Evidence review. Vacuum Assisted Closure therapy CEP 08017

Transcription

1 Evidence review Vacuum Assisted Closure therapy CEP June 2008

2 Contents 2 Summary... 4 Introduction... 6 Vacuum Assisted Closure therapy...6 Physiology of wound healing...7 Ideal wound healing environment...8 Mechanisms of healing...8 Use of VAC therapy...9 Clinical guidance...10 Application of the VAC device...10 Cycle type, pressure level and dressing change guidelines...12 Contra-indications...12 Adverse effects...13 Wound specific guidelines...13 Methods Literature search strategy...16 Selection criteria...16 Quality assessment...18 Evidence review Diabetic wounds...19 Mixed aetiology ulceration wounds...26 Pressure ulcers...32 Infected sternal wounds...39 Traumatic wounds...43 Wounds requiring skin grafting...47 Unspecified chronic wounds...58 Unspecified acute wounds...69 Unspecified chronic and acute wounds...72 Conclusions... 80

3 Contents 3 Acknowledgements References Appendix 1: Glossary Appendix 2: Search strategy Appendix 3: Supplier and product information Author and report information

4 Summary 4 The product The Vacuum Assisted Closure (VAC) therapy device, manufactured by KCI Medical. Field of use Difficult-to-treat wounds are costly and their care is time-consuming for patients and carers. Innovations which aim to improve healing rates therefore have the potential to benefit health providers, patients and carers alike. VAC therapy involves the application of topical negative pressure to accelerate wound healing and was originally developed as an adjunct to wound care. Whilst the therapy can be used in the treatment of acute wounds such as burns, trauma and skin grafts, it is commonly used within the NHS for complex and non-healing wounds such as pressure sores. VAC therapy uses a combination of vacuum suction and specialised dressings to facilitate wound drainage and influence the growth of surface tissues. Published literature claims that this therapy leads to faster healing rates, therefore reducing the length of hospital stays and associated treatment and labour costs. National guidance There are currently no national guidelines for VAC therapy, although a number of experts in the field have published general and wound-specific guidelines [1-8]. The manufacturer, KCI Medical has developed guidelines which are specific to its device [3] and individual trusts have developed their own guidelines based upon the local population. Evidence reviewed Whilst there are a number of topical negative pressure devices available to the UK market (see appendix 3), the VAC therapy device was, until recently, the only device available for purchase. As a result, all high quality published research evidence relates to this system. Thus, the focus of this report is to assess the clinical and cost effectiveness of the VAC therapy device. Level I, II, and III clinical evidence (where a comparator was used) and all economic evidence was reviewed. The majority of studies reviewed indicated that clinical and economic benefits were associated with the use of VAC therapy. However, most studies had significant methodological limitations, for example low study numbers and inadequate methods of randomisation.

5 Summary 5 CEP s verdict Significant potential Due to the methodological limitations of the studies reviewed it is not possible to draw firm conclusions. However, the evidence suggests that VAC therapy is at least as effective as the treatments it was compared with. The majority of evidence does indicate a benefit in comparison with standard wound care e.g. saline moist gauze, however the benefit is less clear when compared with advanced wound care e.g. hydrocolloids, alginates, in the treatment of chronic and acute wounds. CEP recommends that a high quality independent randomised controlled trial is conducted addressing the methodological limitations of the studies highlighted in this review. CEP also recommends that an independent economic evaluation is undertaken, to include a sensitivity analysis. Further examination of the effectiveness of VAC therapy in the treatment of acute wounds, and costs associated with the treatment of wounds in a community setting, is also required.

6 Introduction 6 Difficult-to-treat wounds are costly in terms of health service resources in both the hospital and community settings and their care is time-consuming for patients and carers. For example, it was estimated in 2004 that the costs to the NHS for treating pressure ulcers was approximately billion [9]. Innovations which aim to improve healing rates therefore offer potential benefit to health providers, patients and carers. Vacuum Assisted Closure therapy Vacuum Assisted Closure (VAC) therapy, involving the application of controlled negative pressure to wounds, is also referred to as topical negative pressure (TNP) therapy, sub-atmospheric pressure (SAP) therapy, and negative pressure wound therapy (NPWT). Negative pressure, as a method of management for difficult to heal wounds, was initially explored in 1970 [10], with the first wound drainage system being introduced in 1989 [11]. The use of negative pressure to heal wounds however, is more commonly associated with the work of Argenta and Morykwas in 1997 [12]. VAC therapy was designed with the aim of improving healing, decreasing morbidity, and decreasing the cost and length of hospital stay for patients with chronic, nonhealing wounds [12]. VAC therapy is now used in the management of both acute and chronic wounds. It is claimed that VAC therapy aids healing by: 1. maintaining a moist wound environment; 2. increasing local blood flow; 3. removing wound exudates; 4. promoting granulation tissue formation; 5. reducing infection; 6. exerting mechanical pressures [13]. Until recently, TNP was delivered solely by the VAC device which KCI Medical has supplied to the United States (US) since 1996 and to the United Kingdom (UK) since However, competing products are now available and this might affect future market prices. TNP is currently delivered by several devices. Appendix 3 provides supplier and product information. In terms of costs, it is claimed that TNP therapy can reduce hospital stay due to faster healing rates and reduced labour costs through a lower frequency of dressing changes. However, additional costs, for example the costs of equipment and consumables, must also be considered [12, 14, 15].

