Insulin Glargine in the intensive care unit: A model-based clinical trial design

Abstract

Introduction: Current successful AGC (Accurate Glycemic Control) protocols require extra clinical effort and are impractical in less acute wards where patients are still susceptible to stress-induced hyperglycemia. Long-acting insulin Glargine has the potential to be used in a low effort controller. However, potential variability in efficacy and length of action prevent direct in-hospital use in an AGC framework for less acute wards. Method: Clinically validated virtual trials based on data from stable ICU patients from the SPRINT cohort who would be transferred to such an approach are used to develop a 24-h AGC protocol robust to different Glargine potencies (1.0×, 1.5× and 2.0× regular insulin) and initial dose sizes (dose = total insulin over prior 12, 18 and 24 h). Glycemic control in this period is provided only by varying nutritional inputs. Performance is assessed as %BG in the 4.0-8.0 mmol/L band and safety by %BG < 4.0 mmol/L. Results: The final protocol consisted of Glargine bolus size equal to insulin over the previous 18 h. Compared to SPRINT there was a 6.9-9.5% absolute decrease in mild hypoglycemia (%BG < 4.0 mmol/L) and up to a 6.2% increase in %BG between 4.0 and 8.0 mmol/L. When the efficacy is known (1.5× assumed) there were reductions of: 27% BG measurements, 59% insulin boluses, 67% nutrition changes, and 6.3% absolute in mild hypoglycemia. Conclusion: Based on current understanding of Glargine behaviour, a robust protocol for a 24-48 clinical trial has been designed to safely investigate possible differences in efficacy and kinetics of Glargine in a critically ill population. This protocol is a first step towards developing a Glargine-based protocol for less acute wards. Ensuring robustness to variability in Glargine efficacy directly affects the performance and safety that can be obtained. © 2012 Elsevier Ltd. All rights reserved.