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    • We hypothesized that elderly have an augmented

    2018-10-30

    We hypothesized that elderly have an augmented inflammatory response associated with an impaired immune response leading to immune paralysis after a severe burn. We could not confirm our hypothesis, but we found that during the early phases after burn elderly were hypo-inflammatory with significantly decreased inflammatory markers in serum and adipose tissue. We found that serum IL-6, MCP-1, and IL-15, as well as adipose neutrophil infiltration, and inflammasome activity are all significantly decreased in elderly during early time points after burn when compared to adults. However, this hypo-inflammatory and immune-senescent response then changed into a hyper-inflammatory response, which is in contrast to adult burn patients. While adults were hyper-inflammatory during the early phases after burn and became less inflammatory at the end of their hospital course, elderly were hypo-inflammatory during early phases changing to a hyper-inflammatory state during later time points. It is not entirely clear what the underlying mechanisms are causing this inverse response. We speculate that this could be due to an unresolved stress and hypermetabolic response, for example by persistent danger associated molecular pattern (DAMP\'s) or stress hormones, which induces the immune system and inflammation but in a delayed fashion (Diao et al., 2014; Lamkanfi et al., 2009). Supporting this hypothesis are the findings that elderly have almost no neutrophil migration into adipose tissue, MPO expression, as well as significantly decreased CD14+IL-1β cells. These results suggest that this population of patients is unable to recruit sufficient inflammatory aconitine to the site of injury. Such defect is expected to have severe consequences as inflammatory cells are required to eliminate dead cells by phagocytosis, as well as stimulate wound healing and prevent potential infections. These results confirm the notion that elderly have an immune-senescent state and decreased immune responses compared to adults. The challenge is to figure out how to modulate this hypo-inflammatory followed by hyper-inflammatory response to change the trajectory from morbidity to recovery in elderly patients. Another discovery of importance was the metabolic response to burns in elderly. Elderly and adults do not seem to be different in terms of hypermetabolism measured by predicted REE during the early phases after burn (Jeschke et al., 2008b). Adults, show a decrease in their metabolic need after 2–3weeks. However, elderly show the opposite, they increase their metabolic requirements which indicate a persistent and increased hypermetabolic response during the later phase after burn. This was reflected in glucose and lipid metabolism. Glucose levels were significantly higher, despite the greater need of insulin, and had a greater variability when compared to adults. Based on the OGTT results and the metabolic profile results, it appears that this is due to a decreased function of the pancreas and β- cell production of insulin. OGTT results indicate that elderly are similarly insulin resistant but the significantly decreased insulinogenic index and decreased HOMA2 index indicate a substantially impaired insulin production by the pancreas. These results are supported by the metabolic Luminex data which showed decreased c-peptide, PP, PYY, and glucagon in elderly after burn. Therefore one would expect that elderly would require higher insulin doses during the acute hospitalization to control glucose level. This is in fact exactly what we found when we determined glucose levels and insulin requirements over time. The clinical relevance of hyperglycemia and high glucose variability is that they have been previously shown to be associated from a metabolic aspect with an increased morbidity and mortality after burn (Jeschke et al., 2010). It is currently not known whether hyperglycemia and insulin resistance can cause organ damage via reactive oxygen species or increased inflammation or whether hyperglycemia and IR are symptoms of attenuated organ function leading poor outcome. We can speculate based on the organ function and multi organ failure scores that elderly have worse organ function compared to adults and therefore high glucose and lack of insulin are a symptom of poor organ function and not the cause. It still remains unclear why elderly have poorer organ function when compared to adults, and we suggest that at the cellular level, mitochondria are dysfunctional or impaired resulting in organ failure. This could be either due to pre-existing medical conditions (co-morbidities) or pre-existing organ dysfunction or due to a lack of a resource to adequately respond to stress or trauma. However, it seems imperative to include mitochondria analyses in future studies in elderly.