Hyperinsulinemic Normoglycemia during Cardiac Surgery Reduces a Composite of 30-day Mortality and Serious In-hospital Complications: A Randomized Clinical Trial

Abstract

Background: Hyperinsulinemic normoglycemia augments myocardial glucose uptake and utilization. We tested the hypothesis that hyperinsulinemic normoglycemia reduces 30-day mortality and morbidity after cardiac surgery.

Methods: This dual-center, parallel-group, superiority trial randomized cardiac surgical patients between August 2007 and March 2015 at the Cleveland Clinic, Cleveland, Ohio, and Royal Victoria Hospital, Montreal, Canada, to intraoperative glycemic management with (1) hyperinsulinemic normoglycemia, a fixed high-dose insulin and concomitant variable glucose infusion titrated to glucose concentrations of 80 to 110 mg · dl; or (2) standard glycemic management, low-dose insulin infusion targeting glucose greater than 150 mg · dl. The primary outcome was a composite of 30-day mortality, mechanical circulatory support, infection, renal or neurologic morbidity. Interim analyses were planned at each 12.5% enrollment of a maximum 2,790 patients.

Results: At the third interim analysis (n = 1,439; hyperinsulinemic normoglycemia, 709, standard glycemic management, 730; 52% of planned maximum), the efficacy boundary was crossed and study stopped per protocol. Time-weighted average glucose concentration (means ± SDs) with hyperinsulinemic normoglycemia was 108 ± 20 versus 150 ± 33 mg · dl with standard glycemic management, P < 0.001. At least one component of the composite outcome occurred in 49 (6.9%) patients receiving hyperinsulinemic normoglycemia versus 82 (11.2%) receiving standard glucose management (P < efficacy boundary 0.0085); estimated relative risk (95% interim-adjusted CI) 0.62 (0.39 to 0.97), P = 0.0043. There was a treatment-by-site interaction (P = 0.063); relative risk for the composite outcome was 0.49 (0.26 to 0.91, P = 0.0007, n = 921) at Royal Victoria Hospital, but 0.96 (0.41 to 2.24, P = 0.89, n = 518) at the Cleveland Clinic. Severe hypoglycemia (less than 40 mg · dl) occurred in 6 (0.9%) patients.

Conclusions: Intraoperative hyperinsulinemic normoglycemia reduced mortality and morbidity after cardiac surgery. Providing exogenous glucose while targeting normoglycemia may be preferable to simply normalizing glucose concentrations.

Figure 1.

Patient flow diagram

Figure 2.

Boxplots comparing randomized groups on time weighted intraoperative glucose concentrations overall and within site. All = combined sites; HN = hyperinsulinemic normoglycemia. Box shows the interquartile range; horizontal line marks the median; whiskers extend to high and low values within 1.5 interquartile range of the box; circles are values beyond 1.5 interquartile range of the box; diamond shows the mean.

Figure 3.

Comparison of the hyperinsulinemic normoglycemia (HN) and standard therapy group on the composite outcome of any major morbidity/30-day mortality and individual components of the composite outcome at combined sites (Figure 3a) and within individual sites (Figure 3b). CI=confidence interval; Interaction P-value (treatment-by-site) = 0.063. Confidence intervals adjusted for group sequential design (using confidence coefficient of 2.633) to maintain overall study alpha of 0.05 for combined sites and confidence coefficient of 2.86 within sites. P-values for combined sites: significant if P < 0.0085 for efficacy (with 99.15% CI); P-values for each site: significant if P < 0.0042 for efficacy (with 99.58% CI); P-values for each component: significant if P < 0.0042/5 = 0.00084 (with 99.92% CI) using Bonferroni correction.

Figure 3.

Comparison of the hyperinsulinemic normoglycemia (HN) and standard therapy group on the composite outcome of any major morbidity/30-day mortality and individual components of the composite outcome at combined sites (Figure 3a) and within individual sites (Figure 3b). CI=confidence interval; Interaction P-value (treatment-by-site) = 0.063. Confidence intervals adjusted for group sequential design (using confidence coefficient of 2.633) to maintain overall study alpha of 0.05 for combined sites and confidence coefficient of 2.86 within sites. P-values for combined sites: significant if P < 0.0085 for efficacy (with 99.15% CI); P-values for each site: significant if P < 0.0042 for efficacy (with 99.58% CI); P-values for each component: significant if P < 0.0042/5 = 0.00084 (with 99.92% CI) using Bonferroni correction.