Periodic Reporting for period 2 - FitteR-CATABOLIC (Survival of the Fittest: On how to enhance recovery from critical illness through learning from evolutionary conserved catabolic pathways)
Berichtszeitraum: 2020-04-01 bis 2021-09-30
Critically ill patients suffer from life-threatening conditions such as severe trauma, infections, or major/complicated surgeries. Modern intensive care medicine bridges these patients 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 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. Even when the primary insult has been adequately dealt with, many long-stay ICU 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. In addition, we recently found that patients and experimental animals who were overweight or obese prior to becoming critically ill were strikingly protected against muscle wasting and weakness during illness, irrespective of whether they received nutrition or were fasted. Furthermore, this protection coincided with a more effective utilization of stored lipids and with substantially increased ketogenesis, again irrespective of whether being fed or fasted. Such activated lipolysis and ketogenesis even in the fed critically ill state, mimics part of a normal fasting response and may thus play a key role.
The general aim of this project is to investigate whether evolutionary conserved catabolic pathways such as lipolysis and ketogenesis can be exploited in the search for prevention of brain dysfunction and muscle weakness in the critically ill patient, with the aim to identify a novel metabolic intervention that can effectively improve recovery from prolonged critical illness. We hypothesize that increased lipolysis and/or ketogenesis observed in obese critically ill patients and mice explain protection against brain damage and muscle weakness. We therefore hypothesize that switching on lipolysis and/or ketogenesis or bringing about nutritional ketosis also in lean prolonged critically ill patients, and thus mimicking that part of a normal fasting response in the fed state, can prevent morbidity and enhance recovery.
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. In addition, we recently found that patients and experimental animals who were overweight or obese prior to becoming critically ill were strikingly protected against muscle wasting and weakness during illness, irrespective of whether they received nutrition or were fasted. Furthermore, this protection coincided with a more effective utilization of stored lipids and with substantially increased ketogenesis, again irrespective of whether being fed or fasted. Such activated lipolysis and ketogenesis even in the fed critically ill state, mimics part of a normal fasting response and may thus play a key role.
The general aim of this project is to investigate whether evolutionary conserved catabolic pathways such as lipolysis and ketogenesis can be exploited in the search for prevention of brain dysfunction and muscle weakness in the critically ill patient, with the aim to identify a novel metabolic intervention that can effectively improve recovery from prolonged critical illness. We hypothesize that increased lipolysis and/or ketogenesis observed in obese critically ill patients and mice explain protection against brain damage and muscle weakness. We therefore hypothesize that switching on lipolysis and/or ketogenesis or bringing about nutritional ketosis also in lean prolonged critically ill patients, and thus mimicking that part of a normal fasting response in the fed state, can prevent morbidity and enhance recovery.
In the first objective, we aimed to study the underlying mechanisms through which obese patients are protected during critical illness for which we used our centrally catheterized, fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis. Obesity-induced muscle protection during sepsis appeared partly mediated by elevated mobilization and metabolism of endogenous fatty acids. Furthermore, increased availability of ketone bodies, either through ketogenesis or through parenteral infusion, appeared to protect against sepsis-induced muscle weakness also in lean mice. The impact on brain damage is still under investigation. Studies on the role of hepatic lipid metabolism and the role of the adipokine leptin are ongoing.
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. We again used our centrally catheterized, fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis. Neither the supplementation of PN with 3-HB 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 early muscle regeneration. Further tracer studies to investigate this objective are ongoing.
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. To document the impact on lipolysis and ketogenesis of lowering blood glucose levels to healthy fasting ranges in the fed state in critically ill adults and children and to assess how this could have contributed to the better outcome, laboratory analyses are ongoing. We have already documented the impact on lipolysis and ketogenesis of macronutrient restriction, while keeping blood glucose levels in the healthy fasting range. 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 plasma ketone levels partly explained the outcome benefit of macronutrient restriction in children, but not in adults.
In the fourth objective, we aimed to test the therapeutic potential of increased ketone body availability for human critical illness. These studies are either ongoing or still have to be started.
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. We again used our centrally catheterized, fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis. Neither the supplementation of PN with 3-HB 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 early muscle regeneration. Further tracer studies to investigate this objective are ongoing.
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. To document the impact on lipolysis and ketogenesis of lowering blood glucose levels to healthy fasting ranges in the fed state in critically ill adults and children and to assess how this could have contributed to the better outcome, laboratory analyses are ongoing. We have already documented the impact on lipolysis and ketogenesis of macronutrient restriction, while keeping blood glucose levels in the healthy fasting range. 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 plasma ketone levels partly explained the outcome benefit of macronutrient restriction in children, but not in adults.
In the fourth objective, we aimed to test the therapeutic potential of increased ketone body availability for human critical illness. These studies are either ongoing or still have to be started.
We have already published several scientific papers with the first results of the project. The project aims to fully close the “translational loop”, starting from a controversial idea, over testing the “why” and the “how” in a clinically relevant in vivo animal model, all the way to finalizing a large multicenter RCT that will test a newly identified metabolic intervention for efficacy and safety in the real-life clinical ICU setting, with the ambition to change practice.