Novel insights into the neuroendocrinology of critical illness

An unexplained hallmark of prolonged critical illness is the fact that food does not prevent or reverse protein wasting, while fat is paradoxically ac crued, This 'wasting syndrome' often persists after the underlying disease has been resolved and thus perpetuates intensive care dependency. Although the crucial role of an intact hypothalamus-pituitary axis for homeostasis d uring stress is well recognized, the differences between the neuroendocrine changes observed in acute and prolonged critical illness were only recentl y described. Novel insights in this area are reviewed here. The initial endocrine stress response consists primarily of a peripheral in activation of anabolic pathways while pituitary activity is essentially amp lified or maintained. These responses presumably provide the metabolic subs trates and host defense required for survival and to delay anabolism, and t hus should be considered as adaptive and beneficial. Persistence of this ac ute stress response throughout the course of critical illness was hitherto assumed. This assumption has now been invalidated, since a uniformly reduce d pulsatile secretion of ACTH, TSH, LH, prolactin (PRL) and GH has been obs erved in protracted critical illness, causing diminished stimulation of sev eral target organs. Impaired pulsatile secretion of anterior pituitary horm ones in the chronic phase of critical illness seems to have a hypothalamic rather than a pituitary origin, as administration of relevant releasing fac tors evoked immediate and pronounced pituitary hormone release. A reduced a vailability of TRH, one of the endogenous ligands of the GH-releasing pepti de (GHRP) receptor (such as the recently discovered ghrelin) and, in very l ong-stay critically ill men, also of GHRH, appear to be involved. This hypo thesis was further explored by investigating the effects of continuous i.v. infusion of GHRH, GHRP, TRH and their combinations for several days. Pulsa tile secretion of GH, TSH and PRL was re-amplified by relevant combinations of releasing factors which also substantially increased circulating levels of IGF-I, GH-dependent binding proteins, thyroxine and tri-iodothyronine ( T3) while avoiding a rise in reverse T3. Active feedback-inhibition loops p revented overstimulation of target organs and metabolic improvement was not ed with the combined infusion of GHRP and TRH. Whether this novel endocrine strategy will also enhance clinical recovery from critical illness remains to be explored.