Cibele Teresinha Dias Ribeiro - repositorio.ufrn.br · Cibele Teresinha Dias Ribeiro Natal 2014 ... à Diana Freitas e Gabriela Chaves, por compartilharmos sempre dúvidas dos nossos

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



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 Pós-Graduação em Fisioterapia.

CDU 616-002.44

iii



Coordenador do Programa de Pós-Graduação em Fisioterapia:

Jamilson Simões Brasileiro

iv



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

Dedicatória

Ao meu esposo, Fernando e a minha filha Bianca.

v

vi

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.

vii

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 e-

mails 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!!

viii

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

ix

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 sali-

na (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

x

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

xi

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.

xii

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.

xiii

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.

xiv

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.

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 meta-

análise.

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 endotélio-

leucocitária, 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

Necessidade da revisão

Contato com o grupo de feridas

Registro do título

Elaboração protocolo para Colaboração

Cochrane

Aprovação e publicação do

protocolo

Busca e identificação dos artigos

Pesquisador 1

Pesquisador 2

Seleção dos estudos

Seleção dos estudos

Reunião de consenso

Estudos incluídos

Estudos excluídos e elaboração da tabela

com a justificativa para a exclusão

Pesquisador 1

Pesquisador 2

Extração dos dados e elaboração da tabela dos estudos incluídos

Extração dos dados e elaboração da tabela dos estudos incluídos


Avaliação do risco de viés dos estudos

incluídos Pesquisador 1

Pesquisador 2


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 pré-

estabelecido (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.

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.


Dias' family

Typewritten Text

21

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iHydrogel dressings for venous leg ulcers (Protocol)


Dias' family

Typewritten Text

Dias' family

Typewritten Text

22

[Intervention Protocol]

Hydrogel dressings for venous leg ulcers

Cibele TD Ribeiro1 , Fernando AL Dias2, Guilherme AF Fregonezi3

1Graduate Program in Physiotherapy, Federal University of Rio Grande do Norte, Natal, Brazil. 2Department of Physiology, Federal

University of Paraná, Curitiba, Brazil. 3Department 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.


A B S T R A C T

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.

B A C K G R O U N D

A glossary of medical terms is available in Appendix 1.

Description of the condition

Venous leg ulcers (VLU) present as open wounds generally irregu-

lar 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, frustra-

tion 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). Addition-

aly, 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 (in-

flammation of veins) (Collins 2010). Insufficiency of the superfi-

cial, 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 be-

tween 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,

1Hydrogel dressings for venous leg ulcers (Protocol)


mailto:[email protected]

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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 pop-

ulation 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 health-

care 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) fac-

tors such as venous thrombosis could cause valve insufficiency that

results in venous stasis and reflux, which are the predominant fac-

tors 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, tor-

tuosity 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 cell-

surface binding molecules that facilitate their migration into tis-

sue. Once leucocytes are in the tissue they become active and pro-

duce a series of molecules that lead to tissue damage (Smith 2006;

Wollina 2006).

The diagnosis of venous ulceration is usually based on clinical ex-

amination. 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 in-

dex equal or lower than 0.9 is the diagnosis criterion for periph-

eral arterial disease (Rooke 2011); however, ABPI measurement

greater than 0.8 is generally used to exclude peripheral arterial dis-

ease 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 al-

terations surrounding the ulcer such as hyperpigmentation, lipo-

dermatosclerosis 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 lim-

ited 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 ther-

apy. It has been shown that compression increases the heal-

ing rates of venous leg ulcers compared with no compression

(O’Meara 2009). This treatment is often applied with other inter-

ventions, 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 com-

pression (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-epithelial-

isation 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; avoid-

ance 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-



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gel (e.g. Aquaflo (Covidien)). Some of the hydrogels are associ-

ated 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 pro-

mote relief and comfort, however, they do require a secondary cov-

ering. 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.

