Background Hyperinsulinemic normoglycemia augments myocardial glucose uptake and utilization. We tested the hypothesis that hyperinsulinemic normoglycemia reduces 30-day mortality and morbidity after cardiac surgery. Methods This dual-center, parallel-group, superiority trial randomized cardiac surgical patients between August 2007 and March 2015 at the Cleveland Clinic, Cleveland, Ohio, and Royal Victoria Hospital, Montreal, Canada, to intraoperative glycemic management with (1) hyperinsulinemic normoglycemia, a fixed high-dose insulin and concomitant variable glucose infusion titrated to glucose concentrations of 80 to 110 mg · dl –1 ; or (2) standard glycemic management, low-dose insulin infusion targeting glucose greater than 150 mg · dl –1 . The primary outcome was a composite of 30-day mortality, mechanical circulatory support, infection, renal or neurologic morbidity. Interim analyses were planned at each 12.5% enrollment of a maximum 2,790 patients. Results At the third interim analysis (n = 1,439; hyperinsulinemic normoglycemia, 709, standard glycemic management, 730; 52% of planned maximum), the efficacy boundary was crossed and study stopped per protocol . Time-weighted average glucose concentration (means ± SDs) with hyperinsulinemic normoglycemia was 108 ± 20 versus 150 ± 33 mg · dl –1 with standard glycemic management, P < 0.001. At least one component of the composite outcome occurred in 49 (6.9%) patients receiving hyperinsulinemic normoglycemia versus 82 (11.2%) receiving standard glucose management ( P < efficacy boundary 0.0085); estimated relative risk (95% interim-adjusted CI) 0.62 (0.39 to 0.97), P = 0.0043. There was a treatment-by-site interaction ( P = 0.063); relative risk for the composite outcome was 0.49 (0.26 to 0.91, P = 0.0007, n = 921) at Royal Victoria Hospital, but 0.96 (0.41 to 2.24, P = 0.89, n = 518) at the Cleveland Clinic. Severe hypoglycemia (less than 40 mg · dl –1 ) occurred in 6 (0.9%) patients. Conclusions Intraoperative hyperinsulinemic normoglycemia reduced mortality and morbidity after cardiac surgery. Providing exogenous glucose while targeting normoglycemia may be preferable to simply normalizing glucose concentrations.

Background Ischemia-reperfusion (I/R) injuries consist of enhanced oxidative and inflammatory responses along with microvascular dysfunction after prolonged ischemia and reperfusion. Because I/R injuries induce chronic postischemia pain (CPIP) in laboratory animals, it is possible that surgical procedures using prolonged ischemia may result in chronic postoperative pain. Glycemic modulation during ischemia and reperfusion could affect pain after I/R injury because glucose triggers oxidative, inflammatory, and thrombotic reactions, whereas insulin has antioxidative, antiinflammatory, and vasodilatory properties. Methods One hundred ten rats underwent a 3-h period of ischemia followed by reperfusion to produce CPIP. Rats with CPIP had previously been divided into six groups with differing glycemic modulation paradigms: normal feeding; fasting; fasting with normal saline administration; fasting with dextrose administration; normal feeding with insulin administration; and normal feeding with insulin and dextrose administration. Blood glucose concentration was assessed during I/R in these separate groups of rats, and these rats were tested for mechanical and cold allodynia over the 21 days afterward (on days 2, 5, 7, 9, 12, and 21 after I/R injury). Results I/R injury in rats with normoglycemia or relative hyperglycemia (normal feeding and fasting with dextrose administration groups) led to significant mechanical and cold allodynia; conversely, relative hypoglycemia associated with insulin treatment or fasting (fasting, fasting with normal saline administration, and normal feeding with insulin administration groups) reduced allodynia induced by I/R injury. Importantly, insulin treatment did not reduce allodynia when administered to fed rats given dextrose (normal feeding with dextrose and insulin administration group). Conclusion Study results suggest that glucose levels at the time of I/R injury significantly modulate postinjury pain thresholds in rats with CPIP. Strict glycemic control during I/R injury significantly reduces CPIP and, conversely, hyperglycemia significantly enhances it, which could have potential clinical applications especially in the surgical field.

