Impact of the nutritional status on metabolic dysregulation during critical illness

Critically ill patients treated in the intensive care unit often develop a pronounced nutritional deficit because of the inability to feed orally and because nutrition administered via nasogastric tubes is poorly tolerated. Withholding parenteral nutrition was previously shown to enhance recovery and reduce infections in critically ill patients, as compared to early supplementing insufficient enteral feeding with parenteral nutrition. These beneficial effects of low caloric intake are partly related to the induction of a fasting response, which powerfully activates cell-protective and cellular repair pathways, promoting resilience to cellular stress. An important fasting-induced pathway is the switch from carbohydrate to lipid metabolism, with activation of hepatic ketogenesis. The fasting induced ketogenesis statistically mediated an important part of the outcome benefit of withholding parenteral nutrition in children, but not in adults, as in the latter the ketogenic fasting response was much smaller and appeared strongly suppressed by other illness-related factors. We postulate that in the context of critical illness related cellular and mitochondrial dysfunction, the beneficial switch from carbohydrate to lipid metabolism in low caloric conditions is hampered by PPARα suppression and a relative carnitine and choline deficiency. We hypothesize that activation of ketogenic pathways by a pharmacological PPARα modulator together with carbohydrate-low nutrition will increase ketogenesis and improve muscle integrity and function. We further postulate that refeeding hypophosphatemia reflects relative carnitine deficiency and lipid/energy provision exceeding the suppressed mitochondrial oxidative capacity in early sepsis or shock. As such an increased acylCarnitine/FreeCarnitine or a decrease in serum phosphate levels could be potential metabolic biomarkers of “not ready to feed” in ICU patients. Our hypotheses will be tested in a validated mouse model of cecal-ligation and puncture induced, antibiotics-treated polymicrobial abdominal sepsis by means of pharmacological treatments, and in 3 human studies.