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To assess the feasibility, biochemical efficacy, and safety of liberal versus conventional glucose control in ICU patients with diabetes.Prospective, open-label, sequential period study.A 22-bed mixed ICU of a tertiary hospital in Australia.We compared 350 consecutive patients with diabetes admitted over 15 months who received liberal glucose control with a preintervention control population of 350 consecutive patients with diabetes who received conventional glucose control.Liberal control patients received insulin therapy if glucose was greater than 14 mmol/L (target: 10–14 mmol/L [180–252 mg/dL]). Conventional control patients received insulin therapy if glucose was greater than 10 mmol/L (target: 6–10 mmol/L [108–180 mg/dL]).We assessed separation in blood glucose, insulin requirements, occurrence of hypoglycemia (blood glucose ≤ 3.9 mmol/L [70 mg/dL]), creatinine and white cell count levels, and clinical outcomes. The median (interquartile range) time-weighted average blood glucose concentration was significantly higher in the liberal control group (11.0 mmol/L [8.7–12.0 mmol/L]; 198 mg/dL [157–216 mg/dL]) than in the conventional control group (9.6 mmol/L [8.5–11.0 mmol/L]; 173 mg/dL [153–198 mg/dL]; p < 0.001). Overall, 132 liberal control patients (37.7%) and 188 conventional control patients (53.7%) received insulin in ICU (p < 0.001). Hypoglycemia occurred in 6.6% and 8.6%, respectively (p = 0.32). Among 314 patients with glycated hemoglobin A1c greater than or equal to 7%, hypoglycemia occurred in 4.1% and 9.6%, respectively (p = 0.053). Trajectories of creatinine and white cell count were similar in the groups. In multivariable analyses, we found no independent association between glucose control and mortality, duration of mechanical ventilation, or ICU-free days to day 30.In ICU patients with diabetes, during a period of liberal glucose control, insulin administration, and among patients with hemoglobin A1c greater than or equal to 7%, the prevalence of hypoglycemia was reduced, without negatively affecting serum creatinine, the white cell count response, or other clinical outcomes. (Trial Registration: Australian New Zealand Clinical Trials Registry; ACTRN12615000216516).