CI: Blood Glucose Control (2009)

Citation:

Van Den Berghe G, Wouter P. Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med. 2003;31(2):359-366.

 

PubMed ID: 12576937
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
The purpose of this research was to determine whether it was the actual lowering of blood glucose levels or the amount of infused insulin per se that was related to protective effects of intensive insulin therapy on morbidity and mortality in critically ill patients.
Inclusion Criteria:

Critically ill patients on mechanical ventilation in a surgical intensive care unit (SICU) were included in the study.

Exclusion Criteria:
Critically ill patients admitted to SICU who were not on mechanical ventilation were excluded from the study.
Description of Study Protocol:

Recruitment

All mechanically ventilated adults admitted to the SICU during a 1 year period; the closest family member gave informed consent.

Design

Randomized Controlled Trial

Blinding used (if applicable)

Assignment to treatment groups was done by blinded envelopes, stratified according to type of critical illness (cardiac surgery; neurologic disease; isolated cerebral trauma or brain surgery; thoracic surgery or respiratory insufficiency; abdominal surgery or peritonitis; vascular surger; multiple trauma and severe burns; transplantation; and others) with use of permuted blocks of ten.

Intervention (if applicable)

Intensive insulin treatment: blood glucose maintained between 80 and 110 mg/dL (mean blood glucose level 103 mg/dL)

vs.

Conventional insulin treatment: blood glucose maintained < 200 mg/dL (mean blood glucose level 153 mg/dL for subjects not requiring additional insulin and 173 mg/dL for those who did require exogenous insulin).

Statistical Analysis

Difference between study groups analyzed by chi-square test, unpaired Student's t-test, Mann-Whitley U test, and Mantell-Cox log-rank test, when appropriate. Bonferroni's correction applied for multiple testing. Investigators calculatedcorrelation coefficients for quantifying relation between variables. Multivariate logistic regression analysis was performed to assess the impact of blood glucose level vs. insulin dones on the observed outcome benefits. After univariate simple regression analysis, stepwise linear regression analysis was done to define the independent determinants of the insulin doese required to maintain normoglyhcemia. Two-sided p values <.05 were considered significant.

Data Collection Summary:

Timing of Measurements

Glucose values obtained from arterial whole blood were tested every one to four hours while in the SICU. 

Dependent Variables

  • Insulin dose (all insulin given by continuous intravenous infusion through a central venous catheter by use of a 50-mL syringe-driven pump).
  • mortality, critical illness polyneuropathy, bacteremia, inflammation, anemia, acute renal failure

Independent Variables

Blood glucose value.

Control Variables

Description of Actual Data Sample:

Initial N: N = 1,548

Attrition (final N): No attrition: N=1,548

Age: Conventional trt: 62.2 ± 13.9; Intensive trt: 63.4 ± 13.6  (71% male gender)

Ethnicity: not described in this article, but was referenced in a previous paper

Other relevant demographics: APACHE II: median 9; IQR 6 - 13

Anthropometrics (e.g., were groups same or different on important measures)

Location: University Hospital Gasthuisberg, Leuven, Belgium

 

Summary of Results:
  • An adjusted odds ratio of 1.300 (95% CI 1.140 - 1.580 p=0.001) for mean blood glucose level (per 20 mg/dL added) indicates that for every 20 mg/dL increase in blood glucose concentration, the risk of death increases by 30%. (For a blood glucose level of 200 mg/dL, the risk of death is 2.5 times higher than for a blood glucose level of 100 mg/dL).
  • Identifying daily insulin dose as a positive rather than a negative risk factor for death in the ICU indicates that it was not the amount of infused insulin per se that mediated the reduction of ICU mortality with intensive insulin therapy. (from Table 1)

From Table 2:

Multivariate logistic regression analysis of all univariate determinants of ICU mortality:

Daily Insulin Dose (per 10 units added)

Odds Ratios, 95%confidence intervals, p-value

Mean Glucose Level (per 20 mg/dL added)

Odds Ratios, 95%confidence intervals, p-value

Comments

 

Critical illness polyneuropathy

OR: 0.990;

CI 0.950-1.030

p-value=0.7

OR: 1.240

1.140-1.360

p-value <.0001

An adjusted odds ratio of 1.240 for mean blood glucose level means every 20 mg/dL increase in blood glucose conc., risk of polyneuropathy increases by 24%; for 200 mg/dL, risk is 2.2 times higher than for 100 mg/dL.

Bacteremia        

OR:1.000

CI: 0.960-1.040

p-value=0.9

OR: 1.140

CI: 1.020-1.280

p-value=0.02

Bacteremia increased as BG levels increased.

>3 Days CRP>150mg/L      

OR: 1.040

CI: 1.010-1.070

p-value=.02

OR: 1.160

CI: 1.060-1.240

p-value=0.0006

 
Acute renal failure requiring renal replacement therapy    

OR: 0.940

CI: 0.880-1.000

p-value=0.03

OR: 1.001

CI: 0.880-1.140

p-value=0.9

 

Author Conclusion:
  • It is the lowering of blood glucose levels rather than the amount of infused insulin per se that was related to the observed protective effects of intensive insulin therapy on morbidity and mortality. However, an exception was the prevention of acute renal failure for which insulin dose was an independent determinant.
  • High admission BG levels were a likely indication of more severe injury.
Funding Source:
Government: Belgium Fund for Scientific Research
Industry:
Novo Nordisk Denmark
Pharmaceutical/Dietary Supplement Company:
Other:
University/Hospital: University of Leuven
Not-for-profit
0
Foundation associated with industry:
Reviewer Comments:
  • This is a further analysis of data previously reported in: Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345-1359-1367.
  • Insulin requirements were corrected for caloric intake. Insulin requirements were 26% higher for patients exclusively on parenteral nutrition versus enteral feedings. Patients on TPN at higher risk for hyperglycemia. Investigators hypothesized that some of reported benefits of early enteral feeding may be explained by concomitant lower risk of hyperglycemia.
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) Yes
  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? N/A
  4.1. Were follow-up methods described and the same for all groups? N/A
  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%.) N/A
  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.) N/A
  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? N/A
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? N/A
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