Hydrogel dressings for venous leg ulcers
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of hydrogel wound dressings for healing venous leg ulcers in people in any care setting.
Background
A glossary of medical terms is available in Appendix 1.
Description of the condition
Venous leg ulcers (VLU) present as open wounds generally irregular and shallow or sores on the lower limb. They are associated with sustained venous hypertension and microcirculatory alterations resulting from chronic venous insufficiency (Grey 2006; Wollina 2006).This condition has psychological and financial impact and also impacts on the physical functioning of affected patients. The impact of leg ulcers on patient's daily life is described in many quantitative and qualitative studies. The major problems reported from the patients are: pain, immobility, sleep disturbance, lack of energy, limitations in work and leisure activities, worry, frustration and lack of self‐esteem (Herber 2007; Persoon 2004). Thus, venous leg ulcers will ultimately impact quality of life. Venous leg ulceration is a chronic health problem that can take years to heal completely, and, as it has a high rate of recurrence, often requires life‐long treatment (Margolis 2002; Van Hecke 2011). Wound size and wound duration (greater than 18 months) were major contributors to a risk of not healing (Margolis 2004). Additionaly, the presence of lipodermatosclerosis, evidence of deep vein thrombosis, superficial thrombophlebitis or poor ankle mobility were individually associated with delayed healing (Lantis 2013).
The incidence of venous ulceration rises with increasing age (De Araujo 2003; Wipke‐Tevis 2000). The primary risk factors are aging, gender (more common in women), obesity, previous leg injuries, deep venous thrombosis (clots in veins) and phlebitis (inflammation of veins) (Collins 2010). Insufficiency of the superficial, perforating or deep veins of the leg is also a risk factor for leg ulceration (Valencia 2001). Venous leg ulcers have been estimated to afflict between 0.2% and 1% of the total population and between 1% and 3% of the elderly population in the United States (USA) and Europe (Margolis 2002).The estimated incidence of venous leg ulcers in the elderly (i.e. aged 65 years or older) per 100 person‐years is around 0.76 for males and 1.42 for females (Margolis 2002). The estimated prevalence of venous leg ulcers ranges between 0.6 and 1.9 per cent in the adult population of the UK, USA, and Europe (Briggs 2003). Epidemiological studies estimate that venous leg ulcers affect 1 million people in the USA, accounting for 70 to 80 per cent of all ulcers of the lower limbs (De Araujo 2003). A cohort study calculated that direct medical care costs attributable to a VLU averaged $2400 (in 1997 value US dollars) per month (Olin 1999). Up to 10 per cent of the population in Europe and North America has valvular incompetence, with 0.2 per cent developing venous ulceration. Venous ulceration represents the most prevalent form of difficult‐to‐heal wounds, and treating these problematic wounds requires significant healthcare resources. Recent data from Germany revealed that the mean total cost per year for a patient with chronic venous leg ulceration was EUR 9569, of which 92% was estimated to be direct costs (non drug treatment, inpatients costs and outpatient care) and 8% indirect costs (inability to work) (Purwins 2010).
The physiopathology of venous ulcers starts as a macrovascular problem due to valve incompetence. Aetiological (causative) factors such as venous thrombosis could cause valve insufficiency that results in venous stasis and reflux, which are the predominant factors in chronic venous insufficiency (Raju 2010). In the normal venous system, pressure decreases during exercise as a result of the action of the muscles pumping the blood vessels. In a system where the valves are incompetent, the venous pressure remains high (Grey 2006). Sustained venous hypertension will ultimately lead to microcirculatory dysfunction and cause alterations in skin perfusion, which can then lead to ulceration.
Alterations in the microcirculation are described as a decrease in the capillary density, which can also be reduced by dilation, tortuosity and convolution of the remaining capillaries (Howlader 2003; Incandela 2001; Junger 2000). This impacts the nutrition and clearance of by‐products in the tissue, leading to skin changes observed in the form of swelling, eczema, hyperpigmentation (skin coloration), lipodermatosclerosis (hard, tight skin) and, ultimately, tissue ulceration. Part of the pathway leading to tissue damage and ulceration is due to leucocyte interaction with endothelial cell‐surface binding molecules that facilitate their migration into tissue. Once leucocytes are in the tissue they become active and produce a series of molecules that lead to tissue damage (Smith 2006; Wollina 2006).