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 en-

vironment for wound healing by donating fluids to dry sloughy

wounds, and by facilitating autolytic debridement of necrotic tis-

sue. Some hydrogel dressings also have the ability to absorb lim-

ited 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.

O B J E C T I V E S

To assess the effects of hydrogel wound dressings for healing venous

leg ulcers in people in any care setting.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs), either published or unpub-

lished, 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 ade-

quate information is either presented in the abstract or available

from the trial author. Studies using quasi-randomisation will be

excluded.

Types of participants

We will include people of any age in any care setting with a di-

agnosed 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 sep-

arately or if the majority of participants (≥ 75% in each arm)

have leg ulcers of venous aetiology. The review authors will at-

tempt 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 in-

cluded, 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’ For-

mulary (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 evaluat-

ing hydrogel dressings impregnated with antimicrobial, antiseptic



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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 hy-

drogel 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. sur-

face 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

Electronic searches

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);

• 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 EM-

BASE 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 Net-

work (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.controlled-

trials.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 iden-

tified by the above strategies will be searched for further studies.

We will attempt to contact researchers to obtain additional infor-

mation 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.

Data collection and analysis

Selection of studies

Two review authors (CR and FD), working independently, will

screen the titles and abstracts of the studies identified from the



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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 full-

text 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, incom-

plete outcome data, selective outcome reporting and other issues

which may potentially bias the study (Appendix 3). For this re-

view, we will consider other risk of bias issues as follows: compara-

bility 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 dis-

agreement 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 quan-

titative data into Review Manager 5.2, another will check it, and

the data will be analysed using the Cochrane Collaboration’s as-

sociated 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 out-

comes (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 es-

timates 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 assess-

ment. The authors will include data from cluster-randomised tri-

als if the information is available. For cluster-randomised trials, we



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will adjust results when the unit of analysis in the trial is presented

as the total number of individual participants instead of the num-

ber 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 16.3 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 incom-

plete or missing data. Where trials report complete healing out-

comes for only those participants who complete the trial (i.e. par-

ticipants 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 signifi-

cance level of P < 0.10 is considered to indicate significant hetero-

geneity) 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 repre-

sent 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 method-

ological quality and true heterogeneity.

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 deci-

sion to include studies in a meta-analysis will depend on the avail-

ability 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 es-

timate 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 pri-

mary outcome using four levels of quality: high, moderate, low

and very low (Schünemann 2011a). We plan to record the qual-

ity 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 out-

come. Quality will be based in the following factors:

1. Limitations in the design and implementation of available stud-

ies suggesting high likelihood of bias.

2. Indirectness of evidence (indirect population, intervention, con-

trol, outcomes).

3. Unexplained heterogeneity or inconsistency of results (includ-

ing 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

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 un-

clear risk of bias will be excluded and the difference between esti-

mates of treatment effect from this analysis and the main analysis

considered.

A C K N O W L E D G E M E N T S



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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 design-

ing the search strategy. In addition Elizabeth Royle for copy edit-

ing and the referees; Wounds Group Editors Joan Webster, Mar-

ian Brady, Statistical advisor Marialena Trivella and referees Mark

Corbett, Una Adderley, Vicki Pennick and Amy Zelmer.

R E F E R E N C E S

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A P P E N D I C E S

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.



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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).



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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 superab-

sorbent 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 (Systa-

genix) and Sorbion (H & R).



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Silicone keloid dressing

These dressings reduce or prevent hypertrophic or keloid scarring. Examples include: Cica-Care (Smith & Nephew) and Ciltech (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 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;



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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


• 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


• 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


• 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.


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.



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Unclear


• 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).


5. Are reports of the study free of suggestion of selective outcome reporting?

Low risk of bias


• 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


• 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.



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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.

C O N T R I B U T I O N S O F A U T H O R S

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.

D E C L A R A T I O N S O F I N T E R E S T

None.

S O U R C E S O F S U P P O R T

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.



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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.

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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

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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)


1. Cicatrização completa das úlceras: esse desfecho não foi analisado pelo estudo.



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.





