Perioperative glucose control

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

The effect of glucose control in liver surgery on glucose kinetics and insulin resistance

Background &amp; aims: Clinical outcome is negatively correlated to postoperative insulin resistance and hyperglycemia. The magnitude of insulin resistance can be modulated by glucose control, preoperative nutrition, adequate pain management and minimal invasive surgery. Effects of glucose control on perioperative glucose kinetics in liver surgery is less studied. Methods: 18 patients scheduled for open hepatectomy were studied per protocol in this prospective, randomized study. In the treatment group (n = 9), insulin was administered intravenously to keep arterial blood glucose between 6 and 8 mmol/l during surgery. The control group (n = 9) received insulin if blood glucose &gt;11.5 mmol/l. Insulin sensitivity was measured by an insulin clamp on the day before surgery and immediately postoperatively. Glucose kinetics were assessed during the clamp and surgery. Results: Mean intraoperative glucose was 7.0 mM (SD 0.7) vs 9.1 mM (SD 1.9) in the insulin and control group respectively (p &lt; 0.001; ANOVA). Insulin sensitivity decreased in both groups but significantly (p = 0.03, ANOVA) more in the control group (M value: 4.6 (4.4-6.8) to 2.1 (1.2-2.6) and 4.6 (4.1-5.0) to 0.6 (0.1-1.8) mg/kg/min in the treatment and control group respectively). Endogenous glucose production (EGP) increased and glucose disposal (WGD) decreased significantly between the pre-and postoperative clamps in both groups, with no significant difference between the groups. Intraoperative kinetics demonstrated that glucose control decreased EGP (p = 0.02) while WGD remained unchanged (p = 0.67). Conclusion: Glucose control reduces postoperative insulin resistance in liver surgery. EGP increases and WGD is diminished immediately postoperatively. Insulin seems to modulate both reactions, but mostly the WGD is affected. Intraoperative EGP decreased while WGD remained unaltered. Registration number of clinical trial: ANZCTR 12614000278639.

The human H3N2 influenza viruses A/Victoria/3/75 and A/Hiroshima/52/2005 preferentially bind to alpha 2-3-sialylated monosialogangliosides with fucosylated poly-N-acetyllactosaminyl chains

Meisen I, Dzudzek T, Ehrhardt C, et al. The human H3N2 influenza viruses A/Victoria/3/75 and A/Hiroshima/52/2005 preferentially bind to alpha 2-3-sialylated monosialogangliosides with fucosylated poly-N-acetyllactosaminyl chains. Glycobiology. 2012;22(8):1055-1076.Among influenza A viruses, subtype H3N2 is the major cause of human influenza morbidity and is associated with seasonal epidemics causing annually half million deaths worldwide. Influenza A virus infection is initiated via hemagglutinin that binds to terminally sialylated glycoconjugates exposed on the surface of target cells. Gangliosides from human granulocytes were probed using thin-layer chromatography overlay assays for their binding potential to H3N2 virus strains A/Victoria/3/75 and A/Hiroshima/52/2005. Highly polar gangliosides with poly-N-acetyllactosaminyl chains showing low chromatographic mobility exhibited strong virus adhesion which was entirely abolished by sialidase treatment. Auxiliary overlay assays using anti-sialyl Lewis(x) (sLe(x)) monoclonal antibodies showed identical binding patterns compared with those performed with the viruses. A comprehensive structural analysis of fractionated gangliosides by electrospray ionization quadrupole time-of-flight mass spectrometry revealed sLe(x) gangliosides with terminal Neu5Ac alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc epitope and extended neolacto (nLc)-series core structures as the preferential virus binding gangliosides. More precisely, sLe(x) gangliosides with nLc8, nLc10 and nLc12Cer cores, carrying sphingosine (d18:1) and a fatty acid with variable chain length (mostly C24:0, C24:1 or C16:0) in the ceramide moiety and one or two additional internal fucose residues in the oligosaccharide portion, were identified as the preferred receptors recognized by H3N2 virus strains A/Victoria/3/75 and A/Hiroshima/52/2005. This study describes glycan-binding requirements of hemagglutinin beyond binding to glycans with a specific sialic acid linkage of as yet undefined neutrophil receptors acting as ligands for H3N2 viruses. In addition, our results pose new questions on the biological and clinical relevance of this unexpected specificity of a subtype of influenza A viruses