Background It has been suggested that diabetes mellitus type 2 amplifies the endocrine-metabolic stress response to surgery, and patients become more catabolic during the postoperative period. The aim of this study, conducted in patients with diabetes mellitus type 2 scheduled to undergo elective colorectal surgery, was to determine whether the anabolic effects of intravenous amino acids are more pronounced when receiving perioperative epidural analgesia compared with patient-controlled analgesia with intravenous morphine. Methods Twelve patients were randomly assigned to receive either epidural analgesia or patient-controlled analgesia with intravenous morphine for perioperative pain control. Protein and glucose kinetics were measured before surgery and on the second postoperative day using L-[1-C]leucine and [6,6H2]glucose infusion during a fasted and a fed (amino acid infusion) state. Results Preoperative parameters for glucose and protein kinetics were comparable in the fasted state for both groups. Postoperative amino acid infusion increased glucose concentration slightly (P = 0.124) and suppressed the endogenous rate of appearance of glucose (P < 0.0001) and glucose clearance (P < 0.0001) regardless of analgesia technique. The rate of appearance of leucine (P = 0.002), leucine oxidation (P < 0.0001), and protein synthesis (P = 0.026) increased, whereas net protein breakdown was decreased (P = 0.002), leading to a positive protein balance (P < 0.0001) in both groups. The increase in protein balance was greater in the epidural group compared with the patient-controlled analgesia group (P = 0.027). Conclusion Diabetic patients receiving an amino acid infusion after surgery achieved a positive protein balance without hyperglycemia. This anabolic effect was greater in patients receiving epidural analgesia compared with patient-controlled analgesia with intravenous morphine.

Background Net loss of body protein is a prominent feature of the catabolic response to surgical tissue trauma. Epidural analgesia with hypocaloric dextrose has been demonstrated to attenuate leucine oxidation but was unable to make protein balance positive. The current study was set to determine whether an infusion of amino acids on the second day after colon surgery would revert the catabolic state and promote protein synthesis while maintaining glucose homeostasis in patients receiving epidural analgesia as compared with patient-controlled analgesia with morphine (PCA). Methods Sixteen patients undergoing colorectal surgery were randomly assigned to receive epidural blockade or PCA as analgesic techniques and underwent a 6-h stable isotope infusion study (3 h fasted, 3 h fed) on the second postoperative day. Whole body glucose kinetics and protein turnover were measured using [6,6-2H2]glucose and l-[1-13C]leucine as tracer. Results The infusion of amino acids caused a decrease in endogenous glucose rate of appearance in both groups (P < 0.05), with greater changes in the PCA group (P < 0.05). Administration of amino acids suppressed the appearance of leucine from protein breakdown in both groups (P < 0.05), although the decrease was greater in the PCA group (P < 0.05). Leucine oxidation increased in both groups (P < 0.05), with greater change in the epidural group (P < 0.05). Protein synthesis increased to the same extent in both groups (P < 0.05). Protein balance became positive after the infusion of amino acids, and the effect was greater in the PCA group (P < 0.05). Conclusions Infusion of amino acids decreased the endogenous glucose production and induced a positive protein balance independent of the type of anesthesia provided, although such effects were greater in the PCA group.

Background The authors tested the hypothesis that the catabolic responses to colorectal surgery are amplified in the presence of type 2 diabetes mellitus. Methods Seven nondiabetic and seven diabetic patients underwent a 6-h stable isotope infusion study (3 h fasted, 3-h glucose infusion at 4 mg . kg . min) on the second postoperative day. Leucine rate of appearance (Ra), leucine oxidation, nonoxidative leucine disposal, and glucose Ra were assessed by L-[1-C]leucine and [6,6-H2]glucose. Circulating concentrations of glucose, lactate, insulin, glucagon, and cortisol also were determined. Results Diabetic patients had a higher leucine oxidation than nondiabetic patients (P = 0.0003), whereas leucine Ra and nonoxidative leucine disposal were not different. Administration of glucose did not affect leucine kinetics regardless of whether patients were diabetic. In diabetic patients, glucose Ra was greater than in the nondiabetic group (P = 0.0032). Glucose infusion suppressed the endogenous glucose Ra to a lesser extent in diabetic than in nondiabetic patients (P = 0.0048). Plasma glucose concentrations were higher in diabetic than in nondiabetic patients (P = 0.0203), both in the postabsorptive and the fed state. Circulating concentrations of glucagon were higher (P = 0.0065) and concentrations of insulin were lower (P = 0.0146) in the presence of diabetes, resulting in a lower insulin/glucagon ratio (P = 0.0002). In diabetic patients, the insulin/glucagon ratio increased during glucose infusion to a lesser extent than in the nondiabetic group (P = 0.0014). Conclusion Protein catabolism after colorectal surgery is increased in patients with type 2 diabetes mellitus as reflected by an increased oxidative protein loss.

