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Should alternative endpoints be considered to evaluate outcomes in chronic recalcitrant wounds?

Author(s)

Stuart Enoch
MBBS, MRCSEd, MRCS(Eng), Clinical Research Fellow (PhD)in Surgery
Wound Healing Research Unit

Patricia Price
BA(Hons), PhD(Wales), AFBPsS, CHPsychol
Director
Wound Healing Research Unit
Medicentre, University of Wales College of Medicine, Cardiff, UK
Email: pricepe@whru.co.uk

Contents
Published: Oct 2004
Last updated: Oct 2004
Revision: 1.0

Keywords: chronic wounds; impaired healing; ageing; surrogate endpoints; intermediate endpoints; outcome; health-related quality of life.

Key Points

  1. Complete wound closure is widely accepted to be an objective endpoint in acute wound healing. However, this feature may not always be appropriate in assessing outcomes for chronic wounds.

  2. For patients whose wounds are unlikely to heal or for whom healing is not the priority of care, non-healing endpoints, either intermediate or surrogate, should be used as prognostic indicators of improvement in such wounds.

  3. Controlling exudate, minimising or eliminating odour, preventing infection, and relieving pain should all be considered as legitimate non-healing endpoints.

Abstract

Despite inherent differences in the pathophysiology of acute and chronic wounds, including those in the aged, and variations in their progression, 'healing' or 'complete wound closure' is considered to be the primary outcome measure of both wound types. This is also the predefined endpoint in most clinical trials or studies involving wound dressings or devices. This article debates the usage of 'complete wound closure' as the primary endpoint to assess the progress of chronic wounds, both from a clinical and research perspective, and argues that alternative endpoints, either intermediate or surrogate, should be considered to evaluate their outcomes. It reasons why accepting non-healing endpoints such as controlling exudate, minimising or eliminating odour, preventing infection, and relieving pain may be appropriate and in the best interests of some patients, particularly the elderly.


Introduction

The majority of chronic wounds are seen in the lower extremity and are predominantly due to venous, arterial, pressure or neuropathic aetiology. There are various factors that contribute to the non-healing nature and the longevity of such wounds: connective tissue disorders, systemic conditions such as sickle cell disease or malakoplakia, arterial compromise (inoperable), osteomyelitis, immobility, end-stage renal or heart disease, dementia, cancer and advancing age. These factors act on their own or in combination, leading to chronicity.

Chronic wounds have traditionally been defined as those that fail to progress through an orderly and timely sequence of repair. Unfortunately, chronic wounds have long been conceptualised as the sequence of neglect, incompetence, misdiagnosis or inappropriate treatment strategies. However, it is important to appreciate and acknowledge that some chronic wounds are resistant to all efforts and treatments aimed at healing. Therefore, a more appropriate definition for chronic wounds might be, 'a wound (and its underlying aetiology) that does not respond to treatment and/or the demands of treatment are beyond the patient's physical health, tolerance or stamina'.

Since acute wound healing follows a well-defined pattern resulting in complete wound closure it is possible to objectively assess its progression throughout the healing process. On the contrary, due to the inherent alterations in the pathophysiology of chronic wounds, the biological effects of ageing on the healing process and the direct confounding effect of associated co-morbidities in the elderly, the healing of chronic wounds is often protracted, variable and non-uniform [1].

It may be clear from the outset that wounds in some patients are unlikely to heal or for whom healing is not the priority of care. In addition, the elderly are further compromised by underlying disease processes that complicate the diagnosis and limit the treatment options available to treat chronic wounds. This is not intended to mean that efforts to improve the wound must be abandoned but, rather, propose alternative treatment approaches to provide relief from suffering. Acknowledging this outcome will avoid unrealistic expectations for both the patient and their caregivers, and pave the way to focus on the effective management of symptoms. Furthermore, in most clinical trials and studies involving wound dressings and devices, 'healing' is considered to be the primary predetermined endpoint for both acute and chronic wounds. However, products that are aimed to achieve healing in acute wounds may not have the same effect in chronic non-healing wounds due to the interaction of various confounding factors such as exudate, an unhealthy wound bed and infection.

In this article, we debate whether alternative endpoints, such as surrogate or intermediate endpoints, should be used to assess outcomes in such wounds, both from a clinical and research perspective. We argue why accepting non-healing endpoints may be appropriate and in the best interests of some patients, particularly the elderly. We present various such endpoints and also look at the relevant health-related quality of life (HRQoL) issues.