7 Introduction 7 Physiology of wound healing VAC therapy can be used for both acute and chronic wounds. Acute wounds are wounds that heal successfully within an expected timeframe [14]. Acute wound healing involves four stages. The first stage, referred to as the haemostasis stage, involves the formation of clots and the release of growth factors. The second stage, the inflammatory phase, involves the removal of unwanted cells and the start of cell repair. The third stage, proliferation, is characterised by angiogenesis (new blood vessel growth), collagen deposition and the formation of granulation tissue. The final stage, remodelling, involves contraction of the wound [16]. If any one of these phases becomes interrupted then a delay in healing will occur. This is when wound healing becomes abnormal and the wound is referred to as chronic [16]. Condition specific factors, for example diabetic neuropathy, may also prevent healing. When a wound becomes chronic, reconstruction of the wound may be necessary. The reconstructive ladder (see Figure 1) identifies the procedures of wound reconstruction and their complexity (with each step down the ladder indicating increased complexity). Figure 1: The reconstructive ladder Adapted from: Banwell P and Teot L (2006) [17]

8 Introduction 8 Ideal wound healing environment Wound healing treatments aim to provide an environment which allows for healing or surgical intervention to cover and close the wound [14]. The ideal intrinsic environment is moist, without being wet, non-infected, has a good supply of blood and a correct balance of inflammatory mediators [18]. To date there is not a dressing or device that can address and accelerate all aspects of healing for all types of wounds [14]. Mechanisms of healing VAC therapy promotes healing in several ways. Firstly, the foam dressing, in combination with an adhesive drape, creates an occlusive dressing [3]. This alone prevents desiccation and increases the rate at which epithelial tissue is developed, therefore aiding healing times. Occlusive dressings, although not totally preventing bacterial colonisation, prevent an increase in infection [19, 20]. Secondly, the suction effect and the mechanical forces generated at the interface of the foam work to decrease interstitial fluid accumulation, control wound exudates, stimulate granulation tissue formation, reverse tissue expansion, decrease bacterial colonisation and increase blood flow and dermal perfusion [17]. Removal of wound fluid and reduction of oedema VAC therapy removes wound exudates, extracellular fluid and reduces oedema [18, 21]. If excess fluid remains around the wound site it can act as both a physical and chemical deterrent to healing [14]. Wound fluid inhibits the proliferation of the keratinocyte, endothelial and extracellular matrix cells, all of which are essential for healing. These cells also contain low levels of glucose, albumin and proteins found in the blood system [22]. Studies have shown that proteases in wound fluid may cause repeated tissue turn over, preventing wound closure [23]. The removal of proteases and cytokines allow for quicker progression through the inflammatory phase of healing which in turn stimulates cellular proliferation allowing granulation to occur [24]. VAC therapy reduces interstitial fluid volume which has the effect of improving vascular density and diffusion distances improve. Tissue pressures are also reduced, increasing blood flow and therefore oxygen and nutrients to the wound site [21]. Formation of granulation tissue Wound closure is promoted through a rapid formation of granulation tissue. TPN treated wounds are reported to experience increased granulation tissue formation when suction from the vacuum directly stimulates increased cell growth [25]. Mechanical stress VAC therapy exerts mechanical stress on the wound which promotes wound closure [26]. VAC therapy claims to produce mechanical forces which directly and indirectly

9 Introduction 9 affect the extracellular matrix. Directly, the mechanical forces lead to a deformation of the extracellular matrix promoting a reduction in the size of the wound [14]. Indirectly, VAC therapy is reported to exert mechanical stress creating a biochemical effect at the cellular level. The biochemical effect is thought to promote keratinocyte growth and protein synthesis, possibly through alterations of integrins [7, 27]. Such effects lead to an increase in cellular reproduction, angiogenesis and granulation tissue formation [26, 28, 29]. Improved flow of blood VAC therapy is reported to aid the increase of blood flow to the wound. At a pressure of 125 mm Hg, blood flow is at its maximum [30]. With optimum blood flow there is improved delivery of oxygen and nutrients to the wound bed [30], as well as the inflammatory mediators essential in reducing bacterial colonisation [13]. Infection prevention The presence of infection leads to a prolonged inflammatory phase, depletes vital immune system proteins, disrupts normal blood clotting, inhibits angiogenesis, disturbs leukocyte function and leads to the creation of brittle granulation tissue [23]. By increasing the delivery of inflammatory mediators, VAC therapy leads to a reduction in the rate of bacterial colonisation within the wound [31]. Increased perfusion Perfusion throughout the wound is essential in ensuring that nutrients and inflammatory mediators, delivered via blood, are received and that oedema is reduced. VAC therapy claims to lead to a decrease in hydrostatic pressure in the capillaries allowing the return of fluid to the wound [13]. Fluid return is essential in the healing of chronic wounds with oedema and patients with poor circulation [13]. Use of VAC therapy VAC therapy was approved for use in the treatment of non healing wounds by the Food and Drug Administration in March In January 2000 this was extended to include chronic, acute, traumatic, subacute wounds, flaps and grafts. VAC therapy can be used as a primary method of closure or as a method of maintaining a wound until reconstructive surgery is possible. As a non invasive procedure, VAC therapy can also be used as an alternative to surgery for patients who make poor surgical candidates (e.g. elderly patients with nutritional deficits or multiple pathologies) [14, 32]. Table 1 details the types of wound for which VAC therapy is suitable.

