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Review: Tight glucose control reduces septicemia, but not death, and increases hypoglycemia in critically ill adults

Question What are the benefits and risks of tight glucose control in critically ill adults? Review scope Studies selected compared tight glucose control (glucose goal <150 mg/dL [8.3 mmol/L], using an insulin infusion) with usual care in patients in adult intensive care units (ICUs) and had one of the outcomes of interest as a primary or secondary endpoint. Outcomes of interest were hospital or 30-day mortality, septicemia (sepsis, septicemia, bacteremia, or positive blood cultures), need for dialysis in patients without prior dialysis, and hypoglycemia (1 blood glucose measurement 40 mg/dL [2.2 mmol/L]). Studies of primarily intraoperative interventions or that could not provide adequate outcome or methodological data were excluded. Review methods MEDLINE (1950 to Jun 2008), Cochrane Library (Issue 1, 2008), trial registries (Aug 2007), conference abstracts of American Thoracic Society (2001 to 2008) and Society of Critical Care Medicine (2004 to 2008), and reference lists were searched for randomized controlled trials (RCTs). Trial investigators were contacted for missing data. 34 trials met the selection criteria, including 9 published only as abstracts and 2 that were unpublished. 29 RCTs (n =8432, mean age 46 to 75 y) that provided full study details and reported 1 event were included in the meta-analysis. Study quality was modest (Jadad scores 3 out of 5) because no trials used blinding. All trials had 80% follow-up (follow-up 28 d to 6 mo, or end of hospital stay), and 2 had group differences in baseline patient characteristics. Main results Meta-analysis showed that tight glucose control and usual care did not differ for short-term mortality or new need for dialysis (Table). Tight glucose control reduced risk for septicemia but increased risk for hypoglycemia more than usual care (Table). Conclusion In critically ill adults, tight glucose control increases risk for hypoglycemia, reduces risk for septicemia, and has no effect on short-term mortality. Tight glucose control vs usual care in critically ill adults* Outcomes Number of trials (n) Weighted event rates RRR (95% CI) NNT (CI) Hospital or 30-day mortality 27 (8315) 22% vs 23% 7% (3 to 15) Not significant Septicemia 9 (3916) 10% vs 13% 24% (3 to 41) 32 (19 to 249) New need for dialysis 9 (3629) 11.6% vs 12.1% 4% (20 to 24) Not significant RRI (CI) NNH (CI) Hypoglycemia 15 (6613) 13% vs 2.5% 413% (309 to 543) 10 (8 to 13) *Abbreviations defined in Glossary. Weighted event rates, RRR, RRI, NNT, NNH, and CI calculated from data in article using a random-effects model. Glucose 40 mg/dL (2.2 mmol/L). Commentary Do the benefits of tight glucose control exceed the risks in critically ill patients? In the absence of compelling data regarding mortality, and while we wait for the results of the large Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial, we need to consider other outcomes analyzed in the meta-analysis by Wiener and colleagues. The meta-analysis was well-conducted, including a comprehensive search strategy and explicit inclusion and exclusion criteria. It addressed the issue of heterogeneity by repeating analyses without heterogeneous studies. Although tight glucose control was associated with a decrease in incidence of septicemia (broadly defined to include sepsis, bacteremia, or a description of positive blood cultures), it was also associated with an increase in severe hypoglycemia. Of interest, this occurred despite findings in a separate study showing that septic shock was independently associated with severe hypoglycemia (1). Based on the number needed to treat or harm identified from the meta-analysis, about 3 cases of hypoglycemia will be caused by tight glucose control for each case of septicemia prevented. Can we reconcile this benefit and harm? Although the attributable hospital mortality of sepsis is about 20% (2), the broad definition of septicemia in this meta-analysis includes positive blood cultures alone, and thus may include patients who have much lower attributable hospital mortality. On the other hand, severe hypoglycemia is independently associated with hospital mortality and its attributable hospital mortality is about 25% (1). Further, hypoglycemia (but not septicemia) is on the list of never events (serious reportable events) of the US National Quality Forum (3). On balance, it appears that the risks of tight glucose control may exceed the benefits, without even considering the costs.