Hypoglycemia in patients in the intensive care unit is strongly associated with increased mortality, according to a subanalysis of the NICE-SUGAR trial published online Sept. 19 in the New England Journal of Medicine.
Researchers performed a more detailed, post hoc analysis of data collected in the previously published NICE-SUGAR (Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation) trial, in which ICU patients assigned to intensive glucose control had a significant, 14% increased risk of death, compared with those assigned to conventional treatment (N. Engl. J. Med. 2009;360:1283-97).
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Hypoglycemia in ICU patients, whether they were treated with usual care or intensive glucose control, was strongly associated with mortality.
In this analysis, the investigators confirmed that both moderate and severe hypoglycemia were significantly more common in ICU patients randomly assigned to receive intensive glucose control than in those assigned to receive conventional glucose control, and that hypoglycemia – in either group – was significantly linked to mortality.
Moreover, the findings show that there is a dose-response relationship between the intensity of glucose control and the rates of hypoglycemia and of death, that the association is consistent across several subgroups of patients, and that the link is strongest for death caused by distributive (vasodilative) shock. All of these findings point to a causal relationship between hypoglycemia and adverse outcomes, but causality cannot be proved because of the design of this study, said Dr. Simon Finfer, of the NICE-SUGAR writing committee and Royal North Shore Hospital and the George Institute for Global Health, University of Sydney, and his associates.
Nevertheless, "it would seem rather prudent to ensure that strategies for managing blood glucose concentration in critically ill patients focus not only on the control of hyperglycemia but also on avoidance of both moderate and severe hypoglycemia," they noted.
Hyperglycemia occurs frequently in ICU patients and is associated with increased morbidity and mortality. A study published in 2001 suggested that intensive glucose control, using insulin if necessary, reduced that morbidity and mortality (N. Engl. J. Med. 2001;345:1359-67), and the practice became widespread.
From that point until the publication of the NICE-SUGAR study in 2009, glucose control in hospital patients was primarily aimed at avoiding hyperglycemia. But NICE-SUGAR and other studies prompted a revision of guidelines for inpatient glycemic control with an increased focus on avoiding hypoglycemia (Diabetes Care 2009;32:1119-31).
For the current analysis, the NICE-SUGAR investigators looked at the associations between moderate hypoglycemia (blood glucose 41-70 mg/dL) and severe hypoglycemia (40 mg/dL or below) and death in 6,026 of the study subjects, who had been randomized to receive either intensive blood glucose control, with a target blood glucose range of 81-108 mg/dL, or conventional control, with a target of 180 mg/dL.
Moderate hypoglycemia developed 45% of patients, and severe hypoglycemia occurred in 3.7% of patients. Broken down by treatment group, moderate hypoglycemia occurred in 74% of the intensive-control group and 16% of the conventional-control group; severe hypoglycemia developed in 6.9% and 0.5%, respectively.
Overall mortality was 26.2%. Mortality in the 3,089 patients with no hypoglycemia was 23.5%. That rate was 28.5% in the 2,714 patients who developed moderate hypoglycemia and 35.4% in the 223 who developed severe hypoglycemia, for highly significant adjusted hazard ratios of 1.41 and 2.10, respectively. The association was stronger in patients whose hypoglycemia lasted more than 1 day than in those with shorter durations of hypoglycemia.
Dr. Simon Finfer
"Even after adjustment for events occurring after the first episode of hypoglycemia, moderate hypoglycemia was associated with an increase in the risk of death of 40%, and severe hypoglycemia with a doubling of the risk," Dr. Finfer and his colleagues said (N. Engl. J. Med. 2012;367:1108-18 [doi: 10.1056/NEJMoa1204942]).
The link between hypoglycemia and death also was robust across subgroups of patients, including patients who had underlying diabetes and those who did not have underlying diabetes.
In a minority of patients, hypoglycemia appears to be a marker, rather than a cause, of an increased risk of death. In these cases it probably signals very severe underlying disease processes and impending death, the investigators said.
This study was supported by the Australian National Health and Medical Research Council, the Health Research Council of New Zealand, and the Canadian Institutes of Health Research. Dr. Finfer reported ties to Edwards, and his associates reported ties to Fresenius Kabi, AstraZeneca, and Eisai.