THE SOMATOTROPIC AXIS IN CRITICAL ILLNESS - EFFECT OF CONTINUOUS GROWTH-HORMONE (GH)-RELEASING HORMONE AND GH-RELEASING PEPTIDE-2 INFUSION

Prolonged critical illness is characterized by protein hypercatabolism and preservation of fat depots, associated with blunted GH secretion, elevated serum cortisol levels, and low insulin-like growth factor I (IGF-I) concentrations. In this condition, GH is readily released in r esponse to a bolus of GHRH and GH-releasing peptide-2 (GHRP-2) and, pa radoxically, to TRH. We further explored the altered somatotropic axis and cortisol secretion in critical illness by examining the effects o f continuous GHRH and/or GHRP-8 infusion. Twenty-six critically ill ad ults (mean age+/-SEM, 63+/-2 yr) were studied during 2 consecutive nig hts (2100-0600 h). According to a weighed randomization, they received one of four combinations of infusions within a randomized cross-over design for each combination: placebo (one night) and GHRP-2 (the other night; n=10), placebo and GHRH (n=4), GHRH and GHRP-2 (n=6), and GHRP -2 and GHRH plus GHRP-2 (n=6). The peptide infusions (duration, 21 h) were started after a bolus of 1 mu g/kg at 0900 h and infused (1 mu g/ kg/h) until 0600 h. Serum concentrations of GH were determined every 2 0 min, cortisol every hour, and IGF-I at 2100 and 0600 h on each study night. The placebo profiles showed pulsatile GH secretion with low se cretory burst amplitude [0.062+/-0.008 mu g/L distribution volume (L(V ))/min], high burst frequency (6.6+/-0.4 events/9 h), and detectable b asal secretion (0.041+/-0.009 mu g/L(V)/min) in the face of low serum IGF-I (106+/-11 mu g/L). IGF-I correlated positively and significantly with the basal component, the pulsatile component, and the total amou nt of nightly GH secretion. GHRH elicited a 2- to 3-fold increase in t he mean GH concentration (P=0.006), the GH secretory burst amplitude ( P=0.007), and basal GH secretion (P=0.03). GHRP-2 provoked a 4- to 6-f old increase in the mean GH concentration (P <0.0001), the GH secretor y burst amplitude (P=0.002), and basal GH secretion (P=0.0007), which were associated with a 61+/-13% increase in serum IGF-I within 24 h (P =0.02). Compared to GHRP-2 alone, GHRH plus GHRP-2 elicited a further 2-fold increase in the mean GH concentration (P=0.04) and GH basal sec retion (P=0.02), and an additional 40+/-6% rise in serum IGF-I (P=0.04 ). GHRH and GHRP-2 infusion did not alter elevated cortisol levels. In critically ill adults, low serum IGF-I levels were positively correla ted with diminished pulsatile and increased basal GH secretion. Both b asal and pulsatile GH secretion were moderately increased by continuou s infusion of GHRH, substantially increased by GHRP-2, and strikingly increased by GHRH plus GHRP-2. GHRP-2 alone or combined with GHRH elic ited a robust rise in circulating IGF-I levels within 24 h without alt ering serum cortisol levels. These findings open perspectives for GH s ecretagogues as potential antagonists of the catabolic state in critic al care medicine.