Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study.

BACKGROUND: Critically ill infants and children often develop hyperglycaemia, which is associated with adverse outcome; however, whether lowering blood glucose concentrations to age-adjusted normal fasting values improves outcome is unknown. We investigated the effect of targeting age-adjusted normoglycaemia with insulin infusion in critically ill infants and children on outcome. METHODS: In a prospective, randomised controlled study, we enrolled 700 critically ill patients, 317 infants (aged <1 year) and 383 children (aged >or=1 year), who were admitted to the paediatric intensive care unit (PICU) of the University Hospital of Leuven, Belgium. Patients were randomly assigned by blinded envelopes to target blood glucose concentrations of 2.8-4.4 mmol/L in infants and 3.9-5.6 mmol/L in children with insulin infusion throughout PICU stay (intensive group [n=349]), or to insulin infusion only to prevent blood glucose from exceeding 11.9 mmol/L (conventional group [n=351]). Patients and laboratory staff were blinded to treatment allocation. Primary endpoints were duration of PICU stay and inflammation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00214916. FINDINGS: Mean blood glucose concentrations were lower in the intensive group than in the conventional group (infants: 4.8 [SD 1.2] mmol/L vs 6.4 [1.2] mmol/L, p<0.0001; children: 5.3 [1.1] mmol/L vs 8.2 [3.3] mmol/L, p<0.0001). Hypoglycaemia (defined as blood glucose median) stay in PICU was 132 (38%) in the intensive group versus 165 (47%) in the conventional group (p=0.013). Nine (3%) patients died in the intensively treated group versus 20 (6%) in the conventional group (p=0.038). INTERPRETATION: Targeting of blood glucose concentrations to age-adjusted normal fasting concentrations improved short-term outcome of patients in PICU. The effect on long-term survival, morbidity, and neurocognitive development needs to be investigated. FUNDING: Research Foundation (Belgium); Research Fund of the University of Leuven (Belgium) and the EU Information Society Technologies Integrated project "CLINICIP"; and Institute for Science and Technology (Belgium).

Intensive insulin therapy in the medical ICU.

BACKGROUND: Intensive insulin therapy reduces morbidity and mortality in patients in surgical intensive care units (ICUs), but its role in patients in medical ICUs is unknown. METHODS: In a prospective, randomized, controlled study of adult patients admitted to our medical ICU, we studied patients who were considered to need intensive care for at least three days. On admission, patients were randomly assigned to strict normalization of blood glucose levels (80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) with the use of insulin infusion or to conventional therapy (insulin administered when the blood glucose level exceeded 215 mg per deciliter [12 mmol per liter], with the infusion tapered when the level fell below 180 mg per deciliter [10 mmol per liter]). There was a history of diabetes in 16.9 percent of the patients. RESULTS: In the intention-to-treat analysis of 1200 patients, intensive insulin therapy reduced blood glucose levels but did not significantly reduce in-hospital mortality (40.0 percent in the conventional-treatment group vs. 37.3 percent in the intensive-treatment group, P=0.33). However, morbidity was significantly reduced by the prevention of newly acquired kidney injury, accelerated weaning from mechanical ventilation, and accelerated discharge from the ICU and the hospital. Although length of stay in the ICU could not be predicted on admission, among 433 patients who stayed in the ICU for less than three days, mortality was greater among those receiving intensive insulin therapy. In contrast, among 767 patients who stayed in the ICU for three or more days, in-hospital mortality in the 386 who received intensive insulin therapy was reduced from 52.5 to 43.0 percent (P=0.009) and morbidity was also reduced. CONCLUSIONS: Intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU. Although the risk of subsequent death and disease was reduced in patients treated for three or more days, these patients could not be identified before therapy. Further studies are needed to confirm these preliminary data. (ClinicalTrials.gov number, NCT00115479.)

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.

Serial lactate measurements using microdialysis of interstitial fluid do not correlate with plasma lactate in children after cardiac surgery.