Assessment of outcomes in chronic wounds

According to the Food and Drug Administration (FDA), USA, a completely healed wound is, 'a wound that has totally re-epithelialised and stays healed for a minimum of 28 consecutive days' [2]. Since acute wound healing proceeds through an orderly and timely reparative process, various parameters such as the size (extent) of the wound, rate of healing, and the status of the wound bed could be used as markers for continuously assessing the healing process in acute wounds. In contrast to acute wounds, the assessment of outcomes in chronic wounds is complex, non-uniform and lacks consistency. This is due to the fact that whilst complete wound closure is widely accepted to be an objective endpoint in acute wound healing, this feature may not always be appropriate in assessing outcomes in chronic wounds. Although various techniques for ascertaining outcomes and predicting the prognosis of chronic ulcers have been proposed, few are objective, consistent, or accurate.

The initial wound size and wound dimensions are not reliable indicators for predicting chronic wound closure as the factors that influence healing (delay healing) are diverse and unpredictable; chronic wounds can become 'inert' or 'static' at any stage along the 'healing' process. Margolis et al [3] noted the presence of fluctuation in healing rates over the first few weeks of treatment and cautioned that while the initial rate of healing may be predictive of complete healing (in some wounds), it cannot be extrapolated to calculate the actual time necessary for complete healing. Likewise, in smaller wounds, the percentage change in area over time exaggerates their healing rates and therefore a prediction of healing based on percentage change in area might be inaccurate [4].

This raises a number of questions. Should alternative endpoints such as decrease in pain, exudate or odour, or an improvement in the quality of the wound bed be considered as legitimate indicators of evaluating the outcomes in chronic wounds? Or could just decreasing the frequency of dressing changes or improvement in the patients' overall HRQoL be considered a marker of progress? In the assessment of chronic wounds, what is the role of intermediate and surrogate endpoints? Are they valid outcome measures?

Health-related quality of life in patients with chronic wounds

Several studies have shown that patients with chronic wounds have a decreased HRQoL[5],[6],[7]. This is due to a multitude of factors: frequency and regularity of dressing changes which affect their daily routine; a feeling of continued fatigue due to lack of adequate sleep; restricted mobility; pain; wound infections; and social isolation. The requirements and consequences of having a chronic wound also have an enormous impact on the patient's social life. The loss of independence associated with functional decline can lead to several, sometimes subtle, changes in overall health and wellbeing. These changes include altered eating habits, depression, social isolation, and a gradual reduction in activity levels. The presence of these factors, along with immobility, not only influences the occurrence of further wounds but also exacerbates their severity and jeopardises their ability to heal.

Studies of people with chronic venous leg ulcers (CVLU) suggest that they experience a reduced HRQoL [8],[9]. This might be due to difficulties in functioning due to limited mobility and activity [10], an altered life situation, a protracted healing process and pain; pain as a symptom of ulceration is an overwhelming characteristic of the experience[11], [12]. Franks et al [13] evaluated the HRQoL in 118 patients with CVLU using the Medical Outcomes Short Form-36 questionnaire and observed that, compared to age-sex adjusted published normative scores, patients with leg ulcers had significantly lower mean scores in the following domains: role-emotional, social-functioning, role-functioning, role-physical and bodily pain. Similarly, in a systematic review of 37 studies looking at the impact of leg ulcers on a patient's daily life, Persoon and colleagues [14] observed that the major limitations were pain and immobility followed by sleep disturbance, lack of energy, limitations in work and leisure activities, worries and frustrations, and a lack of self-esteem.

Abetz et al [15]used the Diabetic Foot Ulcer Scale to measure the impact of diabetic foot ulcers (DFU) on the patients' HRQoL and observed that the following domains were affected: leisure, emotions, finances, physical health, daily activities and friendships. Earlier Ashford and colleagues [16], in an in-depth analysis of patients' experience with foot ulcers, observed that the majority of patients expressed problems with footwear, working life, pain, and mobility, as well as the effects on relationships. Carrington et al [17]observed that those with DFU were significantly more depressed and dissatisfied with their personal lives (p<0.05) than were controls; those with foot ulcers also reported a significantly more negative attitude towards their feet and foot care than did either the diabetic amputees or controls (p<0.05). Meijer et al [18] compared 14 patients with a previous or current (but clinically stable) DFU with 24 controls without ulcers, matched for age, sex and duration of diabetes. They concluded that an existing or previous foot ulcer had a negative influence on the physical and social aspects of their subjects' HRQoL. Similarly, studies looking at the HRQoL issues in patients with other chronic wounds such as pressure ulcers have also found significantly poor physical and social functioning and a reduced HRQoL [19]in this group as observed in patients with CVLU and DFU.

Is the HRQoL always related to ulcer healing or, in some patients with recalcitrant, exuding and malodorous wounds, could amputation of the affected limb lead to an improvement in their overall HRQoL? Since amputation is common in patients with DFU most studies have looked at this group of patients. In the study by Carrington et al [17], 13 diabetic patients with chronic unilateral foot ulceration were matched for sex and age with 13 diabetic patients with lower-limb amputation and 26 diabetic patients with no history of foot ulcers. They found that the HRQoL for mobile amputees was better than that for patients with foot ulcers but not as good as that for the diabetic patients with no history of foot ulceration. To adjust life expectancy for HRQoL as an outcome measure, scores from 1738 diabetic patients on three subscales of the Short Form-36 were used to calculate weighting factors for the decision model by Eckman and colleagues [20]. Compared with diabetic controls, both those with ulceration and those who had amputation rated their HRQoL significantly poorer for physical functioning (p<.01). Mean scores for the ulceration group (44.13) were lower than those who had amputation (49.1).

Although the above studies may suggest that amputation is a positive option, Carrington et al [21] pointed out that the loss of a limb is recognised by both doctors and patients as a "drastic step". Hence it should only be considered to be an option when it is clear that the wound is inert (static) and resists all attempts aimed to achieve healing or progress towards a meaningful surrogate endpoint (see below). The physician should lay out the facts clearly to the patient and discuss the merits and defects of both treatment options before embarking on a radical and irreversible surgical procedure such as an amputation.

Intermediate endpoints

Intermediate endpoints usually occur during the course of treatment and are intended to predict a true, meaningful clinical endpoint. This point could be anywhere along the healing path, either in the early, intermediate or late stages, depending on the criteria (e.g. >75% granulation tissue, no slough) being used. Since they occur sooner than the primary endpoint, they can be used to make clinical trials more efficient (eg less follow-up time, smaller sample size). Unlike a single clinical endpoint, there can be multiple intermediate endpoints, and this provides opportunities for conducting trials and to develop therapies to target a particular aspect (stage) of the healing process. In addition to allowing a clinician to assess a patient's response to therapy during treatment, valid intermediate endpoints help speed the development of new effective therapies and also minimise the exposure of patients to ineffective treatments (in the developing stages).

Surrogate endpoints

A surrogate endpoint is defined as a physical sign or a laboratory measurement that can be used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives [22]. Changes induced by a therapy to achieve a surrogate endpoint are expected to reflect changes in a clinically meaningful fashion. A surrogate endpoint must not be simply a correlate of the true clinical outcome; it must fully capture the net effect of the treatment of the clinical outcome. Therefore, a valid surrogate endpoint is related to the outcome of interest, and is affected by the treatment of interest to the same degree and in a manner that accurately reflects the effect of the treatment on the true outcome.

Distinction has to be made between a surrogate and an intermediate endpoint: Although an intermediate endpoint, like a surrogate, occurs before the true outcome, it represents a clinical state that is progressing towards the final expected outcome; a surrogate endpoint, on the contrary, is a substitute for a clinically meaningful endpoint (that is of true benefit to the patient). Though the FDA guidelines have consistently stated that only a healed wound is of true benefit to a patient [23], due to the complexities of chronic wound healing, it may be that a strong case could be made to consider surrogate and intermediate endpoints as the prognostic indicators of improvement in such wounds. Some realistic endpoints (both intermediate and surrogate) in chronic wounds are tabulated in Table 1 [24].

