Click here for file(37K, doc)AcknowledgementsThe Lenalidomide FDA authors thank Fieke Kloosterman, Ilja te Paske, Peter Casteleijns, Maarten Vrijburcht, Annemieke Leguyt, Robbert v.d. Looij, Margreet Colenbrander and Hans Breepoel for their efforts in spreading and collecting the questionnaires, Larissa Gregorian for her comments and all physicians and nurses for filling in the questionnaires.
Severe sepsis and septic shock are the most common causes of death in intensive care units (ICU) with a mortality rate ranging from 30 to 70% [1]. Most of these related deaths result from multiple organ dysfunction/failure occurring in advanced stages of septic shock [2]. During septic shock, the hypothalamo-pituitary-adrenal (HPA) axis is also dysfunctional and the neuroendocrine stress response system is disrupted [2,3].

One of the best examples is the concept of relative adrenal insufficiency which has recently been denominated CIRCI (critical illness-related corticosteroid insufficiency) [4]. Annane et al. first demonstrated that septic shock patients exhibiting a blunted dynamic cortisol response to corticotropin had more vasopressor-unresponsive shock and a higher 28-day mortality rate [5,6]. The Corticosteroid therapy of septic shock (CORTICUS) study confirmed almost half of septic patients exhibited an inappropriate dynamic response to corticotropin, and that septic shock was more quickly reversed for those receiving hydrocortisone [7].Neuropeptides of the posterior pituitary area may be actively committed in the regulation of the aforementioned corticotropic axis.

Indeed, arginine-vasopressin (AVP) heightens hypothalamic sensitivity to corticotrophin-releasing hormone (CRH), thereby increasing ACTH release and cortisol production, and improves hemodynamics during sepsis [8,9]. Apelin (APL), a new endogenously released peptide discovered in 1998 and co-expressed within vasopressinergic neurons, was found to be implicated in the up-regulation of ACTH pituitary secretion [9-11]. Furthermore, the stromal-derived factor-1�� (SDF-1��), a member of the chemokine family recently reported to co-localize with AVP in the magnocellular neurons of the hypothalamic supraoptic (SON) and paraventricular nuclei (PVN), may potentially interfere with AVP functions [12].

It is unknown whether the stress response to ICU admission leads AV-951 to a uniform pathway, irrespective if the cause of admission is sepsis-related or not, whether neuropeptide release can interact with the neighboring corticotrope axis in stress conditions, and if the outcome can be affected by their ensuing cross-talks. In parallel, the search for biomarkers to improve diagnostic accuracy in systemic infections is especially relevant in an ICU setting. Recent reports have emphasized the value of measuring blood procalcitonin (PCT), C-reactive protein in the initial diagnostic assessment of systemic infection [13].