Integrating adjunctive therapy into practice: recognising ‘hard-to-heal’ wounds

Kathryn Vowden, Peter Vowden

The problem of delayed wound healing has been highlighted in several publications which has stimulated debate on variance and the need for updated care pathways. This paper demonstrates how adjunctive therapy can be added to the ‘standard care’ model, described in the National Wound Care Strategy Programme’s recommendations for lower limb wounds, to enhance outcomes for patients with ‘hard-to-heal’ lower limb wounds (NWCSP, 2020). A decision-making pathway based on published literature is described which uses wound assessment and observed response to treatment to allow the effective and targeted introduction of adjunctive therapies for ‘hard-to-heal’ wounds. This approach will allow the cost-effective introduction of new and evolving therapies, such as WoundExpress™ (Huntleigh Healthcare), which addresses the underlying problems associated with resistant lower limb oedema and compromised venous function. The pathway also indicates how other adjunctive or innovative topical wound-based treatments can be integrated to optimise outcomes while providing cost-effective care.

‘Milne et al (2020) ... reported on an international standardised survey of hard-to-heal wounds, finding that wounds are, in general, treated in the same way, irrespective of whether they are hard-toheal or improving, suggesting that the healing status of a wound is not a major factor in treatment selection.’

The original ‘Burden of Wounds’ studies undertaken by Guest et al (2015; 2017; 2018a) highlighted the cost, poor outcome and national variance in care provision in relation to the management of chronic lower limb ulceration, which was by far the largest category of chronic wounds. As a direct result of these studies, a national wound care strategy group was established (iWoundsnews, 2019). One area of focus for the group was to reduce variance and improve care and outcomes for patients with lower limb wounds. The output from the group, following review and external validation, has been published and provides an updated pathway for lower limb wound management (National Wound Care Strategy Programme [NWCSP], 2020). This pathway emphasises the role of detailed assessment which should be undertaken within 14 days, the recognition and appropriate management of patients with ‘Red Flag’ conditions, and the early introduction of light compression for all other patients. The aim of this pathway being to progress all suitable patients to ‘standard therapy’ with a high compression bandage system or hosiery, and to monitor progress to allow early identification of nonresponding wounds.
 
Guest et al (2018a) reported on the poor outcome for patients with venous leg ulcers who fail to respond to therapy, finding that only 53% healed within a year and that the healing rate for an ulcer present for more than a year was very poor, with only limited use of advanced wound care products and referral pathways. This observation is supported by Milne et al (2020) who reported on an international standardised survey of hard-to-heal wounds, finding that wounds are, in general, treated in the same way, irrespective of whether they are hard-to-heal or improving, suggesting that the healing status of a wound is not a major factor in treatment selection. Oien et al (2016) have demonstrated that treatment costs for the management of hardto-heal ulcers can be reduced with well-developed treatment strategies resulting in shortened healing times.
A ‘hard-to-heal’ wound has been defined as one that fails to heal with ‘standard therapy’ in an orderly and timely manner (Troxler et al, 2006). The non-healing wounds highlighted in the Guest et al papers (2015; 2017; 2018a) and confirmed in a further follow-up study (Guest et al, 2020) represent a hard-to-heal cohort of patients and, as these papers show, represent a considerable cost burden to care providers. Current understanding of the complex pathophysiology of chronic wounds and the mechanisms by which healing is impaired has been ‘Milne et al (2020) ... reported on an international standardised survey of hard-to-heal wounds, finding that wounds are, in general, treated in the same way, irrespective of whether they are hard-toheal or improving, suggesting that the healing status of a wound is not a major factor in treatment selection.’ WOUND CARE JCN 2021, Vol 35, No 5 ?? reviewed by Wilkinson and Hardman (2020). The complex interaction between the pathophysiology of venous hypertension and abnormal cellular and biochemical responses within the wound environment have been described by Raffetto et al (2020). This group emphasise the importance of addressing both wound abnormalities and the underlying venous disease processes to maximise healing if cost-effective care is to be delivered. 

Initial assessment of a patient with a wound should include the identification of factors that help estimate healing potential and the recognition of ‘hard-to-heal’ wounds. This will allow prompt addition of adjunctive therapies to ‘standard therapy’, thus helping to maximise treatment success, avoid protracted, costly, ineffective interventions, and prevent patient disillusionment and clinician frustration (Moffatt and Vowden, 2008; Vowden and Vowden, 2016). Parker et al (2017) and Edwards et al (2018) have developed and validated a risk assessment tool to identify patients at risk of delayed healing or ulcer recurrence, which can assist and guide early treatment decisions to help promote timely healing.

HEALING OF ACUTE AND CHRONIC WOUNDS


The healing of acute wounds is traditionally regarded as being divided into four overlapping phases: haemostasis, inflammatory, proliferation and remodelling (Canedo-Dorantes et al, 2019). 

In contrast with the acute situation, in chronic wounds the highly orchestrated reparative response breaks down. There is a tendency for the inflammatory phase, which is initially so important, to become exaggerated. Increased infiltration of inflammatory cells, greater secretion of proinflammatory cytokine, elevated generation of reactive oxygen species (ROS), and increased production of proteolytic enzymes are combined with reduced inhibitor release, for example tissue inhibitors of metalloproteinases (TIMPs) (Medina et al, 2005; Trengove et al, 1999). Elevated expression of the cytokines, tumour necrosis factor (TNF)-a, interleukin (IL)-1ß and IL-6 upregulates the synthesis of several matrix metalloproteinases (MMP-1, MMP-2, MMP-8, MMP-9) and serine proteases (elastase, plasmin) which, in excess, cause not only deleterious extracellular matrix destruction but also growth factor inactivation (Chen et al, 1997; Lauer et al, 2000; Harding et al, 2002; Medina et al, 2005). The chronic wound environment therefore consists of sustained matrix degradation, reduced growth factor bioavailability and increased fibroblast senescence, which all combine to inhibit cellular proliferation, angiogenesis and tissue repair.
The levels of some biological factors have been related to subsequent wound healing. These include markers of collagen remodelling in venous ulcers and ratios of MMP-9/TIMP-1 in pressure ulcers (Tarlton et al, 1999; Ladwig et al, 2002). It has also been found that a decrease in MMP-1 and MMP-2, but not COX-2, in wound biopsy samples after four weeks can predict better healing of chronic venous ulcers (Bergant Suhodolcan et al, 2021). Despite this information, a Cochrane Systematic Review by Westby et al (2018) identified very low validity evidence regarding any association between protease activity and venous leg ulcer (VLU) healing. In contrast, Lazaro et al (2016) concludes that levels of MMPs can be used to indicate the prognosis of chronic wounds and protease modulating treatments used to improve healing rates. In a systematic review, Tardaguila-Garcia et al (2019) conclude that high levels of metalloproteinases have been correlated with significantly delayed wound healing in wounds of a variety of aetiologies. Despite this, metalloproteinases are not routinely measured in clinical practice and Dissemond et al (2020) concludes that although there is evidence for the superiority of some MMPinhibiting dressings, more research is needed for different types of hardto-heal wounds if the routine use of MMP measurement and of dressings targeting MMPs is to be justified.
Despite these advances in our understanding of wound biology, predicting healing potential in individual patients remains difficult. Several wound and patient characteristics have been found to be associated with delayed healing of both acute and chronic wounds (Table 1). Xu et al (2014) suggest that routine assessment of wounds using stereophotogrammetric imaging can provide personalised predictions of wound healing time. Gethin (2006) emphasises the importance of accurate wound measurement in predicting healing and details the simple methods available to health care providers to document and record wound size.

VENOUS LEG ULCERS

Characteristics predicting delayed healing

Reviews by Raffetto (2016) and Raffetto et al (2020) emphasise that the pathophysiology of VLU is complex with genetic and environmental factors contributing to the development of chronic venous disease. These abnormalities in turn potentiate the inflammatory and biochemical abnormalities within any wound. These reviews highlight the importance of a dual approach addressing both wound and venous abnormalities if venous leg ulcer healing is to be optimised. Shi et al (2021) have addressed the issues relating to compression therapy versus non-compression therapy in the treatment of venous leg ulceration, concluding that compression is probably beneficial in terms of improved wound healing, reduced pain and improved diseasespecific quality of life.

Franks et al (2016) have highlighted the six perceived benefits of sustained compression therapy in the management of lower limb wounds, which include oedema control, reduced inflammatory mediators and improved haemodynamic function, while Young et al (2021) have outlined the potential benefits of intermittent pneumatic compression (IPC), in particular WoundExpress™ (Huntleigh Healthcare), as an adjunct to compression therapy in the management of mixed ulceration and hard-to-heal VLU. These review findings are supported by Nelson et al (2014), who conclude that there is some evidence to suggest that IPC, when added to compression bandaging in the management of venous leg ulcers, may improve healing.
Parker et al (2015) have reviewed the literature identifying risk factors for delayed VLU healing. Twentyseven studies of mostly low-level evidence (levels III and IV) identified risk factors associated with delayed healing. Those that were consistently identified included:
  • Larger ulcer area
  • Longer ulcer duration
  • Previous history of ulceration
  • Venous abnormalities
  • Lack of high compression.
Additional potential predictors with inconsistent or varying evidence to support their influence on delayed healing of VLUs included:
  • Decreased mobility and/or ankle range of movement 
  • Poor nutrition 
  • Increased age.
Guest et al (2018a; 2020) identified that the presence, or suspected presence of infection was associated with delayed healing of many wound types including VLU. Bui et al (2018) conducted a case record review and identified seven factors that were significantly independently associated with infection, including  depression, chronic pulmonary disease, anticoagulant use, calf ankle circumference ratio < 1.3, ulcer area >/= 10 cm2, slough in the wound bed, and ulcers with heavy exudate. Many of these factors have also been noted to be associated with delayed wound healing.

‘Stacey (2020) suggests that combining a validated point of care test of wound healing with a systematic approach to wound therapies, has the potential to create a new paradigm of chronic leg ulcer treatment based on biomarker directed wound therapy.’ 

Bosanquet et al (2019) have suggested that a gene signature can identify people with chronic venous leg ulcers that are unlikely to heal. Stacey (2020) suggests that combining a validated point of care test of wound healing with a systematic approach to wound therapies, has the potential to create a new paradigm of chronic leg ulcer treatment based on biomarker directed wound therapy. These diagnostic markers and their associated therapeutic partners are not, however, yet available for routine practice and fail to address
the associated venous hypertension. 

RESPONSE TO TREATMENT PREDICTS HEALING

Steed et al (2006) have demonstrated the differing, and early separation of, healing trajectories of ulcers that subsequently heal and those that remain unhealed after up to 20 weeks of care. Prince and Dodds (2006) have shown that VLU that respond to treatment do so at an almost constant rate and that the initial response to treatment can be a reliable predictor of estimated healing time. These observations support the earlier findings of Phillips et al (2000) and van Rijswijk (1993), who found that the early response of a VLU to appropriate care was highly suggestive of subsequent healing times. These systems are based on Gilman’s formula (2004), which attempts to compensate for variations in ulcer size and shape at onset, and appear to give a good prediction of healing based on early response to treatment. 

Phillips et al (2000), looking at percentage reduction in ulcer area, found that approximately 77% of outcomes could be predicted based on a size reduction of more than 44% at three weeks. Likewise, van Rijswijk (1993) suggested that a reduction in ulcer area greater than 30% as early as two weeks was predictive of outcome. Gelfand et al (2002), in an analysis of 29,189 patients, confirmed that, based on the area under the receiver operator characteristic (ROC) curve log rate, log area ratio and percentage change in area can indicate which patients will heal at 12 or 24 weeks of care (receiver operator characteristic 0.72–0.80). 