Table 1
FDA product claim categories for chronic wounds Some suggested realistic endpoints in chronic wounds
Category  Description  Category  Description 
Incidence of complete closure  Considered the most clinically meaningful claim; defined as skin closure without drainage or dressing requirements  Wound stabilisation  To ensure that the wound is not deteriorating by providing appropriate supportive treatment such as preventing direct physical pressure over the wound (eg footwear [diabetic ulcers] and pressure relieving devices [pressure ulcers])  
Accelerated wound closure  Products that demonstrate a clinically meaningful reduction in time to healing  Improve vascularity, granulation tissue  Products that assist in improving blood flow and promote good quality healthy granulation tissue 
Minimise bacterial load  Topical antimicrobials that reduce the bacterial burden and minimise or eliminate the risk of infection 
Improved quality of healing  Products that provide improved cosmesis (ie reduced scarring)  Reduce slough, exudate and eliminate odour  Topical dressings or devices that aid in removing slough, reducing exudate and minimising odour 
Infection control  Products that control infection and thereby support healing  Reduce bacterial burden; prevent local or systemic infection and/or osteomyelitis  Topical antimicrobials or antibiotics aimed to minimise bacterial burden 
Debridement  Products must demonstrate thorough removal of necrotic tissue, as this establishes ability to heal  Appropriately targeted selective debridement to expedite granulation tissue formation  Topical debriding agents (chemical, enzymatic etc) that provide safe selective debridement; sharp debridement in static wounds with fibrotic base and 'biosurgery' in sloughy wounds 
Pain control  Must distinguish between products that affect chronic as opposed to procedural pain  Reduce local wound pain  Dressings (devices) and agents that reduce pain and local discomfort 
Other wound care claims  Products that improve certain aspects of daily living  Reduce frequency of dressing changes  Topical antimicrobials with sustained release; Dressings with increased exudate absorptive ability, and better design to reduce the pain and discomfort associated with dressing changes (ease of application and removal, low adherence to wound bed etc) 
*Modified from Alvarez et al[24]

Intermediate endpoints in clinical practice

Changes in the wound bed characteristics are indicative of the healing process and monitoring the type of tissue in the wound bed has long remained one of the mainstays of wound assessment in clinical practice. The percentage of healthy granulation tissue in the wound bed could be used as a marker of the quality of the wound bed. Therefore, could the quality of the wound bed be considered as a valid intermediate point to assess healing?

In assessing the effectiveness of a debriding agent, it does not seem appropriate if complete wound closure is used as an endpoint of the treatment process. This is because the aim of wound debridement is not to achieve immediate healing, but to stimulate the process and facilitate wound closure at a later stage. Many chronic wounds contain excess slough, copious amounts of exudate and large amounts of unhealthy or necrotic tissue, all of which are detrimental to the healing process. These necrotic or unhealthy tissues could also harbour pathogenic bacteria. The aim of debridement - surgical or sharp, chemical, enzymatic, mechanical and biosurgery - therefore is to efface the wound bed of excess exudate, expunge necrotic and sloughy material, disassemble or dislodge bacterial colonies (biofilms), and if possible to improve the vascularity of the wound bed.

The ideal endpoint in debridement trials (eg topical enzymatic products) should be the achievement of a healthy and viable wound bed consisting of good quality granulation tissue. This wound bed would then be suitable for using novel treatments such as tissue-engineered skin substitutes and growth factors requiring cell interaction or receptor binding sites. In addition, this would also provide a suitable bed for skin grafting. An intermediate endpoint such as, 'viable bed' or 'graft ready' might, therefore, seem more appropriate for trials involving debriding agents rather than complete wound closure.

The significance of intermediate endpoints is also demonstrated by a trial conducted on the use of growth factors in pressure ulcers. In a study evaluating the effect of recombinant basic fibroblast growth factor (bFGF) in pressure ulcers, although only a few achieved 100% healing, the rate of healing was significantly higher in the group treated with bFGF than the placebo. When a 70% reduction in volume within the 30-day trial was used as a criteria for assessment, it was observed that ulcers treated with bFGF achieved a quicker reduction in the volume (p<0.05) [25]. The endpoints of all wound products and devices therefore need not necessarily be complete wound closure, but any valid intermediate endpoint that might eventually lead to complete closure or at least to an acceptable surrogate endpoint.