10 Introduction 10 Table 1: Wounds for which VAC therapy is suitable Wound type/process Acute Chronic Example Trauma (upper/lower limb) Burns Pressure sores Leg ulcers Diabetic ulcers Salvage Wound dehiscence Wound infection Postoperative sternum infections Surgical Skin grafts Flap surgery Wound bed preparation Adapted from: Jones SM et al (2005) [14] Clinical guidance Awareness of wound and patient suitability, contra-indications and potential adverse events is essential when using VAC therapy. The following guidelines produced by KCI Medical refer to the VAC device [3]. Application of the VAC device Application of the VAC device involves cutting a foam dressing to the exact shape and size of the wound cavity, which is then inserted. The foam dressings are available in two forms: the most frequently used are black polyurethane dressings designed to encourage granulation and micro debridement in wound beds; the second type are white polyvinyl alcohol (PVA) dressings which are useful in tunnelled or painful wounds and in securing skin grafts, as they work to prevent in-growth of wound bed tissue [33]. The foam dressings contain pores ranging from μm in diameter. This creates an open cell system which facilitates equal distribution of TNP to the entire wound [13]. Following insertion into the wound cavity, the foam is covered with an adhesive dressing to create a sealed and moist environment. The adhesive drape is vapour-permeable which allows gas exchange and protects the wound base. A small hole is cut into the adhesive dressing and a therapeutic regulated accurate care (TRAC) pad is applied over the hole and a tube is attached. The tube, through a canister, attaches to the VAC device. The VAC device can provide a level of TNP between 25 to 200 mm Hg either continuously or intermittently. Levels of TNP are then transmitted to all surfaces in contact with the foam. The canister allows for effluent from the wound bed to be collected and

11 Introduction 11 monitored. The VAC device is also built with an alarm that sounds if an air leak is present. This prevents excessive airflow over the wound which, if left, can cause desiccation of the wound bed, necrosis of tissue and delayed healing [34]. Table 2 provides further independent guidelines for the application and use of the VAC device. Published clinical guidelines are designed to be used in conjunction with the operation manual of the VAC device produced by KCI Medical. Table 2: Guidelines for application of the VAC device Guideline Wound cleansing Removal of devitalised tissue Achieve haemostasis Remove surrounding hair Prepare periwound skin Select an appropriate dressing Ensure the foam fits the cavity Ensure the drape is an adequate size to cover the wound and ensure an airtight seal Place the foam into the wound cavity Position tubing Apply tubing to canister Description Prior to treatment the wound should be cleansed. The Agency for Healthcare Research and Quality recommends cleansing with saline solution under a pressure of 4-15 pounds per square inch. This should be undertaken at each dressing change. Wounds must be cleared of devitalised tissue, including debridement of bone, if osteomyelitis is present. If osteomyelitis is present, then antibiotics should be given to treat the underlying infection. The patient should be haemodynamically stable prior to therapy. Any active bleeding should be controlled. Hair surrounding the wound should be removed to ensure that an adequate seal can be achieved and that unnecessary pain is not caused during dressing changes. The skin should be protected from the adhesive drape using a skin protectant. In order to achieve a seal the skin should be dry, a degreasing medical cleansing agent can be used if the skin is moist. The appropriate foam dressing should be selected. The clinician should take into consideration that the black polyurethane sponge has larger pores and is thought to be more effective in stimulating granulation tissue and wound contraction. The white polyvinylalcohol dressing has smaller pores, is denser and can be used when granulation tissue growth needs to be restricted. However, due to higher density, the TNP needs to be higher when using polyvinylalcohol dressings. Foam should be cut to fit the size and shape of the wound cavity. Multiple pieces of foam can be used if the wound cavity is large, however they must be in contact with the other pieces of foam to ensure uniform compression. The drape should cover the area around the wound leaving enough space to secure the foam and maintain an airtight seal. Fragile periwound skin can be protected with a skin barrier e.g. hydrocolloid, and the drape can be secured to the barrier. If irritation occurs with removal of the drape then the drape can be cut around the foam and the foam removed, the wound cleansed and the foam replaced without removing the whole drape. A new drape can then be placed over the foam. The foam should be placed into the cavity covering the entire wound. The sponge should not be placed directly onto organs or blood vessels as the TNP can cause damage to tissue in body cavities. Instead, a non-adherent and non-toxic barrier should be used to provide protection from the sponge or available muscle or fascia can be moved to cover the exposed structures. The tubing should be positioned away from bony prominences, organs and blood vessels as contact can lead to tissue damage. The tubing can be positioned either on top of the foam or inside the foam. Finally, tubing should be attached to the canister placed in the unit and the appropriate pressure and cycle programmed into the unit. Dressing removal When changing dressings the drape should be lifted gently to avoid damage to periwound skin; a topical adhesive remover can aid removal. Saline solution should be used to loosen the sponge prior to removal. This will decrease the trauma to fragile capillaries in the wound bed and decrease pain if granulation tissue has grown into the sponge. Adapted from: Mendez-Eastman (2001) [4]