3.3.3 Comparação entre hidrogel, Intrasite, e mel de Manuka (Gethin e col.

2008).


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.


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).






3.3.4 Comparação entre hidrogel e hidrocolóide (Grotewohl 1994)


49

1. Cicatrização completa das úlceras: esse desfecho não foi analisado pelo estudo.



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.






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. Não existem evidências disponíveis a

respeito da efetividade do hidrogel em relação aos outros tipos de curativo na

cicatrização de úlceras venosas de membros inferiores, por isso há a necessidade

de futuras pesquisas para auxiliar os profissionais da saúde na escolha do adesivo

correto. Estudos futuros devem apresentar melhor rigor metodológico, clara

definição dos critérios de inclusão e exclusão dos estudos, descrição detalhada dos

desfechos que serão analisados para que se possa fazer ou não a indicação do uso

do curativo para o tratamento.

55

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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.

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6 ANEXOS

62

ANEXO 1: Protocolo publicado – Hydrocolloid dressings for venous leg ulcers

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


Hydrocolloid dressings for healing venous leg ulcers (Protocol)



Dias' family

Typewritten Text

63

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iHydrocolloid dressings for healing venous leg ulcers (Protocol)


Dias' family

Typewritten Text

64

[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

1Graduate Program in Physiotherapy, Federal University of Rio Grande do Norte, Natal, Brazil. 2PhD Program in Physical Therapy,

Federal University of Rio Grande do Norte, Natal, Brazil. 3Master Degree Program, Department of Physical Therapy, Federal University

of Pernambuco, Recife, Brazil. 4Physical Therapy, Master Degree Program in Physical Therapy, Federal University of Pernambuco,

Recife, Brazil, Recife, Brazil. 5Department 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.


A B S T R A C T

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 hydrocol-

loid 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.

B A C K G R O U N D

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 af-

fected 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 distur-

bance, 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 ma-

jor contributors to the risk of not healing (Margolis 2004). Ad-

ditionaly, the presence of lipodermatosclerosis (inflammation of

subcutaneous fat layers), evidence of deep vein thrombosis (blood

clot lodged in a leg vein), superficial thrombophlebitis (inflam-

mation 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 ag-

ing, gender (venous leg ulcers are more common in women), obe-

sity, 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 pop-

ulation, and between 1% and 3% of the elderly population in the

United States and Europe (Margolis 2002). The estimated preva-

lence of venous leg ulcers ranges between 0.6% and 1.9% in the

1Hydrocolloid dressings for healing venous leg ulcers (Protocol)


mailto:[email protected]

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adult population of the UK, USA, and Europe (Briggs 2003). Epi-

demiological studies estimate that venous leg ulcers affect one mil-

lion 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 signif-

icant 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 out-

patient 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 exer-

cise 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 hyperten-

sion (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 ex-

amination. 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 pa-

tients 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 me-

dial malleolus (inner ankle). Skin alterations surrounding the ul-

cer, such as hyperpigmentation (discolouration), lipodermatoscle-

rosis and fibrosis (scarring) are usually present (Collins 2010). Fre-

quent 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 ther-

apy. 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 treat-

ment (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 inter-

ventions, 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 ther-

apeutic compression (this may be applied by bandages) in ad-

dition 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 stock-

ings from adhering to the wound bed. The ideal conditions re-

quired for wound healing in terms of dressing application have

been explained as follows: maintenance of a moist wound environ-

ment 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 hydrocol-

loid 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. Aqua-

cel (ConvaTec). Hydrocolloid dressings have also been shown to

reduce pain in painful wounds (Meaume 2004). The purported



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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 tis-

sue and can provoke an unpleasant odour through the reaction of

exudate with the primary active ingredient in the dressing. Dress-

ing 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, ba-

sic, 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 dress-

ing by the Nurse Prescribers’ Formulary, are designed to control

the environment for wound healing, for example maintaining hy-

dration, and by facilitating autolytic debridement of necrotic tis-

sue. They are semi-permeable to water vapour and oxygen. These

dressings form a gel in the presence of exudate to facilitate re-

hydration 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 clin-

icians 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.