In patients with CVLU the major concern might be the copious exudate produced by the wound. Since compression remains the mainstay of treatment for such ulcers, the excess exudate causes soiling of the compression bandages (and dressings), leading to increased frequency of bandage and dressing changes. Exudate also aids the development of surrounding venous eczema resulting in itching, discomfort, and subsequent breakdown of skin in the adjacent tissue. It also provides a haven for microorganisms, causing recurrent wound infections. A reduction in exudate production not only decreases the frequency of bandage and dressing changes leading to an improvement in the patients' HRQoL, but also aids wound healing in the long-term. Therefore in a CVLU that produces copious exudate, a reduction in its quantity could be considered to be a significant achievement, and could be used as a valid intermediate endpoint whilst assessing the effectiveness of products specifically intended to minimise exudate production.

Surrogate endpoints in clinical practice

In some patients with chronic wounds, it may be clear from the outset that complete healing is not a viable option and all attempts to achieve this objective are deemed to be futile. For such patients, merely decreasing the frequency of dressing changes (by reducing the amount of exudate production as in leg ulcers), alleviating pain (vasculitic and ischaemic ulcers), preventing recurrent wound infections, and avoiding further wound deterioration and complications would significantly enhance their HRQoL. This is illustrated by two examples below.

In patients with chronic pressure ulcers (in the sacrum or ischial tuberosity) secondary to congenital conditions such as spina bifida or from traumatic injury to the spinal cord, achieving complete healing by conservative means may never be a realistic outcome. This is due to a combination of factors: decreased sensation, reduced mobility and persistent colonisation of pathogenic bacteria from the perineal/perianal region. In such instances, minimising odour, exudate and preventing recurrent wound infections could be considered a satisfactory or meaningful outcome (surrogate endpoint), both from a clinical and patient perspective. Therefore, therapies or devices aimed to achieve the above characteristics should be considered to be a valid treatment option.

Likewise, in some patients with ulcers secondary to peripheral vascular disease, vasculitis or mixed (arterio-venous) aetiology, it might be known from the onset that complete ulcer healing might not be achieved due to the underlying aetiology and/or other associated co-morbidities. Since these ulcers can be painful, a reduction in pain might be the most important criteria from the patient perspective. In such instances, management of pain or adequate pain relief should be considered to be the primary priority, since this might lead to an improvement in the patient's overall HRQoL. This could also be a valid surrogate endpoint.

Difficulties in distinguishing between intermediate and surrogate endpoints

In chronic, non-healing wounds, a clear distinction between a surrogate and intermediate endpoint is not always possible. For example, in a patient with a CVLU, should achieving an exudate-free wound after three years of treatment be considered an intermediate or a surrogate endpoint? Although the chances of healing are enhanced in an exudate-free environment, due to the vagaries of chronic wound healing, this wound might not proceed beyond this stage and may become a static wound. In this situation, should the exudate-free environment be a true surrogate endpoint since this might decrease the frequency of dressing changes, thus enhancing the patient's HRQoL? Similarly, should a reduction in the pain score from nine to five (on a scale of ten, ten being extreme pain) be considered an intermediate or a surrogate endpoint? Although a reduction in pain may not directly lead to ulcer healing, it nonetheless helps the process by allowing the patient to tolerate increased amounts of compression, which might eventually lead to healing. In addition, reduction in pain might help the patient to have uninterrupted sleep and this may be a significant improvement in HRQoL for the patient rather than complete ulcer healing. Although, in theory, it might be possible to bring down the pain score to zero (thus five being an intermediate endpoint), it is seldom achieved in painful chronic wounds, and therefore, should this reduction in pain be considered a true surrogate endpoint?

The presence of healthy granulation tissue is considered to be a good marker of progress. Hence if a chronic wound has achieved 60-70% granulation over a six-month period, it is quite conceivable to consider this to be an intermediate endpoint. However, further progress of this wound can be impeded due to various factors and the wound may remain static for prolonged periods of time. Nevertheless, the wound bed status may be suitable for grafting or the use of novel treatment modalities such as tissue-engineered skin substitutes or growth factors. In such situations, should this point (ie achieving 60-70% granulation) be considered a valid surrogate endpoint for this particular wound (patient)?

The scenarios discussed above lead to a dilemma: how is it possible to precisely determine whether a particular stage of a wound (in individual patients) is an intermediate or a surrogate endpoint? Could some alternative endpoints be considered as intermediate endpoints in certain wounds (patients) but surrogate endpoints in others, or are they mutually exclusive? Constant re-evaluation of the wound status is therefore necessary in chronic wounds to determine the alterations in wound characteristics in relation to individual patient status and requirements. It also becomes necessary to appropriately modify the endpoints depending on the treatment progress, patient characteristics, the product evaluated or the trial in question.

