Lies Langouche

Intensive insulin therapy protects the endothelium of critically ill patients.

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-kappaB 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.

Reduced Cortisol Metabolism during Critical Illness

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. METHODS In a total of 158 patients in the intensive care unit and 64 matched controls, we tested five aspects of cortisol metabolism: daily levels of corticotropin and cortisol; plasma cortisol clearance, metabolism, and production during infusion of deuterium-labeled steroid hormones as tracers; plasma clearance of 100 mg of hydrocortisone; levels of urinary cortisol metabolites; and levels of messenger RNA and protein in liver and adipose tissue, to assess major cortisol-metabolizing enzymes. RESULTS Total and free circulating cortisol levels were consistently higher in the patients than in controls, whereas corticotropin levels were lower (P<0.001 for both comparisons). Cortisol production was 83% higher in the patients (P=0.02). There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg of hydrocortisone in the patients (P≤0.03 for both comparisons). All these factors accounted for an increase by a factor of 3.5 in plasma cortisol levels in the patients, as compared with controls (P<0.001). Impaired cortisol clearance also correlated with a lower cortisol response to corticotropin stimulation. Reduced cortisol metabolism was associated with reduced inactivation of cortisol in the liver and kidney, as suggested by urinary steroid ratios, tracer kinetics, and assessment of liver-biopsy samples (P≤0.004 for all comparisons). CONCLUSIONS During critical illness, reduced cortisol breakdown, related to suppressed expression and activity of cortisol-metabolizing enzymes, contributed to hypercortisolemia and hence corticotropin suppression. The diagnostic and therapeutic implications for critically ill patients are unknown. (Funded by the Belgian Fund for Scientific Research and others; ClinicalTrials.gov numbers, NCT00512122 and NCT00115479; and Current Controlled Trials numbers, ISRCTN49433936, ISRCTN49306926, and ISRCTN08083905.).

Glycemic and nonglycemic effects of insulin: how do they contribute to a better outcome of critical illness?

Purpose of reviewThis review gives an overview of the clinical outcome benefits associated with intensive insulin therapy administered to critically ill patients and of the progress in the unraveling of the mechanisms underlying these positive effects. Recent findingsIn a large, prospective, randomized, controlled study, strict blood glucose control with intensive insulin therapy strongly reduced mortality and morbidity of surgical intensive care patients. These results were recently confirmed in a more heterogeneous patient population admitted to a mixed medical-surgical intensive care unit. Most of the clinical benefits of intensive insulin therapy appear to be related to prevention of hyperglycemia, which has been demonstrated to adversely affect outcome. Part of the improvement is related to protection of the mitochondrial compartment and innate immunity from glucose toxicity. Also, direct insulin effects contribute to the improved outcome. The beneficial nonglycemic metabolic actions of insulin include a partial correction of the abnormal serum lipid profile and counteraction of the catabolic state evoked by critical illness. The prevention of excessive inflammation and myocardial protection illustrate other nonmetabolic direct anti-inflammatory and anti-apoptotic properties of insulin, although lowering of glucose levels may have played a role in these events as well. SummarySubstantial progress has been made in the understanding of the mechanisms underlying the improved survival and reduced morbidity with intensive insulin therapy in critical illness. More studies, however, are needed to further elucidate the exact pathways involved and the relative contribution of prevention of glucose toxicity and direct nonglycemic effects of insulin.

Endocrine aspects of acute and prolonged critical illness

Critical illness is characterized by striking alterations in the hypothalamic–anterior-pituitary–peripheral-hormone axes, the severity of which is associated with a high risk of morbidity and mortality. Most attempts to correct hormone balance have been shown ineffective or even harmful because of a lack of pathophysiologic insight. There is a biphasic (neuro)endocrine response to critical illness. The acute phase is characterized by an actively secreting pituitary, but the concentrations of most peripheral effector hormones are low, partly due to the development of target-organ resistance. In contrast, in prolonged critical illness, uniform (predominantly hypothalamic) suppression of the (neuro)endocrine axes contributes to the low serum levels of the respective target-organ hormones. The adaptations in the acute phase are considered to be beneficial for short-term survival. In the chronic phase, however, the observed (neuro)endocrine alterations appear to contribute to the general wasting syndrome. With the exception of intensive insulin therapy, and perhaps hydrocortisone administration for a subgroup of patients, no hormonal intervention has proven to beneficially affect outcome. The combined administration of hypothalamic releasing factors does, however, hold promise as a safe therapy to reverse the (neuro)endocrine and metabolic abnormalities of prolonged critical illness by concomitant reactivation of the different anterior-pituitary axes.

Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit

Objective:Critically ill patients are at risk of sepsis, organ failure, and death. Studying the impact of genetic determinants may improve our understanding of the pathophysiology and allow identification of patients who would benefit from specific treatments. Our aim was to study the influence of single nucleotide polymorphisms in selected genes involved in innate immunity on the development of bacteremia or risk of death in patients admitted to a medical intensive care unit. Design, Setting, and Patients:DNA was available from 774 medical intensive care unit patients. We selected 31 single nucleotide polymorphisms in 14 genes involved in host innate immune defense. Serum levels of MASP2 and chemotactic capacity, phagocytosis, and killing capacity of monocytes at admission were quantified. Univariate Kaplan-Meier estimates with log-rank analysis and multivariate logistic regression were performed. Bootstrap resampling technique and ten-fold cross-validation were used to assess replication stability, prognostic importance of the variables, and repeatability of the final regression model. Main Results:Patients with at least one NOD2 variant were shown to have a reduced phagocytosis by monocytes (p = 0.03) and a higher risk of bacteremia than wild-type patients (p = 0.02). The NOD2/TLR4 combination was associated with bacteremia using survival analyses (time to bacteremia development, log-rank p < 0.0001), univariate regression (p = 0.0003), and multivariate regression analysis (odds ratio [OR] 4.26, 95% confidence interval [CI] 1.85–9.81; p = 0.0006). Similarly, the same combination was associated with hospital mortality using survival analysis (log-rank p = 0.03), univariate regression (p = 0.02), and multivariate regression analysis (OR 2.27, 95% CI 1.09–4.74; p = 0.03). Also variants in the MASP2 gene were significantly associated with hospital mortality (survival analysis log-rank-p = 0.003; univariate regression p = 0.02; multivariate regression analysis OR 2.35, 95% CI 1.38–3.99; p = 0.002). Conclusions:Functional polymorphisms in genes involved in innate immunity predispose to severe infections and death, and may become part of a risk model, allowing identification of patients at risk, who could benefit from early introduction of specific preventive or therapeutic interventions.

Tight blood glucose control: what is the evidence?

In two large, randomized studies, maintenance of normoglycemia with intensive insulin therapy largely prevented morbidity and reduced mortality of critically ill patients. Recently, questions have been raised about the efficacy and safety of this therapy. These issues are systematically addressed and discussed with the evidence available from these and other studies. The available studies show that an absolute reduction in risk of hospital death of 3% to 4% is to be expected from intensive insulin therapy in an intention-to-treat analysis. Future studies designed to confirm a statistically significant survival benefit should be adequately powered, with inclusion of ≥5,000 patients. When patients are treated with intensive insulin therapy for >3 days, the absolute reduction in the risk of death increases to approximately 8%. Insulin therapy also improves morbidity, more so when continued for >3 days. Strict blood glucose control to normoglycemia (<110 mg/dL) is required to obtain the most clinical benefit, but this inherently increases the risk of hypoglycemia. It remains unclear whether short hypoglycemic episodes are truly harmful for these patients. In conclusion, demonstration of the clinical benefits of intensive insulin therapy depends on the quality of blood glucose control and the statistical power of the studies.

Impact of early parenteral nutrition on muscle and adipose tissue compartments during critical illness.

