Perioperative glucose control

Abstract: Trauma or surgery elicit a physiological stress response, which among others induces insulin resistance. It could be described as a state where the biological response to a given dose of insulin is reduced, and is associated with an altered glucose metabolism, as well as a disturbed lipid and protein metabolism and dysfunctional immune, inflammatory and coagulation systems. The endogenous glucose production (EGP) is enhanced, whereas the whole-body glucose disposal (WGD) is reduced with the result of hyperglycemia. Hyperglycemia, > 11.1 mmol/l glucose, in surgical patients is associated with increased rates of infection and mortality. On the other hand, hypoglycemia, <3.9 mmol/l glucose, is associated with adverse events and increased mortality. Still, attempts to improve clinical outcome in critically ill patients, by maintaining normoglycemia, have resulted in diverging results for morbidity and mortality. The latter could be the result of increasing glucose variability with the treatment. Reduced glucose variability, independent the glucose range, seems beneficial and could possibly be accomplished by continuous glucose measurement. One suggested method for monitoring mainly tissue metabolism, such as glucose, is microdialysis (MD). The overall aims of this thesis are to better understand the metabolic consequences of insulin treatment on glucose metabolism in relation to major stress and to test a new approach for continuous glucose monitoring. The first half of this thesis investigated the accuracy of intravenous glucose MD measurements using various perfusion rates and length of peripheral catheters in volunteers (paper I), and continuous on-line MD measurements via a central venous catheter performed in surgical patients (paper II). In the second half of the thesis, the effect of glucose control on postoperative insulin resistance and glucose kinetics in liver surgery was investigated by the hyperinsulinemic normoglycemic clamp technique (HNC) (paper III-IV) and the isotopic tracer dilution method (paper IV). In paper I, reduced rate of perfusion fluid and increased length of semipermeable membrane improved the accuracy of microdialysis readings and plasma reference values. In paper II, the use of a continuous on-line real time MD systems proceeded over 20 hours, with measurements every minute, demonstrated good correlation to plasma reference values. All values were found in zone A and B in a Clark Error Grid, indicating safe usage. In paper III and IV, insulin resistance was assessed pre- and postoperatively in patients subjected to liver surgery. During surgery, intravenous insulin was administered to maintain glucose at 6-8 mmol/l in the treatment group, whereas the control group was allowed glucose > 11 mmol/l before intervention. Intraoperative mean glucose was significantly different between groups. Postoperative insulin resistance was significantly higher in the control group (paper III-IV) and glucose kinetics (paper IV) were altered after the surgical trauma, with increased EGP and substantially reduced WGD, without any statistical difference between the groups. Intraoperative kinetic alterations revealed a reduced EGP and an unaltered WGD, despite evolving hyperglycemia, possibly due to undetected rapid changes in glucose kinetics earlier during the surgical procedure. In conclusion, microdialysis is a feasible technique for intravenous continuous on-line glucose measurements monitoring. Intraoperative glucose control during liver surgery maintains insulin sensitivity assessed by HNC. In all patients, reduced WGD is a major contributor to early postoperative insulin resistance. Intraoperative glucose kinetics indicate reduced EGP and stable WGD despite evolving hyperglycemia.