Paul E Marik1, Jean-Charles Preiser. 1. Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA 23507, USA. marikpe@evms.edu
Abstract
BACKGROUND: Following publication of the Leuven Intensive Insulin Therapy Trial in 2001, tight glycemic control became the standard of care in ICUs around the world. Recent studies suggest that this approach may be flawed. The goal of this systematic review was to determine the benefits and risks of tight glycemic control in ICU patients and to explain the differences in outcomes among reported trials. METHODS: Prospective, randomized controlled clinical trials (RCTs) that studied the impact of tight glycemic control (blood glucose 80-110 mg/dL) on mortality in ICU patients were identified through a search of MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, and a citation review of relevant primary and review articles. Data were abstracted on study design, study size, and patient characteristics, as well as on the mean (or median) and SD of the ICU blood glucose level, mean daily dose of insulin administered, average daily caloric intake, percentage of calories given intravenously (parenteral nutrition), incidence of hypoglycemia, need for dialysis, and 28-day/hospital mortality. Metaanalytic techniques were used to analyze the data; subgroup analysis and metaregression were used to explain differences in the treatment effect. RESULTS: We identified seven RCT studies that included 11,425 patients. Overall, tight glycemic control did not reduce the 28-day mortality (odds ratio [OR] 0.95; 95% CI, 0.87-1.05), the incidence of blood stream infections (OR 1.04; 95% CI, 0.93-1.17), or the requirement for renal replacement therapy (OR 1.01; 95% CI, 0.89-1.13). The incidence of hypoglycemia was significantly higher in patients randomized to tight glycemic control (OR 7.7; 95% CI, 6.0-9.9; P < .001). Metaregression demonstrated a significant relationship between the treatment effect (28-day mortality) and the proportion of calories provided parenterally (P = .005). This suggests that the difference in outcome between the two Leuven Intensive Insulin Therapy Trials and the subsequent trials could be related to the use of parenteral nutrition. When the two Leuven Intensive Insulin Therapy Trials were excluded from the metaanalysis, mortality was lower in the control patients (OR 0.90; 95% CI, 0.81-0.99; P = .04; I(2) = 0%). CONCLUSIONS: There is no evidence to support the use of intensive insulin therapy in general medical-surgical ICU patients who are fed according to current guidelines. Tight glycemic control is associated with a high incidence of hypoglycemia and an increased risk of death in patients not receiving parenteral nutrition.
BACKGROUND: Following publication of the Leuven Intensive Insulin Therapy Trial in 2001, tight glycemic control became the standard of care in ICUs around the world. Recent studies suggest that this approach may be flawed. The goal of this systematic review was to determine the benefits and risks of tight glycemic control in ICU patients and to explain the differences in outcomes among reported trials. METHODS: Prospective, randomized controlled clinical trials (RCTs) that studied the impact of tight glycemic control (blood glucose 80-110 mg/dL) on mortality in ICU patients were identified through a search of MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, and a citation review of relevant primary and review articles. Data were abstracted on study design, study size, and patient characteristics, as well as on the mean (or median) and SD of the ICU blood glucose level, mean daily dose of insulin administered, average daily caloric intake, percentage of calories given intravenously (parenteral nutrition), incidence of hypoglycemia, need for dialysis, and 28-day/hospital mortality. Metaanalytic techniques were used to analyze the data; subgroup analysis and metaregression were used to explain differences in the treatment effect. RESULTS: We identified seven RCT studies that included 11,425 patients. Overall, tight glycemic control did not reduce the 28-day mortality (odds ratio [OR] 0.95; 95% CI, 0.87-1.05), the incidence of blood stream infections (OR 1.04; 95% CI, 0.93-1.17), or the requirement for renal replacement therapy (OR 1.01; 95% CI, 0.89-1.13). The incidence of hypoglycemia was significantly higher in patients randomized to tight glycemic control (OR 7.7; 95% CI, 6.0-9.9; P < .001). Metaregression demonstrated a significant relationship between the treatment effect (28-day mortality) and the proportion of calories provided parenterally (P = .005). This suggests that the difference in outcome between the two Leuven Intensive Insulin Therapy Trials and the subsequent trials could be related to the use of parenteral nutrition. When the two Leuven Intensive Insulin Therapy Trials were excluded from the metaanalysis, mortality was lower in the control patients (OR 0.90; 95% CI, 0.81-0.99; P = .04; I(2) = 0%). CONCLUSIONS: There is no evidence to support the use of intensive insulin therapy in general medical-surgical ICU patients who are fed according to current guidelines. Tight glycemic control is associated with a high incidence of hypoglycemia and an increased risk of death in patients not receiving parenteral nutrition.
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