The diagnosis of venous ulceration is usually based on clinical examination. Additional tests such as colour duplex ultrasonography (measurement of blood flow in the veins and arteries of the leg), plethysmography (measures variations in the size or volume of a limb), venography ( x‐ray test that provides an image of the leg veins) and ankle brachial pressure index (ABPI‐ provides the ratio of systolic blood pressure at the ankle to that in the arm) (Cochrane Wounds Group Glossary; The Free Medical Dictionary) may be helpful if the diagnosis is unclear (Collins 2010; Robson 2006). All patient that present an ulcer should be screened for peripheral arterial disease (PAD) by Doppler measurement of ABPI. An index equal or lower than 0.9 is the diagnosis criterion for peripheral arterial disease (Rooke 2011); however, ABPI measurement greater than 0.8 is generally used to exclude peripheral arterial disease as the cause of a leg ulceration, leaving the most likely diagnosis venous ulceration (RCN 2006). Venous ulcers are generally irregular and shallow, and often occur over bony prominences, particularly in the gaiter area (over the medial malleolus). Skin alterations surrounding the ulcer such as hyperpigmentation, lipodermatosclerosis and fibrosis are usually present (Collins 2010). Frequent symptoms for venous ulceration include pain, odour and drainage from the wound (Valencia 2001). Arterial ulcers can be distinguished from venous ulcers because the former typically have round and well‐demarcated borders and the presence of necrotic tissue in the wound bed. Physical symptoms of arterial leg ulcers include: loss of leg hair; atrophic skin (wasting of skin); cold feet; absence of, or decrease in, arterial pulses; and symptoms such as intermittent claudication (pain on walking that goes away with rest). Neuropathic ulcers are more common in, but are not limited to, patients with diabetes mellitus. These differ from venous leg ulcers in having defined borders, they are usually deeper than venous ulcers and are associated with foot numbness, burning and paraesthesia (sensation of "pins and needles") (Valencia 2001).
The standard treatment for venous leg ulcer is compression therapy. It has been shown that compression increases the healing rates of venous leg ulcers compared with no compression (O'Meara 2009). This treatment is often applied with other interventions, such as debridement (Tang 2012), topical agents (Briggs 2012; Robson 2006), physical agents (Aziz 2011; Cullum 2010; Flemming 1999), dressings (Palfreyman 2007).
Description of the intervention
The optimal wound healing environment is one where the wound is kept covered and moist, rather than left open to the air. Standard treatment for venous leg ulcers should include therapeutic compression (may be applied by bandages) in addition to a dressing, except when otherwise indicated (O'Meara 2009; Robson 2006). Dressings are applied underneath bandages or stockings with the aim of protecting the wound and providing a moist environment to aid healing. Nowadays, several types of dressing seek to achieve a moist environment, the aim of which is to promote re‐epithelialisation of the wound, providing comfort, controlling exudate and helping to prevent bandages and stockings adhering to the wound bed. The ideal conditions required for wound healing in terms of dressing application have been explained as follows: maintenance of a moist wound environment without risk of maceration; avoidance of toxic chemicals, particles or fibres in the dressing fabric; minimisation of number of dressing changes; and maintenance of an optimum pH level (NPF 2011).
The primary intervention of interest in this review is hydrogel dressings used in the treatment of venous leg ulcers. The aim of hydrogel dressings is to promote pain relief, comfort and also to favour autolytic debridement (natural enzymic removal of dead tissue) (Mandelbaum 2003). The dressings consist of a starch polymer and up to 96% water. They are supplied in two forms; flat sheets (e.g. ActiFormCool (Activa)), or amorphous hydrogel (e.g. Aquaflo (Covidien)). Some of the hydrogels are associated with alginates (e.g. Nu‐Gel, Purilon Gel) (NPF 2011), which have a higher capacity for absorption and chemical debridement (Mandelbaum 2003). The advantages of hydrogel dressings are that they can be used during several phases of healing, and may promote relief and comfort, however, they do require a secondary covering. Hydrogel dressings also may reduce pain in painful wounds (Bradbury 2008). The interval between dressing changes varies according to the type of hydrogel dressing: amorphous hydrogel may require daily changes (Mandelbaum 2003), while hydrogel sheet dressings may last for up to seven days.
There is a broad choice of dressings available to treat wounds such as venous leg ulcers. For ease of comparison this review has classed dressings into groups according to the broad categories of the Nurse Prescribers' Formulary 2011 (NPF 2011), that is, basic, advanced, anti‐microbial and specialist wound dressings (see Appendix 2). Dressing names, manufacturers and distributors may vary between countries.
