilherme Fregonezi, pela orientação. Obrigada pelas oportunidades oferecidas pelo senhor antes mesmo de iniciar o mestrado e pelos ensinamentos que foram fundamentais durante todo esse tempo. Agradeço a oportunidade de ter participado do curso de Revisão Sistemática com a Prof.ª Andrea Lemos e a sua presença na banca. Seus ensinamentos foram primordiais para que eu conseguisse aprimorar os conhecimentos em revisão sistemática. vi Agradeço também às pessoas que fazem parte do grupo de Feridas da Colaboração Cochrane, Sally Bell-Syer e Ruth Foxlee. Vocês também foram essenciais para a realização desta revisão, pois sempre responderam aos meus emails prontamente, resolvendo minhas dúvidas e enviando sugestões. A todos os colegas de mestrado, principalmente a Fernando Macedo, que nos deixou tão inesperadamente, mas que tive a oportunidade de conhecer melhor no laboratório 6, ajudando-o nos pilotos do projeto por ele desenvolvido. Que você esteja em paz! A todos os amigos que faziam e ainda fazem parte do laboratório 6, pelo convívio e aprendizagem. As pessoas especiais que sempre serão lembradas durante o período no qual vivi em Natal: à professora e amiga Vanessa Resqueti, pela amizade, por todos os momentos juntas, principalmente os de convívio familiar; à Diana Freitas e Gabriela Chaves, por compartilharmos sempre dúvidas dos nossos trabalhos e pelos ótimos momentos que vivenciamos no departamento; à Jaqueline Andruchak, pela amizade; à professora Ana Raquel, uma das primeiras pessoas a qual conheci em Natal e que sempre me apoiou na realização desse mestrado além de ter convivido com ela em muitos momentos em família. Aos funcionários do departamento de Fisioterapia da UFRN, principalmente a Edriene e a D. Eudione, por sempre estarem dispostas a me ajudar, servindo como “babás” para que eu conseguisse participar de cursos e aulas. E a todos que, de alguma forma, fizeram parte de mais essa etapa, o meu sincero Obrigada por tudo!! vii SUMÁRIO Dedicatória v Agradecimentos vi Listas Lista de abreviaturas x Lista de figuras xi Lista de gráficos xii Resumo xiii Abstract xiv 1 INTRODUÇÃO 1 1.1 Doença venosa crônica 2 1.2 Úlceras venosas 5 1.2.1 Processo de cicatrização de uma úlcera 7 1.2.2 Curativos de carboximetilcelulose 8 1.3 Justificativa 11 1.4 Objetivos 12 1.4.1 Objetivo principal 12 1.4.2 Objetivos secundários 12 2 MATERIAIS E MÉTODOS 13 2.1 Caracterização da pesquisa 14 2.2 Etapas de uma revisão pela Colaboração Cochrane 14 2.3 Critérios para considerar os estudos para a revisão 17 3 RESULTADOS 19 viii 3.1 Descrição dos estudos 38 3.1.1 Resultados da busca 38 3.1.2 Estudos incluídos 40 3.2 Risco de viés dos estudos incluídos 41 3.3 Efeitos do hidrogel 44 3.3.1 Comparação entre hidrogel, Quitosana, e gaze com solução salina (He e col. 2008) 44 3.3.2 Comparação entre hidrogel, Intrasite, e gel de alginato (de la Brassine e col. 2006) 46 3.3.3 Comparação entre hidrogel, Intrasite, e mel de Manuka (Gethin e col. 2008) 47 3.3.4 Comparação entre hidrogel e hidrocolóide (Grotewohl, 1994) 48 4 DISCUSSÃO 50 5 CONSIDERAÇÕES FINAIS E CONCLUSÃO 53 6 REFERÊNCIAS BIBLIOGRÁFICAS 55 ANEXOS 61 ANEXO 1: Protocolo publicado-Hydrocolloid for healing venous leg ulcer 62 ANEXO 2: Estudos excluídos e justificativas para exclusão 80 ANEXO 3: Características dos estudos incluídos 87 ix Lista de Abreviaturas DVC- Doença Venosa Crônica IC- Intervalo de Confiança ITB- Índice Tornozelo-Braquial IVC- Insuficiência Venosa Crônica NPF- Nurse Prescriber´s Formulary RevMan- Review Manager RR- Risco Relativo TVP- Trombose Venosa Profunda x Lista de figuras Figura 1: Fluxograma da estratégia de elaboração de uma revisão sistemática pela Colaboração Cochrane. Figura 2: Diagrama com o resultado da seleção dos estudos. Figura 3: Avaliação do risco de viés de todos os estudos incluídos na revisão Figura 4: Avaliação do risco de viés de cada estudo incluído na revisão: julgamento dos autores de cada item para cada estudo incluído. xi Lista de gráficos Gráfico 1: Forest plot representando a comparação do hidrogel com gaze com solução salina para o desfecho cicatrização completa das úlceras. Gráfico 2: Forest plot representando a comparação do hidrogel com o gel de alginato para o desfecho porcentagem de redução da úlcera em 4 semanas de tratamento. Gráfico 3: Forest plot representando a comparação do hidrogel com o mel de Manuka para o desfecho cicatrização completa das úlceras. Gráfico 4: Forest plot representando a comparação do hidrogel com o mel de Manuka para o desfecho incidência de infecção. xii Resumo A doença venosa crônica (DVC) evidencia-se entre as doenças crônicas por acometer a população idosa e ser a principal responsável pelas úlceras de membros inferiores nesta população. O uso de adesivos no cuidado de uma úlcera venosa é parte fundamental no tratamento para a cicatrização, no entanto, as evidências para auxiliar na escolha do melhor adesivo são escassas. O objetivo principal do estudo foi avaliar a eficácia do tratamento com o hidrogel na cicatrização de úlceras venosas mediante métodos de busca, síntese de informação e análise estatística através de uma revisão sistemática com meta-análise. Foram selecionados estudos controlados randomizados nas seguintes bases de dados: CENTRAL; DARE; NHS EED; MEDLINE; EMBASE; CINAHL. Além dessas bases foram consultados três websites para identificar estudos em andamento: ClinicalTrials.gov, OMS ICTRP e ISRCTN. Os desfechos primários analisados foram: cicatrização completa das úlceras e incidência de infecção das úlceras e os secundários foram: alterações no tamanho da úlcera, tempo de cicatrização das úlceras, recorrência das úlceras, qualidade de vida dos participantes, dor e custos do tratamento. Quatro estudos estão atualmente incluídos na revisão com um total de 250 pacientes. O uso do hidrogel parece ser superior ao curativo convencional, gaze embebida em salina, para a cicatrização de úlceras venosas de membros inferiores; 16/30 pacientes apresentaram cicatrização completa das úlceras (RR 5,33, 95%CI [1,73,16,42]). O gel de alginato demonstrou ser mais efetivo quando comparado ao hidrogel quanto à redução da área da úlcera; 61,2% (± 26,2%) com o alginato e 19,4% (± 24,3%) com o hidrogel ao final das quatro semanas de tratamento. O mel de Manuka demonstrou ser similar ao hidrogel em relação à porcentagem de redução da área. Esta revisão mostrou que não existem evidências disponíveis a respeito da eficácia do hidrogel em relação aos outros tipos de curativo na cicatrização de úlceras venosas de membros inferiores, demonstrando assim a necessidade de futuras pesquisas para auxiliar os profissionais da saúde na escolha do adesivo correto. Palavras-chave: Insuficiência Venosa Crônica; úlcera venosa; curativo de hidrogel; revisão sistemática. xiii Abstract Chronic venous disease (CVD) is evident among the chronic diseases and affects the elderly population and primarily is responsible for leg ulcers in this population. The use of dressings in the care of a venous ulcer is a fundamental part of the treatment for healing, however, evidence to assist in choosing the best dressing is scarce. The main objective of this study was to evaluate the effectiveness of treatment with hydrogel in the healing of venous ulcers using search methods, synthesis of information and statistical research through a systematic review and meta-analysis. Randomized controlled trials were selected in the following databases: CENTRAL; DARE; NHS EED; MEDLINE; EMBASE; CINAHL. Beyond these databases three websites were consulted to identify ongoing studies: ClinicalTrials.gov, OMS ICTRP e ISRCTN. The primary outcomes were analyzed: complete wound healing, incidence of wound infection and the secondary were: changes in ulcer size, time to ulcer healing, recurrence of ulcer, quality of life of participants, pain and costs of treatment. Four studies are currently included in the review with a total of 250 participants. The use of hydrogel appears to be superior to conventional dressing, gauze soaked in saline, for the healing of venous leg ulcers; 16/30 patients showed complete healing of ulcers (RR 5,33, 95%CI [1,73,16,42]). The alginate gel was shown to be more effective when compared to the hydrogel dressing in reduction of the wound area; 61,2% (± 26,2%) with alginate e 19,4% (± 24,3%) with hydrogel at the end of four weeks of treatment. Manuka honey has shown to be similar to the hydrogel dressings in percentage of area reduction. This review demonstrated that there is no evidence available about the effectiveness of the hydrogel compared to other types of dressings on the healing of venous leg ulcers of the lower limbs, thus demonstrating the need of future studies to assist health professionals in choosing the correct dressing. Keywords: chronic venous insufficiency, venous ulcers, hydrogel dressings, systematic review. xiv 1INTRODUÇÃO 2 As úlceras venosas de membros inferiores são frequentes e recorrentes, em especial, em idosos. É uma ferida complexa associada a um custo considerável para os pacientes e para saúde pública. O uso de adesivos no cuidado de uma úlcera venosa é parte fundamental no tratamento para a cicatrização, no entanto, as evidências para auxiliar a escolha do melhor adesivo são escassas. Atualmente buscam-se intervenções terapêuticas que possam acelerar o processo de cicatrização das feridas diminuindo assim, a morbidade, as complicações e os gastos oriundos da doença. O presente estudo trata-se de uma revisão sistemática com o objetivo de sintetizar o resultado de pesquisas selecionadas sobre a eficácia do tratamento do hidrogel na cicatrização de úlceras venosas mediante métodos de busca, síntese de informação e análise estatística através de uma revisão sistemática com metaanálise. 1.1 Doença Venosa Crônica A doença venosa crônica (DVC) destaca-se entre as doenças crônicas que acometem a população idosa e é a principal responsável pelas úlceras de membros inferiores nesta população1;2. A DVC refere-se a uma doença que afeta o funcionamento do sistema venoso dos membros inferiores decorrentes de uma hipertensão venosa de longa duração, causada por insuficiência valvular com ou sem obstrução do fluxo venoso podendo afetar o sistema venoso superficial, sistema venoso profundo, ou ambos3. Essa condição abrange uma série de apresentações clínicas que podem variar de telangiectasias a úlceras abertas. A classificação da DVC dos membros inferiores surgiu a partir de um consenso estabelecido por um comitê de especialistas de vários países4 e posteriormente ela foi revisada e atualizada por alguns autores do mesmo comitê5. Ela é classificada segundo a classificação Clinical-Etiology-Anatomy-Patophysiology (CEAP) onde C refere-se aos sinais clínicos da doença; E à etiologia; A refere-se à localização anatômica da doença e P à fisiopatologia. Todas as formas de apresentação clínica da DVC estão divididas em sete categorias que variam de acordo com a gravidade, sendo C0 a ausência de sinais; C1 telangiectasias e/ou veias reticulares; C2 varizes tronculares; C3 edema; C4a pigmentação e/ou eczema 3 dos membros; C4b lipodermatosclerose e/ou atrofia branca; C5 úlcera venosa cicatrizada e C6 úlcera venosa ativa. Em relação à etiologia, a DVC divide-se em três classes: congênita (Ec), primária (Ep), secundária (Es) ou sem causa venosa identificável (Em). No que diz respeito à anatomia venosa do membro inferior, esta se divide em três sistemas: superficial (As), profundo (Ad), perfurante (Ap) e local venoso não identificável (An). Por fim, em termos fisiopatológicos, a DVC poderá resultar de um refluxo (Pr), de uma obstrução (Po), de ambos os processos (refluxo e obstrução – Pr,o) e patofisiologia não identificada (Pn)5. Tendo como base a classificação CEAP, a doença venosa crônica é definida como qualquer forma de doença venosa desde C0 a C6. Existe uma sobreposição de termos, pois alguns autores consideram o termo insuficiência venosa crônica (IVC) como sinônimo de DVC abrangendo assim todas as classes da doença. Por outro lado, alguns consideram IVC apenas casos avançados da doença como aqueles pacientes que apresentam edema (C3), alterações subcutâneas (como lipodermatoesclerose C4b) e úlcera venosa (C5-C6)6. A prevalência da IVC tende a aumentar com a idade7. Um único estudo realizado no Brasil, interior de São Paulo, sobre alterações venosas de membros inferiores estimou a prevalência de varizes em 39,5% e de formas mais graves da IVC, no caso as úlceras abertas ou cicatrizadas em 1,5%8. Nos Estados Unidos estima-se que aproximadamente 2,5 milhões de pessoas tenham IVC, das quais 20% chegam a desenvolver úlcera venosa9. Uma revisão com 11 estudos de prevalência realizados na Austrália e Europa estimou a prevalência de úlceras venosas de membros inferiores em 0,1% a 0,3% na população adulta10. Os dados epidemiológicos têm consistentemente sugerido que a prevalência aumenta com a idade e é maior entre as mulheres11-14. Tem sido estimado que a incidência de úlceras venosas na terceira idade seja de 0,76/100 pessoas por ano em homens e de 1,42/100 pessoas por ano em mulheres13. As úlceras venosas estão associadas a um custo considerável para o paciente e para os profissionais da saúde e apresentam um grande problema para a 4 saúde pública por ser progressiva e apresentar propensão à recorrência15. Duas revisões sistemáticas sobre qualidade de vida em pacientes com úlceras de perna reportaram que a presença de ulceração na perna estava associada com dor, restrição às atividades de trabalho e lazer, mobilidade reduzida, perturbação do sono, redução do bem-estar psicológico e isolamento social16;17 O custo do tratamento de uma úlcera de perna não cicatrizada no Reino Unido foi estimado em cerca de EUR 1,3 mil por ano (valores calculados em 2001)18. Um estudo realizado na Alemanha revelou que o custo médio por ano com um paciente com uma úlcera venosa crônica é de EUR 9569 dos quais 92% estão relacionados a custos diretos como gastos com exames, curativos, taxas médicas e 8% estão relacionados a custos indiretos como perda da produtividade no trabalho19. Um estudo de coorte realizado no USA registrou que os custos diretos com um paciente com uma úlcera venosa de membros inferiores seria em media $2400 por mês (valor estimado em 1997)20. Como descrito, a IVC provém da disfunção do sistema venoso dos membros inferiores decorrentes de uma hipertensão venosa de longa duração. Os fatores predisponentes da hipertensão venosa incluem história de trombose venosa profunda (TVP), tromboflebite, trauma na perna, artrite, obesidade, gravidez e vida sedentária. Esses fatores podem resultar em danos às válvulas nas veias das pernas21;22. Em condições normais, o fluxo de sangue nos vasos venosos ocorre em uma única direção, das veias do sistema superficial para as veias do sistema profundo, orientado pelas inúmeras válvulas contidas no interior das veias desses sistemas e auxiliado pela musculatura dos membros inferiores especialmente das pernas e dessas desembocando no átrio direito. Esse mecanismo faz com que a pressão venosa, que em posição ortostática pode atingir valores de até 80mmHg a 90mmHg seja reduzida para 30 mmHg em resposta a ação valvular e à contração muscular; portanto, uma falha no funcionamento dessas válvulas pode desencadear a hipertensão venosa21;23. Durante a progressão da insuficiência venosa, observam-se alterações da microcirculação representadas pela diminuição do número de capilares associado às alterações morfológicas dos capilares remanescentes que se tornam contorcidos, convolutos e dilatados; concomitantemente ocorre diminuição da pressão tissular de 5 O2 local24-26. Uma teoria importante e provavelmente mais aceita atualmente para a fisiopatologia da ulceração venosa é a teoria do encarceramento dos leucócitos26;27. A estase venosa favorece a marginalização dos leucócitos e a interação endotélioleucocitária, com consequente infiltração leucocitária e produção de citocinas e substâncias químicas por parte destes. Estes fatores contribuirão para a lesão tissular (semelhante ao que ocorre na inflamação crônica)27;28. 1.2 Úlceras venosas A complicação mais importante da IVC é a úlcera venosa representando cerca de 70% de todas as úlceras de perna. Elas apresentam-se como feridas abertas, geralmente irregulares e superficiais nos membros inferiores, predominando no terço inferior da perna e caracteristicamente tendem a se cronificar, serem recidivantes e apresentarem cicatrização lenta, especialmente quando não tratadas prontamente e adequadamente. Estão associadas à hipertensão venosa sustentada e alterações da microcirculação decorrentes de insuficiência venosa crônica26-28;29. Essa condição causa problemas físicos, psicológicos e financeiros que impactam a qualidade de vida dos pacientes. O impacto das úlceras venosas na rotina diária dos pacientes tem sido descrito em vários estudos quantitativos e qualitativos. Os maiores problemas reportados pelos pacientes são: dor, imobilidade, distúrbios do sono, falta de energia, limitações nas atividades de trabalho e lazer, preocupações, frustações e falta de autoestima16;17. A duração de uma úlcera venosa pode variar de algumas semanas a mais de 10 anos e em algumas pessoas elas nunca cicatrizam14;30;31. O tamanho da úlcera bem como a sua duração (tempo maior que 18 meses) são fatores que contribuem para o risco de uma úlcera não cicatrizar32. Outros fatores também estão associados a um atraso da cicatrização das úlceras, como: lipodermatoesclerose, evidência de trombose venosa profunda, tromboflebite superficial e baixa mobilidade do tornozelo33. Margolis et al. 34 mostraram, através de um estudo de coorte com 260 pacientes que apresentavam úlcera venosa e foram tratados por um período de 2 anos com terapia compressiva, os fatores independentes associados com o 6 insucesso da cicatrização de uma úlcera com 24 semanas de duração que foram: tamanho inicial da ferida, duração da ferida no início do tratamento, história de ligadura venosa, história de cirurgia para colocação de prótese de joelho ou quadril, ITB (índice tornozelo-braquial) <0,8, ferida coberta com fibrina em uma área >50% no início do tratamento. O diagnóstico da úlcera venosa é basicamente clínico realizado através da anamnese e do exame clínico. Na anamnese deve-se observar: queixa e a duração dos sintomas; doenças anteriores como a trombose venosa; traumatismos prévios dos membros e a existência de doença varicosa e principalmente a aparência e localização da úlcera. Os sintomas incluem sensação de peso nas pernas e dor nos membros inferiores principalmente ao final do dia35. O diagnóstico clínico juntamente com os exames complementares tem como objetivo estabelecer as possíveis causas da IVC, se ela ocorre por obstrução do retorno venoso, por refluxo ou por ambos. Dentre os exames complementares existentes os mais usados são: o Doppler de ondas contínuas, o eco-Doppler venoso e a pletismografia venosa35;36. Todo paciente que apresenta uma úlcera precisa realizar o índice tornozelo-braquial (ITB) para investigar a presença de doença arterial obstrutiva periférica. É um teste não invasivo, de baixo custo, determinado pelo Doppler vascular que é calculado através da maior pressão sistólica aferida no tornozelo aferida nas artérias tibial posterior ou pediosa dividida pela maior pressão sistólica aferida no membro superior utilizando a artéria braquial. Índices iguais ou menores que 0,9 caracterizam o diagnóstico de doença arterial periférica37. Índices maiores que 0,8 são geralmente usados para afastar a coexistência de doença arterial periférica como causa da úlcera levando ao diagnóstico de úlcera devido a insuficiência venosa38. Devido às características de cronicidade e alta reincidência das úlceras venosas, atualmente buscam-se intervenções terapêuticas que possam acelerar o processo de cicatrização das feridas diminuindo assim, a morbidade, as complicações e os gastos oriundos da doença. Embora o uso de compressão por enfaixamento e cuidados com a ferida seja o tratamento padrão 1;39 , o uso de agentes físicos como o ultrassom40;41, o laser associado à outras terapias como led infravermelho42 e correntes pulsadas de alta voltagem (HVPC)43 tem sido sugerido 7 para a aceleração da cicatrização das feridas além do tratamento promovido pela Fisioterapia através dos exercícios físicos44. De acordo com as Diretrizes sobre Diagnóstico, Prevenção e Tratamento da Doença Venosa Crônica da Sociedade Brasileira de Angiologia e Cirurgia Vascular (SBACV)36, durante o tratamento de uma úlcera venosa é necessário aliar a terapia compressiva com a elevação do membro durante o repouso. Para o tratamento de uma úlcera venosa são necessárias medidas que almejem a rápida cicatrização da úlcera através de cuidados básicos de limpeza do local afetado, uso de curativos, terapia compressiva, uso de agentes físicos, exercícios. 1.2.1 Processo de cicatrização de uma úlcera O processo de cicatrização envolve vários fenômenos entre os mais importantes estão os bioquímicos e fisiológicos que podem atuar de forma harmoniosa para garantir a reconstituição tecidual. A cicatrização depende de vários fatores locais e gerais, como: localização anatômica, tipo de pele, raça, idade, etc. O processo de cicatrização das úlceras envolve três estágios. Inicialmente existe o estágio inflamatório, que é precedido por uma fase de coagulação que se inicia após o surgimento da ferida. Esta fase depende da atividade plaquetária e da cascata de coagulação. Ocorre uma série de liberação de produtos como, substâncias vasoativas, proteínas adesivas, fatores de crescimento e proteases que são liberadas e estabelecem o desenvolvimento de outras fases. A formação do coágulo serve não apenas para coaptar as bordas da ferida, mas também para cruzar a fibronectina, oferecendo uma matriz provisória, em que os fibroblastos, células endoteliais e queratinócitos possam ingressar na ferida45. No estágio inflamatório o macrófago aparece como a célula mais importante, pois ele fagocita as bactérias, desbrida corpos estranhos e direciona o desenvolvimento do tecido de granulação. A fase de proliferação é responsável pelo fechamento da lesão e finalizando o processo ocorre a etapa de reparo tecidual em um estágio de remodelamento45;46. Todo o processo de cicatrização depende da proliferação de fibroblastos e da síntese de colágeno para a reparação tecidual. Os colágenos do tipo I e III são 8 encontrados em abundância no tecido de granulação, sendo o colágeno tipo III em maior quantidade nas bordas da lesão dérmica47. A resposta inicial imunohistoquímica para a cicatrização tecidual depende basicamente da presença de ambos os tipos de colágeno. No entanto são vários os fatores que influenciam o processo de cicatrização, retardando o mesmo e tornando as feridas crônicas. Entre eles interferem a idade, o estado nutricional do paciente e a existência de doenças como a diabetes45. Phillips e colaboradores48 citaram em seu estudo que a área da úlcera bem como sua duração é preditora significativa da cicatrização completa e do tempo para cicatrização total em uma úlcera. O percentual de cicatrização e a área da úlcera na terceira semana são bons preditores de uma cicatrização completa da úlcera. 