The catabolic phase of critical illness

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1 Hospital Pharmacy Volume 36, Number 8, pp Facts and Comparisons NUTRITIONAL SUPPORT CONSULTANT Update on Anabolic Agents Roland N. Dickerson, PharmD Nutrition Support Consultant features issues pertinent to the clinical aspects of pharmacy nutritional support practice. The column is edited by Roland N. Dickerson, PharmD, BCSNP, CNS, FACN, Associate Professor of Clinical Pharmacy, University of Tennessee Health Science Center, Memphis, TN. Send correspondence to: Dr. Roland Dickerson, Department of Clinical Pharmacy, University of Tennessee Health Science Center, 26 South Dunlap St., Memphis, TN The catabolic phase of critical illness is characterized by marked body protein loss, and if the patient survives, it is followed by an anabolic recovery phase. During the catabolic phase, the therapeutic objective is to minimize nitrogen loss. Unfortunately, efforts to maintain body protein mass with conventional nutritional support in septic or traumatized patients have been only modestly successful, because the anabolic effect of such support is not sufficient to overcome the markedly increased catabolism that accompanies critical illness. 1,2 As a result of this limited success with conventional nutritional support, alternative methods for modulating the metabolic response to critical illness are under investigation. One technique that is actively being pursued by clinicians and researchers is the use of anabolic agents as adjuvant therapy to nutritional support during the critical illness and the postinjury recovery phases. This article presents what I consider to be the most pertinent recent literature on the use of anabolic agents in adult nutritional-support patients. Abstracts from the literature, organized by agent and potential clinical use, provide a quick synopsis of the available research.. Abstract topics are as follows: (1) the use of anabolic steroids in trauma, burns, respiratory disease, HIV disease, liver disease, and hemodialysis patients; (2) the use of insulin-like growth factor-1 in thermal injury, trauma and critical illness, and renal disease; and (3) use the of growth hormone in short bowel syndrome, thermal injury, critical illness, and postsurgical care. One particular publication worthy of note and elaboration is by Takala et al., on the use of growth hormone during critical illness in adults. 3 Takala et al. s results, from two large prospective, randomized, double-blind trials, prompted the manufacturer s letter that informed clinicians that they should not use growth hormone in critical illness. In Takala et al. s study, the mortality rate of the growth-hormone group was double that of the placebo-control group. In the Finnish trial, of the 119 patients who received growth hormone, 47 died compared with 25 deaths out of 123 patients in the placebo group. In the multinational trial, 61 out of 141 patients who received growth hormone died, whereas 26 of the 141 patients in the placebo group died. These data provide strong evidence to discourage the use of growth hormone in critically ill patients. However, there are other potential uses for growth hormone in postcritical illness and other clinical situations, as indicated by some of the studies listed below. The intent of this article is to provide you with an updated, helpful synopsis of the literature on anabolic agents as adjuvant therapy to nutrition support. However, I strongly encourage you to read the entire papers carefully, and related papers as well, before making any final decisions about policies at your institution or in your practice. ANABOLIC STERIODS Trauma Gervasio, STUDY OBJECTIVE: To determine the effect of oxandrolone administration on nutritional and clinical outcomes after multiple trauma. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Level 1 trauma center in a university teaching hospital. PATIENTS: 62 patients requiring enteral nutrition, 60 of whom completed the study. INTERVENTION: Patients were randomized to receive either oxandrolone 10 mg or placebo twice daily for a maximum of 28 days. MEASUREMENTS AND MAIN RESULTS: Total urinary nitrogen, prealbumin, nitrogen balance, total body water, and body cell mass were measured on day 1 of enteral nutrition and then at day 7, day 10, and study exit. Patients were assessed daily for metabolic and infectious complications. The two groups were similar for demographics and dosage of enteral nutrition. Measurement of total urinary nitrogen at study entry showed both groups to be highly catabolic (oxandrolone 17.2 ± 4.9, placebo 19.1 ± 10.8 g/day, NS). On days 7 and 10, total urinary nitrogen increased in both groups; however, there was no significant difference between groups. Nitrogen balance was Hospital Pharmacy 907

2 negative throughout the study in each group. Body cell mass decreased slightly in both groups over the study period. Prealbumin serum concentrations increased significantly in both groups at day 10 and study exit compared with study entry. The groups did not differ significantly for length of hospital stay (oxandrolone 30.8 ± 17.9, placebo 27.0 ± 25.7 days), length of intensive care unit stay (oxandrolone 17.1 ± 7.8, placebo 15.5 ± 9.7 days), and frequency of pneumonia or sepsis (oxandrolone 48, placebo 43 episodes). CONCLUSION: Oxandrolone 20 mg/day does not have obvious benefit in nutritional and clinical outcomes during the first month after multiple trauma. Hausmann, Severe trauma leads to considerable losses of nitrogen in the first days after the accident. As nutritional efforts cannot reduce these losses sufficiently, an adjunctive therapy using the anabolic steroid nandrolone decanoate (Nd) was applied. In a double-blind study, 10 male multiple-traumatized patients each received 50 mg of Nd on day 3 and 25 mg of Nd on day 6 after the trauma; an additional 10 patients received placebo only. Both groups had identical nutritional support. Nitrogen balance, total nitrogen excretion, plasma amino acid concentration, and urine amino acid excretion were measured daily. The anabolic agent improved the nitrogen balance mainly by reducing nitrogen excretion. 3-Methylhistidine excretion and renal amino acid losses were decreased. Nandrolone decanoate increased the concentration of total plasma amino acids. The underlying principle seems to be an amino acid-saving mechanism with a renal site of action. It is shown that in the early posttraumatic period nandrolone decanoate improves nitrogen metabolism. Further studies are required to determine whether this offers a clinical benefit to trauma patients. Moseback, Twenty head-injured patients GCS 5-6 were randomized to be given nandrolone (deca-durabolin) 50 mg on day 3 post injury or placebo. Caloric intake was designed to be at 1.5 to 1.75 X BEE. Nandrolone significantly decreased nitrogen losses. Plasma levels of total protein, albumin, prealbumin and transferrin were similar; however, 3- meh excretion was significantly decreased in the nandrolone group. Burns Demling, PURPOSE: Severe burn injury leads to marked catabolism and decreased lean mass, which can impair healing. Anabolic agents can attenuate net catabolism. Our purpose was to determine whether the testosterone analog, oxandrolone, given during the acute post burn period decreased the degree of nitrogen loss and loss of body weight while also increasing the healing rate of a skin donor site. MATERIALS AND METHODS: Patients with burns between 40% and 70% of body surface were studied. A randomized double-blinded placebo-controlled study design was used. Patients were given oxandrolone 20 mg/day (n = 11) or a placebo 20 mg/day (n = 9) beginning between days 2 and 3 post burn. Net nitrogen balance and the healing time of a standardized donor site were measured. Patients were monitored until transferred to a burn rehabilitation facility, an average time period of 33 ± 9 days. RESULTS: Mean burn size was 49 ± 8% for placebo and 53 ± 9% of total body surface for the oxandrolone group. Smoke inhalation was present in approximately 50% of patients in both groups. All patients survived the burn injury. Net weight loss was 8 ± 3.1 kg in the placebo group compared with 3 ± 1.9 kg in the oxandrolone group, a statistically significant decrease. Net daily nitrogen loss over a 3- week period (days 7 to 28) was 13 ± 4 g in placebo treated compared with 4 ± 1.9 g for the oxandrolone group, a statistically significant decrease. The healing time of a standardized donor site, decreased from the placebo group value of 13 ± 3 days to 9 ± 2 days for oxandrolone treated patients, a significant improvement. No major liver dysfunction, or other complication attributable to an anabolic steroid was seen in either group. CONCLUSION: We found the anabolic agent, oxandrolone, significantly decreased weight loss and net nitrogen loss and increased donor site wound healing compared with placebo controls. We noted no complications with the use of oxandrolone. Demling, This study compared the anticatabolic and wound healing effects of the anabolic agents human growth hormone, HGH, and the testosterone analogue, oxandrolone, after severe burn injury. A randomized prospective study design was used. Patients were given HGH at a dose of 0.1 mg/kg/day (n = 20) or oxandrolone, 20 mg/day (n = 16), beginning between days 7 to 10 post-burn. Data was compared with burn patients not placed on either agent (n = 24). Patients were monitored until they were sufficiently healed to be transferred to a rehabilitation center. The results of our study were as follows. All patients survived. Net weight loss was 8 ± 2.1 kg in the control group compared with 4 ± 1.8 kg with HGH and 3 ± 1.2 kg with oxandrolone, a significant decrease. Net daily nitrogen loss was 12 ± 3 g in nontreated compared with 3 g or less for each of the anabolic groups, a significant decrease. The metabolic rate in untreated burns was 155 ± 25% of predicted normal, compared with 178 ± 28% for HGH and 156 ± 20% for oxandrolone treated patients. The complete healing time of a standardized donor site, decreased from the control value of 14 ± 2 days to 10 ± 3 days for HGH and 10 ± 2 days for oxandrolone treated patients, a significant improvement. Hyperglycemia (glucose over 225 mg/dl 12.5 mm) was present in 100% of HGH patients compared with 55% for control and 50% for oxandrolone treated. We found that both anabolic agents significantly decreased weight and nitrogen loss and increased healing with nearly identical benefits. However HGH resulted in the significant complications of hyperglycemia and accentuated hypermetabolism. We noted no side effects with oxandrolone. Demling, We studied the relationship between restoration of weight loss and healing of the non-healing wound. Eight consecutive patients with large non-healing wounds of an average of 12 months duration, despite good local wound care, were studied. All had a weight loss of 10% or more of body weight, mainly lean body mass. Optimizing nutrition (4 weeks) did not significantly increase weight or healing. The addition of the oral anabolic agent oxandrolone increased restoration of weight (4 lbs/week) over a 12-week period. Five wounds completely closed and three closed by 75% during this period. We noted a significant correlation (r = 0.67) between restoration of weight loss and closure of the previously non-healing wound. The rate of wound healing was most prominent after 50% of weight loss had been restored. This finding reflects the key relationship between restoring body weight, body protein stores, and wound healing. Demling, We studied the effect of an anabolic steroid, oxandrolone, combined with a high-protein diet (2 g/kg/day) on the rate 908 Volume 36, August 2001

3 of weight gain and restoration of muscle function in the recovery phase after deep burns of 30 of 50% of total body surface (n = 7). The findings were compared with findings from an isocaloric (2 g/kg/day protein) diet alone (n = 6). The study was prospective and randomized. Data were also compared retrospectively with data from a group of burn patients treated in the same fashion using a high-calorie, high-protein diet with a protein content of 1.3 to 1.4 g/kg/day (n = 10). Muscle function was quantified using a physical therapy index defining rate of progress (0 = lowest, 10 = highest). Oxandrolone was given in the beginning of the recovery phase in a dosage of 10 mg orally twice a day. The recovery phase was defined as resolution of the hypermetabolic state using physiologic criteria. The study was performed in an acute burn rehabilitation facility where patients were transferred once entering the recovery phase. Patients in each group were not different with regard to age and burn size. We found that mean weight loss for all patients was 11 ± 2% of preburn weight during the catabolic phase despite optimum nutrition and early wound closure. Data are presented as mean ± SD. We found that the average weight gain during the first 3 weeks was 14.5 ± 2.5 pounds and that the physical therapy index was 8.8 ± 0.5 of recovery in the oxandrolone-protein group (n = 7); both of these values were significantly greater than the corresponding values in the other groups. In the high-protein alone group (n = 6), weight gain was 7.5 ± 1.7 pounds and physical therapy index was 7.0 ± 0.8. In the retrospective group (n = 10), weight gain was 4.4 ± 0.8 pounds and function index was 4.1 ± 0.5. The daily caloric intake was not different between groups. Protein content and oxandrolone were the variables. No side effects were noted with oxandrolone. We can conclude that an anabolic steroid combined with increased protein intake can significantly increase the rate of restoration of weight gain postburn. Respiratory Disease Spungen, BACKGROUND: Pulmonary complications are a major cause of morbidity and mortality among individuals with cervical spinal cord lesions. Strengthening of the respiratory musculature may reduce these complications. Anabolic steroids have been used to increase muscle mass and improve muscle performance. Oxandrolone, an anabolic steroid, may have beneficial effects on breathing in persons with tetraplegia. METHODS: The effect of one-month treatment with oxandrolone on weight gain and pulmonary function was studied in ten subjects with complete motor tetraplegia. Spirometry, maximal inspiratory and expiratory pressures, and resting self-rating of dyspnea (Borg Scale) were measured at baseline and repeated again at the end of one month of oxandrolone therapy (20 mg/day). Serum lipid profiles and liver function tests were performed before and after treatment. A paired t- test was used to determine pre- and post-treatment differences on the dependent variables. Percent change from baseline was calculated for each variable and tested using a one-sample t-test. RESULTS: On average, the subjects gained 1.4 ± 1.5 kg, a 2 ± 2% increase in weight (p = 0.01). A significant, 9 ± 2% improvement was found in the combined measures of spirometry (p < 0.005). Maximal inspiratory pressure improved an average of 10 ± 7% (p < 0.001). Maximal expiratory pressure improved 9 ± 13% (nonsignificant). Subjective self-rating of dyspnea decreased an average of 37 ± 28% (p < 0.01). CONCLUSIONS: In healthy subjects with tetraplegia, the use of oxandrolone was associated with significant improvements in weight and pulmonary function, and a subjective reduction in breathlessness. Therefore, oxandrolone may be indicated to strengthen respiratory musculature in individuals who have tetraplegia and ventilatory insufficiency aggravated by superimposition of pneumonia or other such conditions. However, long-term use of oxandrolone may not be indicated due to the adverse complications associated with this class of agents. Ferreira, STUDY OBJECTIVE: To evaluate the influence of oral anabolic steroids on body mass index (BMI), lean body mass, anthropometric measures, respiratory muscle strength, and functional exercise capacity among subjects with COPD. DESIGN: Prospective, randomized, controlled, double- blind study. SETTING: Pulmonary rehabilitation program. PARTICIPANTS: Twenty-three undernourished male COPD patients in whom BMI was below 20 kg/m 2 and the maximal inspiratory pressure (PI max ) was below 60% of the predicted value. INTERVENTION: The study group received 250 mg of testosterone IM at baseline and 12 mg of oral stanozolol per day for 27 weeks, during which time the control group received placebo. Both groups participated in inspiratory muscle exercises during weeks 9 to 27 and cycle ergometer exercises during weeks 18 to 27. MEASUREMENTS AND RESULTS: Seventeen of 23 subjects completed the study. Weight increased in nine of 10 subjects who received anabolic steroids (mean, +1.8 ± 0.5 kg; p < 0.05), whereas the control group lost weight ( 0.4 ± 0.2 kg). The study group's increase in BMI differed significantly from that of the control group from weeks 3 to 27 (p < 0.05). Lean body mass increased in the study group at weeks 9 and 18 (p < 0.05). Arm muscle circumference and thigh circumference also differed between groups (p < 0.05). Changes in PI max (study group, 41%; control group, 20%) were not statistically significant. No changes in the 6- minute walk distance or in maximal exercise capacity were identified in either group. CONCLUSION: The administration of oral anabolic steroids for 27 weeks to malnourished male subjects with COPD was free of clinical or biochemical side effects. It was associated with increases in BMI, lean body mass, and anthropometric measures of arm and thigh circumference, with no significant changes in endurance exercise capacity. Schols, Nutritional depletion commonly occurs in patients with COPD, causing muscle wasting and impaired physiologic function. Two hundred seventeen patients with COPD participated in a placebocontrolled, randomized trial investigating the physiologic effects of nutritional intervention alone (N) for 8 weeks or combined with the anabolic steroid nandrolone decanoate (N + A). Nandrolone decanoate or placebo (P) was injected intramuscularly (women, 25 mg; men, 50 mg) in a double-blind fashion on days 1, 15, 29, and 43. Nutritional intervention consisted of a daily high-calorie supplement (420 kcal; 200 ml). Also, all patients participated in an exercise program. In the depleted patients, both treatment regimens induced a similar significant body weight gain (2.6 kg) but different body compositional changes. Particularly in the last 4 weeks of treatment, weight gain in the N group was predominantly due to an expansion of fat mass (p < 0.03 versus P and N + A), whereas the relative changes in fat-free mass (FFM) and other measures of muscle mass were more favorable in the N + A group (p < 0.03 vs P). Maximal inspiratory mouth pressure improved within both treatment groups in the first 4 weeks of treatment, but after 8 weeks only N + A was significantly different from P (p < 0.03). Nutritional supplementation in combination 910 Volume 36, August 2001

4 with a short course of anabolic steroids may enhance the gain in FFM and respiratory muscle function in depleted patients with COPD without causing adverse side effects. HIV Fox-Wheeler, OBJECTIVE: To determine the safety and efficacy of anabolic therapy to prevent or reverse wasting and malnutrition in human immunodeficiency virus (HIV)- infected pediatric patients. The anabolic steroid, oxandrolone, was evaluated because of its safe and effective use in other pediatric conditions. METHODS: Nine HIV-positive children who were malnourished or at risk for malnutrition (4 females, 5 males; 4 14 years of age) took oxandrolone for 3 months (.1 mg/kg/day orally). Quantitative HIV ribonucleic acid polymerase chain reaction and CD 4 (+) T-cell levels, complete blood cell count (CBC) and chemistry profile, endocrinologic studies, resting energy expenditure, respiratory quotient, nutritional measures, body composition assessment with quantitative computed tomography, and skinfold body composition measurements were determined before treatment, during treatment (3 months), and for 3 months after treatment. Statistical analyses were completed using the Friedman two-way analysis of variance and Spearman correlation tests. RESULTS: No adverse clinical or laboratory events or changes in Tanner staging or virilization occurred. Quantitative HIV ribonucleic acid polymerase chain reaction and CD 4 (+) T-cell levels did not change significantly. Insulin-like growth factor 1 increased, suggesting an anabolic effect of treatment. The rate of weight gain increased during treatment and was maintained after treatment. Linear growth continued and was maintained throughout treatment, whereas bone age did not increase significantly. Anthropometric assessments indicated an increase in muscle mass and a decrease in fat while patients were on treatment, and a mild decrease of muscle and increased fat posttreatment. Likewise, computed tomography scan results demonstrated similar changes in muscle mass. Resting energy expenditure and respiratory quotient remained stable throughout treatment and follow-up. No significant changes were seen in the quality of life questionnaire. CONCLUSIONS: Treatment with oxandrolone for 3 months in HIV-infected children was well-tolerated, safe, and associated with markers of anabolism. The latter effect was maintained partially for 3 months after discontinuation of a 3-month course of therapy. Additional studies are needed to assess the potential benefits and risks of a longer course of therapy or a higher dose of oxandrolone in HIV-infected children. Strawford, CONTEXT: Repletion of lean body mass (LBM) that patients lose in human immunodeficiency virus (HIV) infection has proved difficult. In health, HIVseronegative men, synergy between progressive resistance exercise (PRE) and very high-dose testosterone therapy has been reported for gains in LBM and muscle strength. OBJECTIVE: To determine whether a moderately supraphysiologic androgen regimen, including an anabolic steroid, would improve LBM and strength gains of PRE in HIV-infected men with prior weight loss and whether protease inhibitor antiretroviral therapy prevents lean tissue anabolism. DESIGN: Doubleblind, randomized, placebo-controlled trial; post hoc analysis for effect of HIVprotease inhibitor therapy conducted from January to October SET- TING: Referral center in San Francisco, CA. PATIENTS: Volunteer sample of 24 eugonadal men with HIV-associated weight loss (mean, 9% body weight loss), recruited from an AIDS clinic, by referral, and by advertisement. INTERVENTION: For 8 weeks, all subjects received supervised PRE with physiologic intramuscular testosterone replacement (100 mg/week) to suppress endogenous testosterone production. Randomization was between an anabolic steroid, oxandrolone, 20 mg/day, and placebo. MAIN OUTCOME MEASURES: Lean body mass, nitrogen balance (10-day metabolic ward measurements), body weight, muscle strength, and androgen status. RESULTS: Twenty-two subjects completed the study (11 per group). Both groups showed significant nitrogen retention and increases in LBM, weight, and strength. The mean (SD) gains were significantly greater in the oxandrolone group than in the placebo group (5.6 [2.1] vs 3.8 [1.8] g of nitrogen per day [p =.05]; 6.9 [1.7] vs 3.8 [2.9] kg of LBM [p =.005]; greater strength gains for various upper and lower body muscle groups by maximum weight lifted [p =.02.05] and dynamometry [p = ]). The mean (SD) high-density lipoprotein cholesterol level declined 0.25 (0.14) mmol/l (9.8 [5.4] mg/dl) significantly in the oxandrolone group (p <.001 compared with placebo). Results were similar whether or not patients were taking protease inhibitors. One subject in the oxandrolone group discontinued the study because of elevated liver function test results. CONCLUSIONS: A moderately supraphysiologic androgen regimen that included an anabolic steroid, oxandrolone, substantially increased the lean tissue accrual and strength gains from PRE, compared with physiologic testosterone replacement alone, in eugonadal men with HIV-associated weight loss. Protease inhibitors did not prevent lean tissue anabolism. Segal, Antiviral agents are the primary therapy for patients infected with HIV- 1. However, supportive therapies are often also necessary because of the devastating wasting process associated with HIV-1 infection and AIDS. Oxandrolone, an anabolic steroid, is used in promoting weight gain and, most importantly, lean body mass (LBM) in patients with HIV-1 disease. We investigated whether oxandrolone interferes with the antiviral activity of zidovudine (ZDV), dideoxyinosine (ddi), and dideoxycytidine (ddc) on HIV-1 replication in peripheral blood Hospital Pharmacy 911

5 lymphocytes and macrophage-monocytes. The nucleoside analogues had nanomolar 50% inhibitory concentrations (IC50) in peripheral lymphocytes. Combinations of nucleoside analogues and oxandrolone did not result in increased IC50 values. Oxandrolone used alone exhibited micromolar IC50 values in peripheral blood lymphocytes. Lack of interference was consistent for nucleoside concentrations up to 5 microm and for oxandrolone concentrations up to 100 microm in several combinations of drugs, viral strains, and peripheral lymphocytes and macrophages. We conclude that oxandrolone can be used for the promotion of weight gain in patients with AIDSrelated wasting without interference with the antiviral effects of ZDV, ddi, or ddc. Berger, OBJECTIVE: To evaluate oxandrolone, an oral anabolic steroid with potent anabolic activity and minimal androgenic effects, for the treatment of AIDS-associated myopathy and wasting. METHODS: In a multicenter, doubleblind study, 63 HIV-seropositive men with > 10% loss of body weight were randomized to receive either placebo, 5 mg/day oxandrolone, or 15 mg/day oxandrolone for 16 weeks. Body weight, neuromuscular evaluation, and measures of well-being were repeatedly assessed. RESULTS: Patients who received 15 mg/day oxandrolone showed weight gain throughout the 16-week treatment period. Overall, the 5 mg/day oxandrolone group maintained their weight gain over the 16-week period, whereas the placebo group showed continual weight loss. At week 16, significantly more patients in the 15 mg/day dose group reported increases in appetite and activity than those receiving placebo. There were no consistent, doserelated, statistically significant differences from baseline in laboratory values or adverse events. CONCLUSION: Oxandrolone, at a dose of either 5 mg/day or 15 mg/day, in contrast to placebo, had a positive impact on the weight and well-being of HIVseropositive patients suffering from wasting and weakness. Measurable improvement in muscle strength was not noted at the doses employed in this study. Oxandrolone was well tolerated in all the patients who were enrolled in the study. Based on the results reported here, additional studies using higher doses of oxandrolone seem warranted. Dialysis Johansen, Patients receiving dialysis commonly experience malnutrition, reduced muscle mass (sarcopenia), and fatigue for which no effective treatment has been identified. Anabolic steroids are known to increase muscle mass and strength in healthy individuals, but their effect on the sarcopenia and fatigue associated with long-term dialysis has not been evaluated. OBJECTIVE: To assess the effects of an anabolic steroid, nandrolone decanoate, on lean body mass (LBM), functional status, and quality of life in dialysis patients. DESIGN: Randomized, double-blind, placebo-controlled trial conducted between April 1996 and July SETTING: Hospital-based outpatient dialysis unit. PATIENTS: Twenty-nine patients undergoing dialysis for at least 3 months. INTERVENTION: Nandrolone decanoate, 100 mg (n = 14), or placebo (n = 15) by intramuscular injection once a week for 6 months. MAIN OUTCOME MEASURES: Weight, LBM, fatigue, grip strength, walking and stair- climbing times, and treadmill performance after 3 and 6 months of treatment. RESULTS: Lean body mass increased significantly in patients given nandrolone compared with patients given placebo (mean change [SD], [2.3] kg; p <.001 compared with baseline). This effect was significantly greater than the change in LBM in the placebo group (mean change [SD], [1.6] kg; p =.003 compared with baseline; [p =.005 compared with nandrolone group). Serum creatinine levels increased in the nandrolone group (+ 168 [203] mmol/l [1.9 [2.3] mg/dl]; p =.02) but not in the placebo group ( 4.0 [177] mmol/l [0.04 [2.0] mg/dl]; p =.95), suggesting an increase in muscle mass. Time to complete the walking and stair-climbing test decreased from 36.5 to 32.7 seconds in the nandrolone group, while those in the placebo group increased from 38.7 to 42.1 seconds (p =.05). Peak oxygen consumption increased in the individuals in the nandrolone group who performed treadmill tests, but not to a statistically significant degree. Grip strength did not change in either group. CONCLUSIONS: Treatment with nandrolone for 6 months resulted in a significant increase in LBM associated with functional improvement in patients undergoing dialysis. Alcoholic Hepatitis Mendenhall, BACKGROUND: Active nutrition therapy and the anabolic steroid oxandrolone (OX), in selected patients with severe alcoholic hepatitis, significantly improved liver status and survival. We report here on the changes in their nutritional parameters. METHODS: Protein energy malnutrition (PEM) was evaluated and expressed as percent of low normal in 271 patients initially, at 1 month and at 3 months. Active therapy consisted of OX plus a high caloric food supplement vs a matching placebo and a low calorie supplement. RESULTS: PEM was present in every patient; mean PEM score 60% of low normal. Most of the parameters improved significantly from baseline on standard care; the largest improvement seen in visceral proteins, the smallest in fat stores (skinfold thickness). Total PEM score significantly correlated with 6 month mortality (p =.0012). Using logistic regression analysis, creatinine height index, hand grip strength and total peripheral blood lymphocytes were the best risk factors for survival. When CD lymphocyte subsets replaced total lymphocyte counts in the equation, CD8 levels became a significant risk factor (p =.004). Active treatment produced significant risk factor (p =.004). Active treatment produced significant improvements in those parameters related to total body and muscle mass (ie, mid arm muscle area, p =.02; creatinine height index, p =.03; percent ideal body weight, p =.04). CONCLUSION: Deterioration in nutritional parameters is a significant risk factor for survival in severe patients with alcoholic hepatitis. This deterioration is reversible with standard hospital care. Active therapy further improves creatinine height index, mid arm muscle area and total lymphocyte counts. Hence, these later parameters appear to be the best indicators for follow-up assessments. Mendenhall, A Veterans Affairs cooperative study involving 273 male patients was performed to evaluate efficacy of oxandrolone in combination with an enteral food supplement in severe alcoholic hepatitis. All patients had some degree of protein calorie malnutrition. On an intention-to-treat basis, only minimal changes in mortality were observed. However, in patients with moderate malnutrition mortality on active treatment at 1 month was 9.4% compared with 20.9% in patients receiving placebo. This beneficial effect was maintained so that after 6 month on active treatment, 79.7% of patients were still alive, compared with 62.7% of placebo- treated patients (p = 0.037). Improvements in 912 Volume 36, August 2001

6 both the severity of the liver injury (p = 0.03) and malnutrition (p = 0.05) also occurred. No significant improvement was observed with severe malnutrition. To better determine the effect on therapeutic efficacy, we compared results with those from a nearly identical population (cooperative study 119) treated with oxandrolone but not given the food supplement. Patients were stratified according to their caloric intake (greater than 2,500 kcal/day was considered adequate to supply energy needs and promote anabolism). For patients with moderate malnutrition and adequate caloric intake, oxandrolone treatment reduced 6-mo mortality (4% active treatment vs 28% placebo [p = 0.002]). For patients with moderate malnutrition and inadequate calorie intake, oxandrolone had no effect on mortality (30% active treatment vs 33% placebo). In cases of severe malnutrition, oxandrolone had no effect on survival. However, adequate caloric intake was associated with 19% mortality, whereas patients with inadequate intake exhibited 51% mortality (p = ). These results indicate that nutritional status should be evaluated in patients with alcoholic hepatitis. When malnutrition is present, vigorous nutrition therapy should be provided, and in patients with moderate malnutrition oxandrolone should be added to the regimen. Bonkovsky, The present studies were designed to provide careful measures of effects of oxandrolone, an anabolic steroid, intravenous nutritional supplementation, and the combination of these two treatments on liver functions, metabolic balances, nitrogen metabolism, and nutritional status in patients with moderate to severe alcoholic hepatitis. Of 43 patients originally recruited, 39 (19 men, 20 women) with typical clinical and laboratory features of alcoholic hepatitis (11 Child's Pugh class B; 28 class C) were admitted to a metabolic unit and completed a 35-day three-phase protocol. Phase I was a 10-day baseline period of observation, during which routine and special quantitative tests of liver function (galactose and antipyrine metabolism), a 7-day elemental balance study, and a 15N, 13C-leucine metabolism study were done. Phase II was a 21-day treatment period during which patients were randomly assigned to receive one of four regimens: (1) standard therapy, consisting of abstinence, a balanced, nutritionally adequate diet, and multivitamins; (2) oxandrolone (20 mg orally four times a day) plus standard therapy; (3) nutritional supplementation, consisting of 2 L daily of 3.5% crystalline amino acids (in 5% dextrose), given by peripheral vein; or (4) a combination of oxandrolone and nutritional supplementation, along with standard therapy. Metabolic balances were repeated during phase II. Phase III was 2 or 3 days posttreatment, during which special studies of liver functions and volumes and leucine metabolism were repeated. All patients who completed phase I of study and were randomly allocated to one of the four treatment groups completed the subsequent two phases. Overall, with time, patients showed highly significant improvements in most clinical and laboratory features. For most standard laboratory tests (eg, serum albumin, transferrin, prothrombin time), improvements were more marked in patients treated with nutritional supplementation and/or oxandrolone than in those given standard therapy alone. Liver volumes fell in all treatment groups, with greater improvement in those treated with nutritional supplementation. Improvements in galactose and antipyrine metabolism rates were significant only in those treated with nutritional supplementation or oxandrolone. Effects of treatments on metabolic balances, nitrogen metabolism, and measures of nutrition are described in this issue in a companion paper. We conclude that the addition of nutritional supplementation and oxandrolone to standard therapy of moderately severe or severe alcoholic hepatitis is well tolerated, and leads to more rapid improvement in the laboratory parameters measured. Bonkovsky, 1991 Part 2 22 Patients with moderately severe or severe alcoholic hepatitis, described in a companion paper in this issue, had serial studies of energy and protein metabolism and elemental balances before and during treatment for 21 days with one of four randomly assigned regimens: (1) standard therapy, consisting of abstinence, a balanced, nutritionally adequate diet, and multivitamins; (2) oxandrolone (20 mg orally four times a day) plus standard therapy; (3) nutritional supplementation, consisting of 2 liters of 3.5% crystalline amino acids in 5% dextrose given by peripheral vein (PPN) plus standard therapy; and (4) a combination of the other three treatments. Dietary and intravenous intakes and weights were recorded daily, and weekly averages were calculated. Anthropometric measurements and blood studies were done weekly; blood studies included white blood cell counts and differentials, serum prealbumin, transferrin, and total protein and plasma aminograms. Four-days complete balance studies and measures of 15N,1 13C-leucine metabolism also were performed at baseline and after the treatment period. Major findings were as follows: (a) Intakes of total calories and protein were significantly higher in PPN-treated than in other groups. (b) All patients had positive elemental balances, both at baseline and at the end of the treatment period. However, those treated with PPN (with or without oxandrolone) had higher positive balances of nitrogen, potassium, phosphorus, and magnesium, indicating improvement in lean body mass. (c) Anthropometric measurements showed no significant changes, but measures of the visceral protein compartment (serum prealbumin, transferrin, total protein, total lymphocyte count) improved significantly with time. For most of these variables, increases were significantly greater in those treated with PPN with or without oxandrolone than in the other groups. However, for prealbumin, the increase was greatest in the oxandrolone-treated group. (d) PPN treatment produced dramatic increases in levels of branchedchain amino acids and improvement in the ratio of plasma branched chain to aromatic amino acids. Other treatments had no effect on plasma aminograms. (e) Metabolism of 15N,1-13C-leucine was normal and was not affected significantly by treatment. Therapy with PPN and/or oxandrolone was tolerated well. We conclude that PPN has favorable effects on energy and protein metabolism in florid alcoholic hepatitis; oxandrolone has lesser effects, although it may exert some additional action and particularly increases serum prealbumin levels. The results support the use of nutritional supplementation in therapy of moderately severe or severe alcoholic hepatitis. Miscellaneous Rasmussin, Androstenedione is the immediate precursor of testosterone. Androstenedione intake has been speculated to increase plasma testosterone levels and muscle anabolism. Thus, androstenedione supplements have become widely popular in the sport community to improve performance. This study was designed to determine whether 5 days of oral androstenedione (100 mg/day) supplementation increases skeletal muscle anabolism. Six healthy young men were studied before the treatment period and after 5 days of oral androstenedione supplementation. Muscle protein turnover parameters were compared with those of a control group studied twice as well and receiving no treatment. We measured muscle Hospital Pharmacy 913