How the intervention might work
The most appropriate dressing for wound management depends not only upon the type of wound but also on the stage of the healing process. Dressings for moist wound healing need to ensure that the wound remains moist, and free of clinical infection and excessive slough (dead tissue), but avoid peri‐wound maceration (NPF 2011).
Hydrogel dressings, classified as an advanced wound dressing by the Nurse Prescribers' Formulary, are designed to control the environment for wound healing by donating fluids to dry sloughy wounds, and by facilitating autolytic debridement of necrotic tissue. Some hydrogel dressings also have the ability to absorb limited amounts of exudate or rehydrate a wound, depending on the wound's moisture levels (NPF 2011).
Why it is important to do this review
Chronic venous ulcer healing is a complex clinical situation that causes considerable economic impact, and adversely affects the quality of life for those who suffer from them.
Hydrogel dressings can be used to deslough wounds by promoting autolytic debridement through moisture to re‐hydrate, soften and liquefy non‐viable tissue present on the wound surface. There is no current up‐to‐date evidence to inform clinicians of the effects of hydrogel dressings in treating venous leg ulcers (Palfreyman 2007). The effect of hydrogel dressings compared with other dressings and conventional methods of care for venous ulcers needs to be established.
Objectives
To assess the effects of hydrogel wound dressings for healing venous leg ulcers in people in any care setting.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs), either published or unpublished, that have evaluated the effects of any type of hydrogel wound dressing in the treatment of venous leg ulcers irrespective of publication status or language will be included. Trials reported in abstract form only will be eligible for inclusion, provided adequate information is either presented in the abstract or available from the trial author. Studies using quasi‐randomisation will be excluded.
Types of participants
We will include people of any age in any care setting with a diagnosed venous leg ulcer determined either by clinical evaluation, or complementary laboratory tests (e.g. duplex ultrasonography, plethysmography and venography), or both (Collins 2010), using the definition of a positive diagnosis given by the authors. Trials that include people with wounds of other aetiology (e.g. pressure ulcers), or trials of mixed populations (venous ulcers along with arterial or diabetic ulcers) will be excluded, unless the results for the subgroup of people with venous leg ulcers are reported separately or if the majority of participants (≥ 75% in each arm) have leg ulcers of venous aetiology. The review authors will attempt to contact trial authors to obtain the relevant data, if data from subgroups of people with venous leg ulcers are not reported separately. Studies of people with infected wounds will not be included, because hydrogel dressings are not indicated (prescribed) for this type of wound.Trials evaluating skin grafting are covered elsewhere and will be excluded from this review (Jones 2007).
Types of interventions
The intervention will be hydrogel dressings used as a treatment for venous leg ulcers. Comparators will be any other dressing, no dressing or another hydrogel dressing. For ease of comparison we will categorise dressings according to the Nurse Prescribers' Formulary (NPF 2011). We will use generic names where possible, also providing trade names and manufacturers where these are available. It is important to note, however, that manufacturers and distributors of dressings may vary from country to country, and dressing names may also differ.We will not include trials evaluating hydrogel dressings impregnated with antimicrobial, antiseptic or analgesic agents as these interventions are evaluated in other Cochrane reviews (Briggs 2012; O’Meara 2010). Trials that use larval therapy will be excluded.
We will include any RCT in which the presence or absence of a hydrogel dressing is the only systematic difference between treatment groups; and in which a hydrogel dressing is compared with other wound dressings, non‐dressing treatments (for example, topical applications) or another hydrogel dressing. We will include RCTs of hydrogel dressings, irrespective of whether compression therapy is reported as a concurrent therapy.
Types of outcome measures
Primary outcomes
1. Complete wound healing measured by the number of ulcers completely healed within the duration of the trial.
2. Incidence of wound infection, using diagnosis of infection as described in individual trials.
Secondary outcomes
1. Changes in ulcer size measured by reduction in original wound area within the duration of the trial expressed as absolute (e.g. surface area changes in cm2 since baseline) or relative (e.g. percentage change in area relative to baseline) changes.
2. Time to ulcer healing
3. Recurrence of ulcer.
4. Health‐related quality of life (measured using a standardised generic questionnaire such as EQ, SF‐36 , SF‐12 or SF‐6 (http://www.sf‐36.org/) or disease‐specific questionnaire). We will not include ad‐hoc measures of quality of life that are likely to be un validated and will not be common to multiple trials.