12 Introduction 12 Cycle type, pressure level and dressing change guidelines The cycle of therapy (e.g. intermittent or continuous) and the degree of TNP is dependent on the wound type. Table 3 provides details of the recommended cycle, pressure and frequency of dressing changes for a number of wound types. Guidelines should be used in conjunction with the manufacturer s instructions. Table 3: VAC therapy pressure, cycle and dressing change guidelines Wound type Initial cycle Subsequent cycles Acute/traumatic wounds Chronic wounds Pressure ulcers Diabetic foot ulcers Surgical wounds dehiscence Continuous for first 48 hrs Continuous for first 48 hrs Continuous for first 48 hrs Continuous for first 48 hrs Continuous for first 48 hrs Intermittent (5 min on/ 2 min off) Intermittent (5 min on/ 2 min off) Intermittent (5 min on/ 2 min off) Intermittent (5 min on/ 2 min off) Intermittent (5 min on/ 2 min off) Target pressurepolyurethane 125mmHg mmHg 125mmHg mmHg 125mmHg Target pressurepolyvinyl alcohol mmHg; titrate up for more drainage mmHg; titrate up for more drainage mmHg; titrate up for more drainage mmHg; titrate up for more drainage mmHg; tritate up for more drainage Abdominal wounds Continuous Continuous 125mmHg 150mmHg; titrate up for more drainage Meshed graft Continuous Continuous mmHg mmHg; titrate up for more drainage Fresh flap Continuous Continuous mmHg mmHg; titrate up for more drainage Adapted from: KCI (2006) [3] Dressing change interval Every 48 hrs (every 12 hrs with untreated infection) Every 48 hrs (every 12 hrs with untreated infection) Every 48 hrs (every 12 hrs with untreated infection) Every 48 hrs (every 12 hrs with untreated infection) Every 48 hrs (every 12 hrs with untreated infection) Every 48 hrs (every 12 hrs with untreated infection) None; remove dressings after 4-5 days when using either foam Every 72 hrs postoperatively. If complications occur, every 48 hrs (every hrs with untreated infection) Contra-indications VAC therapy should not be used on wounds with untreated osteomyelitis, grossly infected wounds, when necrotic tissue is present or when there is an unspecified disorder of the blood [13, 35]. VAC therapy should also not be used on wounds with malignancy present because the therapy increases wound bed blood flow and vascularisation [36]. Dressings should not be placed over any exposed vessels or organs and VAC therapy should be used with caution in patients with active bleeding, difficult wound haemostasis and in patients taking anticoagulants [37].

13 Introduction 13 Adverse effects The most common adverse effect of VAC therapy is pain and discomfort. This can occur when high pressure is being exerted and when there is excessive growth of tissue into the foam dressing, which when removed can cause bleeding. This is more likely to happen when dressings have been in place for more than 48 hours [38, 39]. However, it is reported that sensitivity to treatment will reduce over time; pain can be managed with analgesics and by decreasing the pressure. Prior to dressing changes, instilling saline or topical anaesthetic directly into the sponge or tubing can also decrease the pain associated with dressing changes [3]. In addition to pain, it is also possible for tissue to become eroded if the evacuation tube is positioned directly over bone or if the patient lies on the tube [3]. The adverse effects of VAC therapy can often be managed or avoided. However, if there is no healing response after two successive dressings, if there is frank pus in the canister or evident in the dressing, or if excessive bleeding occurs under the dressing, VAC therapy should be discontinued [3]. Wound specific guidelines Diabetic foot wounds Recent clinical guidelines state that when other forms of treatment are ineffective VAC therapy should be considered [5]. If VAC therapy is undertaken, the wound should be debrided of all non-viable tissue prior to dressing application. The use of a dressing between the foam and the wound is not advised as it may impact the mechanical effects of the therapy. The rationale for using such a dressing is often to reduce pain, however if the diabetic foot wound is neuropathic in nature this is not required. The standard regime for diabetic foot wounds is continuous pressure of 125mmHg. The pressure level however, can be adjusted according to wound response and patient comfort. Dressings should be changed every 48 hours or earlier if infection is present [1]. Clinicians need to be aware that if diabetic foot wounds are due to neuropathy, patients may be unable to identify skin breakdown. The area in which tissue has died needs to be managed appropriately to reduce the risk of infection or amputation. Weight placed on the VAC tubing can cause damage to the surrounding tissue. Careful consideration should then be given to patient mobilisation and the use of offloading devices [1]. Pressure ulcers Pressure ulcers are graded according to the layers of tissues involved in the wound; stage I involves the fewest layers and stage IV the most. Stage III and stage IV involve full thickness skin loss [2]. Clinical guidelines suggest that VAC therapy should be considered for stage III and stage IV pressure ulcers that fail to heal with

