Wound bed preparation and oxygen balance – a new component?

Abstract

Chronic wounds have traditionally been treated by conservative means. It was Winter’s moist wound healing research, in 1962, that stimulated a proliferation of a moist interactive dressing technologies. Even considering this advancement in thinking, chronic wounds continue to be a problem for many clinicians. An increasing delineation of the science of healing in the past 20 years has redefined the way in which we both evaluate and treat wounds. This scientific understanding has raised wound care from the clinical problem arena to that of clinical specialty, where many now cross refer patients to specialists in this field. Wound bed preparation (WBP) has played a significant role in this change in practice. The concept has changed an ‘art’ of switching at random from one dressing to another, into a clinical science. WBP has come to the forefront as a major educational aid to help others develop appropriate treatment of the underlying disease causing the wound and patient requirements. The concept of WBP evolved over the recent years, becoming more and more sophisticated with time. Recent adaptations have brought together many of the current components. This article proposes yet another element of WBP, that of ‘oxygen balance’.

Background

Chronic wounds are often resistant to healing and do not follow the expected trajectory (30% smaller in 12 weeks) (1). Increasing scientific evidence suggests that many chronic wounds contain phenotypically altered cells with diminished molecular and cellular responses to promote healing (2). There may also be impaired cell migration and insufficient angiogenesis to support complete closure with an imbalance favoring tissue destruction modulated by matrix metalloproteases (3). The debilitating and chronicity of these wounds constitute a significant burden, especially in the older population (4). As our society continues to age, this demographic shift demands a different approach to delivering chronic wound care.

The optimal care of individuals with chronic wounds is complex and interpolated with local wound issues, patient‐centred concerns of individual patients, and problems with healthcare systems that may potentially thwart healing. As wound care knowledge has evolved since Winter (5) established the importance of moist healing in 1962, a plethora of modern dressings had emerged with varying abilities to interact with the wound environment (6). However, wound healing does not always follow delivery of appropriate local wound care, especially if the underlying cause and patient centred concerns are not taken into account (7).

To ensure a systematic approach to wound care, Sibbald et al. (8) proposed the wound bed preparation (WBP) paradigm that links treatment to the underlying cause and patient‐centred concerns with three key components of local wound care: debridement, control of infection (bioburden)/prolonged inflammation and moisture balance.

Treat the underlying cause

This is the first step in a professional approach to chronic wounds including examples such as, compression in venous disease and plantar pressure redistribution for diabetic neuropathic foot ulcers (where infection is kept under control and tissue perfusion is adequate for healing). For pressure ulcers, clinicians need to optimise pressure relief and they should also optimise nutritional status, prevent friction and shear, control excess moisture from incontinence of stool and urine, maximise mobility and promote frequent turning (Table 1) (8).

Table 1.

Important elements of treating the cause of various wound types (28)

Conditions	Treatment
Venous disease	High compression in the absence of significant arterial disease (ABI ≥ 0·8)
Diabetic foot ulcer	Think VIPS: Vascular supply: adequate for healing; Infection: Bacterial balance; Pressure: plantar redistribution; Sharp surgical debridement
Pressure ulcers	Pressure redistribution, nutrition, friction and shear, moisture control, increase mobility

Although complete healing may seem to be the logical goal for most patients, some wounds do not have the ability to heal because of one or more of the following: inadequate vasculature, a cause that is not treatable/correctable, coexisting medical conditions or prescribed drugs that impede the healing process (7). Health care professionals and patients must be cognisant of the fact that not all chronic wounds are healable or have the ability to heal (9). Healable wounds have several requirements starting with adequate tissue perfusion. In addition, patients with these wounds do not have any coexisting medical conditions (e.g. advanced cancer) or prescribed medication (e.g. immunosuppressive drugs) that would prevent normal healing. A maintenance wound is a wound with the ability to heal but either the patient does not consistently adhere to treatment or the health care system may restrict access to appropriate resources. A patient with a non healable wound has inadequate vasculature, a cause that is not treatable, coexisting medical conditions exist or medications prohibit the healing process. To put this in a meaningful context, this type of wound classification system helps clinicians and patients to identify common realistic outcomes (Table 2). By instituting and translating the WBP paradigm into practice, Woo et al. showed that healing can be improved in 4  weeks (t = 2·67, P = 0·01) in a cohort of 111 patient with leg and foot ulcers (10).

Table 2.

