Perioperative catabolism.

PURPOSE: This article reviews the pathophysiology, clinical relevance, and therapy of the catabolic response to surgical stress. PRINCIPLE FINDINGS: The key clinical features of perioperative catabolism are hyperglycemia and loss of body protein, both metabolic consequences of impaired insulin function. Muscle weakness and (even moderate) increases in perioperative blood glucose are associated with morbidity after major surgery. Although the optimal glucose concentration for improving clinical outcomes is unknown, most medical associations recommend treatment of random blood glucose > 10 mmol·L(-1). Neuraxial anesthesia blunts the neuroendocrine stress response and enhances the anabolic effects of nutrition. There is evidence to suggest that the avoidance of preoperative fasting prevents insulin resistance and accelerates recovery after major abdominal surgery. CONCLUSIONS: Current anticatabolic therapeutic strategies include glycemic control and perioperative nutrition in combination with optimal pain control and the avoidance of preoperative starvation. All these elements are part of Enhanced Recovery After Surgery (ERAS) programs.

Feasibility and precision of subcutaneous continuous glucose monitoring in patients undergoing CABG surgery.

OBJECTIVES: To evaluate if subcutaneous continuous glucose monitoring (sCGM) is feasible in cardiac surgery and if reliable glucose values are reported under hypothermic extracorporeal circulation. DESIGN: Feasibility trial. SETTING: University hospital. PARTICIPANTS: Ten consecutive patients undergoing coronary artery bypass grafting. INTERVENTIONS: Prior to surgery, during hypothermic extracorporeal bypass, and 48 hours postoperatively, arterial blood glucose samples were compared with sCGM every 30 minutes. Statistical analysis utilized Clarke's error grid and Bland-Altman plot. MEASUREMENTS AND MAIN RESULTS: Three hundred fifty-one pairs of glucose measurements were recorded including 59 during hypothermic extracorporeal circulation. Agreement between these measurements was acceptable, with a regression line slope of 0.88 and an offset of 17.4 (p = 0.87). Error grid analysis indicated a safe margin of 99.1% within zone A (no clinical action needed) or zone B (values would not lead to inappropriate treatment). Only 0.9% were plotted in zone D (potentially dangerous failure). Measurements during hypothermic extracorporeal circulation were comparable. Correlation coefficient was 0.760. The offset regression line was more pronounced (50.9) with a flatter slope (0.640). Within the error grid all plot values were in zone A or B. CONCLUSIONS: sCGM compared with arterial blood gas glucose monitoring under hypothermic extracorporeal circulation appears to be feasible and reliable.

The anabolic effect of perioperative nutrition depends on the patient's catabolic state before surgery.

OBJECTIVE: We tested the hypothesis that the anabolic effect of hypocaloric, isonitrogenous nutrition in patients undergoing colorectal surgery depends on the patient's preoperative catabolic state. BACKGROUND: Although there is evidence to suggest that total parenteral nutrition more effectively spares protein in depleted than in nondepleted cancer patients, the influence of preoperative catabolism on the anabolic effects of hypocaloric nutrition in patients undergoing elective surgery is unknown. METHODS: Seventeen patients undergoing colorectal surgery received intravenous infusion of glucose with amino acids. Feeding was administered over 72 hours, from 24 hours before until 48 hours after surgery. Glucose provided 50% of the patient's measured resting energy expenditure. Amino acids provided 20% of the resting energy expenditure. Whole-body leucine balance (difference between the incorporation of leucine into protein = protein synthesis and endogenous leucine release = proteolysis) was determined using L-[1-(13)C]leucine kinetics before and 2 days after surgery. We analyzed the association between the postoperative increase in leucine balance and the following factors: preoperative leucine balance, protein breakdown, weight loss, oxygen consumption, circulating concentrations of glucose, free fatty acids, insulin, glucagon, cortisol, albumin, age, duration of surgery, and blood loss. RESULTS: Of 6 potentially relevant variables, 4 (weight loss, protein breakdown, albumin, and cortisol) were removed because they were not significant during the stepwise linear regression procedure. Leucine balance and age were the remaining 2 factors that remained with the final regression model: Δleucine balance = 19.1 - (0.20 × age [years]) - (0.58) × leucine balance(preOP)). CONCLUSIONS: We demonstrate a significant association between the degree of preoperative catabolism, the patient's age, and the anabolic effect of hypocaloric nutrition (ClinicalTrials.gov registration ID: NCT01414946).