14 Introduction 14 conventional therapy [8]. The wound should be large enough to ensure there is good contact between the wound bed and the foam. A consensus panel agreed that when using VAC therapy for the treatment of pressure ulcers, the larger the wound size the more beneficial the therapy [2]. Whilst the frequency of dressing changes is largely a decision made by the treating clinician, manufacturers suggest changes every 48 hours or sooner if infection is present [3]. However, guidelines produced by experts state that dressing changes of pressure ulcers can be extended up to every 72 hours [2]. More frequent dressing changes should be considered if the wound is grossly infected or if there is necrotising fasciitis. The optimum pressure for pressure ulcers is 125 mm Hg for polyurethane foam and mm Hg for PVA dressings. However, if pain occurs then the pressure can be reduced in 25 mm Hg increments to a minimum of 75 mm Hg. The mode of therapy should be continuous for the first 48 hours and intermittent thereafter. Consideration should be given to the type of foam to be used. Polyurethane foam is best used for stimulating granulation tissue whilst PVA dressings are best for controlling granulation tissue growth into the foam and for tunnelled areas. Use of the polyurethane foam may cause pain, in which case clinicians may prefer to use PVA foam. If pressure wounds fail to respond to treatment in two to four weeks then clinicians need to reconsider the suitability of VAC therapy [2]. Sternal wounds A consensus panel noted that the duration of therapy for sternal wounds is unclear and should be determined by clinical judgement. The physician should regularly monitor the wound and consider alternative therapies if the wound fails to respond [27]. Due to discomfort associated with intermittent therapy, it is suggested that a continuous mode of therapy is used and that VAC therapy is used only as a bridge to surgical closure. Prior to application, wounds should be debrided. Foam dressings should be cut and placed directly to superficial wounds (type 1 - fascia intact). However, for type II and type III wounds a purpose made abdominal dressing should be used in combination with polyurethane foam [40]. A non-adherent dressing that is fluid permeable should be placed over vital structures. Particular care should be taken when placing dressings close to blood vessels or organs, which should be protected. Caution should be exercised when applying VAC therapy close to the heart, due to the risk of inducing haemodynamic changes. Wounds with enteric fistula require special precautions in order to ensure optimum treatment. VAC therapy should be discontinued if excessive bleeding occurs, if there is wound sepsis, unresolved necrotising fasciitis or if VAC therapy leads to haemodynamic changes [27]. Skin grafting Guidelines from 2006 state that VAC therapy may be useful prior to, or after, a skin graft/flap application [3]. VAC therapy should begin as soon as possible after graft placement. In order to provide a constant bolster, a continuous mode of therapy

15 Introduction 15 should be used. Target pressure is mm Hg with polyurethane foam and 125 mm Hg with PVA foam. In areas that are not subject to shearing forces, a pressure of 75 mm Hg can be used if the patients experience pain with higher pressures [3]. In areas where shearing forces are present, or if the area is highly contoured, then the higher pressure of 125 mm Hg can be used. If polyurethane foam is being used, a wide meshed non adherent dressing should be placed over the graft, leaving a 10 mm border. The polyurethane foam should then be cut to the same size and placed over the top. If PVA foam is being used, a non adherent dressing is not required. The foam should be cut and placed over the graft, again leaving a 10 mm border [3].

16 Methods 16 Literature search strategy The search strategy was designed in consultation with a senior healthcare librarian. An English language literature search was conducted using the following databases: The Cochrane Library, Centre for Reviews and Dissemination (CRD) databases, Embase, Medline, Cumulative Index to Nursing and Allied Health (CINAHL), British Nursing Index (BNI), and PubMed. The reference lists of articles which met the inclusion criteria were also hand searched. The above databases were searched using a combination of key words and thesaurus headings extrapolated from a previously developed PICO table [41-43] and were adapted for each database (Appendix 2). Search terms included vacuum (MeSH) OR suction (MeSH) OR negative pressure (MeSH) OR vacuum assisted closure OR topical negative pressure OR negative pressure wound therapy OR subatmospheric pressure dressing OR vacuum sealing technique OR VAC therapy OR subatmospheric pressure therapy AND wounds and injuries (MeSH) OR diabetic foot (MeSH) OR diabetes complications OR wound infection (MeSH) OR skin ulcer (MeSH) AND wound healing (MeSH) OR occlusive dressing (MeSH) OR bandages (MeSH) OR debridement (MeSH). Selection criteria Outcome measures The outcome measures used to examine VAC therapy were: Primary outcomes - wound closure/healing rates, skin graft take rates; Secondary outcomes - hospitalisation rates, length of hospital stay, adverse events, contraindications, safety, pain, quality of life, surgery avoidance. A subset of outcomes was used to examine the economic effectiveness of VAC therapy. Inclusion criteria Studies were included if they examined the primary outcome measures, included human participants, were available in the English language and published between 1993 and May Studies which were either a meta analysis, systematic review, randomised controlled trial, non-randomised controlled trial, or a comparative study were included. Level I, II and III evidence, as determined by the hierarchy of evidence, were selected (Table 4). Case series studies were excluded due to the lack of a comparator group. Reviews were also included if they demonstrated a systematic, reproducible methodology, as determined by the reviewers (CH, MC).

17 Methods 17 Table 4: Hierarchy of evidence Level I II Type of evidence Evidence from systematic reviews, meta analysis or randomised controlled trials. Evidence from controlled studies without randomisation, non-experimental comparative studies. III Evidence from non-experimental descriptive studies, such as comparative studies, correlation studies and case control studies. Adapted from: Hierarchy of evidence and grading of recommendations. Thorax 2004 [44] The criteria for the inclusion of economic evidence were expanded to include any level of study. This was due to the limited amount of economic evidence available. However, cost studies without a comparator or effectiveness measure, clinical reviews citing fewer than two economic evaluations, and conference posters were excluded. The abstracts of studies identified through the search were examined by one reviewer (JA). Articles which potentially met the inclusion criteria were then obtained and the full text independently assessed for inclusion by two reviewers (CH, JA). When disagreements regarding inclusion occurred, a third reviewer (MC) determined eligibility. A total of 183 full text articles were identified and all abstracts reviewed (CH, MC). Thirty articles met the inclusion criteria of the clinical evidence review and an additional four studies were included as part of the economic evidence review. These studies were classified according to wound and study type for reporting purposes (Table 5).

