Pieter J. Wouters

Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control.

ObjectivesMaintenance of normoglycemia with insulin reduces mortality and morbidity of critically ill patients. Here we report the factors determining insulin requirements and the impact of insulin dose vs. blood glucose control on the observed outcome benefits. DesignA prospective, randomized, controlled trial. SettingA 56-bed predominantly surgical intensive care unit in a tertiary teaching hospital Patients and InterventionA total of 1,548 patients were randomly assigned to either strict normalization of blood glucose (80–110 mg/dL) with insulin infusion or the conventional approach, in which insulin is only given to maintain blood glucose levels at 180–200 mg/dL. Measurements and Main ResultsIt was feasible and safe to achieve and maintain blood glucose levels at <110 mg/dL by using a titration algorithm. Stepwise linear regression analysis identified body mass index, history of diabetes, reason for intensive care unit admission, at-admission hyperglycemia, caloric intake, and time in intensive care unit as independent determinants of insulin requirements, together explaining 36% of its variation. With nutritional intake increasing from a mean of 550 to 1600 calories/day during the first 7 days of intensive care, normoglycemia was reached within 24 hrs, with a mean daily insulin dose of 77 IU and maintained with 94 IU on day 7. Insulin requirements were highest and most variable during the first 6 hrs of intensive care (mean, 7 IU/hr; 10% of patients required >20 IU/hr). Between day 7 and 12, insulin requirements decreased by 40% on stable caloric intake. Brief, clinically harmless hypoglycemia occurred in 5.2% of intensive insulin-treated patients on median day 6 (2–14) vs. 0.8% of conventionally treated patients on day 11 (2–10). The outcome benefits of intensive insulin therapy were equally present regardless of whether patients received enteral feeding. Multivariate logistic regression analysis indicated that the lowered blood glucose level rather than the insulin dose was related to reduced mortality (p < .0001), critical illness polyneuropathy (p < .0001), bacteremia (p = .02), and inflammation (p = .0006) but not to prevention of acute renal failure, for which the insulin dose was an independent determinant (p = .03). As compared with normoglycemia, an intermediate blood glucose level (110–150 mg/dL) was associated with worse outcome. ConclusionNormoglycemia was safely reached within 24 hrs and maintained during intensive care by using insulin titration guidelines. Metabolic control, as reflected by normoglycemia, rather than the infused insulin dose per se, was related to the beneficial effects of intensive insulin therapy.

Early versus Late Parenteral Nutrition in Critically Ill Adults

BACKGROUND Controversy exists about the timing of the initiation of parenteral nutrition in critically ill adults in whom caloric targets cannot be met by enteral nutrition alone. METHODS In this randomized, multicenter trial, we compared early initiation of parenteral nutrition (European guidelines) with late initiation (American and Canadian guidelines) in adults in the intensive care unit (ICU) to supplement insufficient enteral nutrition. In 2312 patients, parenteral nutrition was initiated within 48 hours after ICU admission (early-initiation group), whereas in 2328 patients, parenteral nutrition was not initiated before day 8 (late-initiation group). A protocol for the early initiation of enteral nutrition was applied to both groups, and insulin was infused to achieve normoglycemia. RESULTS Patients in the late-initiation group had a relative increase of 6.3% in the likelihood of being discharged alive earlier from the ICU (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.13; P=0.04) and from the hospital (hazard ratio, 1.06; 95% CI, 1.00 to 1.13; P=0.04), without evidence of decreased functional status at hospital discharge. Rates of death in the ICU and in the hospital and rates of survival at 90 days were similar in the two groups. Patients in the late-initiation group, as compared with the early-initiation group, had fewer ICU infections (22.8% vs. 26.2%, P=0.008) and a lower incidence of cholestasis (P<0.001). The late-initiation group had a relative reduction of 9.7% in the proportion of patients requiring more than 2 days of mechanical ventilation (P=0.006), a median reduction of 3 days in the duration of renal-replacement therapy (P=0.008), and a mean reduction in health care costs of €1,110 (about

Intensive Insulin Therapy in Mixed Medical/Surgical Intensive Care Units: Benefit Versus Harm

1,600) (P=0.04). CONCLUSIONS Late initiation of parenteral nutrition was associated with faster recovery and fewer complications, as compared with early initiation. (Funded by the Methusalem program of the Flemish government and others; EPaNIC ClinicalTrials.gov number, NCT00512122.).