High-dose insulin administration improves left ventricular function after coronary artery bypass graft surgery.

OBJECTIVE: To test the hypothesis that the intravenous administration of high doses of insulin while maintaining normoglycemia (GIN therapy) improves myocardial function after coronary artery bypass graft (CABG) surgery. DESIGN: A prospective, randomized clinical trial. SETTING: A university hospital. PARTICIPANTS: Forty patients undergoing elective CABG surgery. INTERVENTIONS: Patients were randomized to the GIN or control group. Applying the principles of the hyperinsulinemic-normoglycemic clamp technique in the GIN group, insulin was administered at 5 mU/kg/min during surgery. Glucose 20% was infused at a rate adjusted to maintain blood glucose (BG) between 4.0 and 6.0 mmol/L. Patients in the control group received insulin on a sliding scale, also aiming at normoglycemia. MEASUREMENTS AND MAIN RESULTS: Systemic hemodynamic parameters included heart rate, mean arterial pressure, pulmonary artery wedge pressure, vascular resistance index, and cardiac index (CI). Left ventricular function was assessed by transesophageal echocardiography using the myocardial performance index (MPI) as a parameter of global left ventricular function, the fractional area change (FAC) for systolic function, and flow propagation velocity for diastolic function before and after surgery. All patients receiving GIN therapy were hyperinsulinemic (3,474 ± 1,204 pmol/L) and normoglycemic, showing a lower mean BG concentration (4.9 ± 0.5 mmol/L) than patients in the control group (8.2 ± 2.0 mmol/L). Patients receiving GIN therapy had an increased CI after surgery compared with the control group (p = 0.005). The GIN therapy was associated with improved MPI and FAC values when compared with standard care. Also, there was no difference in the parameters indicating left ventricular diastolic function. CONCLUSIONS: Intraoperative GIN therapy improves global and systolic left ventricular function after CABG surgery.

Randomised controlled trial of the effect of oral premedication with dexamethasone on hyperglycaemic response to abdominal hysterectomy.

BACKGROUND: This study was performed to evaluate the metabolic effects of a single oral dose of 8 mg dexamethasone in women undergoing hysterectomy. METHODS: Ninety non-diabetic women undergoing abdominal hysterectomy were randomised to receive 8 mg dexamethasone or placebo 2 h before surgery. Patients' perioperative care was standardised (fasting from midnight before surgery, balanced anaesthesia using propofol, fentanyl, remifentanil, cisatracurium, desflurane in oxygen/air). At five defined time points after drug administration (approximately 2, 4, 6, 10 and 14 h), blood samples were drawn under fasting conditions to measure blood glucose and free (non-esterified) fatty acids (NEFA). Data were analysed using analysis of variance for repeated measures. RESULTS: Data of 82 patients (dexamethasone: 44 and placebo: 38) were eligible for analysis. There was a statistically significant increase in blood glucose in both groups (P = 0.008). This increase was more pronounced in patients receiving dexamethasone (interaction term: P = 0.02) with maximum values at 6 h after surgery (or approximately 10 h after dexamethasone administration). There were 36 patients (placebo: 9 = 24% and dexamethasone: 27 = 61%) presenting with elevated glucose concentrations (>7 mmol l⁻¹) and 11 patients (placebo: 2 = 5% and dexamethasone: 9 = 20%) with hyperglycaemia (>8.5 mmol l⁻¹). There were no statistically significant changes in the plasma concentrations of NEFA during the perioperative period. CONCLUSION: Amounts of dexamethasone frequently used for prophylaxis of post-operative nausea and vomiting can cause short-lasting hyperglycaemia in the post-operative period, but no relevant alterations in fat metabolism. Thus, the benefits of administering corticosteroids should be weighed against the potential side-effects of short-lasting hyperglycaemia.

Perioperative glucose and insulin administration while maintaining normoglycemia (GIN therapy) in patients undergoing major liver resection.

BACKGROUND: Although hyperglycemia is a well-recognized risk factor in the context of cardiac surgery, the relevance of perioperative glycemic control for patients undergoing major noncardiac operations has received little attention. We designed this study to assess the hyperglycemic response to liver resection, and to test the hypothesis that perioperative glucose and insulin administration while maintaining normoglycemia (GIN therapy) provides glycemic control superior to that achieved by the conventional use of insulin. METHODS: Patients were randomly assigned to GIN therapy or standard therapy (control group). In the GIN therapy group, insulin was administered at 2 mU . kg(-1) . min(-1) during surgery. At the end of surgery, the insulin infusion was decreased to 1 mU . kg(-1) . min(-1) and continued for 24 hours. Dextrose 20% was infused at a rate adjusted to maintain blood glucose within the target range of 3.5 to 6.1 mmol . L(-1) (63-110 mg . dL(-1)). Patients in the standard therapy group received a conventional insulin sliding scale during and after surgery. The mean and SD of blood glucose as well as the percentage of blood glucose values within the target range were calculated. To evaluate intrasubject variability, the coefficient of variability (CV) of blood glucose was calculated for each patient. Episodes of severe hypoglycemia, i.e., blood glucose <2.2 mmol . L(-1) (40 mg . dL(-1)), were recorded. The primary outcome was the proportion of normoglycemic measurements. RESULTS: We studied 52 patients. The mean blood glucose value in patients receiving GIN therapy always remained within the target range. The blood glucose levels were lower in the GIN therapy group than in the standard therapy group (during surgery, P < 0.01; after surgery, P < 0.001). In nondiabetic patients receiving GIN therapy (n = 19), target glycemia was achieved in 90.1% of the blood glucose measurements during surgery and in 77.8% of the measurements after surgery. In diabetic patients receiving GIN therapy (n = 7), target glycemia was achieved in 81.2% of the blood glucose measurements during surgery and in 70.5% of the measurements after surgery. In nondiabetic patients receiving standard therapy (n = 19), target glycemia was achieved in 37.4% of the blood glucose measurements during surgery and in 18.3% of the measurements after surgery. In diabetic patients receiving standard therapy (n = 7), target glycemia was achieved in 4.3% of the blood glucose measurements during surgery and in 2.9% of the measurements after surgery. The SD and CV of blood glucose were smaller in the GIN therapy group than in the standard therapy group, especially in nondiabetic patients after surgery (SD, P < 0.001; CV, P = 0.027). No patients receiving GIN therapy experienced severe hypoglycemia during surgery. One patient receiving GIN therapy experienced hypoglycemia in the intensive care unit after surgery without neurological sequelae. CONCLUSIONS: GIN therapy effectively provides normoglycemia in patients undergoing liver resection (clinicaltrials.gov, NCT00774098).

Anticatabolic effects of avoiding preoperative fasting by intravenous hypocaloric nutrition: a randomized clinical trial.

OBJECTIVE: We tested the hypothesis that the avoidance of preoperative fasting by hypocaloric nutrition attenuates protein catabolism after surgery. SUMMARY BACKGROUND DATA: Prolonged fasting before major abdominal procedures has been demonstrated to accentuate the catabolic response to surgery. METHODS: Twenty-two patients undergoing colorectal cancer surgery were randomly assigned to receive glucose and amino acids intravenously starting either 20 hours before the operation or with surgical skin incision. Nutrition was administered until the second postoperative day, with glucose providing 50% and amino acids 20% of each patient's measured resting energy expenditure. Whole body leucine and glucose kinetics were assessed by L-[1-(13)C]leucine and [6,6-(2)H(2)]glucose before and after surgery. Fractional synthesis rates of muscle protein, albumin, and fibrinogen were determined using primed continuous infusions of L-[(2)H(5)]phenylalanine postoperatively, whereas the expression of mRNA of proteolytic genes in muscle (Mafbx/atrogin-1, ubiquitin, Murf 1) was determined by quantitative RT-PCR. Circulating concentrations of glucose, lactate, amino acids, insulin, glucagon, and cortisol were also measured. This study has been registered at ClinicalTrials.gov (Identifier: NCT00614133). RESULTS: Preoperative feeding inhibited endogenous protein breakdown (fasting group: 128 +/- 23 micromol . kg(-1) . h(-1); nutrition group: 96 +/- 22 micromol . kg(-1) . h(-1); P = 0.02) and blunted the increase in amino acid oxidation (fasting group: 27 +/- 5 micromol . kg(-1) . h(-1); nutrition group: 20 +/- 5 micromol . kg(-1) . h(-1); P = 0.03), resulting in positive whole-body protein balance after surgery (fasting group: -10 +/- 4 micromol . kg(-1) . h(-1); nutrition group: 1 +/- 3 micromol . kg(-1) . h(-1); P < 0.001). This anabolic response was associated with decreased muscle proteolytic gene expression and increased hepatic albumin synthesis. Total plasma protein, fibrinogen, and muscle protein synthesis were not affected. CONCLUSIONS: Hypocaloric nutrition decreases protein catabolism, with a contribution from the ubiquitin pathway in muscle, and stimulates albumin synthesis after colorectal surgery if initiated 1 day before the operation.

Hepatic protection by perioperative metabolic support?

OBJECTIVE: We report the case of a 63-y-old woman undergoing left hepatectomy for hilar cholangiocarcinoma who was at high risk of postoperative liver failure due to an atrophic right liver lobe. She participated in a randomized clinical trial investigating the effect of perioperative glucose infusion on hepatic function after major liver resection. METHODS: Intravenous glucose was initiated the night before the operation at 2 mg x kg(-1) x min(-1). During and after the operation, glucose was administered with a continuous insulin infusion until the first postoperative day. Postoperative liver function was assessed by the score proposed by Schindl, evaluating total serum bilirubin and plasma lactate concentrations, prothrombin time, and the grade of encephalopathy. RESULTS: The patient's liver dysfunction was classified as "mild" on postoperative day 1 and as "none" on postoperative day 2. Postoperative liver function scores were better than those observed in a control group of patients who underwent hepatic resection of similar magnitude without glucose/insulin therapy. CONCLUSION: Perioperative glucose/insulin administration was associated with a surprisingly small deterioration of liver function after left lobe liver resection in the presence of an atrophic right lobe. A randomized clinical trial will have to determine whether glucose/insulin therapy can improve hepatic function after major liver resections.

A randomized controlled trial of the anticatabolic effect of epidural analgesia and hypocaloric glucose.

BACKGROUND AND OBJECTIVES: The goal of the present study was to investigate whether epidural analgesia exerts a protein-sparing effect after colorectal surgery in the presence of hypocaloric glucose supply initiated with surgical skin incision. METHODS: We randomly allocated 10 patients to receive general anesthesia combined with epidural anesthesia with bupivacaine, followed by epidural analgesia using bupivacaine/fentanyl, and 10 patients to receive general anesthesia, followed by patient-controlled analgesia with intravenous morphine. All patients received a 48-hour infusion of glucose 10% from surgical skin incision until the second day after surgery. The glucose infusion rate provided 50% of the patient's resting energy expenditure. Kinetics of protein and glucose metabolism were assessed by a stable-isotope tracer technique (L-[1-(13)C]leucine and [6,6-(2)H(2)]glucose). RESULTS: The rate of appearance of leucine increased in the intravenous-analgesia group (112 +/- 29 to 130 +/- 25 micromol/kg/h) 2 days after surgery, and this increase was more pronounced than in the epidural analgesia group (preoperative 120 +/- 24, postoperative 123 +/- 22 micromol/kg/h, P < .05). Leucine oxidation rate increased in the intravenous analgesia group from 17 +/- 8 to 23 +/- 8 micromol/kg/h and in the epidural group from 17 +/- 6 to 19 +/- 7 micromol/kg/h without the difference between the groups reaching statistical significance (P = .067). Nonoxidative leucine disposal remained unaltered in both groups. No differences in glucose metabolism were seen between the groups. CONCLUSIONS: Epidural analgesia inhibits the increase in whole-body protein breakdown in patients receiving perioperative hypocaloric glucose infusion initiated with surgical skin incision. However, oxidative protein loss, protein synthesis, and glucose metabolism are not affected by epidural analgesia.

Intraoperative protein sparing with glucose.