18 Methods 18 Table 5: Literature search findings Meta analysis Systematic review Randomised Control Trial Non Randomised Control Trial Comparative study Cost effectiveness review Diabetic wounds 3 [45-47] 1 [48] Ulceration wounds 2 [49, 50] 1 [51] Pressure ulcers 1 [52] 1 [53] 1 [54] 1 [55] Infected sternal woundss 2 [56, 57] Traumatic wounds 1 [58] Healing of skin grafts 4 [50, 59-61] 2 [62, 63] Unspecified chronic wounds Unspecified acute wounds 2 [64, 65] 3 [66-68] 1 [48] 2 [69, 70] 1 [71] Unspecified chronic and acute wounds 5 [72-76] 1 [77] 1 [78] [50] is reported in both ulceration wounds and skin graft wounds, [58] is published in two sections The individual trial results within the systematic reviews are not reported. All trials included in the systematic reviews that met the inclusion criteria were examined individually on their own merit. Results of the studies are presented in the relevant wound section of the report. An overview of evidence per wound type is provided at the beginning of each wound section. It includes the number and type of articles appraised, a study synopsis, and a summary of the quality assessment carried out per article. In addition, a summary of study outcomes is provided, indicating those outcomes where VAC therapy was found to be more effective and less effective than the control therapy, further divided according to statistical significance. More detailed study findings are presented later in the report using key criteria appropriate to the study type: trials (RCT, non-rct, and comparative study); reviews (clinical and cost); and meta analyses. Quality assessment An independent quality assessment was conducted by CEP for all included studies. The quality of the randomised and non-randomised controlled trials, and comparative studies was determined using guidelines provided by the NHS Centre for Reviews and Dissemination [79]. The quality of the systematic reviews and meta analyses was determined using the Critical Appraisal Skills Programme (CASP) checklists developed by the Public Health Resource Unit (PHRU) [80].

19 Evidence review 19 Diabetic wounds Overview Four studies examined the effectiveness of VAC therapy in the treatment of diabetic wounds (Table 6). Figure 2 provides a summary of study outcomes for diabetic wounds according to statistical significance. Table 6: Overview of evidence for diabetic wounds Studies Study type Randomised controlled trial = 3 [45-47] Comparative study = 1 [48] Randomised controlled trial Synopsis VAC therapy was compared with moist dressings in all studies (n=1 saline moist gauze, n=1 hydrocolloid wound gel, n=1 alginates, hydrocolloids, foams or hydrogel). VAC therapy led to significant improvements in time to complete closure and wound surface area in two studies [45, 46]. VAC therapy decreased wound surface area and time taken to achieve healing in the third study [47], however statistical significance was not determined. The quality of the studies was variable: Only one of the three studies was powered to detect differences [45]; the remaining two Quality included small numbers of patients (range n= 6-12) [46, 47]. The methods of randomisation and allocation concealment were poor in two of the studies [45, 47]. Comparative study Synopsis Quality One comparative study compared VAC therapy with saline moist gauze dressing. VAC therapy was examined for clinical and cost effectiveness. VAC therapy led to a higher percentage of healed wounds and reduced costs in comparison with saline moist gauze dressings. However, tests of statistical significance were not performed. The quality of the comparative study was poor: The authors acknowledge that the amount of available data was limited, preventing a thorough analysis. Treatment groups could not be examined for homogeneity as information used to compare the groups was lacking.

20 Evidence review 20 VAC therapy MORE EFFECTIVE than control therapy Significant finding (p>0.05) Healed wounds, time to achieve closure [45]. Wound depth, wound volume [46]. Non-significant finding (p<0.05) Second amputation, intervention related adverse events [45]. Mean time taken to achieve satisfactory healing, wound surface area decrease, definitive closure by secondary intention [47]. Wound area, wound width, wound length [46]. Percentage of wounds healed, mean treatment costs (per day), total annual costs (per 100) (tests of statistical significance not performed) [48]. VAC therapy LESS EFFECTIVE than control therapy (Not applicable) Wound infection [45]. Figure 2: Summary of study outcomes for diabetic wounds Detailed findings An overview of the key results for diabetic wounds per study type is outlined below. Detailed findings from these studies can be found in Table 7 & 8. Randomised controlled trials Armstrong and Lavery (2005) conducted a multi-centred randomised controlled trial (RCT) examining diabetic foot wounds following amputation [45]. A total of 162 patients aged 18 years or older were recruited into a 16 week, 18 centre United States (US) trial. The objective of the study was to determine if VAC therapy was clinically efficacious in treating amputation wounds of the diabetic foot. Patients were randomised to receive either VAC therapy or moist wound therapy (alginates, hydrocolloids, foams or hydrogels). A total of 19 patients in the VAC group and 19 in the control group withdrew before the end of the study. An intention to treat analysis was used, where patient data were analysed despite drop outs and according to the treatment they were assigned to, rather than what they received in the case or crossover. The assessors were not blinded to treatment allocation as the authors felt an experienced assessor would readily recognise a VAC treated wound e.g. suction marks. The results of the study show that VAC treatment leads to significantly higher proportions of healed wounds and faster time to wound closure [45]. McCallon et al (2000) conducted a RCT comparing the use of VAC therapy with saline-moistened gauze in diabetic foot ulcers [47]. The study included ten patients attending a diabetic foot clinic in the US. Patients were included if they were diabetic,

