Lorraine S. Young

Clinical and Metabolic Efficacy of Glutamine-supplemented Parenteral Nutrition after Bone Marrow Transplantation: A Randomized, Double-Blind, Controlled Study

OBJECTIVE To determine whether glutamine-supplemented parenteral nutrition improves nitrogen retention and reduces hospital morbidity compared with standard parenteral nutrition after bone marrow transplantation. DESIGN Double-blind, randomized, controlled clinical trial. SETTING University teaching hospital. PATIENTS Forty-five adults receiving allogeneic bone marrow transplants for hematologic malignancies. INTERVENTION Parenteral nutrition was initiated the day after bone marrow transplantation (day 1). The experimental solution was supplemented with L-glutamine (0.57 g/kg body weight per day) and provided estimated requirements for energy and protein. The control solution was a standard, glutamine-free, isonitrogenous, isocaloric formula. MEASUREMENTS Nitrogen balance was determined between days 4 and 11 in the initial 23 patients. The incidence of clinical infection and microbial colonization, time until bone marrow engraftment, indices of clinical care, and other data related to hospital morbidity were recorded for all patients. RESULTS The glutamine-supplemented patients (n = 24) were clinically similar to the controls (n = 21) at entry. Nutrient intake was similar in both groups; however, nitrogen balance was improved in the glutamine-supplemented patients relative to the controls (-1.4 +/- 0.5 g/d compared with -4.2 +/- 1.2; P = 0.002). Fewer experimental patients developed clinical infection (three compared with nine in the control group; P = 0.041), and the incidence of microbial colonization was also significantly reduced. Hospital stay was shortened in patients receiving glutamine supplementation (29 +/- 1 d compared with 36 +/- 2 d; P = 0.017). CONCLUSION Patients receiving glutamine-supplemented parenteral nutrition after bone marrow transplantation had improved nitrogen balance, a diminished incidence of clinical infection, lower rates of microbial colonization, and shortened hospital stay compared with patients receiving standard parenteral nutrition. These effects occurred despite no differences between groups in the incidence of fever, antibiotic requirements, or time to neutrophil engraftment.

Safety and Metabolic Effects of L-Glutamine Administration in Humans

A series of dose-response studies was conducted to evaluate the clinical safety, pharmacokinetics, and metabolic effects of L-glutamine administered to humans. Initial studies in normal individuals evaluated the short-term response to oral loads of glutamine at doses of 0, 0.1, and 0.3 g/kg. A dose-related increase in blood glutamine occurred after oral loading and elevation of amino acids known to be end products of glutamine metabolism occurred (including alanine, citrulline, and arginine). No evidence of clinical toxicity or generation of toxic metabolites (ammonia and glutamate) was observed. Glutamine was infused intravenously in normal subjects over 4 hr at doses of 0.0125 and 0.025 g/kg/hr. In addition, glutamine was evaluated as a component of parenteral nutrition solutions (0.285 and 0.570 g/kg/day) administered for 5 days to normal subjects. Intravenous administration of glutamine was well tolerated without untoward clinical or biochemical effects. Subsequent studies in patients receiving glutamine-enriched parenteral nutrition for several weeks confirmed the clinical safety of this approach in a catabolic patient population. In addition, nitrogen retention appeared to be enhanced when glutamine was administered at a dose of 0.570 g/kg/day in a balanced nutritional solution providing adequate calories (145% of basal) and protein (1.5 g/kg/day). Nitrogen balance in patients receiving lower doses of glutamine (0.285 g/kg/day) was similar to that in patients receiving standard formulations. Further controlled clinical trials of the metabolic efficacy, tolerance, and dose response of glutamine in other patient groups are necessary to determine the appropriate use of glutamine enrichment of nutrient solutions.

Use of Human Growth Hormone Combined with Nutritional Support in a Critical Care Unit

The administration of growth factors may potentially accelerate recovery during critical illness by reducing body protein catabolism, enhancing wound healing, and improving skeletal muscle function. The purpose of this phase 1 study was to evaluate the safety and initial efficacy of a recombinant growth factor, human growth hormone (GH), combined with nutritional support in a critical care unit. Following an initial control week, 11 individuals received GH (10 mg/day) daily for 1-6 consecutive weeks. Near constant nutrient intake was provided via parenteral and/or enteral feedings throughout the study period. Vital signs and other clinical parameters, blood values, and nutrient excretion were monitored daily. GH administration was not associated with clinically significant adverse effects. During the first 2 weeks of study, nitrogen excretion decreased from 1356 +/- 157 mmol/day (19.0 +/- 2.2 g/day) during control to 899 +/- 107 mmol/day (12.6 +/- 1.4 g/day) with growth hormone (p less than 0.002) in association with markedly reduced urea generation. Significant reductions in potassium excretion (control 100 +/- 11 mmol/day vs 69 +/- 6 with GH; p less than 0.01) and phosphorus excretion (31 +/- 5 mmol/day vs 18 +/- 3; p less than 0.025) also occurred during GH. The protein-conserving effects of GH were sustained during several weeks of treatment. Growth hormone enhanced the efficiency of administered protein and facilitated nitrogen retention without clinically significant adverse effects in this small patient group. Controlled trials are indicated to determine whether use of this anabolic hormone reduces hospitalization time and improves other clinical outcomes in severely injured patients when combined with appropriate nutritional support.

Metabolic effects of recombinant human growth hormone in patients receiving parenteral nutrition.

Recombinant human methionyl growth hormone (Protropin) (Genetech, Inc., San Francisco, CA) administered to normal volunteers receiving hypocaloric parenteral nutrition minimized weight loss and induced positive nitrogen balance. To evaluate whether growth hormone (GH) can promote anabolism in surgical patients, 11 stable malnourished individuals were studied. In the initial trial, subjects received a constant parenteral infusion of a hypocaloric diet that provided approximately 1100 kcal/24 hr and 1.3 g protein/kg/24 hr for at least 2 weeks. During 1 week, GH 10 mg was given subcutaneously daily, whereas the other week served as the control. Daily balance studies demonstrated that administration of GH resulted in significant retention of nitrogen (+3.4 g/24 h) and phosphorus (+218 mg/24 h), despite provision of only 60% of caloric requirements. With GH, serum blood urea nitrogen (BUN) and potassium fell, whereas glucose and insulin tended to rise, and levels of insulin-like growth factor 1 increased three to fourfold. Weight gain occurred with GH and was associated with positive mineral and water balance. Six patients received GH (10 mg subcutaneously daily) for 13-25 consecutive days after an initial control week. Significant nitrogen and phosphorus retention occurred over the entire period of GH administration, and no significant side effects were observed. In these depleted patients, GH caused significant and sustained nitrogen retention over a wide range of nutritional support. GH appears to enhance the efficacy of parenteral nutrition in stable individuals requiring repletion of body protein.

Glutamine-enriched intravenous feedings attenuate extracellular fluid expansion after a standard stress.

A double-blind, randomized controlled trial was performed to determine the effect of glutamine (GLN)-enriched intravenous feedings on the volume and distribution of body fluids in catabolic patients. Subjects with hematologic malignancies in remission underwent a standard treatment of high-dose chemotherapy and total body irradiation before bone marrow transplantation. After completion of this regimen, they were randomized to receive either standard parenteral nutrition (STD, n = 10) or an isocaloric, isonitrogenous nutrient solution enriched with crystalline L-glutamine (0.57 g/kg/day, GLN, n = 10). Extracellular water (ECW) and total body water (TBW), determined by bromide and heavy water dilution techniques, were measured before the conditioning treatment and after termination of the intravenous feedings that were administered for 27 +/- 1 days. In addition electrical resistance (R, in ohms, omega) and reactance (Xc, omega) of the body to a weak alternating current were measured at these time points. Both study groups were comparable for age, weight, height, sex, and diagnosis. Initial TBW was highly related to electrical resistance (r = -0.93, p less than 0.001). After conditioning therapy, bone marrow infusion, and intravenous feedings, a 20% expansion in ECW was observed in the STD group (ECW: 18.0 +/- 1.1 L vs. 14.9 +/- 1.0, p = 0.012), and this fluid retention was associated with a marked decrease in electrical resistance (R: 514 +/- 28 omega vs. 558 +/- 26, p less than 0.05). In contrast the extracellular fluid compartment in patients receiving GLN-supplementation did not change (ECW: 15.8 +/- 0.9 L vs. 15.4 +/- 0.8, p = 0.49), and the bodys resistance was maintained (R: 552 +/- 27 omega vs. 565 +/- 23, p = 0.42). Expansion of ECW could not be related to differences in fluid or sodium intake, or to the use of diuretics or steroids. Patients receiving the STD solution, however, exhibited a greater number of positive microbial cultures (p less than 0.01) and a higher rate of clinical infection compared with the GLN patients (5/10 vs. 0/10, p less than 0.05); the fluid expansion in infected STD patients was greater compared with uninfected individuals (delta ECW: + 5.0 +/- 1.4 vs. 0.7 +/- 0.5, p = 0.007). In this model of catabolic stress, fluid retention and expansion of the extracellular fluid compartment commonly observed after standard total parenteral nutrition can be attenuated by administering glutamine-supplemented intravenous feedings, possibly by protecting the host from microbial invasion and associated infection.

