Is normoglycemia a reachable state in safe, effective glycemic control in critical care? A review and steady-state analysis showing the need for dual insulin and nutrition control

Abstract

Critically ill patients frequently experience stress-induced hyperglycemia, leading to increased morbidity and mortality. Safe, effective glycemic control (GC) with insulin therapy alone has proven difficult to achieve consistently. One successful, personalized and model-based GC system overcomes this issue by modulating nutrition, as well as insulin, to control glucose levels. However, no other published protocol takes this approach. Thus, the question arises on whether both control inputs are required to be able to reach normoglycemia safely and effectively.

This work uses a well-validated metabolic system model to show how nonlinear insulin saturation dynamics, and the interaction of insulin sensitivity with nutrition and insulin inputs, combine to require modulation of nutrition as well as insulin to achieve a desired outcome glycemic level – effectively analysing the ability of glycemic control to reach normoglycemia. In doing so, it also shows without nutrition control, insulin resistant patients will be uncontrollable to a given glycemic level in a theoretical sense and derives the mathematical conditions when this situation occurs. Next, it derives how insulin sensitivity variability, common in intensive care unit (ICU) patients as condition evolves, leads to changes in glucose levels, increasing hyper- and hypo- glycemic risk if nutrition is not controlled to allow lower insulin doses and thus a reduced range of glycemic variability. The analysis is augmented by a shared visual analysis, illustrating the metabolic dynamics to provide better insight and understanding.

The primary result is a mathematical, clinical, and control centred review and analysis of the clinical glycemic control problem in the context of assessing the conditions for normoglycemia to be reached safely and consistently. It mathematically demonstrates the necessity of using nutrition modulation, along with controlling insulin, to achieve safe, effective GC for all patients when nonlinear clinical and physiological limits are considered. This main outcome is contrary to a lot of current clinical practice and thinking, and contrary to a strictly mathematical analysis without consideration of known, but often ignored, nonlinear physiological and clinical limitations.