1.2.2 Curativos de carboximetilcelulose Os curativos em geral são aplicados nas feridas diretamente ou sobre outro adesivo ou bandagem. O ambiente ideal para a cicatrização é aquele no qual a ferida é mantida coberta e úmida. Existem vários tipos de adesivos que promovem esse meio úmido com o objetivo de reepitelização da ferida, promover conforto ao paciente, controlar o exudato da ferida, prevenir que as bandagens não permaneçam em contato direto com a ferida, minimizar o número de trocas dos adesivos e o risco de maceração49. De acordo com a Nurse Prescriber´s Formulary (NPF)49, o adesivo apropriado para o tratamento das feridas não depende somente do tipo de ferida, mas do estágio em que se encontra o processo de cicatrização da mesma. A NPF classifica os adesivos em quatro categorias: Básicos: Esta categoria é subdividida em adesivos absorventes e adesivos de baixa aderência. Os de baixa aderência são compostos de algodão e podem ser colocados diretamente em contato com a ferida. Eles podem conter algum medicamento como a clorexidina ou não apresentar medicamento como a gaze de parafina. Os adesivos absorventes são aplicados diretamente na ferida e podem ser usados como uma camada secundária a um tratamento com feridas com muito exudato, exemplo: Primapore (Smith & Nephew). 9 Avançados - Esta categoria é composta por oito tipos de adesivos: - Adesivos de Hidrogel: será descrito com mais detalhes abaixo por ser o adesivo utilizado como tratamento proposto pela revisão. - Adesivos de Hidrocolóide: são geralmente compostos por uma matriz absorvente de hidrocolóide sobre uma película permeável ao vapor ou espuma de apoio, exemplo: Granuflex (ConvaTec). - Adesivos de alginato: esses adesivos são altamente absorventes e possuem em sua composição alginato de cálcio ou alginato de cálcio de sódio que podem ser combinados com o colágeno. O alginato forma um gel quando em contato com a superfície da ferida. Esse gel pode ser retirado no momento da troca do adesivo ou lavado com solução salina estéril, exemplo: Curasorb (Covidien). - Adesivos de espuma: esses adesivos contém espuma de poliuretano hidrofílica e são designados para absorver o exudato da ferida e manter a superfície da mesma úmida. Existem vários tipos, algumas, por exemplo, contém material absorvente adicional como a viscose e fibras de acrilato, exemplo: Allevyn (Smith & Nephew). - Adesivos macios de polímero: são compostos de um polímero de silicone macio mantidos em uma camada não aderente. Eles são moderadamente absorventes, exemplo: Urgotul (Urgo). - Adesivos de membrana e filmes permeáveis: esses adesivos são permeáveis ao vapor de água e oxigênio, mas não são permeáveis a água no estado líquido ou micro-organismos, exemplo: Opsite (Smith & Nephew). - Adesivos de efeito capilar: esses adesivos contem um núcleo absorvente de fibras hidrofílicas mantidas entre duas camadas de contato de baixa aderência, exemplo: Vacutx (Protex). - Adesivos de absorção de odores: esses adesivos contem carvão na sua composição e são usados para absorver o odor das feridas. Eles são usados 10 frequentemente com um adesivo secundário para melhorar a absorção, exemplo: CarboFLEX (ConvaTec). Anti-microbial - Existem três tipos nessa subdivisão: - Adesivos impregnados com mel: esses adesivos contém mel de pureza médica com propriedades anti-inflamatórias e anti-microbiais. Podem ser usados em feridas agudas e crônicas, exemplo: Medihoney (Medihoney). - Adesivos impregnados com prata: eles são usados para tratar feridas infectadas, exemplo: Acticoat (Smith & Nephew). - Adesivos impregnados com iodo: esses adesivos liberam iodo livre no qual pode agir como um antiséptico para a ferida quando esta é exposta ao exudato, exemplo: Iodozyme (Insense). Existem ainda outros tipos de adesivos antimicrobiais compostos de gaze ou adesivos de baixa aderência impregnados com solução oleosa que apresentam propriedades antimicrobiais. Adesivos especializados - Nessa categoria existem dois tipos: - Adesivos de silicone para queloides: esses adesivos reduzem ou previnem a cicatriz hipertrófica ou queloides, exemplo: Cica-Care (Smith & Nephew). - Adesivos de matriz moduladora de proteinase: eles alteram a atividade de enzimas proteolíticas em feridas crônicas, exemplo: Promogran (Systagenix). O hidrogel utilizado como curativo primário (curativo usado em contato direto com a ferida) é um adesivo que pode apresentar-se sob a forma de gel transparente, amorfo ou placa. As placas são geralmente compostas por água, propileno glicol e carboximetilcelulose ou água e polivinilpirridona. A NPF49 descreve os hidrogéis como adesivos compostos de polímeros de amido possuindo até 96% de água. Os hidrogéis bem como os adesivos em geral, têm como objetivo proteger a ferida promovendo um ambiente úmido visando a cicatrização da mesma. Eles são usados em feridas secas ou com pouco exudato e deve ser evitado o uso em feridas 11 com muito exudato, pois, o excesso de hidratação pode provocar a maceração do tecido ao redor da ferida. É necessário um curativo secundário (usado sobre o curativo primário; não aderente) para cobrir a ferida (NPF). As trocas deste tipo de curativo não necessitam ser diárias, porém dependem do curativo secundário e podem ocorrer entre um período de cinco a sete dias. Elas devem ser feitas quando for observado um extravasamento de exsudato para fora do curativo45. Além da vantagem da manutenção do meio úmido, os hidrogéis favorecem a angiogênese e promovem o desbridamento autolítico. Esse último processo é responsável pela digestão das células mortas através de enzimas sendo favorecido pela manutenção do meio úmido50. Outra vantagem dos curativos de hidrogéis é que eles protegem as terminações nervosas reduzindo assim a dor dos pacientes51 e causando menos desconforto durante as trocas. 1.3 Justificativa O uso de curativos no cuidado de uma úlcera venosa é parte fundamental no tratamento para a cicatrização. Existem muitos tipos disponíveis no mercado e os custos variam consideravelmente. Para a escolha correta do uso do curativo para cada paciente deve-se levar em consideração além do tipo da ferida e suas características o estágio de cicatrização. No entanto, a base de evidências para guiar qual o curativo correto para o tratamento ideal da úlcera é escassa. São necessárias orientações para ajudar os profissionais de saúde a tomar decisões a respeito do melhor curativo disponível para o tratamento visando uma rápida cicatrização da úlcera. Além disso, apesar do uso de diversos curativos ainda existe carência de análises sistemáticas que avaliem a efetividade do uso destes na cicatrização de úlceras venosas, incluindo o uso de hidrogel e adesivos de carboximetilcelulose (hidrocolóides) embora estes sejam amplamente utilizados na rotina clínica. Portanto, este estudo propôs avaliar a evidência clínica sobre a efetividade do tratamento do hidrogel para a cicatrização de úlceras venosas através de uma revisão sistemática. Além disso, a fisioterapia aplicada às doenças vasculares periféricas tem aumentado sua abrangência e este profissional está cada vez mais 12 em contato com pacientes acometidos por úlceras de pele; portanto necessitando conhecer a indicação e a efetividade destes curativos. 1.4 Objetivos 1.4.1 Objetivo principal Avaliar o resultado de estudos sobre a eficácia do hidrogel comparado com outros tratamentos e outros adesivos para a cicatrização de úlceras venosas. 1.4.2 Objetivos secundários - Selecionar, avaliar e incluir os ensaios clínicos controlados e randomizados no qual apresentem os efeitos dos tratamentos de hidrogel para a cicatrização de úlceras venosas comparados com outros nas alterações do tamanho da úlcera, tempo até a cicatrização bem como sua recorrência; - Avaliar a eficácia do tratamento de hidrogel na melhora da qualidade de vida e da dor; - Avaliar os custos do tratamento das úlceras venosas. 13 2 Materiais e Métodos 14 2.1 Caracterização da pesquisa O presente estudo trata-se de uma revisão sistemática com metanálise desenvolvida em parceria com a Colaboração Cochrane (The Cochrane Collaboration). A revisão seguiu as recomendações para realização de revisões sistemáticas e meta-análise propostas pelo Cochrane Handbook for Systematic Reviews of Interventions disponível no site da Colaboração Cochrane52. 2.2 Etapas de uma revisão pela Colaboração Cochrane A Colaboração Cochrane, fundada em 1992 no Reino Unido é uma organização internacional sem fins lucrativos cujos objetivos são preparar, manter e assegurar o acesso a revisões sistemáticas sobre efeitos de intervenções na área da saúde. A estrutura organizacional da Colaboração Cochrane divide-se em: rede de consumidores, centros, comitê diretor, campos, grupos de metodologia e grupos de revisão. Os grupos de revisão, por sua vez, estão divididos nas diversas áreas da saúde. A presente revisão faz parte do “Grupo de Feridas” (Wounds Group), com sede localizada na cidade North Yorkshire, York, United Kindom. Para iniciar uma revisão sistemática pela Colaboração Cochrane é necessário inicialmente contatar o (a) coordenador (a) do grupo de interesse a fim de discutir possíveis títulos para a revisão, os quais não entrem em choque com outros títulos já existentes nos grupos de revisões e assegurar a viabilidade da revisão proposta. O site da Colaboração Cochrane disponibiliza todas as informações e dados do corpo editorial e coordenadores de cada grupo, além das revisões já existentes. Após checar a viabilidade do tema sugerido, é então necessário preencher o formulário de registro do título ou o formulário de atualização, os quais contém uma breve descrição sobre a revisão, bem como algumas informações dos autores. O formulário é então submetido ao corpo editorial do grupo o qual é responsável pelo aceite da revisão sugerida. Para iniciar a presente revisão, os autores contataram a coordenadora do Grupo de Feridas e enviaram uma proposta de titulo. O grupo então sugeriu dividir uma revisão já publicada53 e que precisava ser atualizada em quatro outras revisões. A partir desse consenso foi então enviado a proposta através do formulário de 15 registro de dois títulos sugeridos no qual foi aprovado pelos editores do grupo. Todas as etapas a seguir foram realizadas de acordo com o Cochrane Handbook for Systematic Reviews of Interventions52 fornecido pela Colaboração Cochrane. Devido ao tempo necessário para desenvolvimento de uma revisão sistemática e alguns atrasos durante o desenvolvimento do estudo, o resultado de uma das revisões está sendo apresentado aqui nesta dissertação54 (Hidrogel dressings for venous leg ulcers) e a outra revisão ainda se encontra em andamento55 (Anexo 1). A Colaboração Cochrane recomenda que a revisão sistemática seja efetuada em sete passos: formulação da pergunta; localização e seleção dos estudos; avaliação crítica dos estudos; coleta de dados; análise e apresentação dos dados e aprimoramento e atualização da revisão52. Segue abaixo o fluxograma completo com todas as etapas para a realização da revisão sistemática pela Colaboração Cochrane: 16 Formulação da pergunta Contato com o grupo de feridas Registro do título Pesquisador 1 Seleção dos estudos Estudos excluídos e elaboração da tabela com a justificativa para a exclusão Necessidade da revisão Elaboração protocolo para Colaboração Cochrane Busca e identificação dos artigos Reunião de consenso Pesquisador 1 Pesquisador 2 Seleção dos estudos Estudos incluídos Pesquisador 1 Extração dos dados e elaboração da tabela dos estudos incluídos Aprovação e publicação do protocolo Pesquisador 2 Reunião de consenso Avaliação do risco de viés dos estudos incluídos Extração dos dados e elaboração da tabela dos estudos incluídos Pesquisador 2 Reunião de consenso Tabulação e análise dos dados Interpretação dos dados e Redação do manuscrito Figura 1: Fluxograma da estratégia de elaboração de uma revisão sistemática pela Colaboração Cochrane. 17 2.3 Critérios para considerar os estudos para a revisão Os seguintes critérios foram considerados para a inclusão dos estudos na revisão: tipos de estudos; tipos de participantes; tipos de intervenções; tipos de desfecho (primários e secundários); métodos de busca para identificação dos estudos (busca eletrônica e outras fontes de pesquisa). Para a coleta e análise dos dados foi considerada a avaliação do risco de viés; mensuração do efeito do tratamento; dados incompletos ou ausentes; avaliação da heterogeneidade; análise de subgrupo e análise de sensibilidade. Foram incluídos estudos controlados randomizados que apresentassem os efeitos do hidrogel na cicatrização de úlceras venosas de membros inferiores em pacientes de qualquer idade. Os desfechos primários analisados foram: cicatrização completa da ferida medida pelo número de úlceras completamente cicatrizadas durante a duração de cada estudo e a incidência de infecção na ferida. Os desfechos secundários foram: mudanças no tamanho da úlcera medidas pela redução no seu tamanho original expresso em valores absolutos (cm²) ou relativos (%); tempo de cicatrização da úlcera; recorrência da úlcera; qualidade de vida avaliada através de questionários genéricos padronizados como o SF-36, SF-12 ou SF-6; dor avaliada no momento da troca do adesivo ou durante o tratamento através de instrumentos validados como questionários ou escala visual analógica; e custos. Foram pesquisados estudos nas seguintes bases de dados eletrônicas: CENTRAL 2013, Issue 8; DARE 2013, Issue 8; NHS EED 2013, Issue 8; MEDLINE (1948 a agosto de 2013); EMBASE (1980 a setembro de 2013); CINAHL (1982 a agosto de 2013). Além dessas bases foi consultado 3 websites para identificar estudos em andamento: ClinicalTrials.gov, OMS ICTRP e ISRCTN. A busca de artigos foi realizada pela própria equipe do grupo de revisão de acordo com o protocolo préestabelecido (Wounds group). No entanto a escolha dos descritores e a decisão de quais estudos entrariam para a revisão foi função dos autores. Foi utilizado o software Review Manager (RevMan) versão 5.2 disponível para download no site da Colaboração Cochrane para a combinação e análise dos dados. Os seguintes dados foram extraídos dos estudos e inseridos no RevMan de maneira independente por dois autores: detalhes metodológicos como design do estudo, 18 método de randomização e sigilo de alocação, mascaramento dos participantes e dos avaliadores, desistências e exclusões, entre outros. Foram extraídos também descrição dos participantes, como: amostra total, idade, tipo e duração da úlcera, critérios de inclusão e exclusão. Na descrição da intervenção foi extraído o tipo de adesivo usado como tratamento, duração do tratamento e a descrição dos resultados. Na intenção de evitar a possibilidade de viés, aumentando assim a qualidade dos resultados, foi utilizada uma tabela para avaliação do risco de viés (The Cochrane Collaboration´s tool for assessing risk of bias) fornecida pela Colaboração Cochrane, no qual inclui os seguintes itens: sequência de randomização (random sequence generation), sigilo de alocação (allocation concealment), mascaramento dos participantes e dos avaliadores (blinding of participantes and personnel), mascaramento dos avaliadores envolvidos com a análise dos desfechos de cada estudo (blinding of outcome assessment), descrição seletiva do desfecho (selective reporting) e outros vieses (other bias). Cada item recebeu uma das seguintes classificações: “alto risco de viés”, “baixo risco de viés” ou “risco incerto de viés” de acordo com o Handbook for Systematic Reviews of Interventions da Colaboração Cochrane. A avaliação do risco de viés foi realizada de maneira independente por dois autores. Para a análise estatística foi utilizado o software RevMan 5.2 onde a mensuração do efeito do tratamento foi analisada através das variáveis contínuas que foram expressas como diferença de média com um intervalo de confiança (IC) de 95% e das variáveis dicotômicas foram expressas através da estimativa do risco relativo (RR) também com um intervalo de confiança de 95%. Todos os critérios citados acima estão descritos detalhadamente na seção de resultados na publicação que descreve o protocolo intitulado: Hydrogel dressings for venous leg ulcers que foi publicado na Cochrane Database of Systematic Reviews54. 19 3 RESULTADOS 20 Os resultados estão divididos em duas partes: na primeira encontra-se o protocolo publicado na base de dados da Colaboração Cochrane e em seguida a análise dos dados e discussão descritiva dos resultados que ainda não foram publicados. 21 Hydrogel dressings for venous leg ulcers (Protocol) Ribeiro CTD, Dias FAL, Fregonezi GAF This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2013, Issue 9 http://www.thecochranelibrary.com Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 22 TABLE OF CONTENTS HEADER . . . . . . . . . . ABSTRACT . . . . . . . . . BACKGROUND . . . . . . . OBJECTIVES . . . . . . . . METHODS . . . . . . . . . ACKNOWLEDGEMENTS . . . REFERENCES . . . . . . . . APPENDICES . . . . . . . . CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 1 3 3 6 7 9 15 15 15 i 23 [Intervention Protocol] Hydrogel dressings for venous leg ulcers Cibele TD Ribeiro1 , Fernando AL Dias2 , Guilherme AF Fregonezi3 1 Graduate Program in Physiotherapy, Federal University of Rio Grande do Norte, Natal, Brazil. 2 Department of Physiology, Federal University of Paraná, Curitiba, Brazil. 3 Department of Physical Therapy, Federal University of Rio Grande do Norte, Natal, Brazil Contact address: Guilherme AF Fregonezi, Department of Physical Therapy, Federal University of Rio Grande do Norte, Avenida Senador Salgado Filho, 3000, Lagoa Nova, Natal, Rio Grande do Norte, 59078-470, Brazil. [email protected]. Editorial group: Cochrane Wounds Group. Publication status and date: New, published in Issue 9, 2013. Citation: Ribeiro CTD, Dias FAL, Fregonezi GAF. Hydrogel dressings for venous leg ulcers. Cochrane Database of Systematic Reviews 2013, Issue 9. Art. No.: CD010738. DOI: 10.1002/14651858.CD010738. Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACT This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of hydrogel wound dressings for healing venous leg ulcers in people in any care setting. BACKGROUND A glossary of medical terms is available in Appendix 1. Description of the condition Venous leg ulcers (VLU) present as open wounds generally irregular and shallow or sores on the lower limb. They are associated with sustained venous hypertension and microcirculatory alterations resulting from chronic venous insufficiency (Grey 2006; Wollina 2006).This condition has psychological and financial impact and also impacts on the physical functioning of affected patients. The impact of leg ulcers on patient’s daily life is described in many quantitative and qualitative studies. The major problems reported from the patients are: pain, immobility, sleep disturbance, lack of energy, limitations in work and leisure activities, worry, frustration and lack of self-esteem (Herber 2007; Persoon 2004). Thus, venous leg ulcers will ultimately impact quality of life. Venous leg ulceration is a chronic health problem that can take years to heal completely, and, as it has a high rate of recurrence, often requires life-long treatment (Margolis 2002; Van Hecke 2011). Wound size and wound duration (greater than 18 months) were major contributors to a risk of not healing (Margolis 2004). Additionaly, the presence of lipodermatosclerosis, evidence of deep vein thrombosis, superficial thrombophlebitis or poor ankle mobility were individually associated with delayed healing (Lantis 2013). The incidence of venous ulceration rises with increasing age (De Araujo 2003; Wipke-Tevis 2000). The primary risk factors are aging, gender (more common in women), obesity, previous leg injuries, deep venous thrombosis (clots in veins) and phlebitis (inflammation of veins) (Collins 2010). Insufficiency of the superficial, perforating or deep veins of the leg is also a risk factor for leg ulceration (Valencia 2001). Venous leg ulcers have been estimated to afflict between 0.2% and 1% of the total population and between 1% and 3% of the elderly population in the United States (USA) and Europe (Margolis 2002).The estimated incidence of venous leg ulcers in the elderly (i.e. aged 65 years or older) per 100 person-years is around 0.76 for males and 1.42 for females (Margolis 2002). The estimated prevalence of venous leg ulcers ranges between 0.6 and 1.9 per cent in the adult population of the UK, USA, and Europe (Briggs 2003). Epidemiological studies estimate that venous leg ulcers affect 1 million people in the USA, Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 24 accounting for 70 to 80 per cent of all ulcers of the lower limbs (De Araujo 2003). A cohort study calculated that direct medical care costs attributable to a VLU averaged $2400 (in 1997 value US dollars) per month (Olin 1999). Up to 10 per cent of the population in Europe and North America has valvular incompetence, with 0.2 per cent developing venous ulceration. Venous ulceration represents the most prevalent form of difficult-to-heal wounds, and treating these problematic wounds requires significant healthcare resources. Recent data from Germany revealed that the mean total cost per year for a patient with chronic venous leg ulceration was EUR 9569, of which 92% was estimated to be direct costs (non drug treatment, inpatients costs and outpatient care) and 8% indirect costs (inability to work) (Purwins 2010). The physiopathology of venous ulcers starts as a macrovascular problem due to valve incompetence. Aetiological (causative) factors such as venous thrombosis could cause valve insufficiency that results in venous stasis and reflux, which are the predominant factors in chronic venous insufficiency (Raju 2010). In the normal venous system, pressure decreases during exercise as a result of the action of the muscles pumping the blood vessels. In a system where the valves are