OBJECTIVES: Serial postoperative blood lactate (BL) concentrations have been shown to predict outcome of children after congenital heart surgery (CHS), and interventions aimed at lowering lactate can improve the outcome of these children. The cumulative blood loss for diagnostic purposes, such as repetitive arterial blood sampling in the intensive care unit, contributes, especially in small children, to anemia. Techniques to limit blood loss can therefore be of use. Microdialysis is a technique to monitor tissue chemistry in various clinical settings, and we hypothesized that it may be a valuable alternative for frequent blood sampling to monitor lactate in children after CHS. METHODS: Fifteen children with a mean age of 40 months (range, 4-118 months) were prospectively enrolled after CHS. A CMA double lumen microdialysis catheter was inserted into the subcutaneous adipose tissue of the abdominal wall and infused with an isotone mannitol 5% solution at 1 microL/min via the inlet tubing. Microdialysate fluid was collected every hour for 48 hrs and stored at -80 degrees C for lactate determination (interstitial fluid lactate, IFL). Every hour arterial blood was taken for lactate determination. Individual profiles, correlation coefficient, and Bland-Altman analysis were used to compare BL and IFL results. RESULTS: There were no complications with the microdialysis technique. All patients were discharged alive from hospital. Six hundred twenty paired samples were analyzed. Mean recovery of microdialysate fluid was 84%. Median (interquartile range) was 0.95 (0.70-1.15) mmol/L for BL and 1.13 (0.86-1.48) mmol/L for IFL (p < 0.0001). Individual profiles showed that IFL follows changes in BL in some, but not all children. With this study, we could not explain this discrepancy. The correlation between BL and IFL was poor (r = .77 (p < 0.0001) r = .59). Bland-Altman analysis confirmed the insufficient performance of the current microdialysis-based procedure compared with BL. CONCLUSION: Serial lactate measurements in microdialysis fluid of subcutaneous adipose tissue are feasible, but cannot be used as a reliable interchangeable method for plasma lactate analysis in children after CHS at this time. Whether this technique has its own place in the assessment of the overall hemodynamic status and tissue perfusion in children after CHS needs to be addressed in future studies.

Effect of insulin therapy on coagulation and fibrinolysis in medical intensive care patients.

OBJECTIVE: Most intensive care deaths beyond the first few days of critical illness are attributable to nonresolving organ failure, either due to or coinciding with sepsis. One of the mechanisms that is thought to contribute to the pathogenesis of organ failure is microvascular thrombosis. Recently, we reported significant improved survival and prevention of organ failure with the use of intensive insulin therapy to maintain normoglycemia for at least several days. We hypothesize that intensive insulin therapy also prevents severe coagulation abnormalities thereby contributing to less organ failure and better survival. DESIGN: This was a preplanned subanalysis of a large randomized controlled study, conducted at a university hospital medical intensive care unit. The intervention was strict blood glucose control to normoglycemia with insulin. RESULTS: Mortality of intensive insulin-treated patients was lower than that of conventionally treated patients for all classes of upon-admission disseminated intravascular coagulation (DIC) scores, except for those patients with overt DIC scores of 6 or higher (for DIC < 5, p = 0.003; for DIC > or = 5, p = 0.4). There was no effect of insulin therapy on any of the fibrinolytic, coagulation, or inflammatory parameters tested. CONCLUSIONS: This negative observation does not support a key role for these systems in explaining the clinical benefit of intensive insulin therapy, although a short-lived effect within 5 days of treatment cannot be excluded.

Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm.

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.

Tight glycemic control protects the myocardium and reduces inflammation in neonatal heart surgery.

