Abstract:
Background: Obesity is now a global pandemic with over a third of patients being admitted to the intensive care being obese. This is relevant particularly to acute pancreatitis and sepsis; where obesity has been associated with modulating the course of the diseases. The ‘obesity paradox’ is a reported phenomenon whereby obese patients in some illness states have been observed to have better outcomes than their lean counterparts. The impact of obesity on severe acute illness states, like sepsis and acute pancreatitis is therefore likely to be complex and the impact unexplored. These two diseases are also associated with variable degrees of organ failure for which there are no specific treatments. In severe acute illness, the gut lymph hypothesis states that toxic factors travel via the lymph and mediate organ failure. The role of gut lymph in mediating organ failure in the setting of obesity has not been elucidated. I hypothesised that obesity may have a paradoxical effect on the physiology, biochemistry and metabolomic composition of key organs, namely left ventricle and kidney in sepsis and acute pancreatitis states. I also hypothesised that mesenteric lymph drainage is likely to have a beneficial effect on these diseases by altering these parameters.
Methods: A rodent model of obesity with an overlay of either sepsis or severe acute pancreatitis was established. Intra-operative parameters were captured, ex-vivo cardiac function analysed, and tissue metabolomics performed on the left ventricle and kidney. Tissue metabolomics for kidney and left ventricle was also undertaken after mesenteric lymph drainage in sepsis state only.
Results: Analysis demonstrated there was no important differences in the intra-operative parameters between obese and lean rats. Ex-vivo cardiac function analyses however demonstrated there was a significant improvement in cardiac output in the obese sepsis rats relative to the lean rats consistent with demonstrating the ‘obesity paradox’ seen in patients. Metabolomic compositional studies demonstrated many changes including an increase in fatty oxidation in the obese sepsis and acute pancreatitis left ventricle, relative to the lean state, which could also explain the improved cardiac output observed in sepsis. In the obese left ventricle and kidney, metabolomic profile in both diseases was associated with a reduction in the toxic metabolite profile relative to the lean rats. Post-mesenteric lymph drainage, there was greater evidence of alteration to the metabolite profile of the obese sepsis relative to the lean sepsis drainage state.
Conclusion: Ex-vivo cardiac function was improved in the obese sepsis rats and was associated with a “better” metabolomics profile in the left ventricle and kidney. It would appear mesenteric lymph demonstrates a protective effect in the obesity and critical illness. Some of these changes may contribute to explaining the “obesity paradox” findings in the model.