Wound classification according to healability

Wound prognosis	Treat the cause	Blood supply	Coexisting medical condition/drugs
Healable	Yes	Adequate	Does not prevent healing
Maintenance	No*	Adequate	Possibly prevents healing
Non healable or palliative	No	Usually inadequate	May prevent healing

^* Cause not treated because of lack of patient adherence or health system factors preventing access to resources. © Woo and Sibbald (24)

Patient‐centred concerns

A chronic wound may exert a devastating effect on patients by influencing many domains associated with quality of life including limited physical mobility, decreasing activities of daily living, as well as disruption to work, leisure activity (11) and social functioning (12). Patient‐centred concerns may also include treatment of pain (nociceptive and/or neuropathic) and related symptoms. Patients’ input into treatment preferences must be taken into account to enhance adherence. This model describes the extent to which a person is willing to follow through on agreed recommendations between the patient and the health care provider. The term adherence conveys a willingness on the patient’s part to actively participate in his or her care. Successful treatment of a chronic wound entails a spectrum of recommendations, often requiring significant lifestyle changes that are complex, intrusive and inconvenient. Oosterber and Blaschke (13) suggested several strategies to enhance adherence including patient education, regular follow‐up and support.

Local wound care

Tissue debridement

The wound bed is optimally prepared by aggressive and regular debridement of any firm eschar or soft slough (14). A firm eschar serves as a proinflammatory stimulus inhibiting healing, while the slough promotes bacteria proliferation (15). In persons with diabetes, callus is usually associated with increased local pressure and debridement should be accompanied by appropriate assessment of plantar pressure redistribution and patient adherence (15).

Infection

Early recognition and management of increased bacterial burden and infection is vital during the ongoing care of a patient with a chronic wound. Bacterial damage will cause wound deterioration, delaying wound healing and thereby increasing the risks of further morbidity and mortality (16). Critical colonisation and wound infection is common in certain patient populations such as those with diabetes partly related to their relative immunodeficiency (17) (high glucose levels, other impairment of granulocytic function or inflammatory cell chemotaxis defects). External contamination of the wound bed by microorganisms can occur from the environment, dressings, the patient’s secretions and their own hands along with the hands of health care provider (18). In view of the ubiquitous presence of microorganisms, the clinician must determine whether bacterial balance (contamination or colonisation) or bacterial damage (critical colonisation or infection) is present. The assessment of infection in a chronic wound is a bedside skill.

Cutting and Harding (19) proposed that evidence of red friable, exuberant granulation, increased discharge and new devitalised tissue along with other criteria are related to infection. In Gardner et al.’s study (20), additional symptoms and signs including pain, increase wound size, new areas of breakdown and odour were associated with wound infection. Patients with diabetes and neuropathy that have wounds probed to bone are more likely associated with osteomyelitis (21). However, in a systematic review of existing high quality Randomised Controlled Trail (RCT) evidence, Nelson et al. (22) could not find any conclusive evidence that individual signs and symptoms are reliable to identify wound infection.

Sibbald et al. (23) created a mnemonic NERDS© and STONES© (Figure 1) that represents the initials of the signs to categorise the two levels of bacterial damage or infection. This is a theoretical framework that requires further validation or modification. With the current proposal, two or three of these signs should be sought for the diagnosis in each level. If increased exudate and odour are present, additional signs are needed to determine if the damage is superficial, deep or both. This concept has been preliminarily validated in a study of 96 patients with leg and foot ulcers (24).

Figure 1.

Principles of NERDS and STONES.

Clinicians may consider different strategies to control bacterial burden dependent on involvement in the superficial or deep/surrounding compartment of the wound. The promotion of bacterial balance helps to maximise host resistance and prevent further contamination, colonisation and critical colonisation from setting the scene for infection (25).

Increased surface bacterial burden may be treated with antibacterial dressings or topical antimicrobial agents (26). Silver is a commonly used topical antimicrobial agent that has been shown to be effective against yeast, mould and a large number of Gram‐positive and Gram‐negative microorganisms, and several antibiotic resistant strains such as MRSA and VRE (27). Silver requires ionisation in an aqueous media to exert its antimicrobial effect (28).

Other antimicrobial agents that can be considered include iodine (29), chlorhexidine derivative (e.g. polyhexamethylene biguanide). Deeper infection would require with systemic antimicrobial therapies (30). The decision to prescribe antibiotics should be based primarily on clinical evaluation and supplemented by bacterial testing including culture results (30). Alternatively, non infective processes can produce an inflammatory response that can mimic infection (31).

Moisture balance

Appropriate moisture is required to facilitate the action of growth factors, cytokines and migration of cells including fibroblasts and keratinocytes (32). Previous systemic reviews failed to ascertain the superiority of one dressing class over another in various chronic wound types. There was no significant difference between modern advanced moisture controlling dressing and normal saline gauze 33, 34. However, saline gauze usually requires frequent dressing changes to maintain adequate moisture balance causing pain and trauma, damage to newly laid granulating tissue and this process is nursing time intensive and therefore costly (35).