Intensive insulin therapy protects the endothelium of critically ill patients.

Intensive insulin therapy (IIT) improves the outcome of prolonged critically ill patients, but concerns remain regarding potential harm and the optimal blood glucose level. These questions were addressed using the pooled dataset of two randomized controlled trials. Independent of parenteral glucose load, IIT reduced mortality from 23.6 to 20.4% in the intention-to-treat group (n = 2,748; P = 0.04) and from 37.9 to 30.1% among long stayers (n = 1,389; P = 0.002), with no difference among short stayers (8.9 vs. 10.4%; n = 1,359; P = 0.4). Compared with blood glucose of 110–150 mg/dl, mortality was higher with blood glucose >150 mg/dl (odds ratio 1.38 [95% CI 1.10–1.75]; P = 0.007) and lower with <110 mg/dl (0.77 [0.61–0.96]; P = 0.02). Only patients with diabetes (n = 407) showed no survival benefit of IIT. Prevention of kidney injury and critical illness polyneuropathy required blood glucose strictly <110 mg/day, but this level carried the highest risk of hypoglycemia. Within 24 h of hypoglycemia, three patients in the conventional and one in the IIT group died (P = 0.0004) without difference in hospital mortality. No new neurological problems occurred in survivors who experienced hypoglycemia in intensive care units (ICUs). We conclude that IIT reduces mortality of all medical/surgical ICU patients, except those with a prior history of diabetes, and does not cause harm. A blood glucose target <110 mg/day was most effective but also carried the highest risk of hypoglycemia.

Reduced Cortisol Metabolism during Critical Illness

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.

Dynamic characteristics of blood glucose time series during the course of critical illness: Effects of intensive insulin therapy and relative association with mortality

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.).

Acute outcomes and 1-year mortality of intensive care unit-acquired weakness. A cohort study and propensity-matched analysis

Objectives:To assess the effect of intensive insulin therapy on blood glucose amplitude variation and pattern irregularity in critically ill patients. To assess the association of these blood glucose signal characteristics with hospital mortality, independent of blood glucose level. Design:Retrospective analysis of the databases of two previously published randomized controlled trials. Setting:University hospital, 56-bed adult surgical intensive care unit and 17-bed medical intensive care unit. Patients:One thousand five-hundred forty-eight surgical intensive care unit patients, admitted between February 2000 and January 2001, and 1200 medical intensive care unit patients, admitted between March 2002 and May 2005. Interventions:In the two randomized controlled trials, patients were randomized to receive either intensive insulin therapy (targeting normoglycemia, between 4.4 and 6.1mmol/L) or conventional insulin therapy (infusing insulin when blood glucose levels were >12 mmol/L and stopping at 10 mmol/L). Measurements and Main Results:Intensive insulin therapy significantly lowered mean blood glucose (5.8 vs. 8.4 mmol/L), hyperglycemic index (0.8 vs. 3.2 mmol/L), and glycemic penalty index (26 vs. 53), but it increased the mean daily difference between minimum and maximum blood glucose (mean daily &dgr; blood glucose; 4.0 vs. 3.3 mmol/L). There was no significant effect on the standard deviation of the blood glucose measurements or on jack-knifed approximate entropy. In multivariable logistic regression analysis, corrected for baseline risk factors, blood glucose levels outside the normoglycemic range, higher mean daily &dgr; blood glucose, higher standard deviation blood glucose, and higher jack-knifed approximate entropy were independently associated with hospital mortality. Conclusions:The Leuven intensive insulin therapy strategy increased mean daily &dgr; blood glucose while not affecting standard deviation blood glucose and jack-knifed approximate entropy. Increased blood glucose amplitude variation and pattern irregularity were associated with mortality, irrespective of blood glucose level. The reduced mortality observed with intensive insulin therapy in the Leuven trials cannot be attributed to an effect on blood glucose amplitude variation or entropy. Reducing amplitude variation and entropy of the blood glucose signal, irrespective of blood glucose concentration, may produce clinical benefits.

