Jennifer J. James, MD

Introduction

Wound healing is a multifactorial process. The presence of an open wound can create a complex catabolic state that can both cause and propagate systemic deficiencies.1 This catabolic state can result in nutritional compromise and the loss of lean body mass (LBM). Conversely, a common complication of involuntary loss of LBM is the development of pressure ulcers—a frequent and serious complication of any disorder characterized by immobility. Involuntary weight loss (IWL) increases the risk of pressure ulcer development by 74 percent, according to the National Pressure Ulcer Long-Term Care Study. 2 Individuals at greatest risk for IWL include those with major burns and trauma (80% prevalence), spinal injury rehabilitation (50%), outpatient rehabilitation (20% to 40%), and nursing home residents (up to 85% prevalence).3 Approximately 10 percent of all hospitalized patients, 20 percent of nursing home residents, and up to 50 percent of individuals with spinal-cord injury (SCI) develop pressure ulcers.4-6 Catabolic breakdown of LBM is significantly associated with pressure ulcer development in hospitalized patients with SCI. In a study by Rochon, et al., those with serum albumin <3.5g/dL had a 45.2-percent incidence of pressure ulcers, compared to only 14.5 percent of patients with normal albumin.7 In the development of a pressure-ulcer risk assessment scale specifically for SCI, Salzberg, et al., cited low albumin as well as the presence of other comorbid conditions as significant factors.8 Loss of LBM significantly compromises immune system function, resulting in an increased incidence of infections.9 This adds to the vicious cycle of nonhealing wounds and perpetuation of the catabolic state, nutritional compromise, and multiple comorbid medical conditions.

Mutually interdependent systemic factors that adversely affect wound healing and predispose a patient to develop pressure ulcers can be placed in four broad categories:
1. Endocrine system: diabetes, testosterone deficiency
2. Immune system function
3. Wound bed perfusion: cardiovascular status, anemia, and oncotic anasarca
4. Nutritional status: malnutrition and vitamin deficiencies.
Identifying and correcting systemic factors that deter wound healing, as well as implementing metabolic and anabolic interventions, have enabled clinicians to heal pressure ulcers of several months’ (or years’) duration.10

Systemic Factors that Contribute to Catabolism

The catabolic state is the response to a variety of stressors, such as trauma, infection, wounds, and malnutrition. The stress response is governed by the endocrine system, central nervous system, inflammatory mediators, and an increase in the production of stress hormones. Catabolism triggers a biochemical cascade that results in IWL, reduced LBM, and systematic devastation, making it almost impossible to heal the wound.

Comorbid Conditions that Contribute to the Catabolic State and
Nonhealing Status

Endocrine system: Diabetes and testosterone deficiency. Diabetes. Spinal-cord injury predisposes individuals to develop metabolic abnormalities in comparison to the normal population. These abnormalities include altered carbohydrate and lipid metabolism, largely as a consequence of reduced activity associated with loss of innervated musculature. This not only results in younger onset of cardiovascular disease but also in an increased incidence of type 2 diabetes mellitus.11 The presence of an open wound can deplete LBM, which further increases insulin resistance. Diabetes and its associated complications also can impede wound healing; thus, wound healing and diabetes are mutually interdependent.

Testosterone. Testosterone is an endogenous anabolic stimulus for protein synthesis. Low levels of growth hormone and testosterone have been reported in patients with acute and chronic SCI.12
The immune system/LBM connection. Loss of LBM significantly compromises immune system function, resulting in an increased incidence of infections.9 Involuntary weight lost as a result of stress response to injury is primarily LBM. The greater the percentage of LBM lost, the more serious the complications. It is imperative to diagnose osteomyelitis underlying a pressure ulcer, as this will deter healing.13 Diagnosis and treatment of osteomyelitis is beyond the scope of this article but must be addressed in order to accomplish healing and reverse catabolism.

Wound bed perfusion. Wound bed perfusion will be affected by multiple factors. The presence of peripheral vascular disease, atherosclerotic cardiac disease, and pulmonary compromise can all affect wound perfusion. The catabolism associated with chronic pulmonary disease represents an additional challenge. Diagnosis and optimal treatment are important.

Albumin is the primary protein in intravascular space, and low levels can lead to reduced oncotic pressure. Hypoalbuminemia thus causes interstitial edema, which can lead to third spacing of fluid throughout the body (oncotic anasarca). The interstitial edema tends to accumulate in dependent areas (such as posterior trunk and lower extremities), which reduces tissue oxygenation as well as tissue tolerance for pressure. Low serum albumin and oncotic pressure also can cause pulmonary edema, pleural effusions, and right heart failure, which further deplete tissue oxygenation.

Various types of anemia can cause wound bed perfusion. Anemia of chronic disease is not uncommon in this population and is one of the markers for malnutrition.14

Nutritional status: Malnutrition and vitamin deficiencies. Malnutrition in patients with pressure ulcers. Wound healing requires both macronutrient and micronutrient support. The combination of an open wound, the catabolic state, and malnutrition presents a significant challenge. Low levels of serum albumin, low serum zinc, and reduced weight/height ratio are all markers for malnutrition in patients with pressure ulcers.14 Low albumin levels correlate closely to presence, severity, and healing of pressure ulcers.15

The stage of the pressure ulcer can be correlated with the degree of malnutrition as determined by albumin levels.16 Elderly nursing home residents with pressure ulcers show significant nutrition depletion compared to a control group.17 Adequate nutrition is imperative for postoperative wound healing. According to the results of the National VA Surgical Risk Study, serum albumin was the best predictor of postoperative morbidity and mortality when compared to 61 other factors.18 A significant decrease in preoperative serum albumin was associated with up to 29-percent greater mortality and 10- to 65-percent greater morbidity post-operatively. Therefore, hypoalbuminemia, as a marker for malnutrition and the catabolic state, was associated with the greatest risk of adverse outcomes.

Sources indicate that nutritional substrate in the presence of an open wound requires up to 50-percent more calories, with up to 2 to 2.5 times more protein.19 Liu compared caloric intake and resting energy expenditure in groups of quadriplegics with pressure ulcers to control-matched quadriplegics without pressure ulcers. The results showed that the pressure ulcer group had a significantly higher caloric intake; however, this was not sufficient to meet caloric needs.20

Vitamin deficiencies. Numerous vitamins are needed to accomplish wound healing. Vitamin A is needed for the stimulation of fibroblasts for protein deposition. Zinc and copper are necessary cofactors for collagen cross-linking. Vitamin B12 is a cofactor in protein synthesis.21 Vitamin B12 deficiencies are more prevalent in SCI individuals and the elderly due to atrophic gastritis and achlorhydria. Atrophic gastritis increases with age. Achlorhydria may be caused by common medications, such as aspirin, H2 blockers, proton-pump inhibitors, or large doses of vitamin C. Achlorhydria also may be caused by bacterial overgrowth due to chronic constipation. Sources indicate that two out of every three individuals with B12 deficiency lack hematological abnormalities (elevated mean corpuscular volume MCV).22 Treatment for B12 deficiency no longer necessitates intramuscular injection but may be addressed through oral replacement at 1,000 micrograms per day, which may improve patient compliance.23

Conversely, the anabolic state is a constructive metabolic milieu that allows for exogenous protein to be used as a substrate for healing and protein synthesis. The catabolic state must be reversed to restore LBM and heal the nonhealing wound.

From Catabolism to Anabolism

Recognition of the catabolic state and reversing the downward spiral of systemic devastation are imperative for wound healing. The first step for the clinician is to identify malnutrition and the catabolic state, using low albumin levels as the marker. The next step entails identifying comorbid conditions that contribute to the catabolic state. Wound healing requires a high-protein substrate of 1.5 to 2g/kg/day, as well as necessary vitamin micronutrients. The provision of substrate in the presence of an open wound is not sufficient to reverse the catabolic state.20,24 Multiple studies show that the use of an anabolic agent with proper nutrition plays a critical role in reversing catabolism and facilitation of wound healing.

Anabolic intervention. Anabolic hormones increase protein synthesis by stimulating amino acid influx into skeletal and visceral organ cells. The anabolic hormones include testosterone, testosterone analogs, and growth hormone. Testosterone is not used for IWL as it has lower anabolic potential and carries increased risks of hepatotoxicity and negative androgenic side effects.25 Growth hormone is not approved by the Food and Drug Administration (FDA) for the treatment of IWL due to the high incidence of negative side effects. Oxandrolone is an oral medication approved by the FDA to treat IWL.

The use of oxandrolone for treatment of IWL and wound healing. Oxandrolone has been shown to be effective in multiple studies in patients with IWL and delayed wound healing.24,26 Spungen demonstrated a significant correlation between restoration of weight lost and healing of pressure ulcers in the SCI
population.27

All individuals reported an increase in appetite while on oxandrolone. The usual length of treatment in the pressure ulcer population is approximately four to five months, on a dosing schedule of 10mg twice daily. Safety and efficacy studies favor the use of oxandrolone over other anabolic agents. In clinical trials with 450 men and women, 99 percent experienced no negative androgenic side effects.28 In one trial, 273 individuals with pre-existing severe hepatic injury were given four times the recommended dose of oxandrolone. In comparison to placebo, no significance in negative hepatic side effects were noted.29 Oxandrolone has been formulated to be 3 to 13 times more anabolic than its analog testosterone and is the only analog that is primarily cleared by the kidney. Although oxandrolone is classified as an anabolic steroid, it actually counteracts glucocorticoid receptors, thus attenuating the catabolic state. Recent animal studies indicate that oxandrolone also may act directly by binding to fibroblast receptors, improving wound healing through enhanced collagen deposition and strength.30 Oxandrolone is contraindicated for patients with prostate or breast cancer, pregnancy, and nephritic syndrome. Drug interactions include oral anticoagulants, such as warfarin and oral sulfonylureas; therefore, these should be decreased before administering oxandrolone, with careful monitoring of the international ratio (INR) and blood sugars.

Clinicians frequently ask about the use of megestrol acetate, which is a progesterone derivative and appetite stimulant. Studies indicate that any weight gained tends to be fat, not LBM.31 Megestrol has been associated with increased risk of thromboembolic disease.32

Summary

Wound healing is a complex multifactorial process. The presence of malnutrition, the catabolic state, comorbid medical conditions, and vitamin deficiencies can preclude wound healing. Recognizing and reversing the catabolic state and providing a high-protein substrate with vitamin supplementation are imperative factors. The anabolic agent oxandrolone may be used to promote weight gain composed largely of LBM and promote wound healing.

Case Studies

RM, a 53-year-old C6 quadriplegic patient injured for 30 years, had nonhealing stage 4 bilateral pressure ulcers of two years’ duration. Several comorbid conditions, including diabetes, anemia, hypothyroidism, functional hypogonadism, hypoalbuminemia, oncotic anasarca, and B12 deficiency, deterred his ability to heal his chronic wounds. Although obese, he was in a severe catabolic state and malnourished. He was given B12 transfusions and supplements. On admission, his albumin was 2.6. After four weeks of anabolic agent therapy and a high-protein diet, his albumin climbed to 3.6. The improvement helped ameliorate his oncotic anasarca, improve wound oxygenation, increase LBM, and enhance diabetic control. After six weeks of multifaceted metabolic and anabolic interventions, his pressure ulcers healed completely.

WE was a 51-year-old T8 ASIA A paraplegic patient with a 13-year-long history of a nonhealing stage 3 pressure ulcer. His comorbidities included B12 deficiency, chronic infections, anemia of chronic disease, functional hypogonadism, hypothyroidism, oncotic anasarca, pleural effusions, and right heart failure. His admittance weight was 106 lb and his albumin was 2.9. After three months of metabolic and anabolic intervention, his weight increased to 136 lb, his albumin was 3.7, and his ulcer was successfully healing.
CWM, a 55-year-old T5 paraplegic, entered the hospital with stage 4 bilateral trochanteric decubitus ulcers, along with significant weight loss, hypoalbuminemia, and B12 deficiency. Anabolic agents and nutritional supplements were administered, as well as a high protein diet and placement on an air-fluidized therapy bed. He healed one ulcer without surgery and had a successful myocutaneous flap surgery six weeks later.

A 65-year-old man with T12 ASIA A paraplegia, RW had a 12.5cm stage 4 sacral pressure ulcer of 13 months’ duration in addition to hypoalbuminemia, oncotic anasarca, pleural effusions, and function hypogonadism. Multifaceted metabolic interventions and the addition of an anabolic agent were so successful that previously scheduled myocutaneous flap surgery was canceled. His ulcer was healed with a split-thickness skin graft, in lieu of a myocutaneous flap surgery.