We examined the hypothesis that glucose infusion inhibits amino acid oxidation during colorectal surgery. We randomly allocated 14 patients to receive intravenous glucose at 2 mg x kg(-1) x min(-1) (glucose group) starting with the surgical incision or an equivalent amount of normal saline 0.9% (control group). The primary endpoint was whole body leucine oxidation; secondary endpoints were leucine rate of appearance and nonoxidative leucine disposal as determined by a stable isotope tracer technique (L-[1-(13)C]leucine). Circulating concentrations of glucose, lactate, insulin, glucagon, and cortisol were measured before and after 2 h of surgery. Leucine rate of appearance, an estimate of protein breakdown, and nonoxidative leucine disposal, an estimate of protein synthesis, decreased in both groups during surgery (P < 0.05). Leucine oxidation intraoperatively decreased from 13 +/- 3 to 4 +/- 3 micromol x kg(-1) x h(-1) in the glucose group (P < 0.05 vs. control group) whereas it remained unchanged in the control group. Hyperglycemia during surgery was more pronounced in patients receiving glucose (9.7 +/- 0.5 mmol/l, P < 0.05 vs. control group) than in patients receiving normal saline (7.1 +/- 1.0 mmol/l). The administration of glucose caused an increase in the circulating concentration of insulin (P < 0.05) resulting in a lower glucagon/insulin quotient than in the control group (P < 0.05). Intraoperative plasma cortisol concentrations increased in both groups (P < 0.05), whereas plasma concentrations of lactate and glucagon did not change. The provision of small amounts of glucose was associated with a decrease in amino acid oxidation during colorectal surgery.

Integrated analysis of glucose, lipid, and urea metabolism in patients with bladder cancer. Impact of tumor stage.

OBJECTIVE: The aim of the study was to characterize the metabolic changes in non-weight-losing patients with cancer of the bladder and to investigate the effect of tumor stage. The kinetics of glucose, glycerol, and urea metabolism were assessed in 22 weight-stable patients with non-metastatic bladder cancer (tumor stage p T2, n = 14) and 10 patients with benign uterine myoma (controls). METHODS: The kinetics of glucose, glycerol, and urea metabolism were assessed by [6,6-(2)H(2)]glucose, [1,1,2,3,3-(2)H(5)]glycerol, and [(15)N(2)]urea. Plasma concentrations of glucose, glycerol, urea, lactate, free fatty acids, insulin, glucagon, cortisol, epinephrine, and norepinephrine also were determined. RESULTS: Plasma concentrations of glucose, urea, and insulin were higher in cancer patients than in controls (P < 0.05). Whereas glucose production was similar in both groups, glucose clearance was lower in patients with bladder cancer (P < 0.05). Glycerol turnover rate was comparable between groups. Whole-body urea synthesis rate was higher in the cancer group than in the control group (P < 0.05), but there was no difference in urea synthesis when calculated per kilogram of fat-free body mass. Plasma concentrations of glycerol, lactate, free fatty acids, glucagon, cortisol, epinephrine, and norepinephrine were similar in both groups. There was no difference in any parameter between patients with an early tumor stage (p < T2) and patients with a later tumor stage (p > T2). CONCLUSION: Patients with bladder cancer had a lower rate of glucose clearance than did control subjects. Lipid metabolism was not affected, whereas urea synthesis rate was elevated in cancer patients. However, when expressed per kilogram of fat-free body mass, no difference in protein breakdown could be observed. The tumor stage had no effect on glucose, lipid, or protein metabolism.

Effect of i.v. dextrose administration on glucose metabolism during surgery.

BACKGROUND: The inhibitory influence of exogenous dextrose on glucose production has been shown to be less pronounced during injury and sepsis. This protocol was designed to investigate the effect of i.v. hypocaloric dextrose on glucose metabolism during elective abdominal surgery. METHODS: Fourteen patients with rectal cancer were studied under fasting conditions and toward the end of a 3-hour infusion of dextrose (2 mg.kg-1 per minute) either in absence (control group, n = 7) or presence of colonic surgery (surgery group, n = 7). Endogenous glucose production was determined by using primed continuous infusions of [6,6-2H2]glucose before and during dextrose administration. We also measured the plasma concentrations of glucose, lactate, cortisol, glucagon, and insulin. RESULTS: The administration of dextrose decreased the endogenous glucose production in all patients (p < .05). This decrease was less pronounced during surgery (p < .05). Plasma glucose concentration increased during dextrose infusion in both groups (p < .05), with higher values in the surgery group than in the control group (p < .05). Plasma concentrations of lactate and glucagon remained unaltered. Dextrose infusion increased the plasma insulin concentrations to the same extent in both groups (p < .05). Cortisol plasma levels increased only in the surgery group (p < .05). CONCLUSIONS: Surgical stress blunts the inhibitory effect of i.v. dextrose on endogenous glucose production.