Objective:The goal of enhanced nutrition in critically ill patients is to improve outcome by reducing lean tissue wasting. However, such effect has not been proven. This study aimed to assess the effect of early administration of parenteral nutrition on muscle volume and composition by repeated quantitative CT. Design:A preplanned substudy of a randomized controlled trial (Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients [EPaNIC]), which compared early initiation of parenteral nutrition when enteral nutrition was insufficient (early parenteral nutrition) with tolerating a pronounced nutritional deficit for 1 week in ICU (late parenteral nutrition). Late parenteral nutrition prevented infections and accelerated recovery. Setting:University hospital. Patients:Fifteen EPaNIC study neurosurgical patients requiring prescheduled repeated follow-up CT scans and six healthy volunteers matched for age, gender, and body mass index. Intervention:Repeated abdominal and femoral quantitative CT images were obtained in a standardized manner on median ICU day 2 (interquartile range, 2–3) and day 9 (interquartile range, 8–10). Intramuscular, subcutaneous, and visceral fat compartments were delineated manually. Muscle and adipose tissue volume and composition were quantified using standard Hounsfield Unit ranges. Measurements and Main Results:Critical illness evoked substantial loss of femoral muscle volume in 1 week’s time, irrespective of the nutritional regimen. Early parenteral nutrition reduced the quality of the muscle tissue, as reflected by the attenuation, revealing increased intramuscular water/lipid content. Early parenteral nutrition also increased the volume of adipose tissue islets within the femoral muscle compartment. These changes in skeletal muscle quality correlated with caloric intake. In the abdominal muscle compartments, changes were similar, albeit smaller. Femoral and abdominal subcutaneous adipose tissue compartments were unaffected by disease and nutritional strategy. Conclusions:Early parenteral nutrition did not prevent the pronounced wasting of skeletal muscle observed over the first week of critical illness. Furthermore, early parenteral nutrition increased the amount of adipose tissue within the muscle compartments.

Critical illness evokes elevated circulating bile acids related to altered hepatic transporter and nuclear receptor expression.

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/RXRα) to increase serum BA levels. (HEPATOLOGY 2011;)

Thyroid function in critically ill patients

Patients in the intensive care unit (ICU) typically present with decreased concentrations of plasma tri-iodothyronine, low thyroxine, and normal range or slightly decreased concentration of thyroid-stimulating hormone. This ensemble of changes is collectively known as non-thyroidal illness syndrome (NTIS). The extent of NTIS is associated with prognosis, but no proof exists for causality of this association. Initially, NTIS is a consequence of the acute phase response to systemic illness and macronutrient restriction, which might be beneficial. Pathogenesis of NTIS in long-term critical illness is more complex and includes suppression of hypothalamic thyrotropin-releasing hormone, accounting for persistently reduced secretion of thyroid-stimulating hormone despite low plasma thyroid hormone. In some cases distinguishing between NTIS and severe hypothyroidism, which is a rare primary cause for admission to the ICU, can be difficult. Infusion of hypothalamic-releasing factors can reactivate the thyroid axis in patients with NTIS, inducing an anabolic response. Whether this approach has a clinical benefit in terms of outcome is unknown. In this Series paper, we discuss diagnostic aspects, pathogenesis, and implications of NTIS as well as its distinction from severe, primary thyroid disorders in patients in the ICU.

Target Cells of γ3-Melanocyte-Stimulating Hormone Detected through Intracellular Ca2+ Responses in Immature Rat Pituitary Constitute a Fraction of All Main Pituitary Cell Types, but Mostly Express Multiple Hormone Phenotypes at the Messenger Ribonucleic Acid Level. Refractoriness to Melanocortin-3 Receptor Blockade in the Lacto-Somatotroph Lineage1

γ3-MSH has recently been shown to be a biologically active peptide in the rat anterior pituitary. It induces a sustained rise in intracellular free calcium levels ([Ca2+]i) in a relatively small population of immature pituitary cells. The present study was intended to identify the target cells of this peptide and to discern the signal-transducing melanocortin (MC) receptor. In dispersed pituitary cells from 14-day-old rats, increasing doses ofγ 3-MSH (0.1, 1, and 10 nm) evoked a sustained oscillating[ Ca2+]i rise in an increasing number of cells (up to 14.5%). Within the responsive cells, 53% showed GH immunoreactivity (-ir), 12% showed PRL-ir, 2% showed TSHβ-ir, 5% showed LHβ-ir, and 10% showed ACTH-ir, whereas 18% did not express any hormone-ir to a detectable level. As assessed by single cell RT-PCR for the presence of pituitary hormone messenger RNA (mRNA), 26% of theγ 3-MSH-responsive cells contained only GH mRNA, 5% contained only PRL mRNA, and 4% contained only TSHβ mRNA. Twenty-two percent contain...