sRAGE in diabetic and non-diabetic critically ill patients: effects of intensive insulin therapy.

INTRODUCTION: Hyperglycemia represents an independent prognostic factor in critically ill non-diabetic patients but not in those with diabetes. In this context, there is an ongoing debate on the benefit of an intensive insulin therapy, particularly in diabetic patients. We tested the hypothesis that expression of the receptor for advanced glycation end-products (RAGE), an important signal transduction receptor that elicits long-lasting nuclear factor kappa B (NF-κB) activation, may underlie this difference. RAGE expression is regulated by multiple ligands, including high mobility group box-1 (HMGB-1), and is reflected by its released soluble form (sRAGE). METHODS: A predesigned analysis was conducted of prospectively collected samples from 76 hyperglycemic critically ill patients (33 type-2 diabetes, 43 non-diabetes) aged ≥ 18 years with blood glucose of > 6.1 mmol/L enrolled in a randomized controlled trial comparing intensive insulin therapy with conventional insulin therapy. sRAGE and its ligand HMGB-1 together with IL-6, and soluble thrombomodulin (as markers of inflammation and endothelial cell injury, respectively) were evaluated in ICU, at Days 1, 3, 5 and 7. Plasma samples from 18 healthy subjects were used as controls. RESULTS: Both diabetic and non-diabetic hyperglycemic patients showed increased plasma sRAGE, HMGB-1 and soluble thrombomodulin levels at the time of admission to ICU. Plasma IL-6 concentration was only increased in non-diabetic patients. Plasma levels of sRAGE were higher in diabetic compared with non-diabetic patients. Intensive insulin therapy resulted in a significant decrease of sRAGE and thrombomodulin at Day 7, in diabetic but not in non-diabetic patients. Circulating sRAGE levels correlated positively with IL-6 and soluble thrombomodulin levels and inversely with HMGB-1. Multivariate regression analysis demonstrated that sRAGE remains independently correlated with HMGB-1 only in diabetic patients. Neither sRAGE nor any inflammatory markers are associated with mortality. CONCLUSIONS: These findings support the hypothesis that sRAGE release, time-course and response to intensive insulin therapy differ between hyperglycemic diabetic and non-diabetic critically ill patients. Whether this difference underlies the dissimilarity in clinical outcome of hyperglycemia in these two conditions warrants further studies.

Permissive underfeeding and intensive insulin therapy in critically ill patients: a randomized controlled trial.

BACKGROUND: Nutritional support has been recognized as an essential part of intensive care unit management. However, the appropriate caloric intake for critically ill patients remains ill defined. OBJECTIVE: We examined the effect of permissive underfeeding compared with that of target feeding and of intensive insulin therapy (IIT) compared with that of conventional insulin therapy (CIT) on the outcomes of critically ill patients. DESIGN: This study had a 2 × 2 factorial, randomized, controlled design. Eligible patients were randomly assigned to permissive underfeeding or target feeding groups (caloric goal: 60-70% compared with 90-100% of calculated requirement, respectively) with either IIT or CIT (target blood glucose: 4.4-6.1 compared with 10-11.1 mmol/L, respectively). RESULTS: Twenty-eight-day all-cause mortality was 18.3% in the permissive underfeeding group compared with 23.3% in the target feeding group (relative risk: 0.79; 95% CI: 0.48, 1.29; P = 0.34). Hospital mortality was lower in the permissive underfeeding group than in the target group (30.0% compared with 42.5%; relative risk: 0.71; 95% CI: 0.50, 0.99; P = 0.04). No significant differences in outcomes were observed between the IIT and CIT groups. CONCLUSION: In critically ill patients, permissive underfeeding may be associated with lower mortality rates than target feeding. This trial was registered at controlled-trials.com as ISRCTN96294863.

Etomidate and mortality in cirrhotic patients with septic shock.

BACKGROUND: Clinical effects and outcomes of a single dose etomidate prior to intubation in the intensive care setting is controversial. The aim of this study is to evaluate the association of a single dose effect of etomidate prior to intubation on the mortality of septic cirrhotic patients and the impact of the subsequent use of low dose hydrocortisone. METHODS: This is a nested-cohort study within a randomized double blind placebo controlled study evaluating the use of low dose hydrocortisone in cirrhotic septic patients. Cirrhotic septic patients ≥ 18 years were included in the study. Patients who received etomidate prior to intubation were compared to those who did not receive etomidate for all cause 28-day mortality as a primary outcome. RESULTS: Sixty two intubated patients out of the 75 patients randomized in the initial trial were eligible for this study. Twenty three of the 62 intubated patients received etomidate dose prior to intubation. Etomidate use was not associated with all cause 28-day mortality or hospital mortality but was associated with significantly higher ICU mortality (91% vs. 64% for etomidate and controls groups, respectively; p = 0.02). Etomidate patients who received subsequent doses of hydrocortisone required lower doses of vasopressors and had more vasopressor-free days but no improvement in mortality. CONCLUSIONS: In this group of septic cirrhotic patients with very high mortality, etomidate increased ICU mortality. Subsequent use of hydrocortisone appears to have no benefit beyond decreasing vasopressor requirements. The lowest mortality was observed in patients who did not receive etomidate but received hydrocortisone.

Magnesium supplementation and the potential association with mortality rates among critically ill non-cardiac patients.

OBJECTIVE: Recent literature showed that development of hypomagnesemia is associated with higher mortality. The objective of this study is to evaluate the impact of magnesium supplementation on mortality rates of critically ill patients. METHODS: All patients admitted to the Intensive Care Unit (ICU) of King Abdul-Aziz Medical City, Riyadh, Saudi Arabia since September 2003 were included. We recorded the demographics data, APACHE score, daily magnesium levels and magnesium supplementation. We collected the data for 30 days or until discharge from ICU. Statistical analysis was performed using the student t-test for continuous data and the Fischers exact test for categorical data. Nothing was carried out to influence the behavior of intensivists in replacing magnesium. RESULTS: During the study period, 71 patients (45 males and 26 females) were admitted to the ICU, the mean age was 54 +/- 18 years for males and 56 +/- 19.2 years for females. The mean magnesium level on admission was 0.78 +/- 0.2 mmol/L and the majority of the patients were medical admissions. Approximately 39.4% had hypomagnesemia on admission and the overall mortality rate was 31%. In able to standardize the supplementation of magnesium among groups, the daily magnesium supplementation index (DMSI = total magnesium supplement in grams/length of stay in days) was calculated. The mortality rates for DMSI with <1 grm/day (low groups) was statistically significant higher than that of DMSI with >or=1 grm/day (high group) (43.5% versus 17%, p=0.035). There was no statistically significant differences between magnesium levels of both groups of DMSI except at admission where DMSI group had higher magnesium levels (<1 grm/day). CONCLUSION: Daily magnesium supplementation index higher than 1 grm/day is associated with lower mortality rates for critically ill patients. This effect was not found to be independent and may be related to severity of illness. Given that magnesium levels were similar between the 2 groups of DMSI at almost all points of the study, magnesium supplementation per se may be beneficial in lowering mortality rates. The exact cause of this effect is unknown. An aggressive magnesium supplementation protocol may be warranted. A larger scale randomized study is necessary to evaluate this effect.