Epidural blockade suppresses lipolysis during major abdominal surgery.

BACKGROUND AND OBJECTIVES: The purpose of the study was to investigate the effect of thoracic epidural administration of local anesthetic, i.e., epidural block on perioperative lipolysis. METHODS: Fourteen patients undergoing elective colorectal surgery were randomly assigned to receive either general anesthesia combined with epidural block (EDA, n = 7) or general anesthesia alone (control, n = 7). The rates of glycerol appearance (R(a) glycerol), i.e., lipolysis, were assessed by the stable isotope tracer [1,1,2,3,3-(2)H(5)]glycerol before, during, and 2 hours after the operation. Plasma concentrations of metabolic substrates (glycerol, free fatty acids [FFA], lactate) and hormones (insulin, glucagon, cortisol) were also determined. RESULTS: In the EDA group, R(a) glycerol decreased to lower intra- and postoperative values than in the control group (P <.05). Perioperative plasma concentrations of glycerol, FFA, lactate, and insulin remained unaltered with both anesthetic techniques. Intraoperative plasma glucagon and cortisol concentrations were lower in the EDA group than in the control group (P <.05). CONCLUSIONS: Epidural block suppresses lipolysis during and 2 hours after major abdominal surgery without affecting plasma glycerol or FFA concentrations.

Insulin preconditioning elevates p-Akt and cardiac contractility after reperfusion in the isolated ischemic rat heart.

Insulin induces cardioprotection partly via an antiapoptotic effect. However, the optimal timing of insulin administration for the best quality cardioprotection remains unclear. We tested the hypothesis that insulin administered prior to ischemia provides better cardioprotection than insulin administration after ischemia. Isolated rat hearts were prepared using Langendorff method and divided into three groups. The Pre-Ins group (Pre-Ins) received 0.5 U/L insulin prior to 15 min no-flow ischemia for 20 min followed by 20 min of reperfusion. The Post-Ins group (Post-Ins) received 0.5 U/L insulin during the reperfusion period only. The control group (Control) was perfused with KH buffer throughout. The maximum of left ventricular derivative of pressure development (dP/dt(max)) was recorded continuously. Measurements of TNF-α and p-Akt in each time point were assayed by ELISA. After reperfusion, dP/dt(max) in Pre-Ins was elevated, compared with Post-Ins at 10 minutes after reperfusion and Control at all-time points. TNF-α levels at 5 minutes after reperfusion in the Pre-Ins were lower than the others. After 5 minutes of reperfusion, p-Akt was elevated in Pre-Ins compared with the other groups. Insulin administration prior to ischemia provides better cardioprotection than insulin administration only at reperfusion. TNF-α suppression is possibly mediated via p-Akt leading to a reduction in contractile myocardial dysfunction.

Glucose and insulin administration while maintaining normoglycemia inhibits whole body protein breakdown and synthesis after cardiac surgery.

We investigated the effect of insulin administered as part of a hyperinsulinemic-normoglycemic clamp on protein metabolism after coronary artery bypass grafting (CABG) surgery. Eighteen patients were studied, with nine patients in the control group receiving standard metabolic care and nine patients receiving insulin (5 mU·kg(-1)·min(-1)). Whole body glucose production, protein breakdown, synthesis, and oxidation were determined using stable isotope tracer kinetics (l-[1-(13)C]leucine, [6,6-(2)H2]glucose) before and 6 h after the procedure. Plasma amino acids, cortisol, and lactate were also measured. Endogenous glucose production (preoperatively 10.0 ± 1.6, postoperatively 3.7 ± 2.5 µmol·kg(-1)·min(-1); P = 0.0001), protein breakdown (preoperatively 105.3 ± 9.8, postoperatively 85.2 ± 9.2 mmol·kg(-1)·h(-1); P = 0.0005) and synthesis (preoperatively 88.7 ± 8.7, postoperatively 72.4 ± 8.4 mmol·kg(-1)·h(-1); P = 0.0005) decreased in the presence of hyperinsulinemia, whereas both parameters remained unchanged in the control group. A positive correlation between endogenous glucose production and protein breakdown was observed in the insulin group (r(2) = 0.385). Whole body protein oxidation and balance decreased after surgery in patients receiving insulin without reaching statistical significance. In the insulin group the plasma concentrations of 13 of 20 essential and nonessential amino acids decreased to a significantly greater extent than in the control group. In summary, supraphysiological hyperinsulinemia, while maintaining normoglycemia, decreased whole body protein breakdown and synthesis in patients undergoing CABG surgery. However, net protein balance remained negative.