5. Pain (e.g. at dressing change, between dressing changes, or over the course of treatment) will be included only if measured by reliable and validated instruments such as surveys, questionnaires, data capture process or visual analogue scale)
6. Costs (including measurements of resource use, such as number of dressing changes, nurse time or health professional time costs, or both, if reported by the authors).
Search methods for identification of studies
Electronic searches
We will search the following electronic databases to identify reports of relevant randomised clinical trials:
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The Cochrane Wounds Group Specialised Register;
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The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library) (Latest issue);
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Ovid MEDLINE (1948 to present);
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Ovid EMBASE (1974 to present);
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EBSCO CINAHL (1982 to present)
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) using the following MESH headings and keywords:
#1 MeSH descriptor Leg Ulcer explode all trees
#2 (varicose NEXT ulcer*) or (venous NEXT ulcer*) or (leg NEXT ulcer*) or (stasis NEXT ulcer*) or (crural NEXT ulcer*) or "ulcus cruris"
#3 (#1 OR #2)
#4 MeSH descriptor Hydrogel explode all trees
#5 hydrogel* or intrasite or curafil or dermagran or duoderm or hydrosorb or hypergel or normlgel or nu‐gel or nugel or purilon or "suprasorb gel" or hypligel or elasto‐gel or elastogel or tegagel or aquaform or granugel or curasol or curatec
#6 (#4 OR #5)
#7 (#3 AND #6)
We will adapt this strategy to search Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL. The Ovid MEDLINE search will be combined with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity‐ and precision‐maximizing version (2008 revision) (Lefebvre 2011). We will combine the EMBASE and CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2011).
We will also search the following Trial Search Registries, as sources of ongoing or, as yet, unpublished trials:
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The Current Controlled Trials http://www.controlled‐trials.com/;
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ClinicalTrials.gov http://www.clinicaltrials.gov/; and
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WHO International Clinical Trials Registry Platform (ICTRP) http://www.who.int/ictrp/en/.
Searching other resources
The bibliographies of all retrieved and relevant publications identified by the above strategies will be searched for further studies. We will attempt to contact researchers to obtain additional information whenever necessary, along with manufacturers to request information about ongoing or as yet unpublished trials. We will attempt to obtain registered trial protocols for all published trial reports identified for inclusion.
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 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):
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Country of origin.
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Study authors and year of publication.
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Care setting.
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Type of ulcer.
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Unit of investigation (per patient) ‐ single ulcer or foot or patient, or multiple ulcers on the same patient.
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Number of participants randomised to each treatment group.
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Eligibility criteria and key baseline participant data (gender, age, ethnicity, baseline ulcer area, ulcer duration, prevalence of co‐morbidities such as diabetes).
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Details of the dressing/treatment regimen received by each group.
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Details of any co‐interventions.
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Primary and secondary outcome(s) (with definitions).
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Outcome data for primary and secondary outcomes (by group).
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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).
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Duration of treatment.
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Duration of follow‐up.
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Number of withdrawals (by group with reasons).
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Statistical methods used for data analysis.
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Risk of bias criteria (sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting).
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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 participants and care providers; blinding of outcome assessors, incomplete outcome data, selective outcome reporting and other issues which may potentially bias the study (Appendix 3). For this review, we will consider other risk of bias issues as follows: comparability of treatment groups in relation to baseline ulcer surface area; choice of analysis where multiple ulcers on the same individuals(s) are studied; and choice of analysis in cluster randomised trials. We will complete a ‘Risk of bias’ table for each eligible study and each study will be classified as being at overall high, low or unclear risk of bias, according to the methods described in chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). Blinding and completeness of outcome data will be assessed for each outcome separately. We will discuss any disagreement amongst all authors to achieve a consensus. We will present the findings using a ‘Risk of bias’ summary figure, which presents all of the judgments in a cross‐tabulation of study by risk of bias domain. This display of internal validity will indicate the weight the reader may give the results of each study. We will classify trials as being at high risk of bias overall if they are rated high for any of three key criteria, namely, allocation concealment, blinding of outcome assessors and completeness of outcome data. For trials that have at least one of the three key domains rated as 'unclear' but none of these judged at high risk of bias, the trial will be classified as being at overall unclear risk of bias. Trials can only be classified as being at low risk of bias overall if all three key domains are rated as low risk individually.