Edge effect

Healing of chronic wounds maybe arrested for many reasons may be stalled for many reasons. The ‘edge effect’ refers to epithelium that is failing to migrate across a firm and level granulation base (36). The epidermal edge may have a steep cliff‐like appearance rather than the tapered edge of advancing purple‐pink epithelium that slopes into the mature granulation base.

Wound healing may be improved by local addition of deficient components including cells, growth factors and tissue matrix components (37). Another approach would include complementary therapies such as oxygen (topical versus systemic).

Could some of these non healing chronic wounds be triggered into a healing trajectory by addressing their oxygen demands?

Oxygen and wound healing

Increasing scientific evidence suggests stalled chronic wounds contain phenotypically altered cells with an increase in senescent cells that are less responsive to cellular signalling. There are also reports documenting decreased growth factors 38, 39 and other diminished cellular responses.

Oxygen and their reactive oxygen species are involved in all stages of wound healing, modulating cell migration, adhesion, proliferation, neovascularisation, remodelling and apoptosis 40, 41.

The key multifaceted roles of oxygen in wound healing include:

• • Energy metabolism – oxygen is the last electron acceptor for mitochondrial cytochrome oxidase leading to the production of high‐energy phosphates that are required for multiple cellular functions 42, 43.
• • Collagen synthesis – oxygen is involved in the hydroxylation of proline and lysine in procollagen that is crucial in collagen maturation 44, 45.
• • Neovascularisation – although relative hypoxia is required to engender neovascularisation, supplemental oxygen administration has been shown to sustain and accelerate vessel growth. Oxygen induces vascular endothelial growth factor mRNA levels in endothelial cells and macrophages in vivo 41, 46, 47. It may also facilitate wound contraction by triggering the differentiation of fibroblasts to active contracting myofibroblasts 48, 49, 50, 51.
• • Antimicrobial action – wound tissues are susceptible to increased bacterial burden under a relative hypoxic environment. Through the respiratory burst activity, oxygen is converted by leucocytic NADPH oxidase to a superoxide ion and other reactive oxygen species that are all lethal to bacteria 52, 53, 54, 55.

Oxygen is often relatively deficient in the local wound base because of disrupted vasculature and the high‐energy demand to support tissue regeneration (56). Diminished circulation and hypoxia increases lactate production secondary to anaerobic metabolism and is deleterious to wound healing (57). These levels will be even lower if the wound does not have enough blood supply to heal.

The function of macrophages, fibroblasts and endothelial cells is impaired if local perfusion and oxygenation are compromised in vitro (58). There is evidence to suggest that insufficient oxygen may lead to an increased bacterial load and poor collagen deposition. Conversely, previous studies (57) have shown that wound healing can be accelerated with hyperoxia. Heng et al. (58) stimulated a 90% healing rate in the topical oxygen group compared with only 22% in the control group (standard treatment). Some studies using hyperbaric oxygen therapy (HBOT) have produced positive effects on wound healing 59, 60, 61. Whether topical oxygen therapy has the same efficacy as HBOT remains to be established and topical therapy is not associated with increased circulating oxygen saturation in contrast to HBOT (62). Recently, Goretti et al. (63) synthesised a superoxidised solution with the electrolysis of water and sodium chloride to generate reactive species of chlorine and oxygen. They showed that healing time for patients with diabetes and foot ulcers was significantly reduced with the application of a superoxidised solution in comparison with their retrospective review of a cohort that were treated with povidone iodine 50% diluted in saline (P = 0·0036). Other authors argue that there is no proven advantage for topical oxygen application (64). While HBOT may improve wound healing, it should be pointed out that oxygen in high doses is toxic particularly to the brain and lungs. Other potential drawbacks of HBOT include damage to the ears and nasal sinuses, time and direct cost associated with daily travel to and from the treatment centre, and the psychological effect of confinement. Topical low dose of oxygen may be a feasible alternative.

Remaining challenges with WBP?

After several years of experience with the WBP model, it has become increasingly clear that microbial infections can lead to severe local hypoxia (65). Hypoxia does not favour healing, especially if anaerobic pathogens are involved. To minimise complications caused by infection, we should avoid hypoxic conditions (Table 3).

Table 3.

Why oxygen?

Large blood vessels	Local wound
Supply oxygen to the tissue for repair and regeneration	Needed for respiration
Provide tissue nutrients	Neutrophil killing and other parts of host resistance versus bacteria
Optimise host resistance	Collagen cross linking
One cigarette will decrease the delivered oxygen 30% or more for an hour	Inhibit anaerobes
	Chronic hypoxia perpetuates neutrophil infiltration

Oxygen balance and WBP?

