BACKGROUND-Critical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism.

The vascular endothelium controls vasomotor tone and microvascular flow and regulates trafficking of nutrients and biologically active molecules. When endothelial activation is excessive, compromised microcirculation and subsequent cellular hypoxia contribute to the risk of organ failure. We hypothesized that strict blood glucose control with insulin during critical illness protects the endothelium, mediating prevention of organ failure and death. In this preplanned subanalysis of a large, randomized controlled study, intensive insulin therapy lowered circulating levels of ICAM-1 and tended to reduce E-selectin levels in patients with prolonged critical illness, which reflects reduced endothelial activation. This effect was not brought about by altered levels of endothelial stimuli, such as cytokines or VEGF, or by upregulation of eNOS. In contrast, prevention of hyperglycemia by intensive insulin therapy suppressed iNOS gene expression in postmortem liver and skeletal muscle, possibly in part via reduced NF-κB activation, and lowered the elevated circulating NO levels in both survivors and nonsurvivors. These effects on the endothelium statistically explained a significant part of the improved patient outcome with intensive insulin therapy. In conclusion, maintaining normoglycemia with intensive insulin therapy during critical illness protects the endothelium, likely in part via inhibition of excessive iNOS-induced NO release, and thereby contributes to prevention of organ failure and death.

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Hyperbilirubinemia is common during critical illness and is associated with adverse outcome. Whether hyperbilirubinemia reflects intensive care unit (ICU) cholestasis is unclear. Therefore, the aim of this study was to analyze hyperbilirubinemia in conjunction with serum bile acids (BAs) and the key steps in BA synthesis, transport, and regulation by nuclear receptors (NRs). Serum BA and bilirubin levels were determined in 130 ICU and 20 control patients. In liver biopsies messenger RNA (mRNA) expression of BA synthesis enzymes, BA transporters, and NRs was assessed. In a subset (40 ICU / 10 controls) immunohistochemical staining of the transporters and receptors together with a histological evaluation of cholestasis was performed. BA levels were much more elevated than bilirubin in ICU patients. Conjugated cholic acid (CA) and chenodeoxycholic acid (CDCA) were elevated, with an increased CA/CDCA ratio. Unconjugated BA did not differ between controls and patients. Despite elevated serum BA levels, CYP7A1 protein, the rate-limiting enzyme in BA synthesis, was not lowered in ICU patients. Also, protein expression of the apical bile salt export pump (BSEP) was decreased, whereas multidrug resistance-associated protein (MRP) 3 was strongly increased at the basolateral side. This reversal of BA transport toward the sinusoidal blood compartment is in line with the increased serum conjugated BA levels. Immunostaining showed marked down-regulation of nuclear farnesoid X receptor, retinoid X receptor alpha, constitutive androstane receptor, and pregnane X receptor nuclear protein levels. Conclusion: Failure to inhibit BA synthesis, up-regulate canalicular BA export, and localize pivotal NR in the hepatocytic nuclei may indicate dysfunctional feedback regulation by increased BA levels. Alternatively, critical illness may result in maintained BA synthesis (CYP7A1), reversal of normal BA transport (BSEP/MRP3), and inhibition of the BA sensor (FXR/RXRa) to increase serum BA levels.

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