In the first objective, we aimed to study the underlying mechanisms through which obese patients are protected during critical illness. Obesity-induced muscle protection during sepsis appeared partly mediated by elevated mobilization and metabolism of endogenous fatty acids. Leptin did not mediate the protective effect of obesity. Instead, obesity—independently of leptin—attenuated inflammation, protein catabolism, and dyslipidaemia, pathways that may play a role in the observed muscle protection. Furthermore, increased availability of ketone bodies, either via activating ketogenesis or via parenteral infusion, protected against sepsis-induced muscle weakness also in lean mice. The impact on brain damage is still under investigation.
In the second objective, we aimed to investigate whether ketone bodies could act as superior energy substrates or whether ketone bodies play a role as signaling molecules during critical illness. Neither the supplementation of parenteral nutrition with 3-hydroxybutyrate nor the infusion of high lipid doses in lean septic mice could replicate the observed obesity-induced protection against muscle wasting. This suggests that the preservation of muscle mass in the overweight/obese is likely related to other pathways. Supplemented ketones appeared to function as signaling molecules rather than energy substrates and increased markers of muscle regeneration. Furthermore, tracer technology revealed that 3-hydroxybutyrate was preferentially taken up by muscle and metabolized into the cholesterol precursor mevalonate, rather than TCA metabolites. Exogenous 3-hydroxybutyrate increased plasma cholesterol and altered cholesterol homeostasis resulting in increased myofiber cholesterol content. Furthermore, circulating cholesterol levels were lower in weak than in non-weak critically ill patients, and in multivariable analysis adjusting for baseline risk factors, circulating cholesterol was inversely correlated with weakness.
In the third objective, we aimed to investigate to what extent ketogenesis can be increased during human critical illness by macronutrient restriction (accepting virtual fasting) when blood glucose is also lowered to normal fasting ranges and to what extent ketogenesis explains the beneficial effects of these interventions. We could demonstrate that macronutrient restriction during the first week of critical illness, indeed moderately increased ketogenesis, more so in critically ill children than in adults, and that this increase in circulating ketone levels partly explained the outcome benefit of macronutrient restriction in children, but not in adults. In contrast, in the fully fed state, lowering blood glucose levels into healthy fasting ranges in critically ill adults and children did not affect ketone levels. In a virtually fasted state brought about by not using parenteral nutrition for up to one week in the ICU, lowering blood glucose levels did not affect mortality, but reduced kidney and liver dysfunction. Whether ketones play a role in this morbidity benefit is currently still under investigation.
In the fourth objective, we aimed to test the therapeutic potential of increased ketone body availability for human critical illness. In the mouse model, exogenous administration of 3-hydroxybutyrate, administered as a sodium salt or as a ketone ester, significantly attenuated the development of muscle weakness. Subsequent dose-response and toxicity studies revealed that ketone esters are superior to ketone salts, with a broader therapeutic window. The efficacy and safety of ketone ester administration in critically ill patients is currently being investigated in an ongoing clinical trial.