Is oxygen balance – making sure that oxygen supply is balanced with oxygen demand – an important issue for every wound?

This concept is certainly not the same as attempting to treat every wound with HBOT, an extreme measure that saturates the body with oxygen, rather than achieving local balance.

Local oxygen balance should not be addressed by continuous exposure of the wound to air or pure oxygen, at the expense of all the other key aspects of WBP (66). Instead, local oxygen delivery may be integrated into our whole approach to good WBP, as part of the attempt to deal with all the needs of a wound (Table 4).

Table 4.

DIME with oxygen balance: an extension of the WBP

Clinical observations	Molecular and cellular problems	Clinical actions	Effect of clinical actions	Clinical outcome
Debridement	Denatured matrix and cell debris impair healing	Debridement (episodic or continuous) autolytic, sharp surgical, enzymatic, mechanical or biological	Intact, functional, extracellular matrix proteins present in wound base	Viable wound base
Infection, inflammation	High bacteria, cause ↑ inflammatory cytokines, ↑ proteases, ↓ growth factor activity, ↓ healing environment	Topical/systemic antimicrobials, anti‐inflammatories, protease inhibitors, growth factors	Low bacteria, cause ↓ inflammatory cytokines, ↓ proteases, ↑ growth factor activity, ↑ healing environment	Bacterial balance and reduced inflammation
Moisture imbalance	Desiccation slows epithelial cell migration, excessive fluid causes maceration of wound base/margin	Apply moisture‐balancing dressings	Desiccation avoided, excessive fluid controlled	Moisture balance
Edge of wound – non advancing or undermined	Non migrating keratinocytes, Non responsive wound cells, abnormalities in extracellular matrix or abnormal protease activity	Reassess cause, refer or consider corrective advanced therapies	Responsive fibroblasts and keratinocytes present in wound	Advancing edge of wound
		Bioengineered skin
		Skin grafts
		Vascular surgery
Oxygen imbalance	Hypoxia prevents optimal cellular function and allows anaerobic proliferation	Oxygenating therapies (e.g. Oxyzyme)	Cellular functions improved and infection controlled	Improved wound healing and bacterial balance

One opportunity presented by this approach is that some non healing wounds could be helped by offering them advanced/adjunctive therapies which combine traditional WBP principles with oxygen balance (Figure 2). Would attention to this additional factor further increase rates of healing in relatively uncomplicated wounds? These important issues need to be addressed as we adapt and refine the WBP concept.

Figure 2.

A new wound bed preparation paradigm?

A new concept for wound healing – oxygen balance via an active oxygen‐concentrating wound dressing?

Oxyzyme™ is an advanced wound dressing technology consisting of a prehydrated, sheet hydrogel. Oxyzyme Sterile Wound Dressings are comfortable, easily removed hydrogel sheets that permit the absorption of fluids. The hydrogel format provides the critical elements of moisture balance and autolytic debridement, essential for optimising WBP (67). Through its unique enzyme‐driven actions, this gel dressing may also help to achieve the third local desired effect – bacterial balance.

When the dressing is removed from its airtight packaging and placed on the wound surface, the built‐in enzyme action is triggered to produce a low level and steady flux of hydrogen peroxide within the dressing over the course of about 12 h. Hydrogen peroxide is not able to escape beyond the dressing surface, as it is instantly decomposed to form dissolved oxygen and water. The overall effect is that hydrogen peroxide is used as an oxygen shuttle, transporting oxygen from the atmosphere to the wound environment. After peaking at around 6–8 hours, the oxygen delivery rate declines in a programmed manner until normoxia or slight hypoxia is achieved by 18–24 hhours. In addition to the metabolic benefits of the oxygen, it also helps inhibit anaerobic bacteria. This antimicrobial effect is further enhanced by the incorporation of a very low level of iodide (<0·04%) in the hydrogel. The hydrogen peroxide and iodide interact to produce molecular iodine and oxygen. Although the iodine is produced at low levels, it enhances the antimicrobial effectiveness of the dressing. This dressing may be considered for use across the whole chronic wound spectrum from the debridement stage through inflammation, remodelling and reepithelialisation 68, 69.

Perhaps oxygen balance may be achieved by this programmed, low‐level, pulsed oxygen concentrating effect. Wound care clinicians will watch with interest to determine its clinical performance through case studies and wider use, as the product becomes available.

Conclusions

The importance of local oxygen balance in the chronic wounds needs to be further substantiated with scientific evidence to decide whether ‘oxygen balance’ is a missing element from WBP. We present this to open the debate providing food for thought!

Conflicts of interest

RGS and DQ have acted as paid consultants to Archimed Ltd. and have received funding for research carried out in this work. KW declares no conflicts of interest.