Non-Healing Wounds
Authors: Nathan B. Menke, MD, Assistant Professor, VCU Reanimation, Engineering and Shock Center, Department of Emergency, Department of Biochemistry, Virginia Commonwealth University Medical Center, Richmond, VA; Robert F. Diegelmann, PhD, Professor, VCU Reanimation, Engineering and Shock Center, Department of Emergency, Department of Biochemistry, Virginia Commonwealth University Medical Center, Richmond, VA; and Kevin Ward, MD, Associate Professor, VCU Reanimation, Engineering and Shock Center, Department of Emergency, Department of Biochemistry, Virginia Commonwealth University Medical Center, Richmond, VA,
Peer Reviewers: David Kramer, MD, FACEP, FAAEM, Program Director, Emergency Medicine Residency, York Hospital, York, PA; and Eric Gross, MD, Attending Physician, Hennepin County Medical Center, Department of Emergency Medicine, Assistant Professor of Emergency Medicine, University of Minnesota Medical School, St. Paul, MN.
Non-healing wounds represent a significant cause of morbidity and mortality for a large portion of the adult population. Wounds that fail to heal are entrapped in a self-sustaining cycle of inflammation. Treatments are aimed at the underlying cause of the wounds. They reset the wound to allow normal progression through the four stages of wound healing, and to prevent further inflammation. This review summarizes the current information regarding the management of wounds that fail to heal normally.
Patients may present to the emergency department with complaints related to their non-healing wound. Alternatively, the wound may be an incidental finding in the evaluation of an unrelated complaint. In my experience, it is easy to overlook and under-assess chronic wounds in emergency department patients. The reasons are many. For example, the chronic wound may be unrelated to the presenting issues and the patient may not express any symptoms related to the wound, so the emergency physician directs the evaluation on the potential emergency conditions and does not assess the wound. Conversely, if hospital admission is planned, the emergency physician may assume, possibly mistakenly, that some other physician down the line will assess the chronic wounds. Often a more practical barrier involved in assessing chronic wounds in the emergency department is the logistical difficulties and time involved in positioning the patient, removing the often complex existing dressings, and being able to reapply the appropriate material. Recognizing these barriers, minimizing the assessment of chronic wounds in the emergency department may lead to further complications and physician regret.
As an emergency physician, it is important to be able to describe the wound, understand the various treatment modalities, and determine the need for consultation or admission to the hospital. Furthermore, the ability to intervene at an early stage in the development of a non-healing wound can save the patient much of the long-term morbidity associated with non-healing wounds.
—J. Stephan Stapczynski, MD, Editor
Introduction
Definition. Non-healing wounds are also known as chronic wounds or chronic ulcers. Chronic wounds are wounds that have failed to progress through the normal stages of healing. The wounds become enmeshed in a pathologic inflammatory state. As a result of abnormal inflammation, the healing process is delayed, is incomplete, and proceeds in an uncoordinated manner, subsequently resulting in poor anatomical and functional outcome.1 These wounds cause a major disability and are characterized by chronicity and frequent relapse.
Relevance. As the prevalence of diabetes and patients over the age of 65 continues to rise, emergency physicians must be prepared to diagnose and treat non-healing wounds. Emergency departments often are used as the point of entry into the healthcare system by many Americans. This fact places emergency physicians at the front line of diagnosis and management for many chronic diseases previously under the purview of primary care physicians. Emergency physicians may find they are required to identify and initiate treatment of medical problems such as chronic wounds to improve outcomes and mitigate potential returns to the emergency department for further care. Lastly, the true medical emergencies associated with such wounds must be recognized in a timely manner to treat limb- and life-threatening conditions.
Differential Diagnosis
The differential diagnosis is aimed toward determining the underlying etiology (see Table 1); however, the majority (approximately 70%) of non-healing wounds are caused by abnormal healing mechanisms related to diabetes mellitus, venous stasis, or pressure.2 Additionally, there are many systemic factors (see Table 2) and underlying diseases (see Table 3) that impair the normal wound healing process and may predispose patients to forming chronic wounds.
| Table 2. Factors That May Impair Normal Wound Healing |
| • Age • Poor nutrition • Poor compliance • Obesity • Immunosuppressive medications • NSAID use • Illicit drug use • Dialysis • Chronic obstructive pulmonary disease (COPD) • Smoking • Transfusion |
| Table 3. Concurrent Illnesses That May Impair Normal Wound Healing |
| • Diabetes mellitus • Congestive heart failure (CHF) • Cancer • Peripheral vascular disease • Renal disease • Endocrine disease • Traumatic injury • Sepsis • Hypertension • Cardiac disease • Connective tissue disease |
Epidemiology
There are no large-scale, population-based studies that examine the prevalence and economic cost of chronic wounds in the United States. The prevalence of the three major types of non-healing wounds (venous stasis, diabetic foot ulcer, and pressure) is estimated to be between 3 million and 6 million in the United States, with patients age 65 and older accounting for about 85% of the wounds.3,4 Given the aging population demographics, it is anticipated that the prevalence of non-healing wounds will continue to increase.
The exact burden on the health care system is unknown; however, non-healing wounds result in enormous health care expenditures with the total cost estimated at more than $3 billion per year.2 None of the financial estimates takes into account the amount of lost work time, decreased productivity, disability payments, nor the cost of rehabilitation. In addition, the resultant psychosocial damage incurred by patients and their families is incalculable.
Complications
Non-healing wounds are prone to complications that not only delay the time to completing the healing process, but also have a negative impact on the patients themselves. Functional limitations that result from non-healing wounds include gait changes and difficulty ambulating. The chronic pain suffered by patients results in a decreased quality of life. Chronic wounds place patients at risk for a long list of infectious complications. Cellulitis, abscess formation, osteomyelitis, gangrene, and even sepsis may occur as a result of an infected wound. Furthermore, all chronic wounds have the potential for malignant transformation (e.g., Marjolin's ulcer).5,6 Lastly, diabetic foot ulcers are the most common causes of non-traumatic amputation in the United States.7
Pathophysiology
Acute wound healing is a carefully choreographed process involving a highly regulated cascade of events with interactions among many cell types, soluble factors, and matrix components. (See Figure 1.) There are four distinct though overlapping phases of acute wound healing consisting of hemostasis, inflammation, proliferation, and remodeling. The hemostatic phase is controlled by platelets, which ensure wound stabilization by providing a provisional fibrin matrix and the release of chemical signals that recruit inflammatory cells into the wounded tissue. The inflammatory phase, which initially is dominated by neutrophils and subsequently by macrophages, prepares the wound bed by killing bacteria and removing devitalized tissue, as well as recruiting fibroblasts. The proliferative phase is characterized by fibroblasts laying down a stable extracellular matrix (ECM). During the remodeling phase, collagen synthesis and degradation continue in an effort to reestablish an equilibrium that results in a stable, mature scar. As the scar matures it eventually achieve approximately 80% of the tensile strength of normal skin.
| Figure 1. Events During Normal Wound Healing |
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The inflammatory reaction of a chronic wound differs markedly from that of an acute healing wound. Under normal conditions, inflammation is a very necessary but self-limiting process. In contrast, inflammation in a chronic wound becomes a self-feeding cycle and serves only to cause further injury and promote inflammation. 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.8-11
It is hypothesized that the reason some wounds fail to progress in a normal fashion is based on a combination of three major factors: changes associated with aging (increased fragility of skin, senescence of fibroblasts, decreased re-epithelialization, depressed collagen synthesis, impaired angiogenesis, etc.) , repeated ischemia-reperfusion injury, and bacterial colonization with resulting inflammatory response.12,13 Neutrophils continue to be recruited and activated by the continued stimulus of tissue trauma, bacterial overgrowth, or leukocyte trapping.
Regardless of the cause, continued up-regulation of the inflammatory cascade leads to a markedly abnormal inflammatory profile for chronic wounds. The large number of activated neutrophils leads to excessive amounts of degradative matrix metallo-proteinases (MMP),14-18 especially MMP-8 and neutrophil-derived elastase. In a normal wound, all of the MMPs can be inhibited by the nonspecific proteinase inhibitor, alpha2-macroglobulin, and specifically by a small group of proteins called tissue inhibitors of matrix metallo-proteinases (TIMP).14,19 In the non-healing wound, the excessive levels of MMPs are not matched by an equal amount of TIMPs. The abnormal ratio of degradative versus protective enzymes results in a wound environment that favors degradation with resultant destruction of ECM.20-22 The excessive number of inflammatory cells also affects the cytokine profile in the wound. The inflammatory cytokines predominate, such as tumor necrosis factor alpha (TNF-alpha), which itself serves as a chemo-attractant factor for neutrophils.2,23 Additionally, there is reduced concentration of factors that promote proliferation such as platelet derived growth factor (PDGF) and matrix deposition such as transforming growth factor beta (TGF-beta).24 Hence, the mitogenic activity of cells is suppressed in chronic wounds.25,26
The end result of the pathologic inflammation in a non-healing wound is more inflammation. The normal feedback mechanisms that end the inflammatory response are short-circuited, leading to an uncontrolled inflammatory positive feedback loop. Neutrophils are activated, resulting in proteolytic enzyme release and tissue degradation that further recruits neutrophils and continues the cycle. In addition, the neutrophils also release reactive oxygen molecules that activate proteolytic enzymes and damage reparative cells. As a result, fibroblasts are unable to make progress in depositing ECM as degradation of collagen occurs more rapidly than its synthesis.27 As previously noted, multiple possible etiologies (see Table 1) including diabetes mellitus, venous stasis, or pressure may result in chronic wound formation; however, regardless of the underlying mechanism, all of these wounds typically heal at a similar rate.28,29 This fact suggests that all chronic wounds have a final common pathway that leads to similar behaviors.
Clinically, the important difference between acute and chronic wounds is the rate of healing. (See Table 4.) The time to complete chronic wound healing is significantly delayed, and in some cases the pathologic protease environment results in wound expansion rather than healing. The lag in closure times increases the wound's vulnerability to local superinfection which further delays healing. In addition, patients are at risk for systemic complications such as cellulitis, osteomyelitis, or sepsis. To properly manage a wound, it is important for the clinician to understand the underlying mechanism of healing. The following section on the management should be considered in light of the pathophysiology background.
| Table 4. Normal vs. Nonhealing Wound Characteristics |
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Clinical Features
Wound assessment begins with determining the extent of the wound. Any ulceration that cannot be evaluated by visual inspection should be debrided surgically and probed to determine the extent of the wound.30 In the absence of a clear contraindication, all wounds should be considered candidates for debridement. The few exceptions are those in which the condition may be worsened by debridement, such as a brown recluse spider bite or pyoderma gangrenosum. A common method of classification for chronic ulcers divides them into four categories based on the amount of tissue breakdown.31 Stage 1 is defined as non-blanchable erythema of intact skin. Stage 2 wounds are defined as partial-thickness skin loss involving the epidermis, dermis, or both. The wound is superficial and may present as an abrasion, blister, or shallow crater. Stage 3 is full-thickness skin loss involving damage to subcutaneous tissue that may extend down to, but not through, fascia. The wound presents clinically as a deep crater with or without undermining of adjacent tissue. Stage 4 is full-thickness skin loss with extensive damage to muscle, bone, or supporting structures. Stage 4 wounds that extend all the way to bone are likely to have deep-seated soft-tissue infections or osteomyelitis. The stage of the wound is important as stage 3 and 4 wounds will have a more prolonged course and have an increased likelihood of requiring surgical management at some point. Wounds that occur on an extremity should be further characterized as non-limb-threatening, limb-threatening, or life-threatening. Furthermore, the following information must be documented: etiology of the wound, duration, location, size, appearance of the wound, appearance of the tissue surrounding the wound, and odor.32,33
The wound needs to be examined thoroughly for any signs of infection including purulent drainage at the wound bed, erythema around the wound concerning for cellulitis, fluctuant mass indicative of an abscess requiring incision and drainage, red streaks indicative of lymphangtic spread of an infection, and enlarged lymph nodes. It is imperative to examine the patient for evidence of systemic spread of an infection such as abnormal temperature (fevers or hypothermia), hypotension, tachycardia, lymphocytosis, and altered mental status.
Diagnostic Studies
Order screening radiographs of the wound site to look for evidence of subcutaneous air, foreign body, and osteomyelitis in all chronic wounds that have not been evaluated previously in this fashion. If clinical suspicion suggests low risk for a complication, this work-up may be done on an outpatient basis; however, the emergency physician should be confident that this follow-up study will occur prior to discharging the patient. If osteomyelitis is suspected based on physical exam or plain radiographs, magnetic resonance imaging (MRI) or radionuclide bone scan is needed to further evaluate the bone itself. Routine superficial wound cultures are not indicated as they are notoriously unreliable. Rather, biopsy from the base of the ulcer has been shown to be the most reliable method for determining the causative bacteria.34 Blood work such as complete blood count (CBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) are not routinely indicated in the emergency department. They may be useful for following the longitudinal course of the wound in consultation with the primary care physician or specialist who is managing the wound. Lastly, for wounds involving the extremities formal evaluation of the vascular system should be considered. This may require venous and arterial dopplers or the more invasive contrast angiography.35 The most important aspect in the evaluation of a wound is determining the etiology of the non-healing wound. If the underlying cause of the wound cannot be addressed, it is difficult to effect wound closure; therefore clinical judgement must guide the decision to order laboratory and diagnostic studies to determine the cause of the wound.
Management
Given that a non-healing wound often is a result of an underlying illness, it is important to treat the underlying cause. This treatment requires tight glycemic control in a diabetic, increasing blood flow in a patient with arterial insufficiency related ischemia, venous compression hosiery, surgery to decrease the effects of venous stasis, pressure relief, etc.31,36-39,40,41 As excessive inflammation is the ultimate cause of the poor healing found in chronic wounds, most treatments initially are aimed at cleaning the wound bed in an effort to reduce the inflammatory response. Initially the wound can be irrigated using saline or lactated Ringer's solution applied using an 18-gauge angio-catheter and a 60-mL syringe. The use of power spray devices should be avoided because excessive pressure causes damage to any granulation that may be present. Furthermore, high pressure can cause bacteria and foreign debris to be forced further into the tissue. Caution also should be used when employing agents such as undiluted hydrogen peroxide and povidone iodine solution (Betadine). These are skin cleansers not intended for use in open wounds. Agents that are powerful enough to kill bacteria will also kill host tissue. There are a number of approved wound cleansers available that can be used (3M Wound Cleanser, Bard Biolex Wound Cleanser, Coloplast, Sea-Clens Wound Cleanser, etc.). Clinical judgment must be exercised when weighing the benefits of wound cleansing to remove bacteria versus the possible damage that can be done to the host's tissue. As a general rule, nothing should be applied to the wound that you would not put in your eye.
Debridement is used to decrease the bacterial load and remove necrotic tissue.30 Both actions serve to decrease further inflammation, and thereby allow the wound healing process to progress normally. Debridement may be achieved by surgical methods using a scalpel, scissors, or enzymatically. Local anesthetic may be needed depending on the innervation of the wound. Enzymatic debridement is accomplished by exogenous proteolytics, fibrinolytics, or collagenases. The final option for debridement is through use of sterile maggots;42,43 chronic wounds may present to the emergency department with contaminated maggot infestation that needs to be removed. The wound then must be cleansed properly. In addition to debridement, local wound care methods are aimed at decreasing the necrotic tissue and protease burden; thus providing a virtual resetting of the wound back into the acute healing phase.
Wound dressings are designed to protect the wound and provide an environment in which the wound is allowed to progress through the normal wound healing process. There are different types of dressing available: hydrocolloids, films, foams, alginates, and hydrogels. Hydrocolloids are occlusive dressings that do not allow fluid to evaporate from the wound bed. In general, occlusive dressings are designed to allow autolytic debridement of the wound by entrapping the patient's endogenous proteolytic enzymes. They allow hypergranulation of tissue, but should not be used in infected wounds that need to be able to drain. If the surrounding tissue is covered by the dressing, it is at risk for damage from the proteolytic enzymes in the wound fluid. Films are also occlusive dressings that are highly adherent. They trap fluid and keep the wound moist; however, they also may result in skin tears and tissue maceration from too much fluid. Foams are made from polyurethane and are very absorbent but do not adhere like films. Secondary dressings may be needed when using foams as they may not be able to provide a strong enough dressing on their own. Alginate dressings are absorbent dressings made from seaweed. They are best used in highly exudative wounds, but if allowed to dry in the wound they may cause damage. Hydrogels are hydrophilic polymers that provide moisture for the wound. They are best suited to wounds that already have good granulation tissue. The choice of dressing will depend on the location, state of the wound, and type of wound.44 (See Table 5.)
The alternative to wound dressings is a topical negative pressure device (Wound VAC). The device is composed of a foam dressing and a tube connecting a unit that generates negative pressures in the range of 50-125 mmHg. The device is hypothesized to work by maintaining a moist wound environment while still removing excessive wound exudates.45,46 It also is thought to increase local blood flow and granulation tissue, and to decrease bacterial colonization. Similar to occlusive dressings, negative pressure devices should not be used on infected wounds. Complications are minimal, but include pain at high negative pressures and hematoma formation. The management of the Wound VAC is best done in consultation with the specialist in charge of the wound management.
Pressure on a wound is a common cause of continued ischemia-reperfusion injury in patients with abnormal sensation due to spinal cord injury or peripheral neuropathy.47 The pressure on the wound decreases blood flow leading to an ischemic state that subsequently is relieved once the patient changes position, resulting in the reperfusion portion of the injury. The continued cycling of pressure injury results in massive amounts of inflammation and tissue damage. Therefore, it is imperative to prevent further injury by providing adequate pressure relief. Pressure relief may be obtained by scheduled turning and repositioning as well as utilizing specialty mattresses for pressure ulcers or therapeutic footwear designed for diabetics depending on the location of the wound.48,49,50 The lack of compliance with these simple interventions often leads to an increase in the wound size. It is very difficult to maintain a proper turning schedule given the amount of time and effort required. The lack of cosmetic appeal results in non-compliance with therapeutic footwear by many diabetics as many only wear them inside their homes. Other factors may induce tissue trauma that impairs healing, including friction, shear stress, and moisture. All of these factors must be addressed in an attempt to maximize the likelihood that the wound will heal successfully.
Another technique for altering the inflammatory profile of a wound involves using exogenous cytokines and growth factors. The exogenous factors are used to shift the degradative microenvironment found in a chronic wound toward a more synthetic mode. In theory, alteration of the molecular environment of the wound may disrupt the inflammatory cycle and allow normal progression of the wound healing process. The only growth factor shown to be clinically efficacious in multi-center randomized controlled trials is recombinant PDGF (Regranex). Unfortunately, PDGF therapy has been of limited clinical value since many chronic wounds do not respond and the therapy itself is very expensive. Limitations of PDGF as a clinical therapy are likely due to the persistent presence of excessive amount of proteases that have been shown to be capable of destroying both PDGF and TGF-beta.51 Therefore, it is not surprising that such growth factor therapy can only be successful once the inflammation and the resulting proteolytic enzymes are controlled. If the inflammation level is subsequently kept low, the wound then is able to progress forward and begin to heal.
The treatment of bacterial wound colonization with topical antibiotics is controversial. The line between colonization and infection has not been well defined. Furthermore, the level at which colonization leads to an inflammatory response has not been elucidated.52 Lastly, bacterial biofilms theoretically serve as a source for an uncontrolled inflammatory response leading to impaired wound healing. The current recommendation is that wounds with a large exudative component are felt to benefit from topical antibiotics. Oral or IV antibiotics should be reserved for patients who have evidence of cellulitis or osteomyelitis. The microbes that are known to cause infections in chronic ulcers include Staphylococcus aureus, Staphylococcus epidermidis, Beta-Hemolytic Streptococcus, Enterococcus species, Klebsiella species, Escherichia coli, Proteus mirabilis, anaerobes, and Pseudomonas aeruginosa. Usually the microflora are polymicrobial in nature. Given the large number of infecting species and the likelihood of multiple pathogens, broad spectrum antibiotics must be used. For outpatient wounds, one possible regimen is oral amoxicillin plus clavulanate (Augmentin) 875 mg PO twice per day plus trimethoprim-sulfamethoxazole 160-800 mg (Bactrim DS) twice per day.53 For wounds requiring IV antibiotics, vancomycin 1 g every 12 hours along with piperacillin plus tazobactam (Zosyn) 3.375 g every six hours is one possible regimen.53
Hyperbaric oxygen (HBO) has been used to try to increase the healing rate in non-healing wounds. HBO is defined as the exposure of a patient to a partial pressure of oxygen greater than one atmosphere, which results in an increased amount of oxygen dissolved in the blood and tissue thereby increasing the pO2 in the wound bed.54 Small studies have shown HBO to be efficacious for some diabetic foot ulcers.55-57 HBO also has been shown to be effective in the treatment of radiation-induced wounds.58 Other situations that have shown some efficacy include refractory osteomyelitis and skin grafts. HBO has not been shown to be beneficial for other chronic wounds. The complications associated with HBO include reversible myopia and central nervous system toxicity in addition to middle ear, dental, and sinus barotraumas. Rarely, pulmonary barotrauma or pneumothorax can occur. The only absolute contraindication to HBO is a tension pneumothorax. Relative contraindications include inability to equalize pressures and coronary artery disease. In short, although referral to an HBO center may be appropriate for radiation-induced wounds or diabetic foot ulcers; not all patients will benefit from this treatment option.
The Wound Healing Society has released a series of guidelines regarding the management of non-healing wounds in the December 2006 issue of Wound Repair and Regeneration.40,41,49,50 Table 6 provides an abridged list of the guidelines/interventions that are most relevant to a practicing emergency physician along with the principles and empiric evidence level behind the recommendations.
Disposition
Criteria for admission include: systemic evidence of illness, such as high fevers, hypotension, leukocytosis, tachypnea, tachycardia, etc.; need for IV antibiotics, such as for osteomyelitis and/or cellulitis; need for debridement in the operating room; any wound that is limb- or life-threatening; or the inability of the patient to adequately care for the wound at home. Furthermore, it is important to recognize that often patients who develop chronic wounds have underlying medical conditions that necessitate a lowering of the threshold for admission.
All patients sent home should have appropriate follow up with a specialist who deals with the particular wound type in question within a few days of discharge. To maximize the probability of wound closure, it is important to establish a relationship between the emergency department and a wound care team. One of the reasons that wounds fail to heal is the lack of early intervention. A primary care physician, who is not an expert in the field of chronic wound healing, may not be equipped to manage complicated non-healing wounds. Given that improper management will not only fail to heal a chronic wound but may result in an increase in size, the emergency physician is in a good position to disrupt this harmful cycle by providing education and appropriate referral to these patients.
Summary
Chronic wounds represent an enormous psycho-socio-economic cost to the individual patient as well as the health care system. There are many causes of chronic wounds, with diabetes, pressure, and venous stasis making up the three most common causes. Chronic wounds are associated with many complications that can further impair the healing process.
The inflammatory profile of a chronic non-healing wound differs greatly from that of an acute wound. The balance between tissue degradation and synthesis is shifted toward degradation resulting in impaired wound healing. Treatment modalities are aimed at restoring the balance.
It is important to use therapeutic modalities in an appropriate manner to maximize the probability of wound closure. The most important factor is addressing any underlying pathology. Next, the wound bed should be prepared by irrigating the wound and debriding necrotic tissue. The most appropriate dressing should be chosen based upon the characteristics of the wound. Alternatively, negative pressure devices help prepare the wound bed to facilitate wound healing. The only growth factor shown to help heal wounds is recombinant platelet derived growth factor. Chronic wounds often are colonized with bacteria, but the use of antibiotics is controversial. PO and IV antibiotics should be reserved for wounds that show clear signs of infection. Hyperbaric oxygen has been proven to help heal radiation-induced wounds and may help diabetic foot ulcers heal, although there are no large randomized controlled trials supporting this therapy.
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Non-healing wounds represent a significant cause of morbidity and mortality for a large portion of the adult population. Wounds that fail to heal are entrapped in a self-sustaining cycle of inflammation. Treatments are aimed at the underlying cause of the wounds.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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