Impact of tight glucose control on circulating 3-hydroxybutyrate in critically ill patients

Abstract

Background Recent evidence suggests a potentially protective effect of increasing ketone body availability via accepting low macronutrient intake early after onset of critical illness. The impact of blood glucose control with insulin on circulating ketones is unclear. Whereas lowering blood glucose may activate ketogenesis, high insulin concentrations may have the opposite effect. We hypothesized that the previously reported protective effects of tight glucose control in critically ill patients receiving early parenteral nutrition may have been mediated in part by activation of ketogenesis. Methods This is a secondary analysis of 3 randomized controlled trials on tight versus liberal blood glucose control in the intensive care unit, including 700 critically ill children and 2748 critically ill adults. All patients received early parenteral nutrition as part of the contemporary standard of care. Before studying a potential mediator role of circulating ketones in improving outcome, we performed a time course analysis to investigate whether tight glucose control significantly affected ketogenesis and to identify a day of maximal effect, if any. We quantified plasma/serum 3-hydroxybutyrate concentrations from intensive care unit admission until day 3 in 2 matched subsets of 100 critically ill children and 100 critically ill adults. Univariable differences between groups were investigated by Kruskal-Wallis test. Differences in 3-hydroxybutyrate concentrations between study days were investigated by Wilcoxon signed-rank test. Results In critically ill children and adults receiving early parenteral nutrition, tight glucose control, as compared with liberal glucose control, lowered mean morning blood glucose on days 1–3 (P < 0.0001) via infusing insulin at a higher dose (P < 0.0001). Throughout the study period, caloric intake was not different between groups. In both children and adults, tight glucose control did not affect 3-hydroxybutyrate concentrations, which were suppressed on ICU days 1–3 and significantly lower than the ICU admission values for both groups (P < 0.0001). Conclusion Tight versus liberal glucose control in the context of early parenteral nutrition did not affect 3-hydroxybutyrate concentrations in critically ill patients. Hence, the protective effects of tight glucose control in this context cannot be attributed to increased ketone body availability.

Modulation of beta-hydroxybutyrate in traumatic brain injury

“…Propofol infusion in TBI patients with KD should be considered carefully due to risk of propofol infusion syndrome and calories needs to be adjusted. In our study, we have safely administered propofol with ketogenic diet and similar results were produced by Bui et al [43] when propofol was given in brief and small infusion [42]. Intensive insulin therapy to lower glucose level, which in turn can cause ketogenesis and raises ketone bodies and BHB concentration.…”

“…Study analysis suggested that tight or liberal glucose control does not affect the BHB concentration in critically ill patients. Therefore, insulin may not offer any additional benefits to such patients [43]. Overall, a ketogenic diet is a more physiological way of inducing ketosis.…”

Nutrition in the intensive care unit: from the acute phase to beyond

“…Mechanistic studies have attributed harm by severe iatrogenic hyperglycemia to glucose overload in vital organs, and not to lack of insulin effect [78]. Indeed, insulin by itself may have unwanted side effects on organ recovery, as insulin is a powerful suppressor of autophagy and ketogenesis [79,80]. This may explain why lower glucose levels independently associated with improved outcome in RCTs, whereas increased insulin doses independently associated with harm [81].…”

The association of hypoglycemia with outcome of critically ill children in relation to nutritional and blood glucose control strategies

“…In the PEPaNIC RCT, the majority of hypoglycemic events occurred in patients not receiving early PN, and the glucose control protocol varied per center, going from tight over intermediate to liberal glucose control [ 10 ]. Different feeding and glucose control strategies have a different risk of iatrogenic hypoglycemia and may variably affect generation of ketone bodies that are vital alternative substrates for the brain during hypoglycemia [ 12 – 14 ].…”