Why it is important to do this review

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 hydrocol-

loid 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

hydrocolloid dressings. The current review will establish the cur-

rent level of evidence of hydrocolloid dressings for the treatment

of venous ulcers.

O B J E C T I V E S

To determine the effects of hydrocolloid dressings compared with

other wound dressings, non-dressing treatments or another hy-

drocolloid 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.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs), either pub-

lished or unpublished, that have evaluated the effects of any type

of hydrocolloid wound dressing in the treatment of venous leg ul-

cers, 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.

Types of participants

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 in-

clude 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 sepa-

rately, 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).



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Types of interventions

The intervention will be hydrocolloid dressings used as a treat-

ment 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 manufac-

turers 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 inter-

ventions 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 com-

pared 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 medi-

honey 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 tri-

als in MEDLINE: sensitivity- and precision-maximising version

(2008 revision) (Lefebvre 2011). We will combine the EM-

BASE 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 Intercolle-

giate 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 at-

tempt to contact study authors to obtain additional information



http://www.who.int/ictrp/en/





http://www.controlled-trials.com/isrctn/





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whenever necessary, along with manufacturers to request informa-

tion about ongoing or as yet unpublished trials. We will attempt

to obtain registered trial protocols for all published trial reports

identified for inclusion.

Data collection and analysis

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 full-

text 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 stan-

dard data extraction sheet. Data will then be entered into Revman

5.2 (Revman 2012), We will resolve any discrepancies by discus-

sion with a third review author (VR). According to methods de-

scribed in the Cochrane Handbook for Systematic Reviews of In-

terventions, 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).

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.

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 and blinding of outcome assessors, in-

complete 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 fol-

lows: comparability of treatment groups in relation to baseline

ulcer surface area; choice of analysis when studying multiple ul-

cers 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 dis-

agreement 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 quantita-

tive data into Review Manager 5.2, another will check it, and the

data will be analysed using RevMan 5.2. We will present the out-

come 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 ul-

cer area) will be expressed as mean differences (MD) and overall

effect size (with 95% CI calculated) or as standardised mean dif-

ferences (SMDs) if different methods of measurement are used in



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the studies. For time-to-event data, we plan to plot, and, if feasi-

ble, 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 par-

ticipants, we will assume that the ulcer is the unit of analysis, un-

less otherwise stated. The authors will include data from cluster-

randomised trials if the information is available. For cluster-ran-

domised 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 Interven-

tions (Higgins 2011e).

Dealing with missing data

The authors will contact the trial investigators in cases of incom-

plete or missing data. Where trials report complete healing out-

comes for only those participants who complete the trial (i.e. par-

ticipants 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 fun-

nel 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. Fun-

nel plots allow a visual assessment of whether small study effects

may be present in a meta-analysis. A funnel plot is a simple scat-

ter plot of the intervention effect estimates from individual RCTs

against some measure of each trial’s size or precision. If asymme-

try 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 asymme-

try, 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 accord-

ing to the comparator intervention, which may include no dress-

ing, 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 heterogene-

ity. For comparisons where there is no apparent clinical hetero-

geneity and the I2 value is 40% or less, we will apply a fixed-effect

model. Where there is no apparent clinical heterogeneity and the I2 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 ad-

verse 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 us-

ing 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 stud-

ies suggesting high likelihood of bias.

2. Indirectness of evidence (indirect population, intervention, con-

trol, outcomes).

3. Unexplained heterogeneity or inconsistency of results (includ-

ing 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



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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.

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

main analysis.

A C K N O W L E D G E M E N T S

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 design-

ing the search strategy. In addition the referees: Wounds Group

Editor, Andrew Jull; Statistical advisor, Giovanni Casazza; and ref-

erees Marissa Martyn-St James, Una Adderley, Nancy Munoz and

Shirley Manknell.