21 Evidence review 21 had a non-healing foot ulcer that had been present for more than one month, and were aged years. It is unclear if the outcome assessor was blinded. Due to the small sample size, data were not examined for statistical significance. The authors concluded that in the treatment of postoperative diabetic foot wounds, VAC therapy reduced the time to satisfactory healing when compared with salinemoistened gauze therapy [47]. Eginton et al (2003) compared the rate of wound healing in diabetic foot wounds [46]. The study took place in a US hospital and included diabetic patients with significant soft tissue defects of the foot that were not expected to heal within one month [46]. A total of ten patients with 11 wounds were enrolled onto the study. The study involved a crossover of treatment, with patients receiving one treatment for two weeks followed by the alternative treatment for two weeks. Patients were treated with either the VAC device or with moist dressings (using hydrocolloid wound gel). Assessors were blind to the treatment allocation. Four patients did not complete the study protocol: one patient did not return for follow up; one patient s insurance coverage was denied; one patient went on to receive treatment elsewhere; and the fourth patient was a clinical failure of VAC therapy. The study showed that VAC therapy resulted in a significant decrease in wound depth and volume when compared with standard moist dressings. VAC therapy did not significantly reduce the wound area, width or length [46]. Comparative study Philbeck et al (2001) retrospectively examined the records of 26 US Medicare patients with diabetic foot ulcers being treated with VAC therapy in a community setting. The study used a published report as a comparator for wound healing rates and treatment costs with comparator data from previously published studies that employed saline gauze [48, 81]. The comparator study examining the use of saline moist gauze dressings in the treatment of diabetic foot ulcers included 721 patients. When comparing data, VAC therapy led to a greater percentage of healed wounds and lower costs than saline moist gauze dressings. The data were not combined, thus the groups were not examined for statistically significant differences [48].

22 Evidence review 22 Table 7: Randomised controlled trials - diabetic wounds Authors Methods Results Complications Study quality Armstrong and Lavery (2005) [45] Clinical Cost Inclusion criteria: Aged 18+, diabetic, foot amputation wounds (transmetatarsal level), evidence of adequate perfusion. Therapies: Intervention: (n=77), VAC therapy, dressings changed every 48 hours (mode e.g. continuous/ intermittent, duration & level of TNP not given). Control: (n=85), standard moist wound care, alginates, hydrocolloids, foam or hydrogels (given at discretion of clinician), dressings changed every day unless clinician recommended otherwise. No examination of cost. Measurement of outcome: Complete closure determined by investigator at bedside, planimentry measures from digital photographs. Healed wounds: Intervention - 56% (n=43). Control - 39% (n=33) (p=0.040). Difference in proportion for complete closure: Intervention compared with control (95% CI ). Median time to achieve complete closure: Intervention - 56 days (IQR 26-92). Control - 77 days (IQR ) (p=0.005). Second amputation: Intervention - 3% (n=2). Control - 11% (n=9) (p=0.060). Relative risk ratio (95% CI ) in favour of VAC therapy. Wound infections: Intervention - 17% (n=13). Control - 6% (n=5) (no p value given). None in the intervention therapy group was related to treatment, two in the control therapy group were related to treatment. Intervention related adverse event: Intervention - 12% (n=9) mean duration 18.0 days (SD 22.3). Control - 13% (n=11) mean duration 24.3 days (SD 34.5) (no p value given). A multi-centred RCT with sample size adequately powered to detect differences. Method of randomisation not given. The study sponsor (KCI) prepared the randomisation scheme & distributed the scheme to sites. Baseline characteristics reported but groups not examined for homogeneity. Outcome assessor was not blinded as an experienced observer would recognise a VAC therapy treated wound. No description of intervention related adverse events. Intention to treat analysis used.

23 Evidence review 23 Authors Methods Results Complications Study quality McCallon et al (2000) [47] Clinical Cost Eginton et al (2003) [46] Inclusion criteria: Diabetic patients, aged with a non-healing foot ulcer present for more than one month. Therapies: Intervention: (n=5), VAC therapy, continuous suction (125mmHg) for first 48 hours after surgical debridement, then intermittent suction (125mmHg) (frequency of dressing changes not given). Control: (n=5), sterile saline-moistened gauze dressings, changed twice daily (wounds were surgically debrided prior to treatment). Clinical Inclusion criteria: Diabetics with significant soft tissue defects of the foot not expected to heal within one month, adequate perfusion (palpable pulses or toe pressures >40) required. All wounds were sharply debrided prior to treatment. Ten patients were included. No examination of cost. Cost No examination of cost. Measurement of outcome: Tracings of the wounds and surface area - measurements quantified using computer biometrics. Mean time taken to achieve satisfactory healing: (Calculated from day of surgical debridement to date of definitive closure) Intervention days (+/- 17.4). Control days (+/- 32.5) (no p value given). Wound surface area: Intervention % (+/- 24.3) mean decrease. Control - 9.5% (+/-16.9) mean increase in surface area (no p value given). Method of closure - definitive closure by secondary intention: Intervention - n=4. Control - n=2 (no p value given). 2 week follow up: Length: Intervention - 4.3% decrease (+/- 4.7%). Control - 6.7% increase (+/- 11.5%) (p>0.05). Width: Intervention % decrease (+/-5.2%). Control - 2.4% increase (+/- 7.5%) (p>0.05) Pain was experienced by some VAC therapy patients during the initial dressing change, however pain was brief in duration (<30 seconds) and was not reported in further dressing changes. Granulation tissue growth into pores of the foam resulted in minor capillary disruption with removal of the VAC dressing. One patient did not complete the study and was deemed a clinical failure of VAC therapy. The negative pressure had been reduced to 50mmHg and wound drainage was not adequately removed. As a result maceration of the surrounding area occurred. Small pilot study, no power calculation. No statistical tests of significance performed. Inadequate method of randomisation and allocation concealment. Groups examined for homogeneity. Eligibility criteria clearly specified. Age and wound size examined for homogeneity. Unclear if outcome assessors were blinded. No withdrawals. Small sample size, no power calculation. Method of randomisation adequate. Adequacy of allocation concealment unclear. Groups analysed for homogeneity - results not reported.