Measures of treatment effect
Data analysis will be performed according to the guidelines of the Cochrane Collaboration. One review author will enter quantitative data into Review Manager 5.2, another will check it, and the data will be analysed using the Cochrane Collaboration's associated software. We will present the outcome results for each trial with 95% confidence intervals (CI). We will report estimates for dichotomous outcomes (e.g. ulcers healed during time period, number of infected ulcers) as risk ratios (RR). Continuous outcomes (such as absolute or relative changes in ulcer area) will be expressed as mean differences (MD) and overall effect size (with 95% CI calculated). For time to event data, we plan to plot estimates of hazard ratios with associated 95% CIs where available from trial reports.
Unit of analysis issues
We will treat the number of ulcers as the unit of analysis in this review; however, we will record whether outcomes in relation to an ulcer were measured on a per‐participant or per‐ulcer basis, and, in studies where multiple ulcers on a person were treated as being independent, we will record that as part of our risk of bias assessment. The authors will include data from cluster‐randomised trials if the information is available. For cluster‐randomised trials, we 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 16.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011d).
Dealing with missing data
The authors will contact the trial investigators in cases of incomplete or missing data. Where trials report complete healing outcomes for only those participants who complete the trial (i.e. participants withdrawing and lost to follow‐up are excluded from the analysis), we will treat the participants who are not included in the analysis as if their wound did not heal. Where trials report results for participants who complete the trial without specifying the numbers initially randomised per group, we will present only complete case data. For other outcomes the same analysis will be applied.
Assessment of heterogeneity
We will consider clinical heterogeneity (that is where trials appear similar in terms of participant characteristics, intervention type and duration and outcome type) and statistical heterogeneity. We will assess statistical heterogeneity using the Chi² test (a significance level of P < 0.10 is considered to indicate significant heterogeneity) in conjunction with the I² statistic (Higgins 2003). The I² statistic estimates the percentage of total variation across trials due to heterogeneity rather than variation due to chance (Higgins 2003). Heterogeneity will be categorized as follow: I² values ≤ 40% to indicate a low level of heterogeneity and ≥75% to represent very high heterogeneity (Deeks 2011).
Assessment of reporting biases
If sufficient studies (i.e. more than ten) are identified, an attempt will be made to check for publication bias using a funnel plot, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011e). If asymmetry is present we will explore possible causes including publication bias, poor methodological quality and true heterogeneity.
Data synthesis
We will present a narrative overview of the studies reviewed and the authors will use Revman 5.2 to combine outcomes when it is possible (Revman 2012). Included trials will be grouped according to the comparator intervention which may include no dressing, alternative hydrogel dressings or other types of dressings. The decision to include studies in a meta‐analysis will depend on the availability of treatment effect data and assessment of heterogeneity.For comparisons where there is no apparent clinical heterogeneity and the I2 value is ≤ 40%, we will apply a fixed‐effect model. Where there is no apparent clinical heterogeneity and the I2 value is > 40%, we will apply a random‐effects model. However, we will not pool data where heterogeneity is very high (I2 values ≥ 75%).
For the dichotomous outcomes we will present the summary estimate as a risk ratio (RR) with 95% confidence intervals (CI). Where continuous outcomes are measured in the same way across trials, we will present a summary mean difference (MD) with 95% CI. We will present a standardised mean difference (SMD) where trials measure the same outcome using different methods. For time to event data, we plan to plot, and if feasible pool, estimates of hazard ratio and 95% CI as presented in the trial reports using the generic inverse variance method in RevMan 5.2.
The authors will grade the quality of the evidence for each primary outcome using four levels of quality: high, moderate, low and very low (Schünemann 2011a). We plan to record the quality in a “Summary of findings” table using the GRADE system, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011b), for the first primary outcome. Quality will be based in the following factors:
1. Limitations in the design and implementation of available studies suggesting high likelihood of bias.
2. Indirectness of evidence (indirect population, intervention, control, outcomes).
3. Unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses).
4. Imprecision of results (wide confidence intervals).
5. High probability of publication bias.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be carried out according to the presence or absence of compression therapy independent of type (elastic or inelastic) or level (moderate or high) compression. If is not clearly indicated in the trial report the presence or absence of compression therapy, we will not include these trials in this subgroup analysis.
Sensitivity analysis
Where data are available, sensitivity analyses will be performed for each comparison that has a meta‐analysis, according to the overall risk of bias of each included RCT. RCTs with overall high or unclear risk of bias will be excluded and the difference between estimates of treatment effect from this analysis and the main analysis considered.
