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Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data

From the Departments of Medicine (Griesdale, Henderson, Chittock) and Anesthesiology, Pharmacology and Therapeutics (Griesdale), University of British Columbia; the Program of Critical Care Medicine (Griesdale, Henderson, Chittock) and the Department of Anesthesia (Griesdale), Vancouver General Hospital, Vancouver, BC; the Department of Nutrition (de Souza, van Dam), Harvard School of Public Health; the Channing Laboratory, Department of Medicine (van Dam), and the Divisions of Pulmonary, Critical Care and Sleep Medicine (Malhotra), Brigham and Women’s Hospital and Harvard Medical School; the Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School (Talmor), Boston, USA; the Department of Medicine (Heyland), Queen’s University; the Clinical Evaluation Research Unit (Dhaliwal), Kingston General Hospital, Kingston, Ont; the Departments of Medicine and of Clinical Epidemiology and Biostatistics (Cook), McMaster University, Hamilton, Ont.; and the Intensive Therapy Unit (Finfer), Royal North Shore Hospital, and the George Institute for International Health and the Faculty of Medicine (Finfer), University of Sydney, Sydney, Australia

Correspondence to: Dr. Donald E.G. Griesdale, Critical Care Medicine, Vancouver General Hospital, Rm. 2438, Jim Pattison Pavilion, 2nd Floor, 855 West 12th Ave., Vancouver BC V5Z 1M9; fax 604 875-5957; dgriesdale{at}post.harvard.edu

Background: Hyperglycemia is associated with increased mortality in critically ill patients. Randomized trials of intensive insulin therapy have reported inconsistent effects on mortality and increased rates of severe hypoglycemia. We conducted a meta-analysis to update the totality of evidence regarding the influence of intensive insulin therapy compared with conventional insulin therapy on mortality and severe hypoglycemia in the intensive care unit (ICU).

Methods: We conducted searches of electronic databases, abstracts from scientific conferences and bibliographies of relevant articles. We included published randomized controlled trials conducted in the ICU that directly compared intensive insulin therapy with conventional glucose management and that documented mortality. We included in our meta-analysis the data from the recent NICE-SUGAR (Normoglycemia in Intensive Care Evaluation — Survival Using Glucose Algorithm Regulation) study.

Results: We included 26 trials involving a total of 13 567 patients in our meta-analysis. Among the 26 trials that reported mortality, the pooled relative risk (RR) of death with intensive insulin therapy compared with conventional therapy was 0.93 (95% confidence interval [CI] 0.83–1.04). Among the 14 trials that reported hypoglycemia, the pooled RR with intensive insulin therapy was 6.0 (95% CI 4.5–8.0). The ICU setting was a contributing factor, with patients in surgical ICUs appearing to benefit from intensive insulin therapy (RR 0.63, 95% CI 0.44–0.91); patients in the other ICU settings did not (medical ICU: RR 1.0, 95% CI 0.78–1.28; mixed ICU: RR 0.99, 95% CI 0.86–1.12). The different targets of intensive insulin therapy (glucose level 6.1 mmol/L v. 8.3 mmol/L) did not influence either mortality or risk of hypoglycemia.

Interpretation: Intensive insulin therapy significantly increased the risk of hypoglycemia and conferred no overall mortality benefit among critically ill patients. However, this therapy may be beneficial to patients admitted to a surgical ICU.

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