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