Restoration of Body Weight, Function, and Wound Healing After Severe Burns Using the Anabolic Agent Oxandrolone is Not Age Dependent

   Severe catabolism, resulting in a rapid loss of lean body mass, is a well recognized complication of major burns.

Significant involuntary weight loss is a predictable occurrence despite optimum nutrition and early wound closure.1-5 The majority of lost weight is lean body mass, due to the overwhelming catabolic response that leads to the use of body protein for energy.3 Complications of lost lean mass are of particular concern for the older patient who already is likely to have sustained pre-injury loss of body protein as the result of decreased endogenous anabolism and decreased physical activity,5-7 including a decrease in healing for any remaining surgical procedures. Also, the restoration of body weight and lean mass occurs at a much slower rate than the rate of loss.6-8 This process of weight and lean mass restoration is even slower in the elderly, as decreased levels of the anabolic hormones, human growth hormone, and testosterone occur with aging.6,7,9 Providing an exogenous anabolic agent, such as the testosterone analog oxandrolone, has been shown to significantly increase the rate of restoration of lost lean mass after injury.10 The restoration of lean mass correlates with improved wound healing and musculoskeletal function.11 However, the effect of anabolic agents on weight and lean mass gain has not been specifically determined for the older burn patient.12 This information would be of value, as a more rapid restoration of function is essential in the older patient to avoid a permanent disability.13, 14 The results of previous report10 on the rate of weight gain in a smaller population of older burn patients have been expanded in this larger study to include the rate of healing of a new skin graft donor site. To determine the effect of the potent anabolic agent oxandrolone combined with optimum nutrition and exercise on restoration of lean mass and function in the older versus young burn patient, a randomized, controlled clinical study was conducted among patients in the post-catabolic or recovery phase when wounds were nearly closed and endogenous anabolic activity was returning to normal. During this phase, investigators tested the effect of increasing anabolism on the rate of restoration of lost lean mass. Methods

   Study design. Using a randomized, prospective study design, patients with deep burns not exceeding 55% of total body surface (TBS) were studied. Participants included major burn patients admitted to the Brigham and Women's Hospital Burn Center between 1998 and 2001. Of all burn patients, 90% have burns less than 50% of TBS; a more severe burn in an older population would result in a very high morbidity and mortality rate, making an assessment of age-related anabolism very difficult.12 In addition, all patients in this category of burn size were considered candidates if they were at least 17 years old and their burn size was sufficient to produce a severe catabolic state. A burn of 20% of body surface is large enough to produce a rate of catabolism and hypermetabolism which exceeds 50% of normal.3 Standard care protocols were used on all patients during the acute care phase of injury, including early debridement and wound closure, along with optimum nutrition.14 Patients included in the study were anticipated to require at least 4 weeks of inpatient rehabilitation care during the recovery phase to restore sufficient lost lean mass and musculoskeletal function before discharge. Although somewhat arbitrary, the beginning of the recovery period was determined to be a stable cardiopulmonary status, no active infection, and metabolic rate at rest (indirect calorimeter) less than 130% of normal. Patients also needed to be on adequate nutrition with supplements (or tube feeding), as well as have the ability to actively participate in a physical therapy program. All study patients were determined to have met recovery phase criteria before entry into the study. Patients were randomly assigned to a nutrition-exercise alone group (standard care) or nutrition-exercise and oxandrolone group (Oxandrin, BTG, Iselin, NJ) - one group of each criteria for the age of 18 to 45 years and one group of each criteria for age 60 years and older, making four groups. All patients met the criteria for the use of oxandrolone (ie, involuntary weight loss). All patients placed on oxandrolone were given 10 mg orally, twice a day, for 4 weeks or until pre-injury function and weight had been restored. The only exclusion criteria were the presence or a history of prostatic cancer, an elevated PSA, or female breast cancer. The research proposal was reviewed and approved by the Brigham and Women's Institutional Review Board with all procedures and consent forms obtained in accordance with AMA guidelines.

   Measurements. Initial measurements during the acute phase included nutritional profile, weight loss, and length of stay before entry into the acute burn-wound rehabilitation unit.11 Initial pre-injury weight was determined by history if resuscitation had been started before admission weight was obtained. Body composition was not obtained initially because post-resuscitation tissue edema would falsely elevate the measurement of lean body mass. Based on prior metabolic studies in this population, 75% of the weight loss sustained during the critical illness phase was considered to be lean mass.1-4 A burn-wound nurse coordinator, along with the burn surgeons at the Brigham and Women's Hospital, monitored all patients. Daily nutritional profiles were obtained. Body composition was measured using bio-electric impedance analysis (Quantrim BA Systems, Clinton, Mich.).15 Weekly changes in lean body mass were calculated and compared with changes in body weight to determine the percent of weight gain that was lean mass. The rate of healing of a standardized skin graft donor site 0.0012 inch deep was assessed. Because patients are transferred to the rehab unit once they enter the recovery phase, 90% require at least one more skin graft procedure during the recovery period. Donor sites were covered with xeroform gauze and time to healing was determined by peeling back the edges of the gauze; healed areas began presenting at 8 days. Healing was defined as 95% epithelialization. An assessment of muscle strength and endurance was obtained twice each week by the physical therapists caring for the patient, using the functional independence method (FIM) scoring system.17 An FIM for a normal young individual (under 45 years) averages 115 to 120; for an older population (> 60 years), the average score is 105 to 110. Functional independence is considered to be present when the FIM exceeds 100. Virilization was assessed in female patients. Liver function tests also were obtained at the beginning of the study period, at 2 weeks, and at the end of 4 weeks.

   Statistical analysis. Within each group, data were analyzed using ANOVA (specifically, the Dunnetts t-test) techniques. Scheffi tests were used for between-group analyses. A value of P <0.05 was considered to be a significant difference.

Results
    Catabolic phase (burns). The younger group (mean age 32 +/- 6 years) had 29 participants and the older group (mean age 64 +/- 4 years) had 22. Compared to the younger group, the older group had a smaller burn injury but a comparable length of stay in the acute burn-trauma center Mean length of stay was 22 +/- 9 days for the young group and 24 +/- 7 days for the older group. Mean burn size for young and older age groups was 45% and 30% of total body surface, respectively. All patients required at least two excision and grafting procedures during the catabolic phase. Mean weight loss during the catabolic phase (wound closure) was 11% +/- 3% and 10% +/- 3% of total weight for the young and older groups, respectively (see Table 1). All patients survived and were eventually discharged.

   Recovery phase (burns). After initial weight loss, the average weight gain in the younger control group was 0.7 +/- 0.2 kg/week over the 4-week period, P <0.05, while for the older group, weight gain per week was only 0.5 +/- 0.2 kg (see Figures 1 and 2). Body composition determined at 4 weeks revealed lean mass gain was approximately 55% of total weight for both groups. In the younger oxandrolone group, average weekly weight gain was 1.7 +/- 4 kg and in the older group the gain was 1.6 +/- 4 kg, both significantly greater than their comparative control groups. Body composition assessment revealed the percent of total weight gain that was lean mass was 78% +/- 5% and 74% +/- 6% in the younger and older groups, respectively. Both values were significantly higher than their age-matched control groups (P <0.05).

   Wound healing. All 29 patients in the younger group and 21 of 22 of the older group required at least one additional skin grafting procedure (they immediately returned to the rehab unit after surgery). The skin graft usually occurred in the second week of the recovery phase to allow an intensive rehabilitation program to begin. A significant decrease in healing time in the oxandrolone groups compared to control group was noted. Mean (+/- SD) days to healing in the younger control and oxandrolone groups was 13 +/- 3 and 10 +/- 2 (P <0.05). Mean (+/-SD) days to healing for the older control and oxandrolone groups was 16 +/- 3 and 12 +/- 2 (P <0.05).

   Function assessment. Mean FIM score for all patients entering the recovery or rehabilitation phase was 79 +/- 7 for the younger and 71 +/- 5 for the older patients. This score reflects a significant impairment in strength and endurance. Time to restoration of function, to a discharge value of more than 100, occurred more rapidly in the oxandrolone groups compared to the control groups in both younger and older patients (see Table 2). The difference in time was statistically significant (P <0.05). The increasing FIM score corresponded with the more rapid gain in lean mass. Time between entry into recovery phase and discharge was 29 +/- 5 days and 36 +/- 7 days for the young and older standard care group, compared to 23 +/- 4 days and 28 +/- 5 days for the younger and older oxandrolone groups, respectively. The differences were statistically significant (P <0.05).

   Androgen-related complications. Of the 15 female patients given oxandrolone, none developed any evidence of hirsutism or androgenic side effect. No behavior changes were noted in any patient that could be attributed to increased androgenic activity. Five patients given oxandrolone developed a transient increase in the liver enzymes ALT and AST, not exceeding a 50% increase above normal. The values returned spontaneously to normal while still on oxandrolone. Discussion The catabolic response to a severe body burn leads to a rapid loss of body weight, mostly lean body mass.1-4 This process of net protein loss is attenuated but certainly not prevented by optimum nutrition, early wound closure, and physical therapy.2,3 The loss of lean mass is particularly devastating for the older patient.13 Because restoration of muscle mass occurs at a very slow rate (due, in part, to a very low endogenous anabolic activity and a decreased functional reserve relevant to the aging process), long-term disability is common due to inability to regain function.13,17 The use of anabolic steroids has been shown to significantly increase the rate of restoration of lost body weight and lean mass, post-burn and post-trauma.10,18,19 However, the reported potential side effects of most of these agents have precluded their more general acceptance as adjuvant therapy to nutrition and exercise.20 Oxandrolone is an orally administered testosterone analog that has 10 times the anabolic activity of testosterone, yet one-tenth of the androgenic activity.21,22 Therefore, androgenic side effects are minimal. Oxandrolone is used in women to regain weight and in young girls to correct small stature.14,21,22 In addition, oxandrolone is metabolized by the kidney, not the liver; thereby, minimizing the hepatotoxicity seen with the other available anabolic steroids.21,22 Oxandrolone is the only approved anabolic agent for restoration of lost weight. The authors have previously demonstrated its effectiveness to rapidly and safely restore lean mass and physical function in relatively young burn patients (mean age 40 years) during the recovery or rehabilitation phase.10-11 With the increasing survival rate of older patients with major injuries, the authors wanted to determine the effect of increasing anabolic activity in this population during the recovery period, arbitrarily defined as the resolution of the "stress response" to injury.9,17 All of the current studies of increasing anabolic activity in the elderly have been performed in normal elders.23-26 Of interest is the fact that noninjured older men, even octogenarians, have been shown to increase lean mass at a rate comparable to young men in response to increasing anabolic activity. Studies using human growth hormone, large-dose testosterone, and resistance training have all demonstrated the effectiveness of increasing anabolism on restoration of lean mass and physical function.24-26 This study is the first to compare the effect of an anabolic agent on younger and older populations of injured men. The recovery phase post-injury was selected for study, as this is a relatively steady period where the variable to be monitored (ie, anabolic activity) could be more precisely determined. Limitations Because the study was performed on a relatively small group of burn patients, conclusions are limited. However, determining significant differences in the variables measured was possible. In addition, the study focused on burn patients, who have a specific type of injury. Therefore, findings may not apply to other patient populations with weight loss.

Conclusion
   The rate of body weight and lean mass gain using oxandrolone was found to be the same in patients 60 to 65 years old as in patients with a mean age of less than 35 years. No significant complications were noted in men or women. In addition, restoration of physical function and time to discharge was also demonstrated to be significantly faster in older patients receiving oxandrolone compared with those receiving optimum nutrition and exercise alone. The ability of the anabolic steroid oxandrolone to more rapidly restore lean mass and physical function is not altered by increasing age. Despite suppositions to the contrary and because advanced age may not prove to be as great an obstacle in specific and important health considerations, further research is warranted and encouraged.

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