Deconstructing the Stalled Wound

  Abstract: The stalled wound refers to a wound that has entered a nonhealing or intransigent phase. This can occur as a progression of an acute wound to one of chronicity dictated by events within the wound milieu or following alterations in host immunity. The occurrence may be related by a number of variable factors that collectively or individually can halt the process of orderly healing. A number of biologic events occurring at the wound bed interface, outside the wound (exudate), and related to systemic chronic disease profiles have been identified. This assists clinicians and researchers in developing a systematic approach to managing and reversing this undesired event. First, host factors related to any background chronic disease are checked and controlled. Second, the focus turns to local wound factors adopting accepted principles of wound care to control the wound environment, adding systemic therapies where necessary. If this fails to change the healing milieu, more sophisticated, specialized local wound interventions are introduced. This systematic approach to the stalled wound in individual steps, or collectively, would be expected to re-advance the wound to a normal healing pattern.

Introduction

  The stalled wound is one that has entered a nonhealing or intransigent phase. This can occur as a progression of an acute wound to one of chronicity dictated by events within the wound milieu or following alterations in host factors. A stalled wound may occur spontaneously and unexpectedly in the midst of a supposedly successful healing plan. Information relating to intracellular signaling and recognition of basic biologic processes occurring at a molecular level has increased significantly in the last decade. Much of this information can be extrapolated and analyzed to give direction and impetus to changing the direction of the stalled wound to one akin to acute healing. Occasionally, simply changing dressing routine or introducing new elements to the wound milieu may be enough to kick-start a new wound healing process. There appears to be a certain tolerance that can occur to a dressing regime where the status quo is not enough to take healing to its natural endpoint. New biologic information that is available will aid in developing a scientific based approach to the stalled wound.