Albumin synthesis in surgical patients.

Albumin plasma concentrations are being used as indicators of nutritional status and hepatic function based on the assumption that plasma levels reflect the rate of albumin synthesis. However, it has been shown that albumin levels are not reliable markers of albumin synthesis under a variety of clinical conditions including inflammation, malnutrition, diabetes mellitus, liver disease, and surgical tissue trauma. To date, only a few studies have measured albumin synthesis in surgical and critically ill patients. This review summarizes the findings from these studies, which used different tracer methodology in various surgical or critically ill patient populations. The results indicate that the fractional synthesis rate of albumin appears to decrease during surgery, followed by an increase during the postoperative phase. In the early postoperative phase, albumin fractional synthesis rate can be stimulated by perioperative nutrition, if enough amino acids are being provided and if nutrition is being initiated before the operation. The physiologic meaning of albumin synthesis after surgery, however, still needs to be further clarified.

Statin intake is associated with decreased insulin sensitivity during cardiac surgery.

OBJECTIVE: Surgical trauma impairs intraoperative insulin sensitivity and is associated with postoperative adverse events. Recently, preprocedural statin therapy is recommended for patients with coronary artery disease. However, statin therapy is reported to increase insulin resistance and the risk of new-onset diabetes. Thus, we investigated the association between preoperative statin therapy and intraoperative insulin sensitivity in nondiabetic, dyslipidemic patients undergoing coronary artery bypass grafting. RESEARCH DESIGN AND METHODS: In this prospective, nonrandomized trial, patients taking lipophilic statins were assigned to the statin group and hypercholesterolemic patients not receiving any statins were allocated to the control group. Insulin sensitivity was assessed by the hyperinsulinemic-normoglycemic clamp technique during surgery. The mean, SD of blood glucose, and the coefficient of variation (CV) after surgery were calculated for each patient. The association between statin use and intraoperative insulin sensitivity was tested by multiple regression analysis. RESULTS: We studied 120 patients. In both groups, insulin sensitivity gradually decreased during surgery with values being on average ∼20% lower in the statin than in the control group. In the statin group, the mean blood glucose in the intensive care unit was higher than in the control group (153 ± 20 vs. 140 ± 20 mg/dL; P < 0.001). The oscillation of blood glucose was larger in the statin group (SD, P < 0.001; CV, P = 0.001). Multiple regression analysis showed that statin use was independently associated with intraoperative insulin sensitivity (ß = -0.16; P = 0.03). CONCLUSIONS: Preoperative use of lipophilic statins is associated with increased insulin resistance during cardiac surgery in nondiabetic, dyslipidemic patients.

High-dose insulin therapy reduces postoperative liver dysfunction and complications in liver resection patients through reduced apoptosis and altered inflammation.