Background The authors examined the hypothesis that epidural administration of local anesthetic, in contrast to epidural analgesia with morphine, inhibits postoperative protein oxidation during administration of glucose. Methods Fourteen patients were randomly assigned to undergo a 6-h stable isotope infusion study (3 h fasted, 3 h feeding with 4 mg.kg(-1).min(-1) glucose) on the second day after colorectal surgery using epidural analgesia with either continuous ropivacaine or intermittent morphine. Protein synthesis, breakdown and oxidation, and glucose production were measured by L-[L-13C]leucine and [6,6-2H2]glucose. Substrate oxidation rates were determined by indirect calorimetry. Plasma concentrations of metabolic substrates and hormones were also measured. Results Whole body protein breakdown, oxidation, synthesis, and glucose production in the fasted state were similar between the two groups. Glucose administration decreased protein breakdown (P = 0.01), protein synthesis (P = 0.001), and glucose production (P = 0.001) to the same extent in both groups, whereas protein oxidation was not significantly affected. The type of epidural analgesia did not significantly influence the circulating concentrations of metabolic substrates and hormones in the fasted or in the fed state. Carbohydrate oxidation rate in the ropivacaine group was greater than in patients receiving morphine (P = 0.04), regardless of whether glucose was infused. Conclusion Epidural analgesia achieved with ropivacaine or morphine does not suppress the catabolic response to surgery, either under fasting conditions or in the presence of an energy supply.

Background The authors examined the hypothesis that continuous thoracic epidural blockade with local anesthetic and opioid, in contrast to patient-controlled intravenous analgesia with morphine, stimulates postoperative whole body protein synthesis during combined provision of energy (4 mg x kg(-1) x min(-1) glucose) and amino acids (0.02 ml x kg(-1) x min(-1) Travasol 10%, equivalent to approximately 2.9 g x kg(-1) x day(-1)). Methods Sixteen patients were randomly assigned to undergo a 6-h stable isotope infusion study (3 h fasted, 3 h feeding) on the second day after colorectal surgery performed with or without perioperative epidural blockade. Protein synthesis, breakdown and oxidation, glucose production, and clearance were measured by L-[1-(13)C]leucine and [6,6-(2)H(2) ]glucose. Results Epidural blockade did not affect protein and glucose metabolism in the fasted state. Parenteral alimentation decreased endogenous protein breakdown and glucose production to the same extent in both groups. Administration of glucose and amino acids was associated with an increase in whole body protein synthesis that was modified by the type of analgesia, i.e., protein synthesis increased by 13% in the epidural group (from 93.3 +/- 16.6 to 104.5 +/- 11.1 micromol x kg(-1) x h(-1) ) and by 4% in the patient-controlled analgesia group (from 90.0 +/- 27.1 to 92.9 +/- 14.8 micromol x kg(-1) x h(-1);P = 0.054). Conclusions Epidural blockade accentuates the stimulating effect of parenteral alimentation on whole body protein synthesis.

Background Multimodal analgesia programs have been shown to decrease hospital stay, but it not clear which functions are restored after surgery. The objective of this study is to evaluate the impact of epidural anesthesia and analgesia on functional exercise capacity and health-related quality of life. Methods Sixty-four patients undergoing elective colonic resection were randomized to either patient-controlled analgesia with morphine or thoracic epidural analgesia with bupivacaine and fentanyl (epidural group). All patients in both groups received similar perioperative care and were offered the same amount of postoperative oral nutrition and assistance with mobilization. Primary outcome was functional exercise capacity as measured by the 6-min walking test, and secondary outcome was health-related quality of life, as measured by the SF-36 health survey. These were assessed before surgery and at 3 and 6 weeks after hospital discharge. Other variables measured in hospital included pain and fatigue visual analogue scale, bowel function, time out of bed, nutritional intake, complication rate, readiness for discharge, and length of hospital stay. Results Although the 6-min walking test and the SF-36 physical health component decreased in both groups at 3 and 6 weeks after surgery, the patient-controlled analgesia group experienced a significantly greater decrease at both times (P < 0.01). Patients in the epidural group had lower postoperative pain and fatigue scores, which allowed them to mobilize to a greater extent (P < 0.05) and eat more (P < 0.05). Length of hospital stay and incidence of complications were similar in both groups, although patients in the epidural group were ready to be discharged earlier. Conclusions The superior quality of pain relief provided by epidural analgesia had a positive impact on out-of-bed mobilization, bowel function, and intake of food, with long-lasting effects on exercise capacity and health-related quality of life.