What parameters could be used to assess clinical outcomes in chronic wounds?

Exudate level: Exudate is usually heavy (+++) at the beginning of the inflammatory phase of a healing wound. However, it gradually subsides as the proliferative phase progresses and persistence of copious amounts of serous exudate is a feature of chronicity. Infection causes a significant increase in the amount of exudation; purulent, creamy-yellow or greenish-yellow exudate suggests infection and may indicate why a wound is not healing. The amount (quantity) of exudation is usually classified as heavy (dressing soaked; +++), medium (dressing wet; ++) or minimal (dressing dry; +). This distinction, though subjective, provides the assessor with information about the state of the wound and a reduction in exudate may indicate wound progress.

Necrosis/slough: Necrosis occurs when tissues are starved of oxygen and nutrients, secondary to compromised blood supply. The affected tissue (cells) die and form a necrotic plug that gradually loses water through evaporation. It finally dries and hardens to form a scab or eschar. Slough is a form of necrosis consisting of dead tissues that are usually creamy-yellow or greenish-yellow. An estimate of necrosis and slough in a wound, though crude, is an indicator of the status of the wound. This could be quantified in terms of amount: excessive (+++), moderate (++), minimal (+) or absent (-). Since necrotic tissue can also harbour pathogenic microorganisms, a reduction in this tissue prevents recurrent wound infections. This may in turn minimise pain and reduces the amount of medication needed - an overall improvement in the HRQoL (surrogate endpoint). In addition, a necrosis- or slough-free wound bed provides an ideal environment for the effective use of various novel treatment modalities such as tissue-engineered skin substitutes or wound modulating therapies, which may lead to healing (thus a clean, healthy wound bed being an intermediate endpoint).

Pain: Pain, a complex sensation strongly modulated by cognitive influences, is a characteristic feature of many chronic wounds. The pain experienced may be constant or intermittent, and may be described by the patient as 'sharp', 'aching', 'stabbing', 'throbbing', 'shooting' etc. Constant pain may be due to ischaemia, neuropathy, tissue oedema, chronic tissue damage (lipodermatosclerosis), infection, or scarring (atrophie blanche). Intermittent pain is often related to dressing removal or the recent application of new dressings [26]. Studies suggest that the pain intensity may be increased at night and there may be variations on a day-to-day basis, or due to weather and seasonal influences [11], [27]. Pain can affect the individual physically, psychologically and socially, and a reduction in pain can significantly improve the patient's overall HRQoL. Pain can therefore be used as a valid surrogate or intermediate endpoint depending on the duration, status and prognosis of the wound.

Accurate assessment of chronic wound pain is important to identify the cause and for its subsequent management. The process however is arduous and may be further complicated in the elderly with concomitant disorientation, confusion and communication deficits. To aid healthcare professionals (HCPs) make an accurate and objective assessment, various pain assessment tools such as the pain ruler, the numerical rating scale, the visual analogue scale, the verbal descriptor scale, Leeds assessment of neuropathic symptoms and signs, and the McGill Pain Questionnaire and its short-form (short-form McGill Pain Questionnaire) have been devised. Detailed analysis of various pain assessment tools are beyond the scope of this chapter. HCPs must take the nature and status of the wound, the type of pain and other individual patient factors into consideration when selecting an appropriate tool.

Odour: The presence of odour in a wound either signifies infection or the presence of necrotic tissue, both of which impede healing. Since traditional tests for the sense of smell such as sniff test, gustatory smell test and trigeminus test are subjective, tests such as olfactory evoked potentials and cognitive negative variation have been developed that permit evaluation of both odour perception and odour discrimination[28]. In a pilot study of 15 patients, Greenwood and colleagues [29] used an AromaScan instrument to detect and correlate the aroma of CVLU with their prognosis and suggested aroma analysis to be a potential tool in monitoring the progress of CVLU. However, no further studies have been published to support or validate this observation and such tests are not in routine clinical use.

Although a decrease in odour may suggest a chronic wound to be improving, all objective assessments available at present are complex, thus precluding their use in everyday practice. Until simpler, objective tests become available, variations in aroma cannot be used to assess the effectiveness of a product intended to minimise this feature in chronic wounds. A scoring system based on patient perception, like the pain score, could be used to assess progress in a wound or to evaluate a product in question. This could then be used to determine an improvement in the patient's experience of symptoms and thus be used as a valid intermediate or a surrogate endpoint.