CONTEXT: An exaggerated inflammatory response in patients undergoing major liver resection coupled with poor nutrition diminishes liver regenerative capacity and increases the risk of postoperative complications. OBJECTIVES: Our objective was to evaluate the biological context leading to better clinical outcomes in patients undergoing liver resection coupled with hyperinsulinemic-normoglycemic clamp vs. standard care (insulin sliding care). DESIGN AND SETTING: This study was a fundamental research analysis of a patient subset from a randomized-controlled study at the McGill University Health Center. PATIENTS AND INTERVENTION: Thirty consenting patients participating in a randomized clinical trial for liver resection received either hyperinsulinemic-normoglycemic clamp technique with 24-h preoperative carbohydrate load (intervention) or standard glucose control through insulin sliding scale treatment (control). MAIN OUTCOME MEASURES: Liver biopsies and plasma samples were taken at various time points before and after surgery. Primary measures included mRNA quantitation for genes related to insulin signaling, inflammation, and proliferation; proinflammatory cytokines at various time points; and liver function markers. These measurements were associated with clinical outcomes. RESULTS: The hyperinsulinemic-normoglycemic clamp technique reduced postoperative liver dysfunction, infections, and complications. Markers of energy stores indicated higher substrate availability. Cytokine expression pattern was altered (TNF-α, IL-8, monocyte chemoattractant protein-1, IL-6, IL-10, and C-reactive protein). Apoptosis was markedly reduced, whereas the complement system was unaltered. CONCLUSION: The hyperinsulinemic-normoglycemic clamp technique reduced postoperative negative outcomes by suppressing apoptosis. This phenomenon appears to be linked with higher substrate availability and altered cytokine secretion profile and may provide a long-term benefit of this therapy on liver resection patients.

Glucose and insulin administration while maintaining normoglycemia during cardiac surgery using a computer-assisted algorithm.

BACKGROUND: applying the principles of the hyperinsulinemic-normoglycemic clamp technique we have introduced glucose and insulin administration while maintaining normoglycemia (GIN therapy) to surgical patients. The objective of this study was to evaluate a novel computer software (GIN Computer Software [GINCS]) program using an algorithm based on the original clamp equation and modified for its use during cardiac surgery. METHODS: thirty-six patients without diabetes undergoing elective cardiac surgery were randomly assigned to manually controlled or computer-guided GIN therapy. In both groups insulin was administered at 5 mU/kg/min during surgery. Simultaneously, 20% dextrose was infused at a rate adjusted to maintain blood glucose (BG) between 4.0 and 6.0 mmol/L. The adjustments were made either following an algorithm based on our previous GIN experience or suggestions made by the software program. The primary outcome was the achievement of target glycemia. RESULTS: normoglycemia was achieved in both groups as reflected by mean BG concentrations of 5.0 ± 0.5 mmol/L and 5.1 ± 0.2 mmol/L. Mean sampling intervals were longer in the GINCS group than in the manual group (21.5 ± 1.9 vs. 14.2 ± 2.2 min, P < 0.001). The GINCS therapy was associated with a greater percentage of BG measurements within target (manual group, before cardiopulmonary bypass [CPB] 79.7%, during CPB 68.1%, and after CPB 69.1%; GINCS group, before CPB 94.1%, during CPB 92.4%, and after CPB 97.7%; P < 0.001). No hypoglycemia was observed. CONCLUSIONS: the use of a computer-guided GIN protocol in patients without diabetes undergoing open heart surgery provided excellent and safe glycemic control.

Cardioprotective effects of glucose and insulin administration while maintaining normoglycemia (GIN therapy) in patients undergoing coronary artery bypass grafting.

CONTEXT: Coronary artery bypass grafting (CABG) is complicated by ischemia-reperfusion injury jeopardizing myocyte survival. OBJECTIVE: The aim of the study was to investigate whether glucose and insulin administration, while maintaining normoglycemia (GIN therapy) using a hyperinsulinemic-normoglycemic clamp technique, is cardioprotective in patients undergoing CABG. DESIGN AND SETTING: We conducted a randomized controlled trial at a tertiary care university teaching hospital. PATIENTS: We studied 99 patients undergoing elective CABG. INTERVENTION: Patients were randomly assigned to receive either GIN from the beginning of surgery until 24 h after CABG (GIN, n = 49) or standard metabolic care (control, n = 50). MAIN OUTCOME MEASURES: We measured plasma concentrations of cardiac troponin I and free fatty acids, cardiac function as assessed by transesophageal echocardiography, glycogen content, glycogen synthase activity, and the expression of AMP-activated protein kinase (AMPK) and protein kinase B (AKT) in cardiomyocytes. RESULTS: Patients receiving GIN therapy showed an attenuated release of cardiac troponin I (P < 0.05) and improved myocardial function (P < 0.05). Systemic free fatty acid concentrations were suppressed (P < 0.05), whereas intracellