Administration of human recombinant insulin-like growth factor-I in critically ill patients

Objectives: To study the pharmacokinetics of a single subcutaneous dose of recombinant human insulin-like growth factor-I (IGF-I) in patients with systemic inflammatory response syndrome in the intensive care unit (ICU). To evaluate the effects of exogenous recombinant human IGF-I on circulating concentrations of IGF-I binding protein-1 (IGFBP-1), IGF-I binding protein-3 (IGFBP-3), and growth hormone in the critically ill patient; to assess the safety of the subcutaneous administration of 40 mu g/kg of recombinant human IGF-I in these patients; and to investigate any effect this dose might have on nitrogen balance, creatinine clearance, and serum electrolyte and lipid concentrations. Design: Open-labeled, noncontrolled, prospective, single-dose study of eight fully evaluable ICU patients with systemic inflammatory response syndrome. Setting: ICUs in a teaching hospital and a linked district gen- eral hospital in England. Patients: Nine patients were examined, eight of whom were fully evaluable. Interventions: Subcutaneous administration of 40 mu g/kg of recombinant human IGF-I. Measurements and Main Results: Blood samples were taken 24 hrs before the subcutaneous injection of 40 mu g/kg of recombinant human IGF-I, and for 48 hrs thereafter, Urine was collected throughout this period. Serum concentrations of IGF-I, IGFBP-1, IGFBP-3, growth hormone, and insulin were measured by radioimmunoassay. IGF-I concentrations (median and range) increased significantly above baseline values (35 ng/mL [20 to 144]) from 15 mins (p <.02) until 10 hrs (p <.02) after injection of recombinant human IGF-I, Peak IGF-I concentrations were sustained from 2 hrs (90.5 ng/mL [23 to 228]) to 5 hrs (88.5 ng/mL [29 to 300]). By 24 hrs, circulating IGF-I concentrations had returned to baseline values, Baseline IGF-I concentrations were extremely low, and although peak values were three times greater, these values only approached the fifth percentile of defined reference ranges for normal values, Compared with values in less seriously ill patients, maximum IGF-I concentrations were reached earlier, the elimination half-life was shorter, clearance was more rapid, and the apparent volume of distribution was similar, IGFBP-3 concentrations also increased after recombinant human IGF-I injection, and at 3 to 4 hrs were significantly elevated, from 30 mins (p =.04) to 8 hrs (p =.04). There was marked between-patient variability in changes in circulating IGF-I, and IGFBP-1, and IGFBP-3 concentrations, More severely ill patients had the lowest circulating IGF-I concentrations and the least response to exogenous recombinant human IGF-I. Elevated baseline circulating growth hormone concentrations (2.3 ng/mL, range 0.8 to 4 [5.1 mU/L, 1.5 to 8]) were significantly depressed from 4 hrs (0.5 ng/mL, 0.5 to 1.5 [1 mU/L, 1 to 3], p =.01) to 6 hrs (0.8 ng/mL, 0.5 to 4 [1.5 mU/L, 1 to 8], p =.02) after recombinant human IGF-I administration. Conclusion: We observed no adverse effects (e.g., hypoglycemia) that could be attributed to recombinant human IGF-I therapy.