incompetent, the venous pressure remains high (Grey 2006). Sustained venous hypertension will ultimately lead to microcirculatory dysfunction and cause alterations in skin perfusion, which can then lead to ulceration. Alterations in the microcirculation are described as a decrease in the capillary density, which can also be reduced by dilation, tortuosity and convolution of the remaining capillaries (Howlader 2003; Incandela 2001; Junger 2000). This impacts the nutrition and clearance of by-products in the tissue, leading to skin changes observed in the form of swelling, eczema, hyperpigmentation (skin coloration), lipodermatosclerosis (hard, tight skin) and, ultimately, tissue ulceration. Part of the pathway leading to tissue damage and ulceration is due to leucocyte interaction with endothelial cellsurface binding molecules that facilitate their migration into tissue. Once leucocytes are in the tissue they become active and produce a series of molecules that lead to tissue damage (Smith 2006; Wollina 2006). The diagnosis of venous ulceration is usually based on clinical examination. Additional tests such as colour duplex ultrasonography (measurement of blood flow in the veins and arteries of the leg), plethysmography (measures variations in the size or volume of a limb), venography ( x-ray test that provides an image of the leg veins) and ankle brachial pressure index (ABPI- provides the ratio of systolic blood pressure at the ankle to that in the arm) (Cochrane Wounds Group Glossary; The Free Medical Dictionary) may be helpful if the diagnosis is unclear (Collins 2010; Robson 2006). All patient that present an ulcer should be screened for peripheral arterial disease (PAD) by Doppler measurement of ABPI. An index equal or lower than 0.9 is the diagnosis criterion for peripheral arterial disease (Rooke 2011); however, ABPI measurement greater than 0.8 is generally used to exclude peripheral arterial disease as the cause of a leg ulceration, leaving the most likely diag- nosis venous ulceration (RCN 2006). Venous ulcers are generally irregular and shallow, and often occur over bony prominences, particularly in the gaiter area (over the medial malleolus). Skin alterations surrounding the ulcer such as hyperpigmentation, lipodermatosclerosis and fibrosis are usually present (Collins 2010). Frequent symptoms for venous ulceration include pain, odour and drainage from the wound (Valencia 2001). Arterial ulcers can be distinguished from venous ulcers because the former typically have round and well-demarcated borders and the presence of necrotic tissue in the wound bed. Physical symptoms of arterial leg ulcers include: loss of leg hair; atrophic skin (wasting of skin); cold feet; absence of, or decrease in, arterial pulses; and symptoms such as intermittent claudication (pain on walking that goes away with rest). Neuropathic ulcers are more common in, but are not limited to, patients with diabetes mellitus. These differ from venous leg ulcers in having defined borders, they are usually deeper than venous ulcers and are associated with foot numbness, burning and paraesthesia (sensation of “pins and needles”) (Valencia 2001). The standard treatment for venous leg ulcer is compression therapy. It has been shown that compression increases the healing rates of venous leg ulcers compared with no compression (O’Meara 2009). This treatment is often applied with other interventions, such as debridement (Tang 2012), topical agents (Briggs 2012; Robson 2006), physical agents (Aziz 2011; Cullum 2010; Flemming 1999), dressings (Palfreyman 2007). Description of the intervention The optimal wound healing environment is one where the wound is kept covered and moist, rather than left open to the air. Standard treatment for venous leg ulcers should include therapeutic compression (may be applied by bandages) in addition to a dressing, except when otherwise indicated (O’Meara 2009; Robson 2006). Dressings are applied underneath bandages or stockings with the aim of protecting the wound and providing a moist environment to aid healing. Nowadays, several types of dressing seek to achieve a moist environment, the aim of which is to promote re-epithelialisation of the wound, providing comfort, controlling exudate and helping to prevent bandages and stockings adhering to the wound bed. The ideal conditions required for wound healing in terms of dressing application have been explained as follows: maintenance of a moist wound environment without risk of maceration; avoidance of toxic chemicals, particles or fibres in the dressing fabric; minimisation of number of dressing changes; and maintenance of an optimum pH level (NPF 2011). The primary intervention of interest in this review is hydrogel dressings used in the treatment of venous leg ulcers. The aim of hydrogel dressings is to promote pain relief, comfort and also to favour autolytic debridement (natural enzymic removal of dead tissue) (Mandelbaum 2003). The dressings consist of a starch polymer and up to 96% water. They are supplied in two forms; flat sheets (e.g. ActiFormCool (Activa)), or amorphous hydro- Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2 25 gel (e.g. Aquaflo (Covidien)). Some of the hydrogels are associated with alginates (e.g. Nu-Gel, Purilon Gel) (NPF 2011), which have a higher capacity for absorption and chemical debridement (Mandelbaum 2003). The advantages of hydrogel dressings are that they can be used during several phases of healing, and may promote relief and comfort, however, they do require a secondary covering. Hydrogel dressings also may reduce pain in painful wounds (Bradbury 2008). The interval between dressing changes varies according to the type of hydrogel dressing: amorphous hydrogel may require daily changes (Mandelbaum 2003), while hydrogel sheet dressings may last for up to seven days. There is a broad choice of dressings available to treat wounds such as venous leg ulcers. For ease of comparison this review has classed dressings into groups according to the broad categories of the Nurse Prescribers’ Formulary 2011 (NPF 2011), that is, basic, advanced, anti-microbial and specialist wound dressings (see Appendix 2). Dressing names, manufacturers and distributors may vary between countries. To assess the effects of hydrogel wound dressings for healing venous leg ulcers in people in any care setting. METHODS Criteria for considering studies for this review Types of studies Randomised controlled trials (RCTs), either published or unpublished, that have evaluated the effects of any type of hydrogel wound dressing in the treatment of venous leg ulcers irrespective of publication status or language will be included. Trials reported in abstract form only will be eligible for inclusion, provided adequate information is either presented in the abstract or available from the trial author. Studies using quasi-randomisation will be excluded. How the intervention might work The most appropriate dressing for wound management depends not only upon the type of wound but also on the stage of the healing process. Dressings for moist wound healing need to ensure that the wound remains moist, and free of clinical infection and excessive slough (dead tissue), but avoid peri-wound maceration (NPF 2011). Hydrogel dressings, classified as an advanced wound dressing by the Nurse Prescribers’ Formulary, are designed to control the environment for wound healing by donating fluids to dry sloughy wounds, and by facilitating autolytic debridement of necrotic tissue. Some hydrogel dressings also have the ability to absorb limited amounts of exudate or rehydrate a wound, depending on the wound’s moisture levels (NPF 2011). Why it is important to do this review Chronic venous ulcer healing is a complex clinical situation that causes considerable economic impact, and adversely affects the quality of life for those who suffer from them. Hydrogel dressings can be used to deslough wounds by promoting autolytic debridement through moisture to re-hydrate, soften and liquefy non-viable tissue present on the wound surface. There is no current up-to-date evidence to inform clinicians of the effects of hydrogel dressings in treating venous leg ulcers (Palfreyman 2007). The effect of hydrogel dressings compared with other dressings and conventional methods of care for venous ulcers needs to be established. OBJECTIVES Types of participants We will include people of any age in any care setting with a diagnosed venous leg ulcer determined either by clinical evaluation, or complementary laboratory tests (e.g. duplex ultrasonography, plethysmography and venography), or both (Collins 2010), using the definition of a positive diagnosis given by the authors. Trials that include people with wounds of other aetiology (e.g. pressure ulcers), or trials of mixed populations (venous ulcers along with arterial or diabetic ulcers) will be excluded, unless the results for the subgroup of people with venous leg ulcers are reported separately or if the majority of participants (≥ 75% in each arm) have leg ulcers of venous aetiology. The review authors will attempt to contact trial authors to obtain the relevant data, if data from subgroups of people with venous leg ulcers are not reported separately. Studies of people with infected wounds will not be included, because hydrogel dressings are not indicated (prescribed) for this type of wound.Trials evaluating skin grafting are covered elsewhere and will be excluded from this review (Jones 2007). Types of interventions The intervention will be hydrogel dressings used as a treatment for venous leg ulcers. Comparators will be any other dressing, no dressing or another hydrogel dressing. For ease of comparison we will categorise dressings according to the Nurse Prescribers’ Formulary (NPF 2011). We will use generic names where possible, also providing trade names and manufacturers where these are available. It is important to note, however, that manufacturers and distributors of dressings may vary from country to country, and dressing names may also differ.We will not include trials evaluating hydrogel dressings impregnated with antimicrobial, antiseptic Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 3 26 or analgesic agents as these interventions are evaluated in other Cochrane reviews (Briggs 2012; O’Meara 2010). Trials that use larval therapy will be excluded. We will include any RCT in which the presence or absence of a hydrogel dressing is the only systematic difference between treatment groups; and in which a hydrogel dressing is compared with other wound dressings, non-dressing treatments (for example, topical applications) or another hydrogel dressing. We will include RCTs of hydrogel dressings, irrespective of whether compression therapy is reported as a concurrent therapy. Types of outcome measures Primary outcomes 1. Complete wound healing measured by the number of ulcers completely healed within the duration of the trial. 2. Incidence of wound infection, using diagnosis of infection as described in individual trials. Secondary outcomes 1. Changes in ulcer size measured by reduction in original wound area within the duration of the trial expressed as absolute (e.g. surface area changes in cm2 since baseline) or relative (e.g. percentage change in area relative to baseline) changes. 2. Time to ulcer healing 3. Recurrence of ulcer. 4. Health-related quality of life (measured using a standardised generic questionnaire such as EQ, SF-36 , SF-12 or SF-6 (http: //www.sf-36.org/) or disease-specific questionnaire). We will not include ad-hoc measures of quality of life that are likely to be un validated and will not be common to multiple trials. 5. Pain (e.g. at dressing change, between dressing changes, or over the course of treatment) will be included only if measured by reliable and validated instruments such as surveys, questionnaires, data capture process or visual analogue scale) 6. Costs (including measurements of resource use, such as number of dressing changes, nurse time or health professional time costs, or both, if reported by the authors). Search methods for identification of studies • Ovid MEDLINE (1948 to present); • Ovid EMBASE (1974 to present); • EBSCO CINAHL (1982 to present) We will search the Cochrane Central Register of Controlled Trials (CENTRAL) using the following MESH headings and keywords: #1 MeSH descriptor Leg Ulcer explode all trees #2 (varicose NEXT ulcer*) or (venous NEXT ulcer*) or (leg NEXT ulcer*) or (stasis NEXT ulcer*) or (crural NEXT ulcer*) or “ulcus cruris” #3 (#1 OR #2) #4 MeSH descriptor Hydrogel explode all trees #5 hydrogel* or intrasite or curafil or dermagran or duoderm or hydrosorb or hypergel or normlgel or nu-gel or nugel or purilon or “suprasorb gel” or hypligel or elasto-gel or elastogel or tegagel or aquaform or granugel or curasol or curatec #6 (#4 OR #5) #7 (#3 AND #6) We will adapt this strategy to search Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL. The Ovid MEDLINE search will be combined with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximizing version (2008 revision) (Lefebvre 2011). We will combine the EMBASE and CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2011). We will also search the following Trial Search Registries, as sources of ongoing or, as yet, unpublished trials: • The Current Controlled Trials http://www.controlledtrials.com/; • ClinicalTrials.gov http://www.clinicaltrials.gov/; and • WHO International Clinical Trials Registry Platform (ICTRP) http://www.who.int/ictrp/en/. Searching other resources The bibliographies of all retrieved and relevant publications identified by the above strategies will be searched for further studies. We will attempt to contact researchers to obtain additional information whenever necessary, along with manufacturers to request information about ongoing or as yet unpublished trials. We will attempt to obtain registered trial protocols for all published trial reports identified for inclusion. Electronic searches Data collection and analysis We will search the following electronic databases to identify reports of relevant randomised clinical trials: • The Cochrane Wounds Group Specialised Register; • The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library) (Latest issue); Selection of studies Two review authors (CR and FD), working independently, will screen the titles and abstracts of the studies identified from the Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 4 27 search strategy against the inclusion criteria. Full versions of articles that appear to fulfil the inclusion criteria will be obtained for further assessment. Another review author (GF) will evaluate any discrepancies, if necessary, and will advise in case of disagreement. We will record all reasons for exclusion of trials for which the fulltext has been obtained. Data extraction and management Two review authors (CR and FD), working independently, will extract data into Revman 5.2 and summarise details of trials using a standard data extraction sheet (Revman 2012). We will resolve any discrepancies by discussion with a third review author (GF). According to methods described in the Cochrane Handbook for Systematic Reviews of Interventions, the following information will be extracted (Higgins 2011a): • Country of origin. • Study authors and year of publication. • Care setting. • Type of ulcer. • Unit of investigation (per patient) - single ulcer or foot or patient, or multiple ulcers on the same patient. • Number of participants randomised to each treatment group. • Eligibility criteria and key baseline participant data (gender, age, ethnicity, baseline ulcer area, ulcer duration, prevalence of co-morbidities such as diabetes). • Details of the dressing/treatment regimen received by each group. • Details of any co-interventions. • Primary and secondary outcome(s) (with definitions). • Outcome data for primary and secondary outcomes (by group). • Overall sample size and methods used to estimate statistical power (relates to the target number of participants to be recruited, the clinical difference to be detected and the ability of the trial to detect this difference). • Duration of treatment. • Duration of follow-up. • Number of withdrawals (by group with reasons). • Statistical methods used for data analysis. • Risk of bias criteria (sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting). • Source of funding. Assessment of risk of bias in included studies Two review authors will independently assess each eligible study for risk of bias using the Cochrane Collaboration ‘Risk of bias assessment tool’. This tool addresses six specific domains, namely sequence generation, allocation concealment, blinding of partic- ipants and care providers; blinding of outcome assessors, incomplete outcome data, selective outcome reporting and other issues which may potentially bias the study (Appendix 3). For this review, we will consider other risk of bias issues as follows: comparability of treatment groups in relation to baseline ulcer surface area; choice of analysis where multiple ulcers on the same individuals(s) are studied; and choice of analysis in cluster randomised trials. We will complete a ‘Risk of bias’ table for each eligible study and each study will be classified as being at overall high, low or unclear risk of bias, according to the methods described in chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). Blinding and completeness of outcome data will be assessed for each outcome separately. We will discuss any disagreement amongst all authors to achieve a consensus. We will present the findings using a ‘Risk of bias’ summary figure, which presents all of the judgments in a cross-tabulation of study by risk of bias domain. This display of internal validity will indicate the weight the reader may give the results of each study. We will classify trials as being at high risk of bias overall if they are rated high for any of three key criteria, namely, allocation concealment, blinding of outcome assessors and completeness of outcome data. For trials that have at least one of the three key domains rated as ’unclear’ but none of these judged at high risk of bias, the trial will be classified as being at overall unclear risk of bias. Trials can only be classified as being at low risk of bias overall if all three key domains are rated as low risk individually. Measures of treatment effect Data analysis will be performed according to the guidelines of the Cochrane Collaboration. One review author will enter quantitative data into Review Manager 5.2, another will check it, and the data will be analysed using the Cochrane Collaboration’s associated software. We will present the outcome results for each trial with 95% confidence intervals (CI). We will report estimates for dichotomous outcomes (e.g. ulcers healed during time period, number of infected ulcers) as risk ratios (RR). Continuous outcomes (such as absolute or relative changes in ulcer area) will be expressed as mean differences (MD) and overall effect size (with 95% CI calculated). For time to event data, we plan to plot estimates of hazard ratios with associated 95% CIs where available from trial reports. Unit of analysis issues We will treat the number of ulcers as the unit of analysis in this review; however, we will record whether outcomes in relation to an ulcer were measured on a per-participant or per-ulcer basis, and, in studies where multiple ulcers on a person were treated as being independent, we will record that as part of our risk of bias assessment. The authors will include data from cluster-randomised trials if the information is available. For cluster-randomised trials, we Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 5 28 will adjust results when the unit of analysis in the trial is presented as the total number of individual participants instead of the number of clusters. Results will be adjusted using the mean cluster size and intra-cluster correlation co-efficient (ICC) (Higgins 2011c). Data from cross-over trials will be assessed at the point of crossover if available. For meta-analysis, data will be combined from individually randomised trials using the generic inverse-variance method as described in chapter 16.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011d). Dealing with missing data The authors will contact the trial investigators in cases of incomplete or missing data. Where trials report complete healing outcomes for only those participants who complete the trial (i.e. participants withdrawing and lost to follow-up are excluded from the analysis), we will treat the participants who are not included in the analysis as if their wound did not heal. Where trials report results for participants who complete the trial without specifying the numbers initially randomised per group, we will present only complete case data. For other outcomes the same analysis will be applied. Assessment of heterogeneity We will consider clinical heterogeneity (that is where trials appear similar in terms of participant characteristics, intervention type and duration and outcome type) and statistical heterogeneity. We will assess statistical heterogeneity using the Chi² test (a significance level of P < 0.10 is considered to indicate significant heterogeneity) in conjunction with the I² statistic (Higgins 2003). The I² statistic estimates the percentage of total variation across trials due to heterogeneity rather than variation due to chance (Higgins 2003). Heterogeneity will be categorized as follow: I² values ≤ 40% to indicate a low level of heterogeneity and ≥75% to represent very high heterogeneity (Deeks 2011). Assessment of reporting biases If sufficient studies (i.e. more than ten) are identified, an attempt will be made to check for publication bias using a funnel plot, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011e). If asymmetry is present we will explore possible causes including publication bias, poor methodological quality and true heterogeneity. alternative hydrogel dressings or other types of dressings. The decision to include studies in a meta-analysis will depend on the availability of treatment effect data and assessment of heterogeneity.For comparisons where there is no apparent clinical heterogeneity and the I2 value is ≤ 40%, we will apply a fixed-effect model. Where there is no apparent clinical heterogeneity and the I2 value is > 40%, we will apply a random-effects model. However, we will not pool data where heterogeneity is very high (I2 values ≥ 75%). For the dichotomous outcomes we will present the summary estimate as a risk ratio (RR) with 95% confidence intervals (CI). Where continuous outcomes are measured in the same way across trials, we will present a summary mean difference (MD) with 95% CI. We will present a standardised mean difference (SMD) where trials measure the same outcome using different methods. For time to event data, we plan to plot, and if feasible pool, estimates of hazard ratio and 95% CI as presented in the trial reports using the generic inverse variance method in RevMan 5.2. The authors will grade the quality of the evidence for each primary outcome using four levels of quality: high, moderate, low and very low (Schünemann 2011a). We plan to record the quality in a “Summary of findings” table using the GRADE system, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011b), for the first primary outcome. Quality will be based in the following factors: 1. Limitations in the design and implementation of available studies suggesting high likelihood of bias. 2. Indirectness of evidence (indirect population, intervention, control, outcomes). 3. Unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses). 4. Imprecision of results (wide confidence intervals). 5. High probability of publication bias. Subgroup analysis and investigation of heterogeneity Subgroup analysis will be carried out according to the presence or absence of compression therapy independent of type (elastic or inelastic) or level (moderate or high) compression. If is not clearly indicated in the trial report the presence or absence of compression therapy, we will not include these trials in this subgroup analysis. Sensitivity analysis Data synthesis Where data are available, sensitivity analyses will be performed for each comparison that has a meta-analysis, according to the overall risk of bias of each included RCT. RCTs with overall high or unclear risk of bias will be excluded and the difference between estimates of treatment effect from this analysis and the main analysis considered. We will present a narrative overview of the studies reviewed and the authors will use Revman 5.2 to combine outcomes when it is possible (Revman 2012). Included trials will be grouped according to the comparator intervention which may include no dressing, ACKNOWLEDGEMENTS Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 6 29 The authors would like to acknowledge the contribution of the Wound’s Group editorial base staff: Sally Bell-Syer for advice on the protocol and editorial assistance and Ruth Foxlee for designing the search strategy. In addition Elizabeth Royle for copy editing and the referees; Wounds Group Editors Joan Webster, Marian Brady, Statistical advisor Marialena Trivella and referees Mark Corbett, Una Adderley, Vicki Pennick and Amy Zelmer. REFERENCES Additional references Aziz 2011 Aziz Z, Cullum N, Flemming K. Electromagnetic therapy for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/ 14651858.CD002933.pub4] Bradbury 2008 Bradbury S, Ivins N, Harding K, Turner A. 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Schünemann 2011a Schünemann HJ, Oxman AD, Higgins JPT, Vist GE, Glasziou P, et al.on behalf of the Cochrane Applicability and Recommendations Methods Group and the Cochrane Statistical Methods Group. Chapter 11: Presenting results and ‘Summary of findings’ tables. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Schünemann 2011b Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, et al.on behalf of the Cochrane Applicability and Recommendations Methods Group. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. SIGN 2011 Scottish Intercollegiate Guidelines Network (SIGN). Search filters. http://www.sign.ac.uk/methodology/filters.html# random (accessed 02 December 2011). Smith 2006 Smith PC. The causes of skin damage and leg ulceration in chronic venous disease. International Journal of Lower Extremity Wounds 2006;5(3):160–8. Tang 2012 Tang JC, Marston WA, Kirsner RS. Wound Healing Society (WHS) venous ulcer treatment guidelines: What’s new in five years?. Wound Repair and Regeneration 2012;20(5): 619–37. The Free Medical Dictionary The Free Medical Dictionary. http:/medicaldictionary.thefreedictionary.com (accessed 3 May 2013). Valencia 2001 Valencia IC, Falabella A, Kirsner RS, Eaglstein WH. Chronic venous insufficiency and venous leg ulceration. Journal of the American Academy of Dermatology 2001;44(3): 401–20. Van Hecke 2011 Van Hecke A, Verhaeghe S, Grypdonck M, Beele H, Defloor T. Processes underlying adherence to leg ulcer treatment: A qualitative field study. International Journal of Nursing Studies 2011;48(2):145–55. Wipke-Tevis 2000 Wipke-Tevis DD, Rantz MJ, Mehr DR, Popejoy L, Petroski G, Madsen R, et al.Prevalence, incidence, management, and predictors of venous ulcers in the long-term-care population using the MDS. Advances in Skin and Wound Care 2000;13 (5):218–24. Wollina 2006 Wollina U, Abdel-Naser MB, Mani R. A review of the microcirculation in skin in patients with chronic venous insufficiency: the problem and the evidence available for therapeutic options. International Journal of Lower Extremity Wounds 2006;5(3):169–80. ∗ Indicates the major publication for the study APPENDICES Appendix 1. Glossary of Terms alginate = a salt of alginic acid. capillary convolution = a rolled up or coiled condition of the capillary vessels. debridement = is the medical removal of dead, damaged, or infected tissue to improve the healing potential of the remaining healthy tissue. It is thought to be an important part of the healing process for wounds. macrovascular = the portion of the vasculature of the body comprising the larger vessels. polymer = a large molecule (macromolecule) composed of repeating structural units. re-epithelialisation = growth of the epithelium across a wound from the wound edges. skin perfusion = the process of nutritive delivery of arterial blood to a capillary bed in the biological tissue. thrombosis = formation of a thrombus (blood clot) within the heart or blood vessels. tortuosity = condition of being twisted or crooked. Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 9 32 valvular incompetence = inability of the valves to keep blood flowing in the direction it should be. vein incompetence = venous insufficiency, that leads to abnormal (inadequate) blood flow through veins. venous stasis = reduction in blood flow or stoppage of blood flow through a vein. venous reflux = blood moving in the wrong direction in veins due to valvular incompetence. Definitions taken from The Free Medical Dictionary and Cochrane Wounds Group Glossary. Appendix 2. Nurse Prescribers Formulary 2011 categories of dressings Basic wound contact dressings Low-adherence dressings and wound contact materials These dressings are usually cotton pads that are placed directly in contact with the wound. They can be either non-medicated (e.g. paraffin gauze dressing) or medicated (e.g. containing povidone iodine or chlorhexidine). Examples include paraffin gauze dressing, BP 1993 and Xeroform (Covidien) dressing - a non-adherent petrolatum blend with 3% bismuth tribromophenate on fine mesh gauze. Absorbent dressings These dressings are applied directly to the wound and may be used as secondary absorbent layers in the management of heavily exuding wounds. Examples include Primapore (Smith & Nephew), Megapore (Molnlycke) and absorbent cotton gauze (BP 1988). Advanced wound dressings Hydrogel sheet and amorphous dressings These dressings consist of a starch polymer and up to 96% water. They can absorb wound exudate or rehydrate a wound, depending on the wound moisture levels. They are supplied in either flat sheets or amorphous hydrogel. Examples of hydrogel sheet dressings include: Actiformcool (Activa) and Aquaflo (Covidien). Examples of amorphous hydrogel dressings include: Purilon Gel (Coloplast) and NuGel (Systagenix). Films-permeable film and membrane dressings These dressings are permeable to water vapour and oxygen, but not to liquid water or micro-organisms. Examples include Tegaderm (3M); Opsite (Smith & Nephew). Soft polymer dressings These dressings are composed of a soft silicone polymer held in a non-adherent layer. They are moderately absorbant. Examples include: Mepitel (Molnlyckye) and Urgotul (Urgo). Hydrocolloid dressings These dressings are usually composed of an absorbant hydrocolloid matrix on a vapour-permeable film or foam backing. Examples include: Granuflex (Conva Tec). NU DERM (Systagenix). Fibrous alternatives have been developed that resemble alginates and are not occlusive: Aquacel (Conva Tec). Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 10 33 Foam dressings These dressings contain hydrophilic polyurethane foam and are designed to absorb wound exudate and maintain moist wound surface. There are various versions; some include additional absorbent materials, such as viscose and acrylate fibres, or particles of superabsorbent polyacrylate, while some are silicone-coated for non traumatic removal. Examples include: Allevyn (Smith & Nephew); Biatain (Coloplast); Tegaderm (3M). Alginate dressings These dressings are highly absorbent and consist of calcium alginate or calcium sodium alginate, which can be combined with collagen. The alginate forms a gel when in contact with wound surface. This gel can be lifted off at dressing removal, or rinsed away with sterile saline. Bonding to a secondary viscose pad increases absorbency. Examples include: Curasorb (Covidien); SeaSorb (Coloplast); Sorbsan (Unomedical). Capillary-action dressings These dressings consist of an absorbant core of hydrophilic fibres held between two low-adherent contact layers. Examples include: Advadraw (Advancis); Vacutx (Protex). Odour-absorbent dressings These dressings contain charcoal and are used to absorb wound odour. Often this type of dressing is used in conjunction with a secondary dressing to improve absorbency. Examples include: CarboFLEX (Conva Tec). Anti-microbial dressings Honey-impregnated dressings These dressings contain medical-grade honey, which is supposed to have antimicrobial and anti-inflammatory properties, and can be used for acute or chronic wounds. Examples include: Medihoney (Medihoney) and Activon Tulle (Advancis). Iodine-impregnated dressings These dressings release free iodine, which is thought to act as a wound antiseptic, when exposed to wound exudate. An example is Iodozyme (Insense). Silver-impregnated dressings These dressings are used to treat infected wounds, as silver ions are thought to have antimicrobial properties. Silver versions of most dressing types are available (e.g. silver foam, silver hydrocolloid etc). Examples include: Acticoat (Smith & Nephew) and Urgosorb Silver (Urgo). Other antimicrobial dressings These dressings are composed of a gauze or low-adherent dressing impregnated with an ointment thought to have antimicrobial properties. Examples include: chlorhexidine gauze dressing (Smith & Nephew) and Cutimed Sorbact (BSN Medical). Specialist dressings Protease-modulating matrix dressings These dressings alter the activity of proteolytic (protein-digesting) enzymes in chronic wounds. Examples include: Promogran (Systagenix) and Sorbion (H & R). Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 11 34 Silicone keloid dressing These dressings reduce or prevent hypertrophic or keloid scarring. Examples include: Cica-Care (Smith & Nephew) and Ciltech (Sumed). Appendix 3. The Cochrane Collaboration’s tool for assessing risk of bias 1. Was the allocation sequence randomly generated? Low risk of bias The investigators describe a random component in the sequence generation process such as: referring to a random number table; using a computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots. High risk of bias The investigators describe a non-random component in the sequence generation process. Usually, the description would involve some systematic, non-random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number. Unclear Insufficient information about the sequence generation process to permit judgement of low or high risk of bias. 2. Was the treatment allocation adequately concealed? Low risk of bias Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based and pharmacy-controlled randomisation); sequentially-numbered drug containers of identical appearance; sequentially-numbered, opaque, sealed envelopes. High risk of bias Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or non opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure. Unclear Insufficient information to permit judgement of low or high risk of bias. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed. 3. Blinding - was knowledge of the allocated interventions adequately prevented during the study? 1. Blinding of participants and care providers; 2. Blinding of outcome assessors; Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 12 35 Low risk of bias Any one of the following: • No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding. • Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken. • Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non-blinding of others unlikely to introduce bias. High risk of bias Any one of the following: • No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding. • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken. • Either participants or some key study personnel were not blinded, and the non-blinding of others likely to introduce bias. Unclear Either of the following: • Insufficient information to permit judgement of low or high risk of bias. • The study did not address this outcome. 4. Were incomplete outcome data adequately addressed? Low risk of bias Any one of the following: • No missing outcome data. • Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias). • Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate. • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes was not enough to have a clinically relevant impact on observed effect size. • Missing data have been imputed using appropriate methods. High risk of bias Any one of the following: • Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups. • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was enough to induce clinically relevant bias in intervention effect estimate. • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes was enough to induce clinically relevant bias in observed effect size. • ‘As-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation. • Potentially inappropriate application of simple imputation. Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 13 36 Unclear Either of the following: • Insufficient reporting of attrition/exclusions to permit judgement of low or high risk of bias (e.g. number randomised not stated, no reasons for missing data provided). • The study did not address this outcome. 5. Are reports of the study free of suggestion of selective outcome reporting? Low risk of bias Either of the following: • The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way. • The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon) High risk of bias Any one of the following: • Not all of the study’s pre-specified primary outcomes have been reported. • One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified. • One or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect). • One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis. • The study report fails to include results for a key outcome that would be expected to have been reported for such a study. Unclear Insufficient information to permit judgement of low or high risk of bias. It is likely that the majority of studies will fall into this category. 6. Other sources of potential bias For example: • comparability of treatment groups in relation to baseline ulcer surface area; • choice of analysis where multiple ulcers on the same individuals(s) are studied; • choice of analysis in cluster randomised trials; Low risk of bias The study appears to be free of other sources of bias. High risk of bias There is at least one important risk of bias. For example, the study: • had a potential source of bias related to the specific study design used; or • had extreme baseline imbalance; or • has been claimed to have been fraudulent; or • had some other problem. Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 14 37 Unclear There may be a risk of bias, but there is either: • insufficient information to assess whether an important risk of bias exists; or • insufficient rationale or evidence that an identified problem will introduce bias. CONTRIBUTIONS OF AUTHORS Guilherme Fregonezi: conceived the review question and secured funding; advised on and developed the protocol; completed part of the first draft of the protocol; made an intellectual contribution to the protocol, and approved the final version prior to submission. Fernando Dias: developed and coordinated the protocol; advised on, completed the first draft of the protocol; approved the final version of the protocol prior to submission; made an intellectual contribution to the protocol. Cibele Ribeiro: developed and coordinated the protocol; advised on, completed and edited the first draft of the protocol; approved the final version of the protocol prior to submission; made an intellectual contribution to the protocol. Contributions of editorial base: Nicky Cullum: edited the protocol; advised on methodology, interpretation and protocol content. Susan O’Meara, Editor: commented on, edited and approved the final protocol prior to submission. Sally Bell-Syer: coordinated the editorial process. Advised on methodology, interpretation and content. Edited the protocol. Ruth Foxlee: designed the search strategy and edited the search methods section. DECLARATIONS OF INTEREST None. SOURCES OF SUPPORT Internal sources • No sources of support supplied External sources • MCT/CT-Saúde and Decit/SCTIE/MS (CNPq - process 559416/2009-1), Brazil. Research grant • NIHR/Department of Health (England), (Cochrane Wounds Group), UK. Hydrogel dressings for venous leg ulcers (Protocol) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 15 38 3.1 Descrição dos estudos 3.1.1 Resultados da busca Os resultados abaixo estão descritos de acordo com a formatação requerida pela Colaboração Cochrane para a submissão da revisão utilizando o RevMan. Foram identificados um total de 460 estudos dos quais 218 estudos foram identificados através de busca em base eletrônica de dados bibliográficos, sendo essas: Cochrane Wounds Group Specialised Register, Central, Medline, Embase e Ebsco Cinhal. Os 242 estudos restantes foram identificados através de buscas realizadas em sites de registros de ensaios controlados, como: controlled-trials, clinicaltrials.gov, who ictrp e nenhum desses estudos foi incluído por não apresentarem informações relevantes aos critérios propostos. Foram contatadas 16 empresas fabricantes de adesivos de carboximetilcelulose para a confirmação da existência ou não de estudos em andamento ou recentemente finalizados, sendo essas: 3M, A1 Pharmaceuticals, Activa, Aspen Medical, Braun, BSN Medical, Coloplast, Convatec, Covidien, Hartmann, MedLogic, Molnlycke, Protex, Synergy Healthcare, Smith & Nephew Healthcare e Systagenix. Das 16 empresas apenas cinco (3M, Activa, Synergy Healthcare, Smith & Nephew Healthcare e Systagenix) responderam ao contato confirmando a não existência de estudos em andamento ou recentemente finalizados. As empresas restantes não responderam ao contato enviado. Não foi obtido nenhum estudo a partir do contato com os fabricantes de adesivos. Após a seleção dos estudos foram excluídos 103 estudos dos 218 restantes baseado nos títulos e resumos por não atenderem aos critérios de inclusão. Outros 80 estudos foram eliminados por serem duplicatas na lista de estudos presentes após a busca. Assim, ao final da seleção restaram 35 estudos dos quais foram obtidas a versão completa para a confirmação dos critérios de elegibilidade. A figura 2 apresenta um diagrama com os detalhes do resultado da busca. As razões de exclusão dos estudos estão descritas no Anexo 2. 39 Figura 2 – Diagrama com o resultado da seleção dos estudos Dos 35 estudos restantes foram excluídos mais 27 estudos por não apresentarem os critérios de elegibilidade propostos. Segue abaixo as razões de exclusão baseada nos critérios de elegibilidade: - 10 estudos não eram estudos controlados randomizados; 40 - 5 estudos eram resumos de conferências com informação limitada; - 5 estudos não apresentavam o hidrogel como tratamento para as úlceras venosas; - 3 estudos utilizavam úlceras de diferentes etiologias, mas não apresentavam a descrição dos resultados separados para os participantes com úlcera venosa. Os autores foram contatados, mas não houve resposta; - 3 estudos apresentavam o hidrogel não sendo a única diferença sistemática entre os grupos; - 1 estudo apresentou uma quantidade menor que 75% para participantes com úlcera venosa não tendo sido reportado os valores apenas para pacientes com úlcera venosa. 3.1.2 Estudos incluídos Quatro estudos foram incluídos apresentando um total de 250 participantes. Dos quatro estudos um foi realizado na China (He e col., 2008)56, um na Alemanha (Grotewohl 1994)57, na Bélgica (de la Brassinne e col., 2006)58 e o último na Irlanda (Gethin e col., 2008)59. Três estudos foram publicados em inglês (Grotewohl 1994, de la Brassinne e col. 2006, Gethin e col. 2008) e um estudo foi publicado em chinês (He e col. 2008). Este último estudo foi traduzido para a língua portuguesa pela empresa All Tasks – Serviço de traduções para análise dos dados para o estudo. Todos os estudos incluídos foram randomizados controlados dos quais dois estudos foram multicêntricos (Gethin e col., 2008; Grotewohl 1994). Em relação à população incluída dos estudos, a média de idade foi entre 45 a 70 anos. Somente um estudo, o de Grotewohl (1994) não reportou a idade dos pacientes incluídos. Em relação aos critérios de inclusão e exclusão dos participantes dos estudos incluídos somente um deles Gethin e col. (2008) reportou o resultado do ITB como critério de diagnóstico para a participação ou não no estudo. 