BACKGROUND: Neonatal cardiac surgery evokes hyperglycemia and a systemic inflammatory response. Hyperglycemia is associated with intensified inflammation and adverse outcome in critically ill children and in pediatric cardiac surgery. Recently we demonstrated that tight glycemic control (TGC) reduced morbidity and mortality of critically ill children. Experimental data suggest that insulin protects the myocardium in the setting of ischemia-reperfusion injury, but this benefit could be blunted by coinciding hyperglycemia. We hypothesized that insulin-titrated TGC, initiated prior to myocardial ischemia and reperfusion, protects the myocardium and attenuates the inflammatory response after neonatal cardiac surgery. METHODS: This is a prospective randomized study at a university hospital. Fourteen neonates were randomized to intraoperative and postoperative conventional insulin therapy or TGC. Study endpoints were effects on myocardial damage and function; inflammation, endothelial activation, and clinical outcome parameters. RESULTS: Tight glycemic control significantly reduced circulating levels of cardiac troponin-I (p = 0.009), heart fatty acid-binding protein (p = 0.01), B-type natriuretic peptide (p = 0.002), and the need for vasoactive support (p = 0.008). The TGC suppressed the rise of the proinflammatory cytokines interleukin-6 (p = 0.02) and interleukin-8 (p = 0.05), and reduced the postoperative increase in C-reactive protein (p = 0.04). Myocardial concentrations of Akt, endothelial nitric-oxide synthase, and their phosphorylated forms were not different between groups. CONCLUSIONS: In neonates undergoing cardiac surgery, intraoperative and postoperative TGC protects the myocardium and reduces the inflammatory response. This appears not to be mediated by an early, direct insulin signaling effect, but may rather be due to independent effects of preventing hyperglycemia during reperfusion.

The effect of strict blood glucose control on biliary sludge and cholestasis in critically ill patients.

BACKGROUND AND AIMS: Cholestatic liver dysfunction and biliary sludge are common problems in critically ill patients. No specific strategies have been described to prevent cholestasis and biliary sludge in the intensive care unit (ICU). We examined liver dysfunction and biliary sludge prospectively in a large medical long-stay ICU population and hypothesized that tight glycemic control with intensive insulin therapy (IIT) reduces cholestasis and biliary sludge. METHODS: This study was a preplanned subanalysis of 658 long-stay (at least a fifth day) ICU patients out of a large randomized controlled trial (n = 1200), studying the effects of IIT on the outcome of medical critical illness. Patients were allocated to either IIT (glycemia 80-110 mg/dl) or conventional insulin therapy (CIT) requiring insulin above a glycemia of 215 mg/dl. Different patterns of liver dysfunction were studied based on daily blood sample analysis, and biliary sludge was evaluated by ultrasonography. RESULTS: On admission, cholestasis was present in 17% of patients (n = 649), increasing to 20% on d 10 (n = 347), whereas ischemic hepatitis decreased from 3.4% (n = 588) to less than 1% (n = 328). IIT significantly decreased biliary sludge on d 5 (50.4 vs. 66.4%, P = 0.01; n = 250). The difference did not remain significant on d 10 (57.4 vs. 66.2%, P = 0.29; n = 136). IIT also lowered the cumulative risk of cholestasis (P = 0.03). CONCLUSIONS: Cholestatic liver dysfunction and biliary sludge are very common during prolonged critical illness but are significantly reduced by IIT.

Blood glucose measurements in arterial blood of intensive care unit patients submitted to tight glycemic control: agreement between bedside tests.

BACKGROUND: Implementing tight glycemic control (TGC) in intensive care unit (ICU) patients requires accurate blood glucose (BG) monitoring. We evaluated the performance of two commercially available bedside glucometers, Accu-Chek and HemoCue, in patients admitted to the ICU and in whom TGC was applied. METHODS: Thirty-seven adult ICU patients were prospectively included. During 48 hours, BG was determined simultaneously on the same arterial blood sample using the two point-of-care testing (POCT) glucometers as compared with the standard technique. Data of 452 paired measurements were analyzed using linear regression, Clark error grid analysis (EGA), the method of Bland-Altman, and the GLYCENSIT procedure. RESULTS: Both tested glucometers showed satisfactory results when evaluated with linear regression and EGA. Correlation coefficients were above 0.9, and 100% of all the glucose readings were within the safe zones A and B using EGA. However, when applying more appropriate tests, both sensors failed to provide sufficient accuracy in the setting of TGC in ICU patients. The Hemocue revealed a bias of >10 mg/dl with a trend to systematically overestimate the actual BG value. The bias for the Accu-Chek was 6 mg/dl with wide limits of agreement and a variable over- and underestimation of the actual BG value depending on the level of BG (hypo-, normo-, or hyperglycemia). CONCLUSIONS: When TGC is implemented in ICU practice, caution is warranted when adjusting insulin rates based only on BG readings obtained by the tested glucometers. ICU practitioners should weigh the advantages and disadvantages of such devices: a greater bias but with a more predictable error and measurement behavior versus a somewhat lower bias but with an unpredictable direction of the difference.

