Sepsis-related stress response: known knowns, known unknowns, and unknown unknowns

The hypothalamic-pituitary-adrenal (HPA) axis response in sepsis remains to be elucidated. Apart from corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol, many other neuroendocrine factors participate in the regulation of HPA stress response. The HPA response to acute and chronic illness exerts a biphasic profile. Tissue corticosteroid resistance may also play an important role. All of these add to the complexity of the concept of ‘relative adrenal insufficiency' and may account for the difficulty of clinical diagnosis and for the conflicting results of corticosteroid replacement therapy in severe sepsis/septic shock. The study by Lesur and colleagues expands our understanding of the mechanism, and further study of HPA stress response is warranted.

However, HPA stress response during sepsis is much more complex and is poorly defi ned. Plasma cortisol levels may be low, normal, or high in sepsis [2,5] but nonetheless inadequate to control the infl ammatory response and meet the elevated metabolic demand [5]. Th is eff ect is termed relative adrenal insuffi ciency (RAI), also known as critical illness-related corticosteroid insufficiency (CIRCI) [2,3,6].
Other factors are involved in the HPA stress response during sepsis [6,7]. In rodent models, arginine vasopressin (AVP) was shown to increase endogenous adrenal ACTH secretion [7]. Apelin, a neuropeptide originating from paraventricular and supraopitc nuclei, acts on HPA axis regulation by releasing CRH and ACTH and by reducing AVP [7]. Copeptin, a 39-amino acid glycopeptide, makes up the pre-pro-vasopressin molecule together with neurophysin II and AVP and serves as a surrogate marker to assess AVP plasma concentrations in septic shock [8]. In normal rats, the chemokine SDF-1α and its receptor colocalize with AVP in magnocellular neurosecreatory neurons, resulting in an inhibition of AVP-induced release [9].
Real life is even more complex. Th e HPA may display a biphasic pattern during the course of a critical illness [4,10]. Th e dissociation of ACTH and cortisol levels in late phase (lasting many days to weeks), which is diff erent from that of the acute phase (hours to a few days) of an illness, indicates that alternative pathways not mediated by ACTH are involved. Moreover, androgens produced by zona reticularis are aff ected in sepsis or CIRCI. Limited clinical studies prove that the dehydroepiandrosterone (DHEA) level is very low in septic shock, whereas its sulphate and the cortisol/DHEA ratio might be prognostic markers and signs of exhausted adrenal reserve in critical illness [11]. Tissue resistance to corticosteroid action may also play an important role in sepsis [6] and can be caused by either defects in the corticosteroid receptor or postreceptor alterations and may not be defi ned accurately based on plasma cortisol levels [3,4].

Abstract
The hypothalamic-pituitary-adrenal (HPA) axis response in sepsis remains to be elucidated. Apart from corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol, many other neuroendocrine factors participate in the regulation of HPA stress response. The HPA response to acute and chronic illness exerts a biphasic profi le. Tissue corticosteroid resistance may also play an important role. All of these add to the complexity of the concept of 'relative adrenal insuffi ciency' and may account for the diffi culty of clinical diagnosis and for the confl icting results of corticosteroid replacement therapy in severe sepsis/ septic shock. The study by Lesur and colleagues expands our understanding of the mechanism, and further study of HPA stress response is warranted.
Despite the uncertainty of the defi nition and diagnostic criteria, clinical studies show that patients with RAI are at a signifi cantly higher risk of hospital mortality [12] and this has been the driver for corticosteroid replacement therapy in severe sepsis/septic shock [2][3][4]. However, clinical trials with stress-dose corticosteroid show confl ict ing results [13,14]. Th is is not surprising upon review of the aforementioned complexity and unknowns of HPA stress response. Furthermore, it must be acknowledged that the decision to treat with stress-dose corticosteroids is based on clinical criteria rather than on the inconclusive results of adrenal function tests.
Th e limitations of the study by Lesur and colleagues [1] should be considered. Th e dissociation of ACTH and cortisol levels observed in the study is more compatible with neuroendocrine characteristics of prolonged critical illness [4], although the authors claimed to include patients within the fi rst 24 hours of admission [1]. Th e clinical signifi cance of the predictive model is hindered by the unavailability of ACTH or cortisol measurements at the bedside and by the fact that the predictive value of sepsis score or PCT has not been consistently validated in clinical trials [15].
Despite all of these limitations, the study by Lesur and colleagues undoubtedly expands our understanding of the complex neuroendocrine network regulating HPA stress response in human sepsis. We believe that further investi gation into the mechanism is warranted before we plan a success ful strategy for corticosteroid replacement in sepsis.