24 Evidence review 24 Authors Methods Results Complications Study quality The study was a crossover trial. Therapies: Intervention: VAC therapy, 125 mmhg continuous negative pressure (frequency of dressing changes not given). (It is unclear how many patients were randomised to intervention therapy at initiation of the trial). Control: moist dressings, using hydrocolloid wound gel and gauze dressings. (It is unclear how many patients were randomised to control therapy at initiation of the trial). Depth: Intervention - 49% decrease (+/- 11.1%). Control - 7.7% decrease (+/- 5.2%) (p<0.05). Area: Intervention % decrease (+/- 6.2). Control - 5.9% increase (+/- 17.4) (p>0.05). Volume: Intervention - 59% decrease (+/- 9.7%). Control - 0.1% decrease (+/- 14.7%) (p=<0.005). 4 week follow up: Change from moist dressings to VAC therapy - 86% wounds resulted in decreased wound depth, 78% decrease in wound volume, 28% increase in wound length, 21% increase in wound width. Eligibility criteria specified. Outcome assessor blinded. Four withdrawals, unclear which treatment they had been initially assigned to, reasons for withdrawal given. Dressings changed daily (frequency of dressings changes not specified). Change from VAC therapy to moist dressings - 71% wounds resulted in decreased wound depth, 57% decrease in wound volume, 57% increase in wound length, 43% increase in wound width (no p values given).

25 Evidence review 25 Table 8: Comparative study - diabetic wounds Authors Methods Results Complications Study quality Philbeck et al (2001) [48] Clinical Inclusion criteria: Medicare patients with a diabetic foot ulcer judged to be similar to control. Published report used as a control group [81]. Therapies: Intervention: (n=26), subgroup of diabetic foot ulcer patients, with debrided wound and judged to be similar to control, from legible clinical records of multiple wound types n=1032. VAC therapy. Patients treated previously with saline gauze or other topical and non-topical interventions, for an average of 45 days prior to VAC therapy. Control: (n=721), patients treated with saline soaked gauze dressings. Cost Perspective: Insurer (Medicare). Setting: Community, USA. Costs: Direct costs - estimates of total costs per day for intervention & control obtained from published literature for saline gauze [81, 82]. Effectiveness measure relating to cost: Wound healed after either 12 weeks or 20 weeks, or not healed. Percentage of wounds healed - 12 wks: Intervention % Control % Percentage of wounds healed - 20 wks: Intervention % Control % Mean treatment costs (US$): Cost per day: Intervention - $99 (from Margolis 1999). Control - $100 (from Mendez-Eastman 1998). Annual costs per 100 wounds (US$): Annual cost to treat wounds healed at 12 wks: Intervention - (39 wounds healed) - $ Control - (24 wounds healed) - $ Annual cost to treat additional wounds healed at 20 wks: Intervention - (11 wounds healed) - $ Control - (7 wounds healed) - $ Annual cost to treat wounds not healed after 12 or 20 weeks: Intervention - (50 wounds) - $ Control - (69 wounds) - $ Total annual cost per patient (total cost/100): Intervention - $ Control - $ None reported. One published study of saline soaked gauze therapy was used as a comparator. It is not clear how this paper was selected. Authors acknowledge the available data was limited e.g. no data relating to duration of previous treatment, medical history. As no data is provided for patient medical history the groups cannot be compared for homogeneity. Data was not combined; tests of statistical significance were therefore not performed.

26 Evidence review 26 Mixed aetiology ulceration wounds Overview Three studies examined the effectiveness of VAC therapy in the treatment of mixed aetiology ulceration wounds; an overview of these can be found in Table 9. Figure 3 provides a summary of study outcomes for mixed aetiology ulceration wounds according to statistical significance. Table 9: Overview of evidence for mixed aetiology ulceration wounds Studies Randomised controlled trial = 2 [49, 50] Study type Cost effectiveness review = 1 [51] Randomised controlled trial Study synopsis Both studies compared VAC therapy with a) the health point system [49] b) hydrogel or alginate dressings [50], in the treatment of ulcer wounds. VAC therapy produced significant improvements in time to complete healing, wound bed preparation time and skin graft take [50]. VAC therapy did not significantly improve ulcer volume [49] and was found to have higher rates of ulcer recurrence, and higher frequency of adverse events [50]. VAC therapy was found to cost significantly less than the control therapy [50]. Quality assessment Cost effectiveness review Study synopsis Quality assessment The quality was variable: One study was high [50], with an adequately powered sample with good methods of stratified randomising. The other study was poor [49], with a small sample not powered to detect differences. One review examined the economic aspects of VAC therapy [51]. The review found that VAC therapy can lead to reduced costs due to quicker mobilisation of patients and decreased frequency of dressing changes [51]. Renner [51] states the study was conclusive - VAC possesses economic advantages. The overall quality was moderate. No inclusion criterion was given and the meta-analysis is based on healing rate increase only [51].