Benefits and risks of tight glucose control in critically ill adults: a meta-analysis1

Wiener RS, Wiener DC, Larson RJ. JAMA. August 27, 2008; 300 (8): 933-944
Journal Club Presentation by Quang Bui, Pharm D. candidate 2010. Touro University. 9/22/08

Background
- An RCT by Van den Berghe et al shows that tight glucose control may reduce hospital mortality
by one third.2
- Recommendations were incorporated into the Surviving Sepsis Campaign and many other
guidelines worldwide.3
- Later RCT studies have not shown the same benefits. Eg. the same investigator find no benefits
for critically ill patients in ICU.4

Methods
- Search strategy: MEDLINE (1950-June 6, 2008) with MeSH, Cochrane Library (issue 1, 2008)
and multiple trial registries such as clinicaltrials.gov (August 2007).
- Study selection – contact investigators of unpublished data to confirm eligibility.

Inclusion criteria of RCTs Exclusion criteria of RCTs

- adult ICU setting - intervention conducted
- intervention grp received tight Glc control (Glc goal primarily during
<150 fr insulin infusion) intraoperative period
- comparison grp received usual care (Glc goal/method instead of ICU
of insulin admin varies fr one another) - no adequate details of
- primary/secondary end points included hospital/short study methods, result
term mortality (≤ 30 day), septicemia, new need for articles, or from
dialysis, or hypoglycemia investigators
- 2 unblinded reviewers independently assessed; any discrepancies between the 2 were resolved via
discussions.

Primary outcome Hospital mortality Death during/within 30 days post admin

Secondary outcome Septicemia Positive blood Cx
New dialysis need Due to ARF
Hypoglycemia Blood Glc ≤ 40 mg/dL
Subgroup analyses Glc goal Very tight control: ≤ 110 mg/dL
Moderate tight control: 111-150 mg/dL
ICU setting surgical (general, cardiothoracic, neuro, trauma)
medical (general, cardiac, neurological)
mixed/nonspecified
Sensitivity analyses Diabetics Cut point = study with 1/3 or less w/ diabetes
Insulin-only infusion As opposed to Glc-insulin-K infusion
Achieved mean glc May biased results to the null
goal in study group
- Quantitative data synthesis: Cochrane Collaboration software to calculate RRs and χ2 test for
variability among the trials.

Results
- 29 RCT in meta-analysis (out of 1358 potential relevant studies identified).
o 19 fully published, 8 abstracts, and 2 unpublished data.
- Study characteristics: mostly single center, 10 - >500 patients (21 with 100 patients, 7 with >500
 patients), ages 46-75, 31-95% males, 0-100% diabetics, and APACHE II scores 9-32; 2 studies
have discrepant baseline between intervention vs control; all have follow-up rate 80% or higher
& no double-blind, none has Jadad quality score higher than 3 of 5; target vs achieved Glc levels
varied.

Primary outcome Hospital mortality 27/29 trials show no differences.

Secondary outcome
No differences in both stratifications.
Funnel plot shows no publication bias.
Septicemia Tight Glc control assoc with significant reduced
(9 trials) risk of septicemia; stratified favor ICU patients &
moderately tight Glc control.
Van den Berghe et al study as outlier.
New dialysis need No significant association; no in stratification.
(9 trials) Van den Berghe et al study as outlier.
Hypoglycemia Tight Glc control assoc with increased risk of
(15 trials) hypoglycemia by 5 fold; fairly consistent across
ICU settings & 2 outliers in medical ICU.

Conclusion
- Tight Glc control was not associated with significant reduction in hospital mortality or new
dialysis need, but had increased hypoglycemia risk.
- In stratified group: reduced septicemia in surgical ICU.
- Therefore, recommend re-evaluation of guidelines.
- 3 reasons why the van der Berghe et al study is an outlier: bias, chance, and atypical clinical
practices.

Discussion
- Weaknesses
o Meta-analysis: are all the studies comparable? Jadad quality scores of 3 or less.
o Only 2 un-blinded reviewers (RSW & DCW) with disputes resolved via discussions.
o Most studies in the study were low powered and single-centered. Can’t get anything that
the studies don’t report.
o External validity: can not apply this findings to larger population
- Strengths
o 1358 relevant studies from MEDLINE, Cochrane, clinical trial registries, and conferences
from different countries.
o High internal validity: meta-analysis is easier to replicate than the van der Berghe et al
study with selective criteria.
o Articles gathered are mostly from 2006. The oldest from 1991.
- Recommendations
o This analysis is a fine example of why guidelines are changing constantly.
o Tight glucose control may be too critical in severely ill patients who are at high risks of
hypoglycemia. A high powered RCT is needed to solidify these results.

Resources
1. Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis.
JAMA. 2008; 300 (8): 933-944.
2. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. NEJM. 2001;
345 (19): 1359-1367.
3. Dellinger RP, Levy M, Carlet J, et al. Surviving sepsis campaign: international guidelines for management of severe
sepsis and septic shock: 2008. Intensive Care Med. 2008; 34 (1): 17-60.
4. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. NEJM. 2006; 354
(5):449-461.