The “Stalled Wound” Concept

  In many cases, the definition of a stalled wound overlaps with that of a chronic wound. A wound that does not decrease in size by 30% in 3 weeks or by 50% in 4–5 weeks is considered chronic. These figures are based on studies, such as Sheehan et al’s,¹ which demonstrated that if the size of the wound does not decrease by 50% in 4 weeks, the wound has a 91% chance of not healing in 12 weeks.¹ However, the stalled wound may not necessarily always be a chronic wound, but may occur in the process of the normal healing of an acute wound that suddenly appears to halt in its tracks, often with no apparent reason.   In searching for a reason, obvious causes need to be excluded—those related to wound management and host factors. Thus, physical factors, as opposed to physiologic factors, should be examined first. These include ruling out infection and vascular complications, ensuring proper offloading, performing adequate debridement, and facilitating a moist healing environment.   Once these basic tenets of wound care are satisfied, molecular biological considerations should follow. The pathologic process of a chronic wound is similar to that of a stalled wound. The chemistry of the wound base encourages efficient healing in an acute wound or retards healing in a chronic wound. The physiology that results in pathology in a chronic wound can be applied to a stalled wound (Figure 1) in many cases, namely:     • As opposed to an acute wound with an immediate injury response, there is no trigger (bleeding, tissue damage) to jumpstart the healing process in a chronic wound (similarly in a stalled wound)     • An extended or exaggerated inflammatory phase is usually present in both^2–4     • Accompanying the lengthened inflammatory phase, a higher level of matrix metalloproteases (MMPs) and lower level of tissue inhibitors of proteases (TIMPs) are present with concomitant matrix destruction^5–8     • Relative and often as a result of the increase in MMPs, a deficiency of growth factor receptor sites and/or growth factor destruction by MMPs is observed^5,8,9     • Fibroblasts and other cell types involved in proliferation of the cellular ground substance appear to become inefficient or senescent^9,10     • Higher levels of planktonic bacteria or the presence of biofilm^11–13     • Dry, dehydrated wound or one with heavy exudate and excess moisture^2,4,14     • Altered levels of nitric oxide.^9,15–17   Balanced inflammation is the “holy grail” of successful wound healing. It is an essential phase to completing wound closure, but its over exuberance and persistence causes delayed healing and chronicity.^2–8 At a cellular level, this exaggerated inflammation is represented by the protracted presence of activated neutrophils. In an acute wound, activated neutrophils are virtually nonexistent after the first 72 hours, whereas in a chronic wound, neutrophils are present throughout the healing process.^3–5 Although there is a paucity of articles in the literature relating to stalled wounds and their biologic background, it is likely that activated neutrophils are present in these wound beds. The continued presence and recruitment of activated neutrophils may result from tissue trauma (pressure in pressure ulcers, irritants from wound agents); increased bioburden; leukocyte trapping (peripheral pooling and white cell margination in venous disease); or the release of reactive oxygen metabolites with ischemia reperfusion injury (pressure ulcers, diabetic wounds, venous ulcers).^3,7,18 The significance of these large amounts of activated neutrophils is the resultant stimulation of MMPs, especially MMP-8 and -9, and neutrophil-derived elastase.^3,6,18 These agents systematically degrade the extracellular matrix (ECM) delaying the process of cellular proliferation and wound closure. More specifically, it will become important to be able to define the inflammatory profile of the wound bed to determine the healing potential of the wound. Thus, MMP-1, -8, -9; IL-1,-6, -8; TGF-b; TNF-a are pro-inflammatory, while IL-4, IL-10, and TIMPs are anti-inflammatory. It is likely that measurements of a CAP (cytokine and protease) profile at the wound bed interface will become important in predicting healing capacity of a wound.   MMP-9 levels may predict poor healing in both pressure ulcers and diabetic foot ulcers.^19–21 Fibronectin appears to act as a substrate for MMP-9 action, leading to its degradation, thus promoting leukocyte infiltration and ongoing inflammation.²² While MMP-8 destroys the collagen matrix to prevent the wound from healing, elastase destroys cytokine receptor sites, further impeding the healing process.²³ Additionally, elastase destroys the growth factors (GFs) in the wound that are either extrinsic (such as therapy with platelet-derived growth factor) or intrinsic.²³ This is an important fact that has been overlooked in many therapeutic interventions—feeding a stalled, nonhealing, or chronic wound with GFs of varying types is often an expensive waste of time. If the MMP levels are high (as in most cases of nonhealing wounds), these need to be controlled before applying GFs to the wound, otherwise these GFs are digested as quickly as they are introduced to the wound milieu. Thus, a sequential modality of therapy is likely to be adopted in the future—controlling, MMPs, controlling bacteria, including biofilm, and then feasibly adding GFs to the mix.   Acting in concert, these proteases are capable of degrading every known constituent of soft connective tissue. The nonhealing wound fluid can therefore be regarded as a breakdown-provoking agent in its own right by virtue of these proteases and their “corrosive” tissue destroying capability. Targeting of the wound fluid exudate is, thus, a new suggested strategy in dealing with the nonhealing wound.²⁴ Chronic wound fluid exudate has been proven to be anti-angiogenic as opposed to the angiogenic stimulatory nature of acute wound fluid.^6,7,25,26 Angiogenesis, the formation of new capillaries, is the prelude to granulation tissue formation. The absence of this tissue is a typical feature of chronic wounds, such as decubitus, diabetic, and venous ulcers. Matrix metalloproteinase activity is now thought to be the principal protease activity responsible for generating the angiogenesis inhibitor angiostatin.²⁶ Certain matrix metalloproteinases, including MMP-9, can degrade plasminogen to generate angiostatin that inhibits endothelial cell proliferation. In this way, matrix metalloproteinases may be antiangiogenic²⁶ and CWF thus inhibits granulation tissue and is also considered anti-angiogenic.   The MMPs are usually kept in check by tissue inhibitors (TIMPs) and a-2 macroglobulin, but in nonhealing and chronic wounds, levels of these endogenous inhibitors are not in balance with those of increased proteases, which creates this degradative background.^6–8,19 This results in fragmented and denatured extracellular matrix (ECM) that impedes the healing sequence, especially when the process of absorption and replacement of ECM is delayed.⁵³ One of the critical fragments within the ECM that influences epithelialization is fibronectin. Studies have demonstrated that fragmented fibronectin is present in chronic wound fluid and following successful intervention in venous ulcer patients intact fibronectin collects and epithelialization proceeds.^53,54 Thus, intact ECM components are extremely important to progressive healing pathways.   The processes of matrix synthesis and remodeling are also finely orchestrated. Fibroblasts travel within the ground substance by migrating along the path of the collagen fibrils and following their alignment. They bind first to matrix components, such as collagen, fibronectin, vitronectin, and fibrin via integrin receptors situated on the fibroblast cell surface. While one end of the fibroblast remains bound to the matrix component, the cell extends a cytoplasmic projection to find another binding site. When the next site is found, the attachment to the original site is broken by proteases secreted by the fibroblast, and the cell uses its cytoskeletal network of actin fibers to pull itself forward. Thus, MMPs are essential for fibroblast migration within the ECM.^27,28 However, an abundance of MMPs results in excessive cleavage of fibroblast integrins bonds, lack of migration, and senescence of these fibroblasts.   The bioburden is the number of bacteria on the wound base. The higher the bioburden the slower the healing rate. This appears obvious and simplistic, and is made infinitely more complex by the discovery that in colonized, critically colonized (particularly), and infected wounds, the presence of biofilm may substantially halt the healing process. It accomplishes this by means of its own unique characteristics—the glycocalyx of surrounding armor and the method of self propagation of this bacterial variation make diagnosis, identification, and control difficult.^11–13 Bioburden should be foremost in the mind of the clinician when analyzing the cause of intransigence in the healing sequence. Removal of tissue that is colonized with substantial bioburden that may include biofilms is an essential component of continuous wound management. Debridement, in order to remove biofilm, is an avenue used to “jump start” the wound healing process in a stalled wound.^11–13   Moisture control is a well-recognized prerequisite to efficient wound healing. Ideally, the clinician chooses a dressing that moistens a dry wound or absorbs copious drainage in an excessively wet wound. Moist wound healing is the gold standard for wound care.^2,4,14 Evidence has shown that dry wounds increase the chance of infection, increase pain, and facilitates poor scar formation.¹⁴ The treatment plan also includes an evaluation of the patient’s pain level. Does the patient only have pain with dressing changes or is it chronically present in the wound site area? Pain control is essential to wound healing.   Nitric oxide (NO) is formed by the enzymatic combination of molecular oxygen and the amino acid L-arginine. Nitric oxide activates guanylate cyclase, which elevates intracellular concentrations of cyclic guanosine monophosphate (cGMP), which is frequently used as an indirect measure of nitric oxide production. Because of its high diffusion coefficient, short half-life of about 5 seconds, and prompt decomposition, NO is ideal as a dynamic intercellular signal for wound repair.^9,15–17 Once induced, production of NO within tissue can increase as much as 1000-fold, producing an environment that is toxic to invading microorganisms. NO from keratinocytes and endothelial cells is intimately involved in epithelial migration¹⁷ wound angiogenesis¹⁸ and granulation tissue formation.^9,16,17 Ongoing research suggests that wound fluid NO measurements may predict wound outcomes, particularly for diabetic foot ulcers.⁹   Pain resulting from tissue trauma, infection, dressing changes, and poor moisture balance (too much or too little) complicates the wound healing process.^29–31 Logically, as a result of pain, patients restrict their physical activities, which impacts their lifestyle and has psychological implications and increased general health risks. Compounding this, physiologic release of inflammatory and pain mediators may have direct consequences on wound healing itself.^29–31 These mediators sensitize inflamed tissue to pain, lowering the threshold of nociceptors to pain, resulting in the hyperlagesia and an exaggerated response to pain that is often seen in these patients.¹⁸ Additionally, these mediators often cause the release of each other increasing the pain, compounding the exaggerated inflammation, and negatively affecting wound healing itself.¹⁸ The pain mediators include bradykinin, prostaglandins, leukotrienes, nerve growth factor, histamine, serotonin, substance P, TNF-b, and nitric oxide. Thus, pain control takes on an added dimension related to general wound healing.

