Novel insights into the neuroendocrinology of critical illness

Abstract

An unexplained hallmark of prolonged critical illness is the fact that food does not prevent or reverse protein wasting, while fat is paradoxically accrued. 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 during stress is well recognized, the differences between the neuroendocrine changes observed in acute and prolonged critical illness were only recently described. Novel insights in this area are reviewed here.The initial endocrine stress response consists primarily of a peripheral inactivation of anabolic pathways while pituitary activity is essentially ampli®ed or maintained. These responses presumably provide the metabolic substrates and host defense required for survival and to delay anabolism, and thus should be considered as adaptive and bene®cial. Persistence of this acute stress response throughout the course of critical illness was hitherto assumed. This assumption has now been invalidated, since a uniformly reduced pulsatile secretion of ACTH, TSH, LH, prolactin (PRL) and GH has been observed in protracted critical illness, causing diminished stimulation of several target organs. Impaired pulsatile secretion of anterior pituitary hormones in the chronic phase of critical illness seems to have a hypothalamic rather than a pituitary origin, as administration of relevant releasing factors evoked immediate and pronounced pituitary hormone release. A reduced availability of TRH, one of the endogenous ligands of the GH-releasing peptide (GHRP) receptor (such as the recently discovered ghrelin) and, in very long-stay critically ill men, also of GHRH, appear to be involved. This hypothesis was further explored by investigating the effects of continuous i.v. infusion of GHRH, GHRP, TRH and their combinations for several days. Pulsatile secretion of GH, TSH and PRL was re-ampli®ed 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 prevented overstimulation of target organs and metabolic improvement was noted 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.

Prevalence of anterior pituitary insufficiency 3 and 12 months after traumatic brain injury

“…It is known that reproductive function is downregulated in episodes of severe illness (15,20). Moreover, in studies of the early phase after TBI, a reversible, severity-dependent decline of testosterone has been described (21,22).…”

“…In a recent study, hormonal assessments in a very early phase after TBI (mean 12 days after trauma) indicated a substantial prevalence of pituitary deficiencies (14). However, in this early phase, it is not clear whether these hormonal changes are specifically due to brain trauma or are an unspecific reaction to critical illness (15). To date, only one longitudinal study on clinical course of post-traumatic hypopituitarism has been published (13).…”

Hypopituitarism after traumatic brain injury

“…Peripheral GH resistance, manifested by elevated GH levels with low IGF-I concentrations, has been observed in patients with acute critical illness (44). A decrease in GH bursts frequency has been detected 24 -48 h after severe trauma, indicating a relative hyposomatotropinism (45).…”

DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome)

“…Patients in the intensive care unit for long periods of time have significant loss of muscle mass and catabolism mediated in part by hypercortisolism (61). Increases in cortisol have also been observed in healthy women undergoing low-calorie dieting and increased morning cortisol levels have been demonstrated in women with significant weight loss after bariatric surgery (62).…”