Thyrotrophin and prolactin release in prolonged critical illness: dynamics of spontaneous secretion and effects of growth hormone-secretagogues†

RATIONALE Intensive care unit (ICU)-acquired weakness is a frequent complication of critical illness. It is unclear whether it is a marker or mediator of poor outcomes. OBJECTIVES To determine acute outcomes, 1-year mortality, and costs of ICU-acquired weakness among long-stay (≥8 d) ICU patients and to assess the impact of recovery of weakness at ICU discharge. METHODS Data were prospectively collected during a randomized controlled trial. Impact of weakness on outcomes and costs was analyzed with a one-to-one propensity-score-matching for baseline characteristics, illness severity, and risk factor exposure before assessment. Among weak patients, impact of persistent weakness at ICU discharge on risk of death after 1 year was examined with multivariable Cox proportional hazards analysis. MEASUREMENTS AND MAIN RESULTS A total of 78.6% were admitted to the surgical ICU; 227 of 415 (55%) long-stay assessable ICU patients were weak; 122 weak patients were matched to 122 not-weak patients. As compared with matched not-weak patients, weak patients had a lower likelihood for live weaning from mechanical ventilation (hazard ratio [HR], 0.709 [0.549-0.888]; P = 0.009), live ICU (HR, 0.698 [0.553-0.861]; P = 0.008) and hospital discharge (HR, 0.680 [0.514-0.871]; P = 0.007). In-hospital costs per patient (+30.5%, +5,443 Euro per patient; P = 0.04) and 1-year mortality (30.6% vs. 17.2%; P = 0.015) were also higher. The 105 of 227 (46%) weak patients not matchable to not-weak patients had even worse prognosis and higher costs. The 1-year risk of death was further increased if weakness persisted and was more severe as compared with recovery of weakness at ICU discharge (P < 0.001). CONCLUSIONS After careful matching the data suggest that ICU-acquired weakness worsens acute morbidity and increases healthcare-related costs and 1-year mortality. Persistence and severity of weakness at ICU discharge further increased 1-year mortality. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial

Infusion of GH secretagogues appears to be a novel endocrine approach to reverse the catabolic state of critical illness, through amplification of the endogenously blunted GH secretion associated with a substantial IGF‐I rise. Here we report the dynamic characteristics of spontaneous nightly TSH and PRL secretion during prolonged critical illness, together with the concomitant effects exerted by the administration of GH‐secretagogues, GH‐releasing hormone (GHRH) and GH‐releasing peptide‐2 (GHRP‐2) in particular, on night‐time TSH and PRL secretion.

Insufficient Activation of Autophagy Allows Cellular Damage to Accumulate in Critically Ill Patients

BACKGROUND Patients who are critically ill can develop so-called intensive-care unit acquired weakness, which delays rehabilitation. Reduced muscle mass, quality, or both might have a role. The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) trial (registered with ClinicalTrials.gov, number NCT00512122) showed that tolerating macronutrient deficit for 1 week in intensive-care units (late parenteral nutrition [PN]) accelerated recovery compared with early PN. The role of weakness was unclear. Our aim was to assess whether late PN and early PN differentially affect muscle weakness and autophagic quality control of myofibres. METHODS In this prospectively planned subanalysis of the EPaNIC trial, weakness (MRC sum score) was assessed in 600 awake, cooperative patients. Skeletal muscle biopsies, harvested from 122 patients 8 days after randomisation and from 20 matched healthy controls, were studied for autophagy and atrophy. We determined the significance of differences with Mann-Whitney U, Median, Kruskal-Wallis, or χ(2) (exact) tests, as appropriate. FINDINGS With late PN, 105 (34%) of 305 patients had weakness on first assessment (median day 9 post-randomisation) compared with 127 (43%) of 295 patients given early PN (absolute difference -9%, 95% CI -16 to -1; p=0·030). Weakness recovered faster with late PN than with early PN (p=0·021). Myofibre cross-sectional area was less and density was lower in critically ill patients than in healthy controls, similarly with early PN and late PN. The LC3 (microtubule-associated protein light chain 3) II to LC3I ratio, related to autophagosome formation, was higher in patients given late PN than early PN (p=0·026), reaching values almost double those in the healthy control group (p=0·0016), and coinciding with less ubiquitin staining (p=0·019). A higher LC3II to LC3I ratio was independently associated with less weakness (p=0·047). Expression of mRNA encoding contractile myofibrillary proteins was lower and E3-ligase expression higher in muscle biopsies from patients than in control participants (p≤0·0006), but was unaffected by nutrition. INTERPRETATION Tolerating a substantial macronutrient deficit early during critical illness did not affect muscle wasting, but allowed more efficient activation of autophagic quality control of myofibres and reduced weakness. FUNDING UZ Leuven, Research Foundation-Flanders, the Flemish Government, and the European Research Council.