Treatment Alternatives

  Having defined likely background physiologic causes of the stalled wound, treatment strategies can be aligned with these biologic alterations. The more obvious strategies are defined by common wound care principles—debridement, moisture control, control of edema, appropriate dressing selection at the local wound interface, and host factor disease and nutrition control at a systemic level (including a ban on smoking). A variety of physiologic and environmental factors related to the past and present host health status can divert the healing cascade, alter the wound bed environment, and stall healing. The first sign the wound bed environment is not conducive to healing is an extended inflammatory stage without progress to the proliferative phase. Visually, healing compromise is evident in a lack of pink vascular tissue and no significant decrease in wound size, followed by a pale white or yellow wound bed, a brown/black wound bed, and increased exudate, odor, and periwound erythema.^2,14 Any of these signs calls for re-evaluation of the overall status of the patient and his or her wound.   Sharp debridement may serve a number of purposes; removal of tissue associated with exaggerated inflammation, activation of a new acute response in the wound bed, and possible removal or exposure of burrowed bacterial biofilm. Leptospermum honey (ALH) dressings are claimed to have debriding and antimicrobial effects.^32,33 ALH’s mechanism of action for debriding includes autolysis and osmosis. The dressing provides a moist environment, aiding the body’s own process of autolysis; the high sugar content of ALH promotes movement of fluid from an area of greater concentration to an area of lower concentration, drawing lymph fluid to the surface of the wound, resulting in a pooling, or osmotic effect that bathes the wound.³⁴ Additionally, circulating plasminogen in the lymph fluid is likely converted to the enzyme plasmin, which disturbs the adherent bonds tethering necrotic tissue to the wound bed.³² Ultrasound debridement devices also have been touted as good methods for debridement. When considering all these reported techniques, it is commonly accepted that sharp debridement, whether it is simply carried out in the wound clinic environment with minimal or no anesthesia, or where more sophisticated technologies are used (VersaJet, Smith & Nephew), is still the method of choice for physically removing unwanted material.³⁵   Various strategies have been employed in the constant quest to mimic the healing sequence seen in acute wounds. These strategies usually involve administering a therapeutic stimulus that is reasoned to trigger a healing response (eg, growth factors, cell lines, tissue substitutes).^2,36,37 Introducing the growth factor at the right time and under the right circumstance appears to be pivotal. Vascular endothelial growth factor (VEGF) might be anticipated to play a greater role in conditions where vascularization is limited, as in the diabetic wound. Keratinocyte growth factor (KGF), supports regeneration and tissue renewal, and thus, may protect against epithelial breakdown, such as the case is with mucositis as a result of radiation therapy (Palifermin recombinant human KGF, Amgen, Thousand Oaks, CA).^2,38 However, as stated previously, if MMP levels are high this therapeutic effort is likely to be fruitless. Thus, recombinant platelet derived growth factor (PDGF) has been of limited clinical value likely because of persistent presence of excessive amount of proteases that have been shown to be capable of destroying PDGF and transforming growth factor-b.^2,36,37 Such growth factor therapy can only be successful once the inflammatory and protease microenvironment are under control.   Controlling the protease microenvironment is an obvious strategy used to try and inhibit the destructive wound milieu. In addition to the tissue inhibitors of matrix metalloproteinases, a number of other naturally occurring and synthetic inhibitors also exist. Reports in relation to doxycycline/tetracyclines are varied and inconclusive,^39,40 but more targeted approaches are being sought in topical dressing applications. Thus nanocrystalline silver (Acticoat, Smith & Nephew) has been demonstrated to have anti- MMP-9 effects in inflamed tissue,^41,42 anti-protease dressings (Promogran and Prisma, Systagenix) are claimed to mop up excess MMPs and cadexomer iodine,43 nanocrystalline silver and a new class of agents, bioflammacides/anti-biofilm gel (Flavonix, Southern Medical Irene, South Africa) have been demonstrated to have anti-biofilm effects.^44,45 The debriding action of honey has been noted above. Dressings with analgesic potential containing ibuprofen (Biatain Ibu, Coloplast) are important developments in local pain control.⁴⁶   A host of new dressings have applicability when attempting to change the local wound milieu in a stalled wound. Simply changing the type of wound dressing may be enough to shift the wound-healing cascade. A form of wound dressing “tolerance” appears to occur in many situations, and merely changing the nature of the dressing may be all that is needed to correct the system.   Empiric antibiotic therapy is not the answer to most cases of stalled wounds unless good evidence of deep-seated infection exists. The practice of treating wounds with antibiotics without evidence of infection has lead to multidrug resistance of bacterial strains. Methicillin-resistant Staphylococcus aureus (MRSA) is just one example.⁴⁷   In cell and tissue therapy, multiple biologic skin substitutes—bioengineered tissue constructs—are being utilized. In a stalled wound situation, it seems to be advantageous to use constructs following tissue debridement. Interestingly, even in cases of minimal debridement, some publications have reported dramatic^48,49 stimulation of wound granulation following introduction of constructs to long standing wounds.⁵⁰ This suggests that regenerative therapies can act in the absence of a significant injury or inflammatory response on the part of the patient. It is uncertain whether the construct itself stimulates a situation similar to fresh injury with an altered inflammatory response or whether it simply stimulates a regenerative response by providing the building blocks for matrix regeneration. What is clear is that in certain instances of stalled wound healing, a tissue construct can significantly change the biologic response and promote or trigger a pro-healing cascade. It appears that the patient response probably does not require a native rekindling of injury and inflammation.⁴⁸   Aside from the obvious nutritional support that should be applied to all patients, deficiencies in arginine should be considered, which can impact wound healing related to nitrous oxide levels noted previously.⁵¹ Other modalities that may help to change wound dynamics include negative pressure wound therapy (NPWT) and hyperbaric oxygen therapy (HBOT).   As noted above, unrelieved pain has detrimental effects on wound healing. A rational approach to pain control should be adopted to try to prevent the situation of chronic pain. This involves starting treatments at a low dose and increasing slowly. It also involves differentiating local nociceptive pain from centrally controlled neuropathic pain. Tissue injury often results in nociceptive pain, in which persistent pain is felt by peripheral nerves in the skin in response to the release of mediators from the damaged tissue.^18,29–31 Treatment of nociceptive pain involves a graded system of analgesics ranging from non-steroidal anti-inflammatory drugs (NSAIDS), acetaminophen weak opioids (eg, codeine) to strong opioids (eg, morphine).   Neuropathic pain is usually associated with a chronic pain state. It may occur following direct injuries to nerve fibers or where tissue injury results in dysfunctional nerves, sending incorrect signals to pain centers. This results in exaggerated, ongoing pain that necessitates treatment with centrally acting agents.^29–31,52 Thus, the range of treatments may involve the sequential prescription of drugs—tricyclic antidepressants (amitriptyline, nortriptyline desipramine); anticonvulsants (gabapentin/pregabalin) ending with third tier options of Serotonin- norepinephrine reuptake inhibitor (SNRIs) antidepressants: duloxetine, venlafaxine and anticonvulsants: (carbamazepine, sodium valproate).^29–31,52   Lastly, it is likely that a range of new diagnostic tools will assist with decision making in stalled wounds. Measurements of MMPs, biofilm identification, and nitrous oxide levels (in wound fluid) would all be of enormous value in aiding therapeutic choices in stalled wounds.

