NEUROENDOCRINOLOGY OF PROLONGED CRITICAL ILLNESS - EFFECTS OF EXOGENOUS THYROTROPIN-RELEASING-HORMONE AND ITS COMBINATION WITH GROWTH-HORMONE SECRETAGOGUES

The catabolic state of prolonged critical illness is associated with a low activity of the thyrotropic and the somatotropic axes. The neuroe ndocrine component in the pathogenesis of these low activity states wa s assessed by investigating the effects of continuous intra venous inf usions of TRH, GH-releasing peptide-2 (GHRP-2), and GHRH. Twenty adult patients, critically ill for several weeks, were studied during two c onsecutive nights. They had been randomly allocated to one of three co mbinations of peptide infusions, each administered in random order: TR H (one night) and placebo (other night), TRH + GHRP-2 (one night) and GHRP-2 (other night), or TRH + GHRH + GHRP-2 (one night) and GHRH + GH RP-2 (other night). The peptide infusions were started after a 1-mu g/ kg bolus and infused (1 mu g/kg per h) until 0600 h. Blood sampling wa s performed every 20 min, and pituitary hormone secretion was quantifi ed by deconvolution analysis. Reduced pulsatile fraction of TSH, GH, a nd PRL secretion and low serum concentrations of T-4, T-3, insulin gro wth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-la bile subunit (ALS) were documented in the untreated state. Infusion of TRH alone or in combination with GH secretagogues augmented nonpulsat ile TSH release 2-to 5-fold; only TRH + GHRP-2 increased pulsatile TSH secretion (4-fold). Average rises in T-4 (40-54%) and in T-3 (52-116% ) were obtained with all three combinations, whereas reverse T-3 level s did not increase, except when TRH was infused alone. Pulsatile GH se cretion was amplified >6- and >10-fold, respectively, by GHRP-2 and GH RH + GHRP-2 infusions, generating mean increases of serum IGF-I (66% a nd 106%), IGFBP-3 (50% and 56%), and ALS (65% and 97%) within 45 h. Th e addition of TRH did not alter the GH secretory patterns. TRH infusio n increased PRL release only when combined with GH secretagogues. No e ffects on serum cortisol were detected. In conclusion, the pathogenesi s of the low activity state of the thyrotropic and somatotropic axes i n prolonged critical illness appears to have a neuroendocrine componen t, because these axes are both readily activated by coinfusion of TRH and GH secretagogues.