Presence of microorganisms: There are several factors known to affect the bacterial burden of chronic wounds and increase the risk of infection. Although Robson and colleagues [30] found that chronic wounds with a bacterial load greater than 1x105; will heal normally, recent studies have demonstrated that healing is impaired when there are more than 1x105 organisms per gram of tissue [31], [32]. In addition to the number of organisms, the type, pathogenicity and the mix of the organisms involved are important determinants of whether infection occurs within a wound. For example, the isolation of any highly virulent beta haemolytic streptococci from a chronic wound should be considered to be significant [33]. Since most chronic wounds contain more than three species of microorganisms [34], some combinations may develop synergy with each other, resulting in previously non-virulent organisms becoming virulent and causing damage to the host [35], [36], [37]. In addition to the above, patient characteristics such as diabetes mellitus, immunosuppression, concomitant disease, medication, and age can all influence whether bacteria present in a wound causes infection and impairs healing [38].

It is therefore important to acknowledge that all chronic wounds intrinsically contain bacteria and healing can still occur in their presence; it is not the presence of bacteria but factors such as type, virulence and host characteristics that determine the organisms' influence on chronic wound healing[37]. Nonetheless, preventing infection minimises pain and leads to an improvement in the HRQoL. In evaluating the effectiveness of a product specifically intended to minimise critical wound colonisation or infection (eg topical antimicrobial), prevention of recurrent infection and reduction of pain should be considered to be a valid endpoint.

Fibrous/fibrotic tissue: Chronic wounds are characterised by the presence of white or yellow shiny fibrous tissue in the wound bed. Fibrous tissue is avascular and this precludes the formation of healthy granulation tissue. The quantification of fibrous tissue is difficult and there are no objective criteria at present. However, the presence of fibrous tissue itself indicates the chronic nature of the wound and healing will proceed only when this tissue is removed (or debrided). It could therefore be quantified as fibrous tissue present (+) or absent (-); if it covers only part of the wound bed, it could be further qualified in terms of percentage.

Granulation tissue: Granulation tissue is an essential prerequisite for re-epithelialisation and is present in abundance during the proliferative phase of wound healing and in healing wounds; absence of granulation tissue in a wound is an indicator of non-healing. The presence of healthy granulation tissue can be quantified in terms of percentage and an increase in the amount of granulation tissue in the wound bed points towards healing. In addition, in chronic wounds there may be variable amounts of healthy and unhealthy granulation tissue (beefy-red in appearance), which can be quantified as a ratio, and this gives a fairly good indicator of the status of the wound. Therefore in trials involving debriding agents (as discussed earlier), achieving good quality granulation tissue should be the primary endpoint (in some instances, it could also be considered to be an intermediate endpoint if the product, in addition to debriding, leads to complete wound closure).

In addition to the parameters outlined above, clinicians and researchers working in the area of chronic wound care need to debate the possibility of HRQoL being a primary endpoint in its own right. Societal outcome measures, including cost-effectiveness and cost-utilities, are also key parameters that need to be explored further if wound care is to compete for scarce resources within the limited health budgets available in each country.

Conclusion

Complete wound closure may not be an appropriate outcome measure in chronic wounds. Alternative endpoints, intermediate or surrogate, should be used in evaluating their outcomes taking both the wound characteristics such as duration, status and progress, and patient requirements into consideration. The significance of managing exudate, controlling infection, relieving pain, and minimising odour in a non-healing wound must be established and accepted as legitimate outcome measures. It needs to be acknowledged that health-care related goals among elderly patients with chronic wounds are not static. Prioritisation of goals will gradually shift as the patient's wound becomes recalcitrant and healing becomes less realistic. Goals shift toward maintaining function, relieving suffering, and generally allowing the patient to engage in activities that are important and fulfilling to them. We must strive to establish a set of care standards that focus on the elimination or reduction of pain, odour, infection, improving HRQoL, enhancing self image and preventing social isolation. Products and services need to be developed that support chronic wound treatments that aim to control or prevent complications in addition to delivering symptomatic relief. When designing trials involving chronic wounds, the endpoints need to be tailored according to the specific action of these dressings or devices rather than using 'healing' as a blanket endpoint for all trials.

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