Discussion

  The difficulty in dealing with the stalled wound is that the biologic processes occurring at a molecular level are often compounded by physical factors relating to the management of the physical environment, (ie, a moist healing environment, control of wound exudate, and control of bacterial contamination). Significantly improving healing in stalled wounds may require going beyond the physical environment to address the biological mechanisms, although the physical factors cannot be ignored and take first place in the sequence of management.   Thus initial factors that need to be addressed as the primary response include host disease control, nutrition, banning smoking, examining concomitant drug therapy that may be influencing wound healing, adequate debridement, controlling edema, exercise program, off-loading, dressing selection, or change of dressing type.   In stalled wounds, an imbalance exists in the production of MMPs and their natural inhibitors (TIMPs). This has been shown to slow down the healing process.^6–8,19 Prolonged MMP expression destroys growth factors, impairing the wound’s ability to heal. Research has revealed that wound bioburden (including biofilm) and protease enzyme imbalance, in particular differential expression of particular MMPs (elastase)8,9 and their inhibitors (TIMPs), are strongly associated with delayed healing.^6–8,19 In many instances, the pathophysiology described above mimics that of the chronic wound with similar molecular events occurring in both. However, an acute wound may also go through stalled healing without becoming chronic and the management techniques described above (debridement, anti-biofilm, etc.) may be enough to trigger a change in pathophysiology and rekindle the healing sequence.   In keeping with the background concepts discussed above, the sequence of investigation and management of the stalled wound would typically involve the following steps (Figure 2):     • Background host disease control (diabetes, hypertension, smoking, drugs, nutrition etc); systemic interventions related to host factors: blood transfusions, pain control, nutritional support     • Standard local wound physical corrections: bacteria, moisture, edema control (debridement, compression if indicated, appropriate dressing selection)     • Specialized local interventions—MMP control; biofilm eradication; introduction of wound scaffold; NPWT; HBOT; pain reducing dressing; protease inhibitor dressings; growth factors (PDGF, VEGF, KGF)     • Additional systemic interventions (antimicrobials).

Conclusion

  Every wound care clinician is periodically faced with the challenge of a wound that has entered an intransigent phase in relation to its healing end point. This stalled wound may be caused by a number of variable factors that collectively, or individually, halt the process of orderly healing. The progressive increase in the knowledge base related to biologic events occurring at the wound bed interface and to systemic nuances of chronic diseases, has provided clinicians direction in sequentially approaching, managing, and reversing this undesired event. Thus, once host factor-related chronic disease background is checked and controlled, the focus shifts to local wound factors adopting accepted principles of wound care to control the wound environment. If this fails to change the healing milieu, more sophisticated, specialized local wound interventions are introduced. Simultaneously, or following this approach, systemic additions to the program are made. This systematic approach to the stalled wound in individual steps, or collectively, would be expected to re-advance the wound to a normal healing pattern.

References

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