CI: Blood Glucose Control (2009)

Citation:

Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Wijngaerden EV, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical icu. N Engl J Med 2006; 354:449-61.  

PubMed ID: 16452557
 
Study Design:
Prospective Cohort Study
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To determine if insulin therapy reduces morbidity and mortality in patients in medical ICUs.

Inclusion Criteria:
  • Adult patients admitted to the medical ICU
  • At least three days of intensive care
  • Study Consent

 

Exclusion Criteria:
  • Surgical ICU
  • Medical patients able to receive oral nutrition
  • Participating in another study
  • Expected to stay ICU <3 days
  • Had DNR orders on admission
Description of Study Protocol:

On admission to the ICU, patients were stratified according to diagnostic category and randomly assigned to receive either conventional or intensive insulin treatments.

  • Intensive insulin treatment: insulin infusion started when blood glucose (BG) level exceeded 110 mg/dL and adjusted to maintain BG between 80 and 110 mg/dL
  • Conventional insulin treatment: insulin infusion started when BG level reached 215 mg/dL and was adjusted to maintain BG between 180 and 200 mg/dL. When BG level fell below 180 mg/dL, insulin infusion was tapered and stopped.

Statistical Analysis

Power analysis (alpha < 0.05 and beta 0.2) of previous study data to determine need for sample size of 1200 patients. Used Student’s t-test, Chi square test, and Mann-Whitney U tests. Used Kaplan-Meier estimates and proportional-hazards regression analysis to determine effect of intervention on time to death in the hospital.

Data Collection Summary:

Timing of Measurements

BG measured on admission and every four hours. Some patients had BG measured more frequently.

Independent Variables

  • Blood glucose

Dependent Variables

  • Mortality: (death in the hospital)
  • ICU mortality: (death occurred while in ICU)
  • Days to weaning from mechanical ventilation
  • Days in the ICU
  • New kidney injury during intensive care (serum creatinine 2 x admission value or peak serum creatinine level of > 2.5 mg/dL
  • Days of inotropic or vasopressor support
  • Presence or absence of hyperinflammation (C-reactive protein level > 150 mg/dL)
  • Presence or absence of bacteremia
  • Prolonged (> 10 days) use of antibiotics
  • Presence or absence of hyperbilirubinemia (bilirubin level >3 mg/dL)

Control Variables

  • Enteral feeding at 22 to 30 kcal/kg body weight per 24 hours was started for all patients when they were hemodynamically stable.
Description of Actual Data Sample:

Initial N:

Total n=1200 randomized
  • Conventional treatment n=605 (64% male)
  • Intensive treatment n=595 (58% male)

Attrition (final N): same

Age: NS differences in age by group.

  • Conventional 64
  • Intensive Treatment 62 ± 16 years

Ethnicity: not described

Other relevant demographics:

Anthropometrics

  • NS differences in BMI between groups (p value 0.06)
  • APACHE II quartiles: < 17, 17 to 22, 23 to 29, and > 29

Location:

Leuven, Belgium

Summary of Results:

 

Variable
Conventional Treatment
Intensive Insulin Treatment
P Value
Deaths after 3 days in ICU
145 (38.1%)
121 (31.3%)
0.05
In-hospital deaths
200 (52.5%)
166 (43.0%)
0.009

  • Intensive insulin therapy reduced BG levels but mortality was not significantly reduced in the intent-to-treat group. Mortality was significantly decreased among patients in the ICU for > 3 days who received intensive insulin therapy.
  • Admission BG levels likely indication of more severe injury.
  • Morbidity was significantly reduced for all groups who received intensive insulin therapy as a result of preventing newly acquired kidney injury, accelerated weaning from ventilator, and decreased length of stay in hospital and ICU. Intensive insulin treatment during ICU appears to have a carry-over effect—patients in previous study had superior long-term rehabilitation.
  • In analysis of 767 total patients who remained in the ICU > 3 days, the 386 patients in the intensive-treatment group had earlier weaning from mechanical ventilation compared to conventional treatment group (hazard ratio 1.21; 95% CI 1.02 to 1.44; p=0.03).
  • Logistic regression identified hypoglycemia induced by insulin therapy as an independent risk factor for death. Intensive treatment with insulin may have reduced the potential benefit.

 

Author Conclusion:
Intensive insulin therapy significantly reduced morbidity for all patients in the medical ICU. Intensive insulin therapy significantly reduced mortality only for patients with stays ≥3 days in the ICU, however, it was not possible to identify these patients before therapy.
Funding Source:
Government: Belgian Fund for Scientific Research
Industry:
HemoCue
Other:
University/Hospital: Catholic University of Leuven (Belgium), Research Council of the University of Leuven
Not-for-profit
0
Foundation associated with industry:
In-Kind support reported by Industry: Yes
Reviewer Comments:

The authors provide excellent analyses by intent-to-treat and randomized to treatment groups. Tables include diagnostic categories, history of cancer, percent of patients who were dialysis-dependent before ICU hospitalization, patients with kidney failure on admission, history of diabetes, and baseline APACHE scores.

Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) N/A
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? Yes
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes