Nutrients, insulin and muscle wasting during critical illness

Abstract

Critical illness develops upon acute life-threatening insults, which require acute intervention to support vital organs in order to avoid imminent death of the patt. This condition is characterized by abiphasic stress response. The acute phase of critical illness is an evolutionary programmed response to a stressor, and the adaptations are considered to be beneficial for short-term survival. Its main purpose is to provide endogenous substrates for protein synthesis and energy metabolism and this by increasing protein catabolism. The evolution of intensive care medicine has allowed patients to survive diseases and trauma that were previously lethal. However, about 30% of thepatients who survive the acute phase remain dependent on vital organ support for a prolonged period and enter a chronic phase of critical illness. During this unnatural phase of critical illness, the hypercatabolic response is sustained. Skeletal muscle is the largest proteinsource and patients can thus lose up to 10% of their muscle mass in one week, despite nutritional support. Muscle atrophy, together with the development of muscle membrane inexcitability, compromises musclestrength and function. This myopathy results in severe muscle weakness, which exposes the patients to serious risks for delayed recovery,prolonged rehabilitation and adverse outcome. Because the gastro-intestinal tract is often dysfunctional during critical illness, intravenous nutrition has been evaluated to counteract hypercatabolism and improve outcome, but unfortunately with poor success. As the nutritional intervention studies were performed without controlling for hyperglycemia, aggravation of hyperglycemia, together with the negativeeffects of untreated hyperglycemia, may explain why intravenous nutrition alone was ineffective. Indeed, the development of hyperglycemia, which is very common in critically ill patients, has been shown to increase the risk for organ failure and death, and to promote catabolism. The general aim of this thesis was to gain more insight in the effect on muscle proteolysis of the combination of intravenous nutrition with the infusion of insulin to maintain normoglycemia. We hypothesized that this intervention would be safe for organ function and survival, and effective to prevent severe muscle wasting during prolonged critical illness. In a first study, we investigated the effect of strict blood glucose control with intensive insulin therapy on proteolytic pathways in skeletal muscle of intravenously fed critically ill patients. Interestingly, markers of muscle atrophy were not ameliorated by this intervention, possibly indicating that the amountof nutrition was insufficient tocounteract the catabolic response. However, we also observed signs of myofiber degeneration and an accumulation of potentially toxic protein aggregates, irrespective of insulin therapy, which is suggestive of incomplete or insufficiently activated autophagy. The fact that nutrients inhibit this pathway, combined with the failure of feeding in the presence of normoglycemia to counteract muscle wasting, emphasizes the importance to study the potentialrole of inadequate (artificial) feeding, either too little or too much, during critical illness in relation to these pathways. We addressed the question on the impact of feeding versus fasting on these catabolic pathways in our animal model of prolonged criticalillness. We assessed the efficacy to attenuate protein degradation as well as safety for vital organ function and survival of different intravenous nutritional interventions.status: publishe