CRITICAL ILLNESS IS ASSOCIATED WITH LOW CIRCULATING CONCENTRATIONS OFINSULIN-LIKE GROWTH-FACTOR-I AND GROWTH-FACTOR-II, ALTERATIONS IN INSULIN-LIKE GROWTH-FACTOR BINDING-PROTEINS, AND INDUCTION OF AN INSULIN-LIKE GROWTH-FACTOR BINDING-PROTEIN-3 PROTEASE

Objectives: To describe the sequential changes in the circulating conc entrations of insulin-like growth factor-I, insulin-like growth factor ll, and insulin like growth factor binding proteins in critically ill patients. To determine whether critical illness is associated with in duction of a specific protease directed against insulin-like growth fa ctor binding protein 3 and to relate these changes to outcome. Design: Prospective, descriptive study. Setting: Intensive care unit (ICU) of a university hospital. Patients: Eighteen heterogeneous critically il l patients, requiring ventilatory support. Interventions: Serial daily blood samples were collected until death or discharge from the ICU. I n five patients, samples were also obtained on the ward before dischar ge from the hospital. Measurements and Main Results: Serum concentrati ons of insulin-like growth factor-I, insulin-like growth factor-II, an d insulin-like growth factor binding proteins 1, 2, and 3 were measure d by radioimmunoassay. After 5 days, insulin like growth factor bindin g protein 3 concentrations were measured on alternate days. Alteration s in binding of insulin-like growth factor-I to insulin-like growth fa ctor binding protein 3 and the presence of protease activity directed against insulin-like growth factor binding protein 3 were investigated by Western ligand blotting. Circulating concentrations of insulin-lik e growth factor-I and insulin-like growth factor-II were low and remai ned low throughout the 7-day study period. Insulin like growth factor binding protein 1 concentrations were initially increased to within th e fasting range, but subsequently decreased. There was considerable va riability in insulin like growth factor binding protein 2 concentratio ns, but generally, concentrations were at the upper end of the normal range throughout. Insulin like growth factor binding protein 3 concent rations were consistently low and Western ligand blotting at the nadir of the insulin-like growth factor-I concentration demonstrated the pr esence of a protease directed against insulin-like growth factor bindi ng protein 3. The last recorded concentrations of insulin-like growth factor-I and insulin-like growth factor binding protein 3 were higher in survivors than in nonsurvivors (p < .05). Two patients were also st udied for a prolonged period. In one patient, a survivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 were low initially, but later increased in association with recovery and c essation of protease activity over a period of 33 days. In another pat ient, a nonsurvivor, insulin-like growth factor-I and insulin-like gro wth factor binding protein 3 remained low and protease activity persis ted until the patient died 38 days after admission to the ICU. Conclus ions: Critical illness is associated with low circulating concentratio ns of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding protein 3 and these low values are associated with induction of protease activity specifically directed against insulin like growth factor binding protein 3. In survivors, re covery is associated with increasing insulin-like growth factor-I and insulin-like growth factor binding protein 3 concentrations and cessat ion of protease activity. The therapeutic effects of exogenous growth factors are likely to be influenced by these changes.