Impact of intensive insulin therapy on neuromuscular complications and ventilator dependency in the medical intensive care unit.

RATIONALE: Critical illness polyneuropathy/myopathy causes limb and respiratory muscle weakness, prolongs mechanical ventilation, and extends hospitalization of intensive care patients. Besides controlling risk factors, no specific prevention or treatment exists. Recently, intensive insulin therapy prevented critical illness polyneuropathy in a surgical intensive care unit. OBJECTIVES: To investigate the impact of intensive insulin therapy on polyneuropathy/myopathy and treatment with prolonged mechanical ventilation in medical patients in the intensive care unit for at least 7 days. METHODS: This was a prospectively planned subanalysis of a randomized controlled trial evaluating the effect of intensive insulin versus conventional therapy on morbidity and mortality in critically ill medical patients. All patients who were still in intensive care on Day 7 were screened weekly by electroneuromyography. The effect of intensive insulin therapy on critical illness polyneuropathy/myopathy and the relationship with duration of mechanical ventilation were assessed. MEASUREMENTS AND MAIN RESULTS: Independent of risk factors, intensive insulin therapy reduced incidence of critical illness polyneuropathy/myopathy (107/212 [50.5%] to 81/208 [38.9%], p = 0.02). Treatment with prolonged (> or = 14 d) mechanical ventilation was reduced from 99 of 212 (46.7%) to 72 of 208 (34.6%) (p = 0.01). This was statistically only partially explained by prevention of critical illness polyneuropathy/myopathy. CONCLUSION: In a subset of medical patients in the intensive care unit for at least 7 days, enrolled in a randomized controlled trial of intensive insulin therapy, those assigned to intensive insulin therapy had a reduced incidence of critical illness polyneuropathy/myopathy and were treated with prolonged mechanical ventilation less frequently.

Strict blood glucose control with insulin during intensive care after cardiac surgery: impact on 4-years survival, dependency on medical care, and quality-of-life.

AIMS: To document the impact of intensive insulin therapy during intensive care on long-term (4 years) outcome of high-risk cardiac surgery patients. METHODS AND RESULTS: In this pre-planned sub-analysis and follow-up study of a large, randomized controlled trial on the effects of intensive insulin therapy during critical illness, we assessed long-term outcome in the 970 patients who had been admitted after high-risk cardiac surgery (mean+/-SD EuroSCORE of 6.0+/-3.7; EuroSCORE-predicted hospital mortality of 9.9%; observed hospital mortality of 7.5% in the conventional insulin group and 3.4% in the intensive insulin group). Long-term outcome was quantified as: (a) 4 years survival; (b) incidence of hospital re-admission; (c) level of activity and medical care requirements at 4 years as assessed by the Karnofsky score; and (d) perceived health-related quality-of-life at 4 years as assessed by the Nottingham Health Profile. Four years after ICU admission, the number of post-hospital discharge deaths was similar in the two study groups, reflecting maintenance of the acute survival benefit with intensive insulin therapy. Survivors who had been treated with intensive insulin during ICU stay revealed a similar risk for hospital re-admission and a comparable level of dependency on medical care. There was no effect on quality-of-life in the total group, whereas the increased survival of sicker patients with at least 3 days of insulin therapy evoked a more compromised perceived quality-of-life, in particular regarding social and family life. CONCLUSION: The short-term survival benefit obtained with insulin-titrated glycaemic control during intensive care after cardiac surgery was maintained after 4 years, without inducing increased medical care requirements but possibly at the expense of compromised perceived quality of social and family life.