7 protein kinetics using a three-compartment model involving infusion of L-[ring- 2H5]phenylalanine, blood sampling from femoral artery and vein, and muscle biopsies. Plasma testosterone, androstenedione, LH, and estradiol concentrations were determined by RIA. After ingestion of oral androstenedione, plasma testosterone and LH concentrations did not change from basal, whereas plasma androstenedione and estradiol concentrations were significantly increased (p < 0.05). Compared with a control group, androstenedione did not affect muscle protein synthesis and breakdown, or phenylalanine net balance across the leg. We conclude that oral androstenedione does not increase plasma testosterone concentrations and has no anabolic effect on muscle protein metabolism in young eugonadal men. Lovejoy, OBJECTIVE: To compare the effects of testosterone enanthate (TE), anabolic steroid (AS). or placebo (PL) on regional fat distribution and health risk factors in obese middle-aged men undergoing weight loss by dietary means. DESIGN: Randomized, double-blind, placebo-controlled clinical trial, carried out for 9 months with primary assessments at 3 month intervals. Due to adverse blood lipid changes, the AS group was switched from oral oxandrolone (ASOX) to parenteral nandrolone decaoate (ASND) after the 3 month assessment point. SUBJECTS: Thirty healthy, obese men, aged 40 to 60 years, with serum testosterone (T) levels in the low-normal range (2 5 ng/ml). MAIN OUTCOME MEASURES: Abdominal fat distribution and thigh muscle volume by CT scan, body composition by dual energy X-ray absorptiometry (DEXA), insulin sensitivity by the Minimal Model method, blood lipids, blood chemistry, blood pressure, thyroid hormones and urological parameters. RESULTS: After 3 months, there was a significantly greater decrease in subcutaneous (SQ) abdominal fat in the ASOX group compared with the TE and PL groups although body weight changes did not differ by treatment group. There was also a tendency for the ASOX group to exhibit greater losses in visceral fat, and the absolute level of visceral fat in this group was significantly lower at 3 months than in the TE and PL groups. There were significant main effects of treatment at 3 months on serum T and free T (increased in the TE group and decreased in the ASOX group) and on thyroid hormone parameters (T4 and T3 resin uptake significantly decreased in the ASOX group compared with the other two groups). There was a significant decrease in HDL-C, and increase in LDL-C in the ASOX group, which led to their being switched to the parenteral nandrolone decanoate (ASND) after 3 months. ASND had opposite effects on visceral fat from ASOX, producing a significant increase from 3 to 9 months while continuing to decrease SQ abdominal fat. ASND treatment also decreased thigh muscle area, while ASOX treatment increased high muscle. ASND reversed the effects of ASOX on lipoproteins and thyroid hormones. The previously reported effect of T to decrease visceral fat was not observed, in fact, visceral fat in the TE group increased slightly from 3 to 9 months, although SQ fat continued to decrease. Neither TE nor AS treatment resulted in any change in urologic parameters. CONCLUSIONS: Oral oxandrolone decreased SQ abdominal fat more than TE or weight loss alone and also tended to produce favorable changes in visceral fat. TE and ASND injections given every 2 weeks had similar effects to weight loss alone on regional body fat. Most of the beneficial effects observed on metabolic and cardiovascular risk factors were due to weight loss per se. These results suggest that SQ and visceral abdominal fat can be independently modulated by androgens and that at least some anabolic steroids are capable of influencing abdominal fat. Young, In this controlled trial we have studied the effect of anabolic steroid on ill surgical patients receiving intravenous hyperalimentation. Body composition, plasma proteins, and amino acids were compared in each of two groups of 12 patients before and after 14 days of intravenous feeding. The patients in one group were given 100 mg of nandrolone decanoate at the commencement of study and again one week later. Body weight, muscle (AMC), plasma transferrin, prealbumin, and retinol- binding protein were increased comparably in both groups. An apparent gain in total body nitrogen was not significant. However, anabolic steroid caused greater gain of water requiring a more liberal use of diuretics, but prevented the gains of fat, triglyceride and insulin that occurred in the control group. Most plasma amino acids increased due to intravenous hyperalimentation but decreased in patients given anabolic steroid. It is concluded that in patients who may be in the catabolic phase of recovery anabolic steroid probably enhances amino acid and water uptake by tissues and increases the utilization of fat but, does not promote any greater increase in visceral proteins than during intravenous hyperalimentation alone. Michelsen, The effect of an anabolic steroid, nandrolone decanoate, on nitrogen balance and plasma and muscle amino acid concentrations was studied in patients undergoing total hip replacement and receiving daily postoperative infusions of 5% dextrose and 3.5% amino acids. An intramuscular injection of 200 mg immediately after operation resulted in a nitrogen balance of 48 mg N/kg/day for the first 3 days, as compared with 102 mg N/kg/day in noninjected controls. After steroid injection, there was also an attenuation of trauma-induced changes in amino acid concentrations in muscle but not in plasma. This suggests that nandrolone decanoate may act directly on muscle to reduce the protein catabolism which follows a major form of operative trauma. Lewis, Nitrogen balance was determined in 48 patients who were entered into a randomized, prospective, double-blind study, comparing anabolic steroids versus placebo in our parenteral nutritional support system. The group included both young and old patients suffering from catabolic illnesses, in whom IV feeding ranged from 14 to 21 days. All participants received the active agent or placebo biweekly throughout the study. During the period of IV nutrition, there was statistically significant difference in nitrogen balance and protein conservation in the patients receiving the active agent. INSULIN-LIKE GROWTH FACTOR-1 Burns Debroy, BACKGROUND: The purpose of this study was to determine the anabolic effects of recombinant human insulinlike growth factor-i (rhigf-1) complexed with its principal binding protein IGF-1 binding protein-3 (IGFBP-3) in severely burned adults. METHODS: Ten burned adults were studied consecutively after receiving saline (pretreatment), then rhigf- 1/IGFBP-3 (treatment) for 5 days. Doses were 1, 2, and 4 mg/kg per day. Glucose, electrolytes, hormones, and leg muscle protein metabolism were determined. Nine other studies were 914 Volume 36, August 2001

8 performed on similarly injured adults at comparable times to the treatment studies to control for time effects. RESULTS: Serum IGF-1 and IGFBP-3 levels increased with all doses, but no incremental increases were found. Leg protein balance improved with rhigf- 1/IGFBP-3, which was associated with an increase in muscle protein fractional synthetic rate. These effects were independent of time. All patients were euglycemic without electrolyte imbalances. CONCLUSION: Net protein synthesis in the isolated leg of severely burned adults improved with rhigf-1/igfbp-3 without development of glucose abnormalities. Pierre, Many of the anabolic effects of growth hormone (GH) act through insulin- like growth factor-i (IGF-I). Systemic administration of GH in combination with IGF- I has been shown to stimulate wound reepithelialization, however, it causes hyperglycemia or hypoglycemia, respectively. We hypothesize that very low doses of IGF-I in a liposome form will have the same positive wound-healing effect when administered locally as the higher doses of GH plus IGF-I given systemically. To test this hypothesis, rats were given a 40% TBSA full-thickness scald injury and received either placebo IGF-I (5.0 mg/kg/day, subcutaneously), IGF-I liposome (0.9 microgram/kg/week, subcutaneously), or a combination of GH and IGF-I, or IGF-I liposomes for 8 weeks. GH in combination with IGF-I showed a significant increase in postburn weight. Wound reepithelialization, measured by computerized planimetry as percentage original wound area, was significantly increased in rats receiving GH plus IGF- I, GH plus IGF-I liposomes, and IGF-I liposomes when compared with sham, or IGF-I (p < 0.05). Results indicate that small doses of IGF-I, delivered in the form of liposomes, are equally effective in increasing burn wound reepithelialization as the higher doses of GH plus IGF-I, or GH plus IGF-I liposomes. Trauma, Sepsis, and ICU Patients Yarwood, BACKGROUND: The purpose of this study was to determine the anabolic effects of recombinant human insulinlike growth factor-i (rhigf-1) complexed with its principal binding protein IGF-1 binding protein-3 (IGFBP-3) in severely burned adults. METHODS: Ten burned adults were studied consecutively after receiving saline (pretreatment), then rhigf- 1/IGFBP-3 (treatment) for 5 days. Doses were 1, 2, and 4 mg/kg per day. Glucose, electrolytes, hormones, and leg muscle protein metabolism were determined. Nine other studies were performed on similarly injured adults at comparable times to the treatment studies to control for time effects. RESULTS: Serum IGF-1 and IGFBP-3 levels increased with all doses, but no incremental increases were found. Leg protein balance improved with rhigf- 1/IGFBP-3, which was associated with an increase in muscle protein fractional synthetic rate. These effects were independent of time. All patients were euglycemic without electrolyte imbalances. CONCLUSION: Net protein synthesis in the isolated leg of severely burned adults improved with rhigf-1/igfbp-3 without development of glucose abnormalities. Hatton, The purpose of this study was to determine the effect of insulin-like growth factor-i (IGF-I) on the catabolic state and clinical outcome of head-injured patients. Thirty-three patients between the ages of 18 and 59 years with isolated traumatic head injury and Glasgow Coma Scale (GCS) scores of 4 to 10 were randomized to one of two groups. All patients received standard neurosurgical intensive care plus aggressive nutritional support; the patients in the treatment group also received intravenous therapy with continuous IGF-I (0.01 mg/kg/hour). During the 14-day dosing period, the control patients lost weight, whereas treated patients gained weight despite a significantly higher measured energy expenditure and lower caloric intake (p = 0.02). Daily glucose concentrations and nitrogen outputs were greater in control patients (p = 0.03) throughout the study period. During Week 1, only treated patients achieved positive nitrogen balance. Fifteen of 17 treated and 13 of 16 control patients survived the 1st week. No deaths occurred in patients whose serum IGF-I concentrations were higher than 350 ng/ml. Dichotomized Glasgow Outcome Scale scores for patients with baseline GCS scores of 5 to 7 improved from poor to good for eight of 12 treated patients but for only three of 11 control patients (p = 0.06). Eight of 11 treated patients with serum IGF-I concentrations that were at least 350 ng/ml achieved moderate-to-good outcome scores at 6 months, compared with only one of five patients with lower concentrations (p < 0.05). These findings indicate that pharmacological concentrations of IGF-I may improve clinical outcome and nitrogen utilization in patients with moderate-to-severe head injury. Dickerson, To determine the influence of insulin-like growth factor-1 (IGF-1) on nitrogen loss and hepatic response to critical illness, 34 male Sprague Dawley rats ( g) were randomized to receive parenteral nutrition (PN) only (Ctrl), PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide at 6 mg/kg/day (LPS), or PN plus LPS plus rhigf-1 (IGF-1) at 3 mg/kg/day for 48 hr. Prior to randomization, all animals underwent IV cannulation and 30 hours of adaptation to PN. All animals received isocaloric and isonitrogenous PN (glucose 170 kcal/kg/day and nitrogen 1.1 g/kg/day) and were kept NPO except for water ad libitum. [15N]glycine was infused in all animals for determination of liver fractional synthetic rate. Cumulative nitrogen balance during endotoxemia was significantly different from each other (+72 ± 42, 217 ± 131, 114 ± 137 mg/kg/48 hours for the Ctrl, LPS, and IGF-1 groups, respectively; ANOVA, p < 0.001). Endotoxin significantly increased the urinary 3-methylhistidine/creatinine ratio (0.24 ± 0.05, 0.55 ± 0.12, 0.48 ± 0.17 for the Ctrl, LPS, and IGF- 1 groups, respectively; ANOVA, p < 0.001); however, IGF-1 did not significantly reduce the ratio. Endotoxin induced a significant increase in liver fractional synthetic rate (29 ± 8, 56 ± 18, 64 ± 12%/day for the Ctrl, LPS, and IGF-1 groups, respectively; ANOVA, p < 0.01) and depressed hepatic cytochrome P450 concentration (0.54 ± 0.19, 0.22 ± 0.07, 0.19 ± 0.07 nmol/mg protein, respectively; ANOVA, p < 0.05) and ethoxycoumarin O-deethylase (ECOD) activity (103 ± 73, 29 ± 13, 17 ± 11, pmol/mg/min, respectively; ANOVA, p < 0.01); however, rhigf-1 did not significantly alter these hepatic variables during endotoxin infusion. Recombinant human insulin-like growth factor-1 significantly improved nitrogen balance without compromising hepatic response as measured by liver fractional synthetic rate, cytochrome P450 concentration, and ECOD activity in endotoxemic parenterally fed rats. Kudsk, OBJECTIVE: To determine the effects of insulin-like growth factor I (IGF-I) and aggressive nutrition on CD4/CD8 ratios following head injury. DESIGN: Randomized controlled trial. Hospital Pharmacy 915