41 As comparações dos adesivos usadas nos estudos incluídos foram as seguintes: - Hidrogel, Opragel, com um hidrocolóide Grotewohl (1994). - Hidrogel, Quitosana, com gaze contendo solução salina (He e col. 2008). - Hidrogel, Intrasite, com um gel de alginato, Flaminal (de la Brassinne e col. 2006). - Hidrogel, Intrasite, com um adesivo composto de mel de Manuka, “Manuka honey” (Gethin e col. 2008). Foi utilizada a terapia compressiva associada ao tratamento com os adesivos em dois estudos (Gethin e col. 2008, Grotewohl 1994). Somente um estudo reportou o uso do adesivo secundário (Allevyn – curativo de espuma hidrocelular)59. A duração do tratamento foi de 12 semanas em um estudo (Gethin e col. 2008), quatro semanas em dois estudos (de la Brassinne e col. 2006, Grotewohl 1994) e 2 semanas em um estudo (He e col. 2008). No Anexo 3 encontram-se todas as características dos estudos incluídos, como: detalhes da metodologia, dos participantes, das intervenções utilizadas por cada estudo e dos desfechos analisados por cada estudo. 3.2 Risco de viés dos estudos incluídos Alocação dos participantes Três estudos (He e col. 2008, Grotewohl 1994 e de la Brassinne e col. 2006) não descrevem o método da sequência de randomização dos pacientes somente citam que foram randomizados por isso foram classificados como risco incerto de viés. Somente um estudo (Gethin e col. 2008) apontou corretamente a sequência de randomização que foi realizada através de telefone remoto sendo assim classificado como baixo risco de viés. Em relação ao sigilo de alocação dos pacientes somente um estudo (Gethin e col. 2008) descreve corretamente que foi realizada através de envelopes opacos 42 numerados em série e foi então classificado como baixo risco de viés. Os outros três estudos não reportaram o sigilo de alocação dos pacientes sendo classificados como risco incerto de viés. Mascaramento Dos quatro estudos incluídos (He e col. 2008, Grotewohl 1994, de la Brassinne e col. 2006 e Gethin e col. 2008) nenhum estudo reportou o mascaramento dos participantes, dos profissionais envolvidos com o tratamento e dos profissionais envolvidos com a análise dos desfechos de cada estudo. Sendo assim todos os estudos foram classificados para esse item como alto risco de viés. Dados incompletos Três estudos (He e col. 2008, Grotewohl 1994 e de la Brassine e col. 2006) foram considerados como risco incerto de viés pois não reportaram nenhuma desistência ou perda durante o tratamento. Um estudo (Gethin e col. 2008) registrou as perdas dos participantes do estudo e para a análise dos dados o número de participantes foi mantido o mesmo (n=54) entre os grupos de intervenção e, portanto foi considerado um estudo com baixo risco de viés, pois a análise foi realizada com intenção de tratar. Descrição seletiva do desfecho Para a análise desse item é necessário o acesso ao protocolo proposto pelos estudos para ser considerado como evidência definitiva. Porém não foi possível obter o protocolo de pesquisa dos estudos incluídos através do contato com os autores. Foi feito uma busca nos sites de registros de protocolos de pesquisa e não foi encontrado nenhum registro. Sendo assim para classificar o grau de viés desse item foi feito uma análise baseada na metodologia e nos resultados reportados por cada estudo. Um estudo (He e col. 2008) foi considerado com alto risco de viés, pois reportou um desfecho (tempo de cicatrização) nos resultados no qual não foi descrito na metodologia do estudo. Os outros três estudos (Grotewohl 1994, de la 43 Brassinne e col. 2006 e Gethin e col. 2008) foram considerados estudos com baixo risco de viés pois apresentaram os resultados para os desfechos descritos na metodologia proposta. As figuras abaixo 3 e 4 apresentam todos os critérios analisados para a análise dos vieses dos quatro estudos incluídos com a classificação para cada estudo. Figura 3 – Avaliação do risco de viés de todos os estudos incluídos na revisão 44 Figura 4 – Avaliação do risco de viés de cada estudo incluído na revisão: julgamento dos autores de cada item para cada estudo incluído. 3.3 Efeitos do hidrogel Foram incluídos quatro estudos que avaliaram os curativos de hidrogéis para o tratamento de úlceras venosas (He e col. 2008, de la Brassine e col. 2006, Gethin e col. 2008, Grotewhol 1994). Os resultados serão apresentados por comparações dos tratamentos aplicados em cada estudo com descrição detalhada por desfechos (primários e secundários) propostos na revisão. 3.3.1 Comparação entre hidrogel, Quitosana, e gaze com solução salina (He e col. 2008) Desfechos primários: 45 1. Cicatrização completa das úlceras: o grupo do hidrogel cicatrizou completamente em 16 participantes nos 14 dias de tratamento enquanto que o grupo controle a cicatrização completa ocorreu em 3 participantes, havendo diferença estatística entre os grupos (RR 5,33, 95%CI 1,73 a 16,42). O gráfico 1 apresenta a análise da comparação do hidrogel com gaze com solução salina para o desfecho cicatrização completa das feridas. Gráfico 1 – Forest plot representando a comparação do hidrogel com gaze com solução salina para o desfecho cicatrização completa das úlceras. 2. Incidência de infecção: esse desfecho não foi analisado pelo estudo. Desfechos secundários: 1. Alterações no tamanho da úlcera: As medidas das úlceras foram realizadas no 7° e no 14° dia de tratamento. No grupo do hidrogel a área da úlcera diminui de 3,4 ± 0,6 cm2 para 1,1 ± 0,2 cm2; e no grupo controle a área da úlcera diminuiu de 3,1 ± 0,4 cm2 para 2,3 ± 0,7 cm2. 2. Tempo de cicatrização: O tempo de cicatrização no grupo do hidrogel foi de 12,0 ± 1,7 dias e no grupo controle foi de 31,0 ± 2,9 dias tendo sido reportado diferença estatística entre os grupos pelos autores (p < 0,05). 3. Recorrência da úlcera: esse desfecho não foi analisado pelo estudo. 4. Qualidade de vida dos participantes: esse desfecho não foi analisado pelo estudo. 5. Dor: esse desfecho não foi analisado pelo estudo. 46 6. Custos do tratamento: esse desfecho não foi analisado pelo estudo. 3.3.2 Comparação entre hidrogel, Intrasite, e gel de alginato (de la Brassinne e col. 2006) Desfechos primários: 1. Cicatrização completa das úlceras: esse desfecho não foi analisado pelo estudo. 2. Incidência de infecção: esse desfecho não foi analisado pelo estudo. Desfechos secundários: 1. Alterações no tamanho da úlcera: as medidas das úlceras foram realizadas antes de iniciar o tratamento, no 7° dia, 14° e no final das quatro semanas. A área de superfície da úlcera diminuiu com o tempo de tratamento nos dois grupos tratados. A porcentagem de redução da área da úlcera no grupo do gel de alginato foi de 27,3% ± 20,6% no 14° dia e de 61,2% ± 26,2% ao final das quatro semanas. No grupo tratado com o hidrogel a porcentagem de redução foi de 3,2% ± 13,3% no 14° dia e de 19,4% ± 24,3% ao final das quatro semanas. O gráfico 2 apresenta a análise da comparação do hidrogel com o gel de alginato para o desfecho porcentagem de redução da úlcera em quatro semanas de tratamento. 47 Gráfico 2 – Forest plot representando a comparação do hidrogel com o gel de alginato para o desfecho porcentagem de redução da úlcera em 4 semanas de tratamento. 2. Tempo de cicatrização: esse desfecho não foi analisado pelo estudo. 3. Recorrência da úlcera: esse desfecho não foi analisado pelo estudo. 4. Qualidade de vida dos participantes: esse desfecho não foi analisado pelo estudo. 5. Dor: esse desfecho não foi analisado pelo estudo. 6. Custos do tratamento: esse desfecho não foi analisado pelo estudo. 3.3.3 Comparação entre hidrogel, Intrasite, e mel de Manuka (Gethin e col. 2008). Desfechos primários: 1. Cicatrização completa das úlceras: esse desfecho foi analisado com 12 semanas de tratamento. No grupo do mel de Manuka 24/54 (44%) pacientes cicatrizaram completamente e no grupo do hidrogel 18/54 (33%) apresentaram uma cicatrização completa da úlcera. O gráfico 3 apresenta a análise da comparação do hidrogel com o mel de Manuka para o desfecho cicatrização completa das úlceras. Gráfico 3 - Forest plot representando a comparação do hidrogel com o mel de Manuka para o desfecho cicatrização completa das úlceras. 48 2. Incidência de infecção: o grupo que foi tratado com o mel de Manuka apresentou seis perdas por infecção na ferida e o grupo de hidrogel apresentou 12 perdas por infecção na ferida (Gráfico 4). A análise dos dados desse estudo foi por intenção de tratar, pois foram incluídas as perdas dos dois grupos na análise estatística para proteger o estudo de um possível viés de seguimento. Gráfico 4 – Forest plot representando a comparação do hidrogel com o mel de Manuka para o desfecho incidência de infecção. Desfechos secundários: 1. Alterações no tamanho da úlcera: o grupo do mel de Manuka apresentou uma redução de 34% e a redução no grupo do hidrogel foi de 13% havendo diferença estatística entre os grupos (p< 0.001). 2. Tempo de cicatrização: esse desfecho não foi analisado pelo estudo. 3. Recorrência da úlcera: esse desfecho não foi analisado pelo estudo. 4. Qualidade de vida dos participantes: esse desfecho não foi analisado pelo estudo. 5. Dor: esse desfecho não foi analisado pelo estudo. 6. Custos do tratamento: esse desfecho não foi analisado pelo estudo. 3.3.4 Comparação entre hidrogel e hidrocolóide (Grotewohl 1994) Desfechos primários: 49 1. Cicatrização completa das úlceras: esse desfecho não foi analisado pelo estudo. 2. Incidência de infecção: esse desfecho não foi analisado pelo estudo. Desfechos secundários: 1. Alterações no tamanho da úlcera: o grupo do hidrogel reduziu 44,6% e o grupo do hidrocolóide reduziu 33,3% do tamanho da ferida com quatro semanas de tratamento. 2. Tempo de cicatrização: esse desfecho não foi analisado pelo estudo. 3. Recorrência da úlcera: esse desfecho não foi analisado pelo estudo. 4. Qualidade de vida dos participantes: esse desfecho não foi analisado pelo estudo. 5. Dor: esse desfecho não foi analisado pelo estudo. 6. Custos do tratamento: esse desfecho não foi analisado pelo estudo. Não foi possível realizar uma meta-análise devido à falta de dados e de estudos que apresentassem comparações de um mesmo tratamento. Devido à escassez de informações não foi possível também realizar a análise de sensibilidade e análise de subgrupo como foi proposto na metodologia da revisão. 50 4 DISCUSSÃO 51 Nesta revisão foi possível analisar os efeitos do tratamento com o hidrogel na cicatrização de úlceras venosas de membros inferiores. Quatro estudos controlados e randomizados envolvendo 250 participantes foram incluídos na revisão. Vários desfechos propostos pela revisão não foram reportados pelos estudos, sendo estes: qualidade de vida, dor, recorrência da úlcera e custos para o tratamento. Embora alguns desfechos avaliados nos estudos incluídos tenham demonstrado uma melhora na cicatrização das úlceras dos pacientes que receberam o hidrogel como tratamento, não foi possível realizar uma meta-análise devido à falta de dados e de estudos que apresentassem comparações de um mesmo tratamento. O uso do hidrogel parece ser superior ao curativo convencional no caso, gaze embebida em salina, para a cicatrização de úlceras venosas de membros inferiores. No entanto, esta análise foi baseada em apenas um estudo que apresentou risco de viés incerto e onde a seleção dos pacientes foi feita baseado no tamanho da úlcera (menor que 4 cm2); portanto, dificultando o extrapolamento dos dados para úlceras crônicas de maior tamanho inicial. A carência de estudos de qualidade relativos a esta comparação não permite a conclusão definitiva da superioridade do hidrogel sobre o curativo convencional para guiar a prescrição clínica. Esta prescrição deverá ser feita levando-se em consideração outras condições clínicas individuais como a acessibilidade ao hidrogel, conforto nas trocas de curativos e presença de tecido necrótico na ferida. A comparação do uso do hidrogel com outros tratamentos, como o mel de Manuka, demonstrou que o efeito do hidrogel é similar em relação à porcentagem de redução da área das úlceras embora exista uma tendência à melhora no debridamento autolítico nas fases iniciais de cicatrização (quatro semanas) para o mel de Manuka que, contudo, não persistiu no “follow up” final do estudo (12 semanas). Apesar do estudo do mel de Manuka apresentar um alto risco de viés (devido ao fato de não ter sido descrito o mascaramento dos avaliadores, embora para os outros critérios ele tenha sido considerado de baixo risco), pode-se considerar em termos metodológicos como o melhor estudo entre os quatro incluídos, pois houve a preocupação de reportar a correta seleção e alocação dos participantes bem como a intenção de tratar os participantes que foram excluídos por motivos descritos pelos autores do estudo. Em relação ao outro tratamento 52 analisado, o gel de alginato demonstrou ser mais eficaz quando comparado ao hidrogel quanto à redução da área e volume da ferida. Em revisão de Palfreyman e col. (2007)53 foram analisados todos os curativos para o tratamento de úlceras venosas de membros inferiores e concluiu-se que não haviam dados suficientes para afirmar que um tipo de curativo foi mais eficaz do que outro na cicatrização de úlceras venosas. Neste estudo os desfechos analisados foram tempo até a completa cicatrização das úlceras ou proporção das úlceras completamente cicatrizadas e porcentagem de cicatrização das úlceras e foram incluídos quatro estudos com hidrogéis dos quais dois estudos comparavam o hidrogel com adesivos de baixa aderência, um estudo comparou o hidrogel com o cadexomer iodine e o último comparou o hidrogel com o dextranômero. Os resultados obtidos na presente revisão sistemática estão de acordo com Palfreyman e col. (2007)53 no qual os desfechos analisados foram os mesmos nas duas revisões sugerindo que não há nenhuma evidência para os hidrogéis como sendo melhor ou pior do que outros curativos para a cicatrização de úlceras venosas. A escolha correta do adesivo ideal para o tratamento com os pacientes que apresentem úlceras venosas depende de estudos que avaliem a dor e a qualidade de vida através de instrumentos de avaliação válidos e confiáveis e que os resultados sejam reportados na íntegra e de maneira clara para que se possa fazer uma correta análise de todos os parâmetros (a avaliação desses dois itens não foi reportada em nenhum dos estudos incluídos). Os resultados obtidos nessa revisão sistemática mostram claramente a necessidade de mais estudos controlados randomizados de alta qualidade metodológica abordando o uso do hidrogel no tratamento de pacientes com úlceras venosas de membros inferiores. Os dados dos estudos não apontam consistência para suportar o uso de um ou outro adesivo. Parte dessa inconsistência é dada pela baixa qualidade dos artigos. Estudos futuros devem relatar aspectos metodológicos, como, randomização e alocação dos participantes do estudo e mascaramento dos avaliadores dos resultados, e considerar outros critérios importantes como o tamanho adequado da amostra a fim de detectar os efeitos do tratamento para que se possa orientar de maneira correta e clara a decisão pelos profissionais da saúde do tratamento adequado para cada paciente. 53 5 CONSIDERAÇÕES FINAIS E CONCLUSÃO 54 Sugere-se, baseado nas evidências atuais pela presente revisão sistemática que, os curativos de hidrogéis podem ser melhores que gaze embebida em solução salina para a cicatrização de úlceras venosas de membros inferiores e menos efetivo que o gel de alginato para a redução da área e volume da ferida, porém ainda existem incertezas em relação a essa decisão. 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Roche C, West J. A controlled trial investigating the effect of ultrasound on venous ulcers referred from general practitioners. Physiotherapy 1984; 70(2):475-477. 42. Flemming K, Cullum N. Laser therapy for venous leg ulcers. Cochrane Database Syst Rev 2000;(2):CD001182. 43. Houghton PE, Kincaid CB, Lovell M et al. Effect of electrical stimulation on chronic leg ulcer size and appearance. Phys Ther 2003; 83(1):17-28. 44. Belczak CE, Cavalheri GJr, de Godoy JMP et al. Comparison of reduction of edema after rest and after muscle exercises in treatment of chronic venous insufficiency. Int Arch Med 2009; 2(18):1-5. 45. Mandelbaum SH, di Santis EP, Mandelbaum MHS. Cicatrização: conceitos atuais e recursos auxiliares Parte I. An Bras Dermatol 2003; 78(4):393-410. 46. Field FK, Kerstein MD. Overview of wound healing in a moist environment. Am J Surg 1994; 167(1A):2S-6S. 47. Forrest L. Current concepts in soft connective tissue wound healing. Br J Surg 1983; 70(3):133-140. 48. Phillips TJ, Machado F, Trout R et al. Prognostic indicators in venous ulcers. J Am Acad Dermatol 2000; 43(4):627-630. 49. Joint Formulary Committee. Wound management products and elasticated garments. Nurse Prescriber´s Formulary for Community Practicioners (NPF). Andover,UK: BMJ Group, 2011: 33-54. 49. Flemming K, Cullum N. Laser therapy for venous leg ulcers. Cochrane Database Syst Rev 2000;(2):CD001182. 50. Sackheim K, De Araujo TS, Kirsner RS. Compression modalities and dressings: their use in venous ulcers. Dermatol Ther 2006; 19(6):338-347. 51. Bradbury S, Ivins N, Harding K et al. Measuring outcomes with complex patients: an audit of the complex effect of Actiform Cool on painful wounds. Wounds UK 2008; 4(3):22-31. 52. Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. The Cochrane Collaboration, 2011 53. Palfreyman S, Nelson EA, Michaels JA. Dressings for venous leg ulcers: systematic review and meta-analysis. BMJ 2007; 335(7613):244. 54. Ribeiro CTD, DIAS FAL, Fregonezi GAF. Hydrogel dresing for venous leg ulcer (protocol). Cochrane Database Syst Rev 2013;(9):CD010738 / DOI:10.1002/14651858. 60 55. Ribeiro CTD, Fregonezi GAF, Resqueti VR et al. Hydrocolloid dressing for healing venous leg ulcers. Cochrane Database Syst Rev 2014;(1):CD: 010918 / DOI: 10.1002/14651858. 56. He Q, Wu G, Yu B et al. [A prospective study on wound-healing hydrogel in treating chronic venous ulcer of lower extremities]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2008; 22(3):311-313. 57. Grotewohl JH. The phase-oriented wound dressing of ulcus cruris venosum: Experience with the use of the new hydrogel Opragel. Z Allg Med 1994; 70:351-354. 58. de la Brassinne M, Thirion L, Horvat LI. A novel method of comparing the healing properties of two hydrogels in chronic leg ulcers. J Eur Acad Dermatol Venereol 2006; 20(2):131-135. 59. Gethin G, Cowman S. Manuka honey vs. hydrogel--a prospective, open label, multicentre, randomised controlled trial to compare desloughing efficacy and healing outcomes in venous ulcers. J Clin Nurs 2009; 18(3):466-474. 61 6 ANEXOS 62 ANEXO 1: Protocolo publicado – Hydrocolloid dressings for venous leg ulcers 63 Hydrocolloid dressings for healing venous leg ulcers (Protocol) Ribeiro CTD, Fregonezi GAF, Resqueti VR, Dornelas de Andrade A, Dias FAL This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 1 http://www.thecochranelibrary.com Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 64 TABLE OF CONTENTS HEADER . . . . . . . . . . ABSTRACT . . . . . . . . . BACKGROUND . . . . . . . OBJECTIVES . . . . . . . . METHODS . . . . . . . . . ACKNOWLEDGEMENTS . . . REFERENCES . . . . . . . . APPENDICES . . . . . . . . CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 1 3 3 7 7 9 14 14 15 i 65 [Intervention Protocol] Hydrocolloid dressings for healing venous leg ulcers Cibele TD Ribeiro1 , Guilherme AF Fregonezi2 , Vanessa R Resqueti3 , Armele Dornelas de Andrade4 , Fernando AL Dias5 1 Graduate Program in Physiotherapy, Federal University of Rio Grande do Norte, Natal, Brazil. 2 PhD Program in Physical Therapy, Federal University of Rio Grande do Norte, Natal, Brazil. 3 Master Degree Program, Department of Physical Therapy, Federal University of Pernambuco, Recife, Brazil. 4 Physical Therapy, Master Degree Program in Physical Therapy, Federal University of Pernambuco, Recife, Brazil, Recife, Brazil. 5 Department of Physiology, Federal University of Paraná, Curitiba, Brazil Contact address: Guilherme AF Fregonezi, PhD Program in Physical Therapy, Federal University of Rio Grande do Norte, Avenida Senador Salgado Filho, 3000, Bairro Lagoa Nova, Natal, Rio Grande do Norte, 59078-970, Brazil. [email protected]. Editorial group: Cochrane Wounds Group. Publication status and date: New, published in Issue 1, 2014. Citation: Ribeiro CTD, Fregonezi GAF, Resqueti VR, Dornelas de Andrade A, Dias FAL. Hydrocolloid dressings for healing venous leg ulcers. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD010918. DOI: 10.1002/14651858.CD010918. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACT This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effects of hydrocolloid dressings compared with other wound dressings, non-dressing treatments or another hydrocolloid dressing on the healing of venous leg ulcers, and also the effects on health-related quality of life, pain, medical costs and recurrence of ulcers. BACKGROUND Description of the condition Venous leg ulcers present as open wounds on the lower limb. They are usually associated with sustained venous hypertension which causes chronic venous insufficiency (impaired venous blood flow) (Grey 2006; Wollina 2006). This condition has psychological and financial impacts, and also impairs the physical functioning of affected patients. The impact of leg ulcers on the patient’s daily life is described in many quantitative and qualitative studies. The major problems reported by patients are: pain, immobility, sleep disturbance, lack of energy, limitations in work and leisure activities, worry, frustration and lack of self-esteem (Herber 2007; Persoon 2004). Thus, venous leg ulcers will ultimately impact quality of life. Venous leg ulceration is a chronic health problem that can take years to heal completely, and, as it has a high rate of recurrence, of- ten requires life-long treatment (Margolis 2002; Van Hecke 2011). Wound size and wound duration (longer than 18 months) are major contributors to the risk of not healing (Margolis 2004). Additionaly, the presence of lipodermatosclerosis (inflammation of subcutaneous fat layers), evidence of deep vein thrombosis (blood clot lodged in a leg vein), superficial thrombophlebitis (inflammation of surface veins) or poor ankle mobility are individually associated with delayed healing (Lantis 2013). The incidence of venous leg ulcers rises with increasing age (De Araujo 2003; Wipke-Tevis 2000). The primary risk factors are aging, gender (venous leg ulcers are more common in women), obesity, previous leg injuries, deep venous thrombosis and phlebitis (inflammation of veins) (Collins 2010). Venous leg ulcers have been estimated to afflict between 0.2% and 1% of the total population, and between 1% and 3% of the elderly population in the United States and Europe (Margolis 2002). The estimated prevalence of venous leg ulcers ranges between 0.6% and 1.9% in the Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 66 adult population of the UK, USA, and Europe (Briggs 2003). Epidemiological studies estimate that venous leg ulcers affect one million people in the USA, accounting for 70% to 80% of all ulcers of the lower limbs (De Araujo 2003). A cohort study calculated that monthly direct medical care costs attributable to a venous leg ulcer averaged USD 2400 (at 1997 values) (Olin 1999). Venous ulceration represents the most prevalent form of difficult-to-heal wounds, and treating these problematic wounds requires significant healthcare resources. Recent data from Germany revealed that the mean total cost per year for a person with chronic venous leg ulceration was EUR 9569, 92% of which was estimated to be direct costs (that is, non-drug treatment, inpatients costs and outpatient care) and 8% indirect costs (inability to work) (Purwins 2010). The pathophysiology of venous leg ulcers starts as a macrovascular (see Appendix 1) problem attributable to valve incompetence. In the normal venous system, blood pressure decreases during exercise as a result of the action of muscles pumping blood though the vessels. In a system where the valves are incompetent, venous pressure remains high (Grey 2006). Sustained venous hypertension (high blood pressure) will ultimately lead to microcirculatory dysfunction and cause alterations in skin perfusion (transport of oxygen and other substances), which can then lead to ulceration. A diagnosis of venous leg ulceration is usually based on clinical examination. Additional tests such as colour duplex ultrasonography (measurement of blood flow in the veins and arteries of the leg), plethysmography (measurement of variations in the size or volume of a limb), and venography (X-ray test that provides an image of the leg veins) may be helpful (Cochrane Wounds Group Glossary; Collins 2010; Robson 2006; The Free Medical Dictionary). All patients that present with an ulcer should be screened for peripheral arterial disease (PAD) by Doppler measurement of ankle brachial pressure index (ABPI). An ABPI measurement greater than 0.8 is generally considered as eliminating PAD as the cause of a leg ulceration, leaving the most likely diagnosis as venous ulceration (RCN 2006). Venous leg ulcers are generally irregular and shallow, and often occur over bony prominences, particularly over the medial malleolus (inner ankle). Skin alterations surrounding the ulcer, such as hyperpigmentation (discolouration), lipodermatosclerosis and fibrosis (scarring) are usually present (Collins 2010). Frequent symptoms for venous ulceration include pain, odour and drainage from the wound (Valencia 2001). Arterial ulcers can be distinguished from venous ulcers because the former typically have round and well-demarcated borders and the presence of necrotic tissue in the wound bed. Physical symptoms of arterial leg ulcers include: loss of leg hair; atrophic skin (wasting of skin) in the segment; cold feet; absence of, or decrease in, arterial pulses; and symptoms such as intermittent claudication (pain on walking that is relieved by rest). Neuropathic ulcers (due to diseased nerves) are more common in, but are not limited to, people with diabetes mellitus. These differ from venous leg ulcers in having defined borders, usually being deeper than venous ulcers, and are associ- ated with foot numbness, burning and paraesthesia (sensation of ’pins and needles’) (Valencia 2001). The standard treatment for venous leg ulcers is compression therapy. It has been shown that compression increases the healing rates of venous leg ulcers compared with no compression (O’Meara 2012). The healing rates can range from 30% to 60% after 24 weeks of treatment, and up to 70% to 85% after one year of treatment (Margolis 2000). The maintenance of compression therapy may reduce the risk of recurrence of the ulcer (Phillips 2000). Compression therapy also reduces oedema and pain (Fletcher 1997). In the presence of compression, healing occurs more rapidly in younger people, and those with a smaller initial ulcer area; shorter duration of ulceration; and no deep vein involvement (Skene 1992). This treatment is often applied with other interventions, such as debridement (removal of dead material) (Tang 2012), topical agents (e.g. creams) (Briggs 2010; Robson 2006), physical agents (Aziz 2011; Cullum 2010; Flemming 1999), and dressings (Palfreyman 2006). Description of the intervention The optimal wound healing environment is one in which the wound is kept covered and moist, rather than left open to the air. Standard treatment for venous leg ulcers should include therapeutic compression (this may be applied by bandages) in addition to a dressing, except when otherwise indicated (O’Meara 2012; Robson 2006). Dressings are applied underneath bandages or stockings with the aim of protecting the wound and providing a moist environment to aid healing. Nowadays, several types of dressing seek to achieve a moist environment, the aim of which is to promote re-epithelialisation of the wound, providing comfort, controlling exudate and helping to prevent bandages and stockings from adhering to the wound bed. The ideal conditions required for wound healing in terms of dressing application have been explained as follows: maintenance of a moist wound environment without risk of maceration (tissue breakdown); avoidance of toxic chemicals, particles or fibres in the dressing fabric; a minimal number of dressing changes; and maintenance of an optimum pH level (NPF 2011). The primary intervention of interest in this review is hydrocolloid dressings used in the treatment of venous leg ulcers. The aim of these dressings is to promote pain relief, comfort and also to favour autolytic debridement (natural enzymic removal of dead tissue) (Mandelbaum 2003). They are usually presented as a hydrocolloid layer that is composed of sodium carboxymethylcellulose (or a similar material that forms a gel when wet) on a vapour-permeable film or foam pad. Examples include Granuflex (ConvaTec) and NU DERM (Systagenix). Fibrous hydrocolloids are a sub-set of dressings that are designed for use in wounds with heavy exudate instead of alternate dressing types such as alginates, e.g. Aquacel (ConvaTec). Hydrocolloid dressings have also been shown to reduce pain in painful wounds (Meaume 2004). The purported Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2 67 benefits of hydrocolloid dressings include that they reduce the risk of infection and do not require daily changes,. However, it has also been suggested that they can cause maceration of the adjacent tissue and can provoke an unpleasant odour through the reaction of exudate with the primary active ingredient in the dressing. Dressing changes should be done whenever leakage is observed or the dressing loses its adherence (Mandelbaum 2003). There is a broad choice of dressings available to treat wounds such as venous leg ulcers. For ease of comparison this review will class dressings into groups according to the broad categories of the Nurse Prescribers’ Formulary 2011 (NPF 2011), that is, basic, advanced, anti-microbial and specialist wound dressings (see Appendix 2). Dressing names, manufacturers and distributors may vary between countries. How the intervention might work Animal models suggest that a moist wound environment can aid wound healing. Wound dressings are used to maintain such an environment; they may also keep wounds free of clinical infection and excessive slough (dead tissue)(NPF 2011). Hydrocolloid dressings, classified as an advanced wound dressing by the Nurse Prescribers’ Formulary, are designed to control the environment for wound healing, for example maintaining hydration, and by facilitating autolytic debridement of necrotic tissue. They are semi-permeable to water vapour and oxygen. These dressings form a gel in the presence of exudate to facilitate rehydration in lightly to moderately exuding wounds and promote autolytic debridement of dry, sloughy or necrotic wounds (NPF 2011). There is no current up-to-date evidence to inform clinicians of the effects of hydrocolloid dressings in treating venous leg ulcers (Palfreyman 2006). The effect of hydrocolloid dressings compared with other dressings and conventional methods of care for venous ulcers needs to be established. hydrocolloid dressings. The current review will establish the current level of evidence of hydrocolloid dressings for the treatment of venous ulcers. OBJECTIVES To determine the effects of hydrocolloid dressings compared with other wound dressings, non-dressing treatments or another hydrocolloid dressing on the healing of venous leg ulcers, and also the effects on health-related quality of life, pain, medical costs and recurrence of ulcers. METHODS Criteria for considering studies for this review Types of studies We will include randomised controlled trials (RCTs), either published or unpublished, that have evaluated the effects of any type of hydrocolloid wound dressing in the treatment of venous leg ulcers, irrespective of language of publication or publication status. Trials reported in abstract form only will be eligible for inclusion, provided adequate information is presented in the abstract or is available from the trial author. Studies using quasi-randomisation will be excluded. Why it is important to do this review Types of participants Chronic venous leg ulcer ulceration is a complex clinical situation that causes considerable economic impact, and adversely affects the quality of life of those who suffer from them. Interventions that aim to shorten healing time or improve quality of life and comfort are desired, and several dressings have been designed to achieve this; however, there are several dressing types available to decision makers and the evidence based has previously been shown to be sparse (Palfreyman 2006). There is no current up-to-date evidence to inform clinicians of the effects of hydrocolloid dressings in treating venous leg ulcers. This review will now update part of the previous Cochrane review (Palfreyman 2006), and will be one of several Cochrane reviews investigating the use of dressings in the treatment of venous leg ulcers. Each review will focus on a particular dressing type which, in this review, will be RCTs recruiting people described in the primary report as having venous leg ulcers, managed in any setting, are eligible for inclusion. As the method of diagnosis of venous ulceration may vary, we will accept definitions as used in the RCTs.Collins 2010 Trials that include people with wounds of other aetiology (causes, e.g. pressure ulcers), or trials of mixed populations (venous ulcers along with arterial or diabetic ulcers) will be excluded, unless the results for the subgroup of people with venous leg ulcers are reported separately, or if the majority of participants (75% or more in each arm) have leg ulcers of venous aetiology. When data from subgroups of people with venous leg ulcers are not reported separately, the review authors will attempt to contact trial authors to obtain the relevant data. Trials evaluating skin grafting are covered elsewhere and will be excluded from this review (Jones 2007). Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 3 68 Types of interventions The intervention will be hydrocolloid dressings used as a treatment for venous leg ulcers. Comparators will include any other dressing, no dressing or another hydrocolloid dressing. For ease of comparison we will categorise dressings according to the Nurse Prescribers’ Formulary 2011 (NPF 2011). We will use generic names where possible, also providing trade names and manufacturers where these are available. It is important to note, however, that manufacturers and distributors of dressings may vary from country to country, and dressing names may also differ. We will not include trials evaluating hydrocolloid dressings impregnated with antimicrobial, antiseptic or analgesic agents, as these interventions are evaluated in other Cochrane reviews (Briggs 2010; O’Meara 2013). Trials that use larval therapy will be excluded. We will include any RCT in which the presence or absence of a hydrocolloid dressing is the only systematic difference between treatment groups; and in which a hydrocolloid dressing is compared with other wound dressings, non-dressing treatments (for example, topical applications) or another hydrocolloid dressing. We will include RCTs of hydrocolloid dressings, irrespective of whether compression therapy is reported as a concurrent therapy. Types of outcome measures Primary outcomes 1. Complete wound healing measured by: • time to complete wound healing (correctly analysed using survival, time-to-event approaches, ideally with adjustment for relevant covariates such as baseline size); • the proportion of ulcers healed during follow up (frequency of complete healing) during the study. 2.Rate of adverse events (as defined by the trial authors). Secondary outcomes 1. Changes in ulcer size measured by reduction in original wound area within the duration of the trial expressed as absolute (e.g. surface area changes in cm2 since baseline) or relative (e.g. percentage change in area relative to baseline) changes. 2. Incidence of wound infection 3. Recurrence of ulcer. 4. Health-related quality of life (measured using a standardised generic questionnaire such as EQ, SF-36, SF-12 or SF-6 (http:// www.sf-36.org/) or a disease-specific questionnaire). We will not include ad-hoc measures of quality of life that are likely to be unvalidated and will not be common to multiple trials. 5. Pain (e.g. at dressing change, between dressing changes, or over the course of treatment) will be included only if measured by reliable and validated instruments such as surveys, questionnaires, data capture process or a visual analogue scale. 6. Costs (including measurements of resource use, such as number of dressing changes, nurse time or health professional time costs, if reported by the trial authors). Search methods for identification of studies Electronic searches The following electronic databases will be searched for potentially relevant studies without any language or date restrictions: 1. The Cochrane Wounds Group Specialised Register; 2. The Cochrane Central Register of Controlled Trials (CENTRAL) (latest issue); 3. Ovid MEDLINE (1946 to present); 4. Ovid EMBASE (1974 to present); 5. EBSCO CINAHL (1982 to present). We will search the Cochrane Central Register of Controlled Trials (CENTRAL) using the following exploded MeSH headings and keywords: #1 MeSH descriptor Leg Ulcer explode all trees #2 ((varicose NEXT ulcer*) or (venous NEXT ulcer*) or (leg NEXT ulcer*) or (stasis NEXT ulcer*) or (crural NEXT ulcer*) or “ulcus cruris” or “ulcer cruris”) #3 (#1 OR #2) #4 MeSH descriptor Bandages, Hydrocolloid explode all trees #5 (hydrocolloid* or activheal or alione or askina or comfeel or duoderm or flexigran or granuflex or hydrocoll or “nu derm” or tegaderm or “ultec pro” or aquacel or versiva or cutinova or medihoney or tegasorb or dermafilm or signadress) #6 (#4 OR #5) #7(#3 AND #6) We will combine the Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision) (Lefebvre 2011). We will combine the EMBASE search with the Ovid EMBASE filter developed by the UK Cochrane Centre (Lefebvre 2011). We will combine the CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2011). We will also search the following Trial Search Registries, as sources of ongoing or, as yet, unpublished trials: 1. World Health Organization International Trials Registry Platform (http://www.who.int/ictrp/en/); 2. ISRCTN (International Standard Randomised Controlled Trial Number) (http://www.controlled-trials.com/isrctn/). Searching other resources The bibliographies of all relevant publications identified by the above strategies will be searched for further studies. We will attempt to contact study authors to obtain additional information Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 4 69 whenever necessary, along with manufacturers to request information about ongoing or as yet unpublished trials. We will attempt to obtain registered trial protocols for all published trial reports identified for inclusion. 16. Statistical methods used for data analysis. 17. Risk of bias criteria (sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting). 18. Adverse events. 19. Source of funding. Data collection and analysis Assessment of risk of bias in included studies Selection of studies Two review authors (CR and GF), working independently, will screen the titles and abstracts of the studies identified from the search strategy against the inclusion criteria. Full versions of articles that appear to fulfil the inclusion criteria will be obtained for further assessment. Another review author (VR) will evaluate any discrepancies, if necessary, and will advise in case of disagreement. We will record all reasons for exclusion of trials for which the fulltext has been obtained. Data extraction and management Two review authors (CR and GF), working independently, will extract Revman 2012and summarise details of trials using a standard data extraction sheet. Data will then be entered into Revman 5.2 (Revman 2012), We will resolve any discrepancies by discussion with a third review author (VR). According to methods described in the Cochrane Handbook for Systematic Reviews of Interventions, the following information will be extracted (Higgins 2011a): 1. Country of origin. 2. Study authors and year of publication. 3. Care setting. 4. Type of ulcer. 5. Unit of investigation (per participant) - single ulcer or foot or participant or multiple ulcers on the same participant. 6. Number of participants randomised to each trial. 7. Eligibility criteria and key baseline participant data (gender, age, ethnicity, baseline ulcer area, ulcer duration, prevalence of co-morbidities such as diabetes). 8. Details of the dressing/treatment regimen received by each group. 9. Details of any co-interventions. 10. Primary and secondary outcome(s) (with definitions). 11. Outcome data for primary and secondary outcomes (by group). 12. Overall sample size and methods used to estimate statistical power (relates to the target number of participants to be recruited, the clinical difference to be detected and the ability of the trial to detect this difference). 13. Duration of treatment. 14. Duration of follow-up. 15. Number of withdrawals (by group, with reasons). Two review authors will independently assess each eligible study for risk of bias using the Cochrane Collaboration ‘Risk of bias’ assessment tool. This tool addresses six specific domains, namely sequence generation, allocation concealment, blinding of participants and care providers and blinding of outcome assessors, incomplete outcome data, selective outcome reporting and other issues which may potentially bias the study (Appendix 3). For this review, we will consider the other risk of bias issues as follows: comparability of treatment groups in relation to baseline ulcer surface area; choice of analysis when studying multiple ulcers on the same individuals(s); and choice of analysis in cluster randomised trials. We will complete a ‘Risk of bias’ table for each eligible study according to the methods described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). Blinding and completeness of outcome data will be assessed for each outcome separately. We will discuss any disagreement amongst all authors to achieve a consensus. We will present the findings using a ‘Risk of bias’ summary figure, which presents all of the judgments in a cross-tabulation of study by risk of bias domain. This display of internal validity will indicate the weight the reader may give the results of each study. We will classify trials as being at high risk of bias overall if they are rated high for any of three key criteria, namely, allocation concealment, blinding of outcome assessors and completeness of outcome data. For trials that have at least one of the three key domains rated as ’unclear’ but none of these judged as being at high risk of bias, the trial will be classified as being at unclear risk of bias overall. Trials can only be classified as being at low risk of bias overall if all three key domains are rated as being at low risk individually. Measures of treatment effect Data analysis will be performed according to the guidelines of the Cochrane Collaboration. One review author will enter quantitative data into Review Manager 5.2, another will check it, and the data will be analysed using RevMan 5.2. We will present the outcome results for each trial with 95% confidence intervals (CI). We will report estimates for dichotomous outcomes (e.g. ulcers healed during time period, number of infected ulcers) as risk ratios (RR). Continuous outcomes (such as absolute or relative changes in ulcer area) will be expressed as mean differences (MD) and overall effect size (with 95% CI calculated) or as standardised mean differences (SMDs) if different methods of measurement are used in Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 5 70 the studies. For time-to-event data, we plan to plot, and, if feasible, pool, estimates of hazard ratio and 95% CI as presented in the trial reports using the generic inverse variance method in RevMan 5.2. Unit of analysis issues We will treat the individual ulcer as the unit of analysis in this review. We will record whether outcomes relating to an ulcer were measured on a per-participant or per-ulcer basis and will note whether the trial authors have analysed the data appropriately. If the number of ulcers appears to be equal to the number of participants, we will assume that the ulcer is the unit of analysis, unless otherwise stated. The authors will include data from clusterrandomised trials if the information is available. For cluster-randomised trials, we will adjust results when the unit of analysis in the trial is presented as the total number of individual participants instead of the number of clusters. Results will be adjusted using the mean cluster size and intra-cluster correlation co-efficient (ICC) (Higgins 2011c). Data from cross-over trials will be assessed at the point of cross-over, if available. For meta-analysis, data will be combined from individually randomised trials using the generic inverse-variance method as described in Chapter 16 (section 16.3) of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011e). Dealing with missing data The authors will contact the trial investigators in cases of