FitteR-CATABOLIC · Survival of the Fittest: On how to enhance recovery from critical illness through learning from evolutionary conserved catabolic pathways

Since a few decades, human patients who suffer from severe illnesses or multiple trauma, conditions that were previously lethal, are being treated in intensive care units (ICUs). Modern intensive care medicine bridges patients from life-threatening conditions to recovery with use of mechanical devices, vasoactive drugs and powerful anti-microbial agents. By postponing death, a new unnatural condition, intensive-care-dependent prolonged (>1 week) critical illness, has been created. About 25% of ICU patients today require prolonged intensive care, sometimes for weeks or months, and these patients are at high risk of death while consuming 75% of resources. Although the primary insult was adequately dealt with, many long-stay patients typically suffer from hypercatabolism, ICU-acquired brain dysfunction and polyneuropathy/myopathy leading to severe muscle weakness, further increasing the risk of late death. As hypercatabolism was considered the culprit, several anabolic interventions were tested, but these showed harm instead of benefit. We previously showed that fasting early during illness is superior to forceful feeding, pointing to certain benefits of catabolic responses. In healthy humans, fasting activates catabolism to provide substrates essential to protect and maintain brain and muscle function. This proposal aims to investigate whether evolutionary conserved catabolic fasting pathways, specifically lipolysis and ketogenesis, can be exploited in the search for prevention of brain dysfunction and muscle weakness in long-stay ICU patients, with the goal to identify a new metabolic intervention to enhance their recovery. The project builds further on our experience with bi-directional translational research - using human material whenever possible and a validated mouse model of sepsis-induced critical illness for objectives that cannot be addressed in patients - and aims to close the loop, from a novel concept to a large randomized controlled trial in patients.