Background Epidural blockade with local anesthetic has been shown to blunt the increase in plasma glucose concentration during and after abdominal surgery. The aim of the study was to test the hypothesis that epidural blockade inhibits this hyperglycemic response by attenuating endogenous glucose production. The authors further examined if the modification of glucose production by epidural blockade has an impact on perioperative protein catabolism. Methods Sixteen patients undergoing colorectal surgery received either general anesthesia and epidural blockade with local anesthetic (n = 8) or general anesthesia alone (control, n = 8). Glucose and protein kinetics were assessed by stable isotope tracer technique ([6,6-2H2]glucose, L-[1-13C]leucine) during and 2 h after surgery. Plasma concentrations of glucose, lactate, free fatty acids (FFA), cortisol, glucagon, and insulin were also determined. Results Epidural blockade blunted the perioperative increase in the plasma concentration of glucose, cortisol, and glucagon when compared with the control group (P < 0.05). Plasma concentrations of lactate, FFA, and insulin did not change. Intra- and postoperative glucose production was lower in patients with epidural blockade than in control subjects (intraoperative, epidural blockade 8.2 +/- 1.9 vs. control 10.7 +/- 1.4 micromol x kg(-1) x min(-1), P < 0.05; postoperative, epidural blockade 8.5 +/- 1.8 vs. control 10.5 +/- 1.2 micromol x kg(-1) x min(-1), P < 0.05), whereas glucose clearance decreased to a comparable extent in both groups (P < 0.05). Protein breakdown (P < 0.05), protein synthesis (P < 0.05), and amino acid oxidation (P > 0.05) decreased with both anesthetic techniques. Conclusions Epidural blockade attenuates the hyperglycemic response to surgery through modification of glucose production. The perioperative suppression of protein metabolism was not influenced by epidural blockade.

Background To interpret correctly the results from studies performed during surgery and anesthesia it is necessary to dissect the separate effect of the anesthetic technique itself. The purpose of this study was to investigate the metabolic effects of epidural blockade (T7-S1) with bupivacaine 0.25% after 12 h fasting and during administration of 4 mg x kg(-1) x min(-1) dextrose in six healthy volunteers. Methods Each volunteer was assigned to randomly undergo a 6-h multiple stable isotope infusion study (3 h fasted, 3 h dextrose infusion) with or without epidural blockade. L-[1-13C]leucine, [6,6-2H2]glucose, and [1,1,2,3,3-2H5]glycerol were infused to measure protein synthesis, breakdown, and amino acid oxidation; glucose production and clearance; and lipolysis. Plasma concentrations of glucose, lactate, glycerol, free fatty acids, insulin, and glucagon were determined. Results Epidural blockade with bupivacaine had no influence on protein oxidation, breakdown and synthesis, glucose production, glucose clearance and lipolysis in the fasted state. Plasma concentrations of metabolic substrates and hormones also were not affected. Dextrose infusion significantly increased glucose clearance and plasma concentrations of glucose and insulin, while endogenous glucose production and lipolysis decreased to a similar degree in both groups. Protein synthesis, breakdown, and oxidation did not change during dextrose infusion. Conclusions Epidural blockade with bupivacaine in the absence of surgery has no effect on fasting protein, glucose, and lipid metabolism. Epidural blockade does not modify the inhibitory influence of dextrose administration on endogenous glucose production and lipolysis.

Background The purpose of this study was to examine the effect of general anesthesia with propofol in the absence of surgical stimulation on whole body protein metabolism. Methods Six unpremedicated patients were studied. General anesthesia included propofol (120 microg x kg(-1) x min(-1)), vecuronium bromide, and oxygen-enriched air. Changes in protein breakdown, protein oxidation, and synthesis were measured by an isotope dilution technique using a constant infusion of the stable isotope tracer L-[1-13C]leucine (0.008 mg x kg(-1) x min(-1)) before and during 100 min of propofol anesthesia. The plasma concentrations of glucose, lactate, non-esterified fatty acids, and cortisol were measured before and during anesthesia. Results An isotopic steady state of plasma [1-13C]alpha-ketoisocaproate (taken to represent the intracellular leucine precursor pool enrichment for protein synthesis) and expired 13C-carbon dioxide were obtained before and during propofol infusion. Whole body protein breakdown decreased during propofol anesthesia by 6% (P < 0.05), whereas protein synthesis and oxidation did not change significantly. Plasma concentration of cortisol decreased after 90 min of propofol anesthesia (P < 0.05). No significant changes of plasma concentrations of glucose, lactate, and non-esterified fatty acids occurred during propofol administration. Conclusions Propofol anesthesia did not significantly affect whole body protein synthesis and oxidation but caused a small, although significant, decrease in whole body protein breakdown, possibly mediated through the suppression of plasma cortisol concentration.