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The Somatotropic Axis in Critical Illness: Effect of Continuous Growth Hormone (GH)-Releasing Hormone and GH-Releasing Peptide-2 Infusion¹

Departments of Intensive Care Medicine (G.V.d.B., P.W., M.A., W.V., M.S., C.V., P.L.), Pediatrics (F.d.Z.), and Medicine, Division of Endocrinology (R.B.), University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium; the Department of Medicine, Division of Endocrinology, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 29908; and the Department of Medicine, Division of Endocrinology, Tulane University Medical Center (C.Y.B.), New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: Dr. Greet Van den Berghe, Department of Intensive Care Medicine, University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium.

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 response to a bolus of GHRH and GH-releasing peptide-2 (GHRP-2) and, paradoxically, to TRH. We further explored the altered somatotropic axis and cortisol secretion in critical illness by examining the effects of continuous GHRH and/or GHRP-2 infusion.

Twenty-six critically ill adults (mean age ± SEM, 63 ± 2 yr) were studied during 2 consecutive nights (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 µg/kg at 0900 h and infused (1 µg/kg/h) until 0600 h. Serum concentrations of GH were determined every 20 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 secretory burst amplitude [0.062 ± 0.008 µg/L distribution volume (L_v)/min], high burst frequency (6.6 ± 0.4 events/9 h), and detectable basal secretion (0.041 ± 0.009 µg/L_v/min) in the face of low serum IGF-I (106 ± 11 µg/L). IGF-I correlated positively and significantly with the basal component, the pulsatile component, and the total amount of nightly GH secretion.

GHRH elicited a 2- to 3-fold increase in the 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-fold increase in the mean GH concentration (P < 0.0001), the GH secretory 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 secretion (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 correlated with diminished pulsatile and increased basal GH secretion. Both basal and pulsatile GH secretion were moderately increased by continuous infusion of GHRH, substantially increased by GHRP-2, and strikingly increased by GHRH plus GHRP-2. GHRP-2 alone or combined with GHRH elicited a robust rise in circulating IGF-I levels within 24 h without altering serum cortisol levels. These findings open perspectives for GH secretagogues as potential antagonists of the catabolic state in critical care medicine.

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