incomplete or missing data. Where trials report complete healing outcomes for only those participants who complete the trial (i.e. participants withdrawing and lost to follow-up were excluded from the analysis), we will treat the participants who were not included in the analysis as if their wound did not heal. Where trials report results for participants who complete the trial without specifying the numbers initially randomised per group, we will present only complete case data. For other outcomes the same analysis will be applied. Assessment of heterogeneity We will consider clinical heterogeneity (that is where trials appear different in terms of participants characteristics, intervention type and duration and outcome type) and statistical heterogeneity. We will assess statistical heterogeneity using the Chi² test (P values less than 0.10 will be considered to be indicative of significant heterogeneity) in conjunction with the I² statistic (Higgins 2003). The I² statistic estimates the percentage of total variation across trials due to heterogeneity rather than variation due to chance (Higgins 2003). Heterogeneity will be categorised as follows: I² values of 40% or less will indicate a low level of heterogeneity, and values of 75% or above will represent very high heterogeneity (Higgins 2011c). Assessment of reporting biases If a sufficient number of studies (i.e. more than ten) are identified, an attempt will be made to check for publication bias using a funnel plot (Higgins 2011d). Publication bias is one of a number of possible causes of ’small study effects’: a tendency for estimates of the intervention effect to be more beneficial in smaller RCTs. Funnel plots allow a visual assessment of whether small study effects may be present in a meta-analysis. A funnel plot is a simple scatter plot of the intervention effect estimates from individual RCTs against some measure of each trial’s size or precision. If asymmetry is present, the effect calculated in a meta-analysis will tend to overestimate the intervention effect. The more pronounced the asymmetry, the more likely it is that the amount of bias will be substantial. We will also explore other possible causes of asymmetry, for example poor methodological quality of included studies. Data synthesis We will present a narrative overview of the studies reviewed and the authors will use RevMan 5.2 to combine outcomes when it is possible (Revman 2012). Included trials will be grouped according to the comparator intervention, which may include no dressing, alternative hydrogel dressings or other types of dressings. The decision to include studies in a meta-analysis will depend on the availability of treatment effect data and assessment of heterogeneity. For comparisons where there is no apparent clinical heterogeneity and the I2 value is 40% or less, we will apply a fixed-effect model. Where there is no apparent clinical heterogeneity and the I 2 value is greater than 40%, we will apply a random-effects model. However, we will not pool data where heterogeneity is very high (I2 values of 75% and above). The authors will grade the quality of the evidence for each primary outcome (complete wound healing measured by the number of ulcers completely healed within the duration of the trial and adverse events, e.g. incidence of wound infection) using four levels of quality: high, moderate, low and very low (Schünemann 2011a). We plan to record the quality in a ’Summary of findings’ table using the GRADE system, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011b). Quality will be based in the following factors. 1. Limitations in the design and implementation of available studies suggesting high likelihood of bias. 2. Indirectness of evidence (indirect population, intervention, control, outcomes). 3. Unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses). 4. Imprecision of results (wide confidence intervals). 5. High probability of publication bias. Subgroup analysis and investigation of heterogeneity Subgroup analysis will be carried out according to the presence or absence of compression therapy independent of type (elastic Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 6 71 or inelastic) or level (moderate or high) of compression. Trials in which the presence or absence of compression therapy is not clearly indicated in the trial report will not be included in this subgroup analysis. main analysis. ACKNOWLEDGEMENTS Sensitivity analysis Where data are available, we will perform sensitivity analyses for each comparison that has a meta-analysis, according to the overall risk of bias of each included RCT. We will exclude RCTs with overall high or unclear risk of bias, and consider the difference between estimates of treatment effect from this analysis and the The authors would like to acknowledge the contribution of the Wound’s Group editorial base staff: Sally Bell-Syer for advice on the protocol and editorial assistance and Ruth Foxlee for designing the search strategy. In addition the referees: Wounds Group Editor, Andrew Jull; Statistical advisor, Giovanni Casazza; and referees Marissa Martyn-St James, Una Adderley, Nancy Munoz and Shirley Manknell. REFERENCES Additional references Aziz 2011 Aziz Z, Cullum N, Flemming K. Electromagnetic therapy for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/ 14651858.CD002933.pub4] Briggs 2003 Briggs M, Closs SJ. The prevalence of leg ulceration:a review of the literature. The Journal of European Wound Management Association 2003;3(2):14–20. Briggs 2010 Briggs M, Nelson EA, Martyn-St James M. Topical agents or dressings for pain in venous leg ulcers. Cochrane Database of Systematic Reviews 2012, Issue 11. [DOI: 10.1002/ 14651858.CD001177.pub3] Cochrane Wounds Group Glossary Wounds Group glossary. http://wounds.cochrane.org/ sites/wounds.cochrane.org/files/uploads/cochrane/wounds/ glossary.pdf (accessed 03 May 2013). Collins 2010 Collins L, Seraj S. 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Cochrane Database of Systematic Reviews 2007, Issue 2 CD001737. [DOI: 10.1002/14651858.CD001737] Lantis 2013 Lantis JC, Marston WA, Farber A, Kirsner RS, Zhang Y, Lee TD, et al.The influence of patient and wound variables on healing of venous leg ulcers in a randomized controlled trial of growth-arrested allogeneic keratinocytes and fibroblasts. Journal of Vascular Surgery 2013;58(2):1–7. Lefebvre 2011 Lefebvre C, Manheimer E, Glanville J, on behalf of the Cochrane Information Retrieval Methods Group. Chapter 6: Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Mandelbaum 2003 Mandelbaum SH, Di Santis EP, Mandelbaum MHS. Cicatrization: current concepts and auxiliary resources Part II [Cicatrização: conceitos atuais e recursos auxiliares – Parte II]. Anais Brasileiros de Dermatologia 2003;78(5): 525–40. Margolis 2000 Margolis DJ, Berlin JA, Strom BL. Which venous leg ulcers will heal with limb compression bandages?. American Journal of Medicine 2000;109:15–9. Margolis 2002 Margolis D, Bilker W, Santanna J, Baumgarten M. Venous leg ulcer: Incidence and prevalence in the elderly. Journal of the American Academy of Dermatology 2002;46(3):381–6. Margolis 2004 Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. The accuracy of venous leg ulcer prognostic models in a wound care system. Wound Repair and Regeneration 2004;12: 163–8. Meaume 2004 Meaume S, Téot L, Lazareth I, Martini J, Bohbot S. The importance of pain reduction through dressing selection in routine wound management: the MAPP study. Journal of Wound Care 2004;13(10):1–9. NPF 2011 NPF-Nurse Prescribers’ Formulary for Community Practitioners. Appendix 5: Wound management products and elasticated garments. British National Formulary 62. British Medical Journal Publishing Group and Pharmaceutical Press, 2011. O’Meara 2012 O’Meara S, Cullum N, Nelson EA, Dumville JC. Compression for venous leg ulcers. Cochrane Database of Systematic Reviews 2012, Issue 11. [DOI: 10.1002/ 14651858.CD000265.pub3] O’Meara 2013 O’Meara S, Al-Kurdi D, Ologun Y, Ovington LG, Martyn-St James M, Richardson R. Antibiotics and antiseptics for venous leg ulcers. Cochrane Database of Systematic Reviews 2013, Issue 12. [DOI: 10.1002/ 14651858.CD003557.pub4] Olin 1999 Olin JW, Beusterien KM, Childs MB, Seavey C, McHugh L, Griffiths RI. Medical costs of treating venous stasis ulcers: evidence from a retrospective cohort study. Vascular Medicine 1999;4:1–7. Palfreyman 2006 Palfreyman S, Nelson EA, Michaels JA. Dressings for venous leg ulcers:systematic review and meta-analysis. BMJ 2007; 335(7613):1–12. Persoon 2004 Persoon A, Heinen MM, Van Der Vleuten CJM, De Rooij MJ, Van De Kerkhof PC, Van Achterberg T. Leg ulcers: a review of their impact on daily life. Journal of Clinical Nursing 2004;13:341–54. Phillips 2000 Phillips TJ, Machado F, Trout R, Porter J, Olin J, Falanga V, et al.Prognostic indicators in venous leg ulcers. Journal of American Academy of Dermatology 2000;43(4):627–30. Purwins 2010 Purwins S, Herberger K, Debus ES, Rustenbach SJ, Pelzer P, Rabe E, et al.Cost-of-illness of chronic leg ulcers in Germany. International Wound Journal 2010;7(2):97–102. RCN 2006 Royal College of Nursing. Clinical practice guidelines. The nursing management of patients with venous leg ulcers. Available from http://www.rcn.org.uk/__data/assets/pdf_ file/0003/107940/003020.pdf (accessed 22 May 2013) 2006. Revman 2012 The Cochrane Collaboration. Review Manager (RevMan). 5.2. Copenhagen: The Nordic Cochrane Centre: The Cochrane Collaboration, 2012. Robson 2006 Robson MC, Cooper DM, Aslam R, Gould LJ, Harding KG, Margolis DJ, et al.Guidelines for the treatment of Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 8 73 venous ulcers. Wound Repair and Regeneration 2006;14: 649–62. Schünemann 2011a Schünemann HJ, Oxman AD, Higgins JPT, Vist GE, Glasziou P, Guyatt GH. Chapter 11: Presenting results and ’Summary of finding tables’. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. The Cochrane Collaboration. Schünemann 2011b Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, Guyatt GH. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. The Cochrane Collaboration. SIGN 2011 Scottish Intercollegiate Guidelines Network (SIGN). Management of chronic venous leg ulcers. A national clinical guideline. Available from www.sign.ac.uk (accessed 02 December 2011) 2011. Skene 1992 Skene AI, Smith JM, Doré CJ, Charlett A, Lewis JD. Venous leg ulcers: a prognostic index to predict time to healing. BMJ 1992;305:1119–21. Tang 2012 Tang JC, Marston WA, Kirsner RS. Wound Healing Society (WHS) venous ulcer treatment guidelines: What’s new in five years?. Wound Repair and Regeneration 2012;20: 619–37. The Free Medical Dictionary The Free Medical Dictionary. http://medicaldictionary.thefreedictionary.com (accessed 03 May 2013). Valencia 2001 Valencia IC, Falabela A, Kirsner RS, Eaglstein WH. Chronic venous insufficiency and venous leg ulceration. Journal of the American Academy of Dermatology 2001;44(3):401–24. Van Hecke 2011 Van Hecke A, Verhaeghe S, Grypdonck M, Beele H, Defloor T. Processes underlying adherence to leg ulcer treatment. A qualitative field study. International Journal of Nursing Studies 2011;48(2):145–55. Wipke-Tevis 2000 Wipke-Tevis DD, Rantz MJ, Mehr DR, Popejoy L, Petroski G, Madsen R, et al.Prevalence, incidence, management,and predictors of venous ulcers in the long-term-care population using the MDS. Advances in skin wound care 2000;13(5): 218–24. Wollina 2006 Wollina U, Abdel-Naser MB, Mani R. A review of the microcirculation in skin in patients with chronic venous insufficiency: the problem and the evidence available for therapeutic options. International Journal of Lower Extremity Wounds 2006;5(3):169–80. ∗ Indicates the major publication for the study APPENDICES Appendix 1. Glossary of terms alginate = substance derived from algic acid, found in seaweed, used as a component in some dressings for wounds. debridement = is the medical removal of dead, damaged, or infected tissue to improve the healing potential of the remaining healthy tissue. It is an important part of the healing process for wounds. deep = situated far beneath the surface; not superficial. dressing = pieces of material, traditionally made of cloth, that act as a contact layer between a wound and outside environment. exudate = fluid that leaks out of a wound. fibrosis = formation of fibrous tissue. hydrocolloid = dressing that reacts with wound exudate to maintain a moist environment at the surface of a wound. hydrophilic = readily absorbing moisture. lipodermatosclerosis = area of pigmentation and hardened skin caused by leakage of red blood cells into the skin. Seen in people with chronic venous insufficiency. macerate/maceration = the softening and breaking down of skin resulting from prolonged exposure to moisture. macrovascular = the larger vessels in the blood system. macrovascular disease = disease of the large veins. Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 9 74 medial malleolus = inner area of the lower leg, between the ankle and calf muscle. microcirculation = the flow of blood or lymph through the smallest vessels of the body, especially the venules, capillaries, and arterioles. necrotic tissue = dead or dying tissue, which may be caused by interruption of the blood supply. occlusive dressings = a dressing that seals a wound from air or bacteria. perfusion = the transfer of fluid through tissue. polymer = a large molecule (macromolecule) composed of repeating structural units. pressure ulcer = area of inflamed skin/broken skin, caused by excessive or prolonged pressure, shear, or friction. This prevents adequate blood flow to the skin and finally the death of skin and underlying tissues. skin perfusion = the process of arterial blood, carrying nutrients (oxygen, glucose etc) to a capillary bed in the biological tissue. slough = a layer, or mass, of dead tissue separated from surrounding living tissue, as in a wound, a sore, or an inflammation. superficial vein = one of a number of veins in the subcutaneous tissue that empty into deep veins. thrombosis = formation of a thrombus (blood clot) within the heart or blood vessels. thrombophlebitis = inflammation of a vein associated with the formation of a thrombus. valvular incompetence = inability of the valves to keep blood flowing in the correct direction. venous stasis = ’pooling’ of blood in a vein, this occurs when the blood vessel’s valves are inactive and its walls inelastic. venous reflux = reversed flow of blood within the veins. Occurs in veins in which the valves have become inactive or incompetent. Definitions taken from The Free Medical Dictionary and Cochrane Wounds Group Glossary. Appendix 2. Nurse Prescribers’ Formulary 2011 Categories of dressings Basic wound contact dressings Low-adherence dressings and wound contact materials: usually cotton pads that are placed directly in contact with the wound, these can be non-medicated (e.g. paraffin gauze dressing) or medicated (e.g. containing povidone iodine or chlorhexidine). Examples include paraffin gauze dressing, BP 1993 and Xeroform (Covidien) dressing - a non-adherent petrolatum blend with 3% bismuth tribromophenate on fine mesh gauze. Absorbent dressings: applied directly to the wound and may also be used as secondary absorbent layers in the management of heavilyexuding wounds. Examples include Primapore (Smith & Nephew), Megapore (Mölnlycke) and absorbent cotton gauze (BP 1988). Advanced wound dressings Hydrocolloid dressings: usually composed of an absorbant hydrocolloid matrix on a vapour-permeable film or foam backing. Examples include: Granuflex (Conva Tec), NU DERM (Systagenix). Fibrous alternatives have been developed that resemble alginates and are not occlusive: Aquacel (Conva Tec). Hydrogel sheet and amorphous dressings: consist of a starch polymer and up to 96% water. These dressings can absorb wound exudate or rehydrate a wound depending upon the moisture levels. They are supplied as either flat sheets or amorphous hydrogel. Examples of hydrogel sheet dressings include: Actiformcool (Activa) and Aquaflo (Covidien). Examples of amorphous hydrogel dressings include: Purilon Gel (Coloplast) and NuGel (Systagenix). Films - permeable film and membrane dressings: permeable to water vapour and oxygen, but not to liquid water or micro-organisms. Examples includeTegaderm (3M); Opsite (Smith & Nephew). Soft polymer dressings: dressings composed of a soft silicone polymer held in a non-adherent layer, these are moderately absorbant. Examples include: Mepitel (Mölnlycke) and Urgotul (Urgo). Foam dressings: contain hydrophilic polyurethane foam and are designed to absorb wound exudate and maintain a moist wound surface. A variety of versions exists, some of which include additional absorbent materials such as viscose and acrylate fibres, or particles of super-absorbent polyacrylate, or are silicone-coated for non-traumatic removal. Examples include: Allevyn (Smith & Nephew); Biatain (Coloplat); Tegaderm (3M). Alginate dressings: highly absorbent dressings composed of calcium alginate or calcium sodium alginate, which can be combined with collagen. The alginate forms a gel while in contact with the wound surface, this can be lifted off at dressing removal or rinsed away with sterile saline. Bonding to a secondary viscose pad increases absorbency. Examples include: Curasorb (Covidien); SeaSorb (Coloplast); Sorbsan (Unomedical). Capillary-action dressings: consist of an absorbant core of hydrophilic fibres held between two low-adherent contact layers. Examples include: Advadraw (Advancis); Vacutx (Protex). Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 10 75 Odour absorbent dressings: dressings that contain charcoal and are used to absorb wound odour. Often this type of dressing is used in conjunction with a secondary dressing to improve absorbency. Examples include: CarboFLEX (ConvaTec) Anti-microbial dressings Honey-impregnated dressings: contain medical-grade honey which is proposed to have antimicrobial and anti-inflammatory properties and can be used for acute or chronic wounds. Examples include: Medihoney (Medihoney) and Activon Tulle (Advancis). Iodine-impregnated dressings: these release free iodine, which is thought to act as a wound antiseptic, when exposed to wound exudate. One example is Iodozyme (Insense). Silver-impregnated dressings: used to treat infected wounds, as silver ions are thought to have antimicrobial properties. Silver versions of most dressing types are available (e.g. silver foam, silver hydrocolloid etc). Examples include: Acticoat (Smith & Nephew) and Urgosorb Silver (Urgo). Other antimicrobial dressings: these dressings are composed of a gauze or low-adherent dressing impregnated with an ointment thought to have antimicrobial properties. Examples include: chlorhexidine gauze dressing (Smith & Nephew) and Cutimed Sorbact (BSN Medical). Specialist dressings Protease-modulating matrix dressings: designed to alter the activity of proteolytic enzymes (i.e. breakdown of protein or dead skin) in chronic wounds. Examples include: Promogran (Systagenix) and Sorbion (H & R). Silicone keloid dressing: designed to reduce or prevent hypertrophic or keloid scarring. Examples include: Cica-Care (Smith & Nephew) and Clitech (Su-med). Appendix 3. The Cochrane Collaboration’s tool for assessing risk of bias 1. Was the allocation sequence randomly generated? Low risk of bias The investigators describe a random component in the sequence generation process such as: referring to a random-number table; using a computer random-number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots. High risk of bias The investigators describe a non-random component in the sequence generation process. Usually, the description would involve some systematic, non-random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number. Unclear Insufficient information about the sequence generation process to permit a judgement of low or high risk of bias. 2. Was the treatment allocation adequately concealed? Low risk of bias Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based and pharmacy-controlled randomisation); sequentially-numbered drug containers of identical appearance; sequentially-numbered, opaque, sealed envelopes. Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 11 76 High risk of bias Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on using: an open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or non opaque or not sequentially-numbered); alternation or rotation; date of birth; case record number; or any other explicitly unconcealed procedure. Unclear Insufficient information to permit a judgement of low or high risk of bias. This is usually the case if the method of concealment is not described, or not described in sufficient detail to allow a definite judgement to be made, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially-numbered, opaque and sealed. 3. Blinding: was knowledge of the allocated interventions adequately prevented during the study? Two types of blinding are considered here: (1) blinding of participants and care providers; and (2) blinding of outcome assessors. Low risk of bias Any one of the following: • No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding. • Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken. • Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non-blinding of others was unlikely to introduce bias. High risk of bias Any one of the following. • No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding. • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken. • Either participants or some key study personnel were not blinded, and the non-blinding of others was likely to introduce bias. Unclear Either of the following. • Insufficient information provided to permit judgement of low or high risk of bias. • The study did not address this outcome. 4. Were incomplete outcome data adequately addressed? Low risk of bias Any one of the following. • No missing outcome data. • Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias). • Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate. Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 12 77 • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes was not enough to have a clinically relevant impact on observed effect size. • Missing data have been imputed using appropriate methods. High risk of bias Any one of the following. • Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups. • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate. • For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size. • ’As-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation. • Potentially inappropriate application of simple imputation. Unclear Either of the following. • Insufficient reporting of attrition/exclusions to permit a judgement of low or high risk of bias (e.g. number randomised not stated, no reasons for missing data provided). • The study did not address this outcome. 