Protein loss leading to reduced lean body mass is recognized to contribute to the high levels of morbidity and mortality seen in critical illness. This prospective, randomized, controlled study compared the effects of conventional parenteral nutrition (TPN), glutamine-supplemented (0.4 g.kg-1.day-1) TPN (TPNGLN), and TPNGLN with combined growth hormone (GH, 0.2 IU.kg-1.day-1) and IGF-I (160 microg.kg-1.day-1) on protein metabolism in critical illness. Nineteen mechanically ventilated subjects [64 +/- 3 yr, body mass index (BMI) 23.8 +/- 1.3, kg/m2] were initially studied in the fasting state (study 1) and subsequently after 3 days of nutritional with/without hormonal support (study 2). All had recently been admitted to the ICU and the majority were postemergency abdominal surgery (APACHE II 17.5 +/- 1.0). Protein metabolism was assessed using a primed constant infusion of [1-13C]leucine. Conventional TPN contained mixed amino acids, Intralipid, and 50% dextrose. TPNGLN, unlike TPN alone, resulted in an increase in plasma glutamine concentration ( approximately 50%, P < 0.05). Both TPN and TPNGLN decreased the rate of protein breakdown (TPN 15%, P < 0.002; TPNGLN 16%, P < 0.05), but during these treatments the patients remained in a net negative protein balance. Combined treatment with TPNGLN + GH/IGF-I increased plasma IGF-I levels (10.3 +/- 0.8 vs. 48.1 +/- 9.1 nmol/l, study 1 vs. study 2, P < 0.05), and in contrast to therapy with nutrition alone, resulted in net protein gain (-0.75 +/- 0.14 vs. 0.33 +/- 0.12 g protein.kg-1.day-1, study 1 vs. study 2, P < 0.05). Therapy with GH/IGF-I + TPNGLN, unlike nutrition alone, resulted in net positive protein balance in a group of critically ill patients.