R E F E R E N C E S

Additional references

Aziz 2011

Aziz Z, Cullum N, Flemming K. Electromagnetic therapy

for treating venous leg ulcers. Cochrane Database of


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


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A P P E N D I C E S

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.



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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 heavily-

exuding 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).



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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.



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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


• 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.


4. Were incomplete outcome data adequately addressed?

Low risk of bias


• 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.



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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


• 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


• 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).


5. Are reports of the study free of suggestion of selective outcome reporting?

Low risk of bias


• 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


• 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.



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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.

C O N T R I B U T I O N S O F A U T H O R S

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.



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D E C L A R A T I O N S O F I N T E R E S T

Guilherme Fregonezi: none known.

Fernando Dias: none known.

Cibele Ribeiro: none known.

Vanessa Resqueti: none known.

Armele de Andrade: none known.

S O U R C E S O F S U P P O R T

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.



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ANEXO 2: Características dos estudos excluídos e justificativa para exclusão

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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).

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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.

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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.

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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.

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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.

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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.

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ANEXO 3: Características dos estudos incluídos

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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.

Informed consent: was obtained after the patients being fully advised about the purpose and consequences of the study.

Participants Total sample: 20 hospitalized patients with chronic leg ulcers of venous origin.

Inclusion criteria: males and females, mobile, 40-70 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): 2,25 years(0,5-10 years) in both groups.

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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.

Data collected: diagnosis, sex, age, ulcer dimension and volume.

Interventions 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).

* The volume measurement of the ulcer was made using high algin impression material (Jeltrate mould from Dentsply Caulk International).

Outcomes 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

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the same days.

Time to ulcer healing: not reported.

Recurrence of ulcer: not reported.

Quality of life: not reported.

Pain: not reported.

Costs: not reported. Notes 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.

Informed consent: was obtained. Participants 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

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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.

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).

Interventions Group 1: hydrogel dressing (IntraSite Gel, Smith & Nephew).

Group 2: Manuka honey dressing (Opr, Lohmann).

*All participants were subjected to a compression therapy.


Follow-up: was reported (at week 12). Outcomes 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

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numbers).

Incidence of wound infection: reported.

Change in ulcer size: reported, planimetry used to measure the wound at baseline; weeks 4, 8 and 12.




Pain: not reported.

Costs: not reported. Notes Number of patients withdrew:

Group 1 (hydrogel dressing): 17 participantsGroup 2 (Manuka honey dressing): 9 participants

Reasons: infection in reference wound and elsewhere; patient request; did not attend follow-up.

3- Grotewhol 1994

Methods Design: multicenter; RCT.

Country: Germany.

Setting: not reported.


Ethical approval: not reported.

Informed consent: was obtained. Participants Total sample: 84 participants with ulcera crurum.

Inclusion criteria: none specified.


Numbers randomized:

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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): 6.3Group 2 (hydrogel dressing): 10.1



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.

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.

Interventions Group 1: hydrocolloid dressing (proprietary name not reported, manufacturer not reported) (control group).

Group 2: hydrogel dressing (Opragel, Lohmann).




Follow-up: not reported. Outcomes 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

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numbers).


Change in ulcer size: reported, planimetry used to measure the wound at day 14 and day 28 of the treatment.




Pain: not reported.

Costs: not reported. Notes 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.


Ethical approval: not reported.

Informed consent: not reported.

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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).


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 (mean) (before treatment): 2.5 – 4.0 cm².

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.


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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.

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.

Interventions Group 1: gaze in saline (control group).

Group 2: hydrogel dressing (Chitosan, Xangai Qisheng).



Length of treatment: 5 months.

Follow-up: not reported. Outcomes 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).


Change in ulcer size: reported, planimetry used to measure the wound at day 14 and day 28 of the treatment.




Pain: not reported.

Costs: not reported.

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