This earlier work was confirmed by Bull et al (2021), who demonstrated that the healing of venous leg ulcers receiving multicomponent compression bandaging follows a linear trajectory over a four-week period, as measured by gross area healed, percentage area healed, and advance of wound margin. Wound margin advance was the most linear and was also independent of initial ulcer size and is therefore a useful tool to assess healing response.
These observations indicate that, with careful assessment and repeated wound measurement, it should be possible to identify a sub-population of patients with hard-to-heal venous ulcers within the first few weeks of treatment (Flanagan, 2003a; 2003b). Accurate measurement will allow tracking wound healing, allow  healthcare professionals to give patients an indication of likely treatment times, facilitate the identification of complications such as infection at an earlier stage, and allow the targeting of adjuvant therapies (Prince and Dodds, 2006). Figure 1 indicates how adjunctive therapy, whether additive physical therapy or the introduction of advanced wound dressings, could be included in a management algorithm based on both the assessment of initial risk factors and the evaluation of treatment response to standard care.

OTHER LOWER LIMB WOUNDS


VLU studies have shown that wound characteristics and early response to treatment can predict outcome and identify a ‘hard-to-heal’ lower limb wound population irrespective of wound aetiology (Troxler et al, 2006).

 Characteristics for diabetic foot ulceration (DFU) were reviewed by Troxler et al (2006), who also detailed research predicting ulcer healing potential. Bender et al (2020) suggest that wound characteristics, as assessed at the bedside, have the potential to predict wound outcome and warrant further research. In a systematic review, Tay et al (2019) note that toe blood pressure (TBP) may be a useful bedside assessment to aid prediction of DFU healing. Atkins et al (2018) emphasise the importance of recognising and appropriately managing lower limb oedema in DFU management, as oedema has been associated with delayed healing. Ho et al (2013) suggest that there is promising evidence that active oedema reduction by IPC in the diabetic foot improves ulcer healing, and Young et al (2021) identify a potential role for thigh IPC as an adjunct therapy in DFU management.

The potential role of compression and oedema control in lower limb skin tear management has been highlighted by LeBlanc et al in Best Practice Guidelines (2014; 2018) and Fletcher et al (2020). Young et al (2021) report the potential role of thigh IPC in oedema management for skin tears and in other lower limb wounds.

‘While standard compression therapy is unlikely to be appropriate for patients with pressure ulcers on the lower limb thigh, IPC could be appropriate where oedema is considered to be a barrier to healing.’

Troxler et al (2006) highlight the paucity of literature on pressure ulcers related to the factors that predict healing. However, the factors that predict ‘hard-to-heal’ venous leg and diabetic foot ulcers are likely to be important in any type of chronic lower limb wound, including pressure ulcers. Certain factors have been associated with pressure ulcer healing and these include increased ulcer severity and greater patient weight (Itoh et al, 1991; Kramer and Kearney, 2000). These findings in relation to pressure ulcer category were confirmed by Guest et al (2018b), who identified worse healing for higher category ulcers but also noted poorer outcome for patients with low body mass index (BMI) (<18.5 kg/2). Horn et al (2015) have suggested and validated a ‘Wound Healing Index’ predictive model for both body and heel pressure ulcer healing, which they suggest can identify patients most likely to require advanced therapeutic interventions to achieve healing.

While standard compression therapy is unlikely to be appropriate for patients with pressure ulcers on the lower limb thigh, IPC could be appropriate where oedema is considered to be a barrier to healing. Arvesen et al (2017) have demonstrated in a series of case studies the benefit of IPC in oedema control and wound healing in difficult-to-manage lower limb wounds, including pressure ulceration.

CONCLUSION


The recently published National Wound Care Strategy for lower limb wounds provides an initial pathway for care which aims to optimise outcomes. Detailed initial assessment and careful wound observation will allow the early identification of patients with hard-to-heal wounds and the early introduction of adjunctive therapy. This may take two forms, manipulation of the wound bed by topical or systemic actions or the addition of physical therapies such as IPC or hyperbaric oxygen to an existing treatment regimen. The introduction of an adjuvant therapy should not, however, be seen as an alternative to good standard care, but as a specific targeted intervention where costeffectiveness can be demonstrated due to a reduction in healing time and/or a reduction in required healthcare professionals’ time.

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