5. Are reports of the study free of suggestion of selective outcome reporting? Low risk of bias Either of the following. • The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way. • The study protocol is not available, but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon). High risk of bias Any one of the following. • Not all of the study’s pre-specified primary outcomes have been reported. • One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified. • One or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect). • One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis. • The study report fails to include results for a key outcome that would be expected to have been reported for such a study. Unclear Insufficient information provided to permit a judgement of low or high risk of bias. It is likely that the majority of studies will fall into this category. Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 13 78 6. Other sources of potential bias Low risk of bias The study appears to be free of other sources of bias. High risk of bias There is at least one important risk of bias. For example, the study: • had a potential source of bias related to the specific study design used; or • stopped early due to some data-dependent process (including a formal-stopping rule); or • had extreme baseline imbalance; or • has been claimed to have been fraudulent; or • had some other problem. Unclear There may be a risk of bias, but there is either: • insufficient information to assess whether an important risk of bias exists; or • insufficient rationale or evidence that an identified problem will introduce bias. CONTRIBUTIONS OF AUTHORS Guilherme Fregonezi: conceived the review question and secured funding; advised on and developed the protocol; completed part of the first draft of the protocol; made an intellectual contribution to the protocol, and approved the final version prior to submission. Fernando Dias: developed and co-ordinated the protocol; advised on, completed the first draft of the protocol; approved the final version of the protocol prior to submission; made an intellectual contribution to the protocol. Cibele Ribeiro: developed and co-ordinated the protocol; advised on, completed and edited the first draft of the protocol; approved the final version of the protocol prior to submission; made an intellectual contribution to the protocol. Vanessa Resqueti: made an intellectual contribution to the protocol and approved the final version of the protocol prior to submission. Armele de Andrade: made an intellectual contribution to the protocol and approved the final version of the protocol prior to submission. Contributions of editorial base: Jo Dumville, Editor: approved the final protocol prior to submission. Sally Bell-Syer: coordinated the editorial process. Advised on methodology, interpretation and content. Edited the protocol. Ruth Foxlee: designed the search strategy and edited the search methods section. Rachel Richardson: edited the protocol. Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 14 79 DECLARATIONS OF INTEREST Guilherme Fregonezi: none known. Fernando Dias: none known. Cibele Ribeiro: none known. Vanessa Resqueti: none known. Armele de Andrade: none known. SOURCES OF SUPPORT Internal sources • No sources of support supplied External sources • MCT/CNPQ/CT- Saúde/MS/SCTIE/DECIT n. 67/2009, process 559416/2009-1), Brazil. • The National Institute for Health Research (NIHR) is the sole funder of the Cochrane Wounds Group, UK. Hydrocolloid dressings for healing venous leg ulcers (Protocol) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 15 80 ANEXO 2: Características dos estudos excluídos e justificativa para exclusão 81 Characteristics of excluded studies (Reasons for exclusion): Altman 1993: Did not report sufficient information to be judged as eligible for inclusion in this review. Unable to obtain the necessary information to make a judgment (no response to email sent trial author). Uncertain if venous leg ulcers was reported separately. Anonymous 1994: Not an RCT (Study translated form German). Anonymous 1997: Not an RCT (Review article translated from German about dermatomycoses). Argoff 2013: Not a treatment of interest. Barbaud 2009: Not treatment of interest. Berard 1986: Not treatment of interest (Evaluation of hydrocolloid). Blume 2008: Study includes ulcers of diabetic aetiology. Bolton 2003: Not an RCT. Bradley 1999: Not an RCT (review article). Brandrup 1990: Not a treatment of interest (RCT comparing zinc oxide medicated and hydrocolloid dressings in people with venous and arterial leg ulcers). Caprio 1995: Not a treatment of interest (Study evaluation of hydrocolloid vs collagen dressing). Chraibi 1994: Not an RCT. Coerper 2004: Not a treatment of interest. Cordts 1992: Not a treatment of interest (Study evaluation of Unna's boot vs hydrocolloid dressing). Couilliet 2001: Not an RCT. D'Alicandro 2003: Includes ulcer of mixed aetiology with no separate reporting by ulcer type. Davis 2010: Not a treatment of interest (Larval therapy no hydrogel dressings). Dereure 2012: Not a treatment of interest. Driver 2009: Not a treatment of interest (Evaluation of vacuum therapy vs advanced moist wound therapy in ulcers of diabetic aetiology). Dumville 2009: Not a treatment of interest (Larval therapy no hydrogel dressings). 82 Dumville 2011: Not an RCT (Review article). Eneroth 2008: Not an RCT (Review article). Farah 2010: Not an RCT (Review article). Farina 1997: Insufficient information to be judged as eligible for inclusion in this review. Unable to obtain the necessary information to make a judgement (no response to email sent trial author). Flanagan 1995: Not an RCT. Fonder 2008: Not an RCT (Review article). Friedman 1984: Not a treatment of interest (Evaluation of hydrocolloid). Gago 2002: Conference abstract with limited information. Unable to obtain the necessary information to make a judgement (no response to email sent trial author). Gibson 1995: Leg ulcers with mixed aetiology presenting less than 75% of venous leg ulcer on each arm study. Guerin 2012: Not an RCT. Hamerlinck 1989: Not a treatment of interest (Study evaluates hydrocolloid vs unitulle- primary wound contact layer impregnated with white soft paraffin). Hampshire 2000: Not a treatment of interest (Study evaluates larval therapy no hydrogel dressings). Hampton 2004: Study did not randomize participants. Hansson 1998: Not a treatment of interest (Study evaluation of iodine vs. hydrocolloid dressing). Harding 1996: Not a treatment of interest (Study evaluation of hydrocellular adhesive dressing vs hydrocolloid). Harding 2001: Not a treatment of interest (Study evaluation of hydrofiber vs. alginate dressings). Hinchliffe 2008: Not an RCT (Review article). Hofman 1994: Conference abstract with limited information. Unable to obtain the necessary information to make a judgment (no response to email sent trial author). Hofman 1996: Not an RCT (Case study and expert opinion). Hoppe 2012: Not an RCT. 83 HQO 2006: Not an RCT (Review article about negative pressure wound therapy). Hu 2011: Not an RCT (Review article). Hunt 2003: Not an RCT (Review article). Hutchinson 1997: Not a treatment of interest. Isner 1996: Not a treatment of interest. Jansen 2009: Not a population of interest. Jensen 1998: Not a population of interest. JNMA 2007: Not an RCT (Info poems - Expert opinion). Jones 2009: Not an RCT (Review article). Karlsmark 2002: Not a treatment of interest. Kaya 2005: Not a population of interest. Kerstein 2001: Not an RCT (Review article of cost effectiveness of venous and pressure ulcer protocols). Kikta 1988: Hydrogel is not the only systematic difference between groups. Not a valid comparison for inclusion in the review. La Grenade 1993: Not a population of interest (Evaluation of sickle cell no venous ulcers). Lammoglia 2012: Not a treatment of interest. Larsen 1997: Conference abstract with limited information. Unable to obtain the necessary information to make a judgment (no response to email sent trial author). Lawall 2012: Not an RCT (Review article). LeBon 2009: Not an RCT (Review article). Lee 2011: Not and RCT (Review about effects of honey in venous leg ulcers). Leite 2011: Not an RCT. Lewis 2001: Not an RCT (Review article). Limova 2002: Not a treatment of interest (study evaluation of two hydrocolloid dressings). Lindholm 1995: Not a treatment of interest. 84 Lyon 1998: Not a treatment of interest. Mansson 1996: Not a treatment of interest (Study evaluation of Iodosorb dressing vs. Hydrocolloid vs. Jenolet). Mason 1999: Not an RCT (Review article). Meaume 2005: Not a treatment of interest (Study evaluation of soft polymer dressing vs. hydrocolloid). Mekkes 2001: Not a treatment of interest. Meyer 1995: Not an RCT. Moffatt 1992: Not a treatment of interest. Mulder 1989: Not a treatment of interest (Evaluation of three hydrocolloid dressings). Mulder 1993: Not a treatment of interest. Nelson 2006: Not an RCT (Review article). Nowak 1996: Conference abstract with limited information. Unable to obtain the necessary information to make a judgement (no response to email sent trial author). O'Donnell 2006: Not an RCT (Review article). O'Meara 2000: Not an RCT (Review article). Ohlsson 1994: Not a treatment of interest. Palfreyman 2007: Not an RCT (Review article). Perez 2000: Not a treatment of interest. Peters 2001: Not a treatment of interest (Evaluation of electric stimulation on diabetic ulcers). Petherick 2006: Not a treatment of interest (Evaluation of larval therapy). Pfeffer 2005: Not an RCT. Phillips 2000: Not a treatment of interest. Pierard 1995: Not a treatment of interest (Study evaluation of hydrocolloid vs. compressive bandages). Pittler 2007: Not a treatment of interest. Raymond 2008: Not an RCT. 85 Raynor 2004: Evaluation of larval therapy (Not a treatment of interest). Renner 2013: Not an RCT. Assessment of contact sensitization and not healing effect of the dressings. Rivera-Arce 2007: Not a treatment of interest. Use of a topical agent concomitant to hydrogel. Robinson 1996: Not separeted report for venous leg ulcer. Romanelli 1999: Not a treatment of interest (Study evaluation of hydrocellular dressing vs. hydrocolloid). Sackheim 2006: Not an RCT (Review article). Samson 1992: Not an RCT. Letter to the editor limited presentation of results. Sandison 2008: Not a population of interest. Scanlon 2003: Not an RCT (Review article). Schulze 2003: Not an RCT. Senet 2011: Not a treatment of interest. Senet 2012: Not a treatment of interest. Sibbald 2003: Not a treatment of interest. Sironi 1994: The hydrogel dressing is not the only systematic difference between groups. Smith 1997: Not a treatment of interest. Soares 2009: Not a treatment of interest (Evaluation of larval therapy). Sparholt 2002: Not enough information to be judged as eligible for inclusion in this review. Unable to obtain the necessary information to make a judgement (no response to email sent trial author). Spilsbury 2008: Evaluation of larval therapy. Not a treatment of interest. Tang 2012: Not an RCT (Review article). Thomas 1997: Not a treatment of interest. Study evaluation of hydrocolloid vs. Polyurethane foam. Valencia 2001: Not an RCT (Review article). Varghese 1986: Not a treatment of interest. 86 Veraart 1994: Evaluation of hydrocolloid. Vernassiere 2005: Not a treatment of interest. Evaluation of topical application of morphine on skin ulcers. Vin 1997: Not a treatment of interest. Walker 1996: Not a treatment of interest. Evaluation of bandage system no hydrogel dressings. The difference between groups is not the hydrogel. Wang 2012: Not a population of interest. Wayman 2000: Not a treatment of interest (Evaluation of larval therapy). Werner 1994: Not a treatment of interest. Use of topical agent. Westerhof 1995: Not a treatment of interest. Zarchi 2012: Not a treatment of interest. Zuccarelli 1992: Not a treatment of interest. Study evaluation of foam dressing vs. hydrocolloid. 87 ANEXO 3: Características dos estudos incluídos 88 Characteristics of included studies 1- de la Brassine 2006 Methods Design: open; Pilot study; RCT. Country: Belgium. Setting: hospital. Sample size calculation: not reported. Ethical approval: was reported. It was granted after the medical ethics committee approved the project. Participants Informed consent: was obtained after the patients being fully advised about the purpose and consequences of the study. Total sample: 20 hospitalized patients with chronic leg ulcers of venous origin. Inclusion criteria: males and females, mobile, 4070 years and ulcers with exudate. Exclusion criteria: none specified. Numbers randomized: Group 1 (hydrogel dressing): 10 participants. Group 2 (alginate dressing): 10 participants. Gender of the participants: 13 female and 7 male from the 20 patients. Mean participant age: 61 years (45-70). ABPI: not reported. Unit of analysis: participant. Ulcer infection: not reported. Participant ulcer duration (current): years(0,5-10 years) in both groups. 2,25 89 Baseline ulcer surface: Group 1 (hydrogel dressing): 20.9 ± 7.5 cm² (p= 0.826). Group 2 (alginate dressing): 20.3 ± 7.6 cm² (p= 0.826). Baseline volume measurement: Group 1 (hydrogel dressing): 128.4 ± 55.2 mm³. Group 2 (alginate dressing): 124.7 ± 49.9 mm³. Interventions Data collected: diagnosis, sex, age, ulcer dimension and volume. Group 1: hydrogel dressing (Intrasite gel) (control group). Group 2: alginate dressing (Flaminal gel). *Both groups had the wound debrided and cleaning with saline before the dressing was applied. Description of compression therapy: not reported. Length of treatment: 4 weeks. Follow-up: 4 weeks (endpoint). Comments: * The surface measurement of the ulcer was made using acetate tracing (Opsite Flexigrid from Smith and Nephew Healtcare). Outcomes * The volume measurement of the ulcer was made using high algin impression material (Jeltrate mould from Dentsply Caulk International). Reporting of outcomes relevant to this review: Complete wound healing: reported. Incidence of wound infection: not reported. Change in ulcer size: reported, planimetry used to measure the wound at baseline, day 7, 14 and 28 days of treatment and also volume measured at 90 the same days. Time to ulcer healing: not reported. Recurrence of ulcer: not reported. Quality of life: not reported. Pain: not reported. Notes Costs: not reported. Number of participants withdrawing and reasons: trial authors did not report on participant withdrawal. 2- Gethin 2009 Methods Design: open; multicentre; RCT. Country: Ireland. Setting: Participants from 10 sites, including vascular centres, acute and community care hospitals and leg ulcer clinics. Sample size calculation: a sample size of 156 participants randomly allocated to two equal groups of 78 estimated as having 80% power to detect a minimum difference of 20% at the 5% two-sided significance level. Ethical approval: was reported. Participants Informed consent: was obtained. Total sample: 108 participants. Inclusion criteria: having a venous ulcer, being over 18 years of age, able to provide written informed consent, having ≥50% of wound bed covered in slough, ulcer size < 100cm², ABPI ≥0.8. Exclusion criteria: less than 18 years, unable to provide written informed consent, having an ulcer > 100 cm², ulcer diagnosed as being malignant, having a cavity wound, clinical diagnosis of 91 wound infection, currently taking antibiotics for any reason, currently taking oral immunosuppressant, having poorly controlled diabetes, having previously enrolled into the study, pregnant women or lactating mothers. Mean participant age: not reported. ABPI: results not reported. Baseline data collected: gender, age, wound size and duration, ulcer location and history of recurrence. Medical information collected: history of deep venous thrombosis (DVT), hypertension, trauma or surgery to the affected limb, diabetes, immunosuppression and current medications Numbers randomized: Group 1 (hydrogel dressing): 54 participants Group 2 (Manuka honey dressing): 54 participants Unit of analysis: ulcer. Ulcer infection: was reported. Interventions Comments: The trial authors reported that each participant could only contribute with one ulcer (the upper most ulcers or the largest ulcer was selected if more than one was present). Group 1: hydrogel dressing (IntraSite Gel, Smith & Nephew). Group 2: Lohmann). Manuka honey dressing (Opr, *All participants were subjected to a compression therapy. Length of treatment: 12 weeks. Outcomes Follow-up: was reported (at week 12). Reporting of outcomes relevant to this review: Complete wound healing: reported that some ulcers were completely healed after 28 days and several participants after 28 days (no reporting of 92 numbers). Incidence of wound infection: reported. Change in ulcer size: reported, planimetry used to measure the wound at baseline; weeks 4, 8 and 12. Time to ulcer healing: not reported. Recurrence of ulcer: not reported. Quality of life: not reported. Pain: not reported. Notes Costs: not reported. Number of patients withdrew: Group 1 (hydrogel dressing): 17 participants Group 2 (Manuka honey dressing): 9 participants Reasons: infection in reference wound and elsewhere; patient request; did not attend followup. 3- Grotewhol 1994 Methods Design: multicenter; RCT. Country: Germany. Setting: not reported. Sample size calculation: not reported. Ethical approval: not reported. Participants Informed consent: was obtained. Total sample: 84 participants with ulcera crurum. Inclusion criteria: none specified. Exclusion criteria: none specified. Numbers randomized: 93 Group 1 (hydrocolloid dressing): 24 participants Group 2 (hydrogel dressing): 39/41 participants Mean participant age: not reported. ABPI: not reported. Unit of analysis: ulcer. Baseline ulcer size cm2 (mean) (before treatment): Group 1 (hydrocolloid dressing): 6.3 Group 2 (hydrogel dressing): 10.1 Ulcer infection: not reported. Data collected: diagnosis, dimension and volume. sex, age, ulcer Participant ulcer duration: not reported. Data collected: ulcer dimension by planimetry. Comments: The study started with 84 participants but only 62 participants followed for 28 days of the study. Interventions The trial author reported that 3 patients from the Hydrogel group had double-sided ulcers; 1 of these patients was treated with hydrogel and hydrocolloid at once. Group 1: hydrocolloid dressing (proprietary name not reported, manufacturer not reported) (control group). Group 2: hydrogel dressing (Opragel, Lohmann). *All participants were subjected to a compression therapy. Description of compression therapy: not reported. Length of treatment: 4 weeks. Outcomes Follow-up: not reported. Reporting of outcomes relevant to this review: Complete wound healing: reported that some ulcers were completely healed after 28 days and several participants after 14 days (no reporting of 94 numbers). Incidence of wound infection: not reported. Change in ulcer size: reported, planimetry used to measure the wound at day 14 and day 28 of the treatment. Time to ulcer healing: not reported. Recurrence of ulcer: not reported. Quality of life: not reported. Pain: not reported. Notes Costs: not reported. No details of total number of ulcers healed at end of trial provided. Exclusions post-randomization: 22 no reasons provided or from which group patients withdrew. The trial author reported that did not observe cases of irritation or allergic reactions with the use of dressings. No details provided from imbalance in allocation to treatment groups. Group 1: 3 ulcers did not demonstrated signs of healing. Group 2: 4 ulcers did not demonstrated signs of healing. 4- He 2008 Methods Design: RCT. Country: China. Setting: not reported. Sample size calculation: not reported. Ethical approval: not reported. Informed consent: not reported. 95 Participants Total sample: 60 patients with chronic venous ulcer of lower extremities. Inclusion criteria: age ≥ 18 years; required to have a venous insufficiency ulcer for more than 1 month of duration, with area ≤ 4cm²; woman not pregnant; not immunosuppression; no history of allergy to polysaccharides (glycans). Exclusion criteria: none specified. Group 1 (gaze in saline): 30 participants. Group 2 (hydrogel dressing): 30 participants. Gender of the participants: Group 1 (gaze in saline): 20 males and 10 females Group 2 (hydrogel dressing): 24 males and 6 females. Side of the ulcers: 32 ulcers from the left side and 28 ulcers from the right side. Baseline ulcer size cm2 treatment): 2.5 – 4.0 cm². (mean) (before Group 1 (gaze in saline): 3.1±0.4 cm². Group 2 (hydrogel dressing): 3.4±0.6 cm². Mean participant age: Group 1 (gaze in saline): 60.1±7.4 years. Group 2 (hydrogel dressing): 57.3±6.8 years. Participant ulcer duration: Group 1 (gaze in saline): 3.3 ±0.9 years. Group 2 (hydrogel dressing): 2.9±0.7 years. ABPI: not reported. Unit of analysis: patient. Ulcer infection: not reported. 96 Data collected: diagnosis, dimension and volume. sex, age, ulcer Participant ulcer duration: not reported. Data collected: ulcer dimension by planimetry. Comments: The study started with 84 participants but only 62 participants followed for 28 days of the study. Interventions The trial author reported that 3 patients from the Hydrogel group had double-sided ulcers; 1 of these patients was treated with hydrogel and hydrocolloid at once. Group 1: gaze in saline (control group). Group 2: hydrogel dressing (Chitosan, Xangai Qisheng). *All participants were subjected to a compression therapy. Description of compression therapy: not reported. Length of treatment: 5 months. Outcomes Follow-up: not reported. Reporting of outcomes relevant to this review: Complete wound healing: reported that some ulcers were completely healed after 28 days and several participants after 14 days (no reporting of numbers). Incidence of wound infection: not reported. Change in ulcer size: reported, planimetry used to measure the wound at day 14 and day 28 of the treatment. Time to ulcer healing: not reported. Recurrence of ulcer: not reported. Quality of life: not reported. Pain: not reported. Costs: not reported.