Effects of glutamine supplementation on circulating lymphocytes after bone marrow transplantation: a pilot study.

Glutamine (Gln) is an important nutrient substrate for lymphocytes and macrophages in vitro. This pilot study evaluated effects of Gln supplementation on circulating lymphocytes and lymphocyte subsets after allogeneic bone marrow transplantation (BMT). Adult patients received either parenteral nutrition supplemented by L-Gln (Gln-PN) or standard Gln-free PN after BMT. Leukocyte and total lymphocyte counts were determined during hospitalization, and flow cytometry studies of peripheral mononuclear cells were performed 1 to 2 weeks after hospital discharge. The Gln-PN group demonstrated a higher percentage of blood lymphocytes during hospitalization. At flow cytometry, patients who received Gln-PN had an increased total lymphocyte count (332 +/- 50 versus 590 +/- 71 cells/microL, P = 0.010); greater numbers of total T lymphocytes (54 +/- 19 versus 229 +/- 70 cells/microL, P = 0.030); and higher CD4+ and CD8+ T-lymphocyte counts in peripheral blood compared with controls. Gln-PN may support lymphocyte recovery after BMT.

A cost-evaluation of glutamine-supplemented parenteral nutrition in adult bone marrow transplant patients

OBJECTIVE In a randomized, double-blind, prospective clinical trial, we evaluated the metabolic effects of glutamine-supplemented parenteral nutrition in patients with bone marrow transplants. We compared hospital charge and cost data for the two groups of patients in the trial. DESIGN Retrospective review. SETTING Bone Marrow Transplant Unit, Brigham and Womens Hospital, Boston, Mass. SUBJECTS Forty-three patients admitted to the Bone Marrow Transplant Unit were assigned randomly to receive either standard parenteral nutrition or an isocaloric, isonitrogenous parenteral nutrition solution containing glutamine starting on day 1 after bone marrow transplant. The two groups were well matched for diagnosis, antineoplastic treatment, and sex. MEASURES The primary clinical end points evaluated were nitrogen balance, length of hospitalization, incidence of infection, and results of microbial culture. After completion of the study, we compared the hospital charges for the categories of room and board, surgery, laboratory, pharmacy, radiology, ancillary, and miscellaneous between the two groups of patients. STATISTICAL ANALYSIS PERFORMED The two groups were compared using the unpaired t test or Mann-Whitney test for nonparametric measurements. A P value of < .05 was considered significant. RESULTS Nitrogen balance improved in the glutamine-supplemented group compared with control subjects (-1.4 +/- 0.5 g/day vs 4.2 +/- 1.2 g/day, respectively; P = .002). Length of hospitalization was significantly shorter in the glutamine-supplemented group than in the control group (29 +/- 1 day vs 36 +/- 2 days, respectively; P = .017). The incidence of positive microbial cultures and clinical infection was also significantly lower with glutamine supplementation. Hospital charges were

Patients receiving glutamine-supplemented intravenous feedings report an improvement in mood

21,095 per patient less in the glutamine-supplemented group compared with charges for patients who received standard therapy. Room and board charges were significantly different:

American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) and American Dietetic Association (ADA): Standards of Practice and Standards of Professional Performance for Registered Dietitians (Generalist, Specialty, and Advanced) in Nutrition Support

51,484 +/- 2,647 for the glutamine-supplemented group vs

A.S.P.E.N. Position Paper Parenteral Nutrition Glutamine Supplementation

61,591 +/- 3,588 in the control group (P = .02). CONCLUSION This intervention study using a new therapy demonstrated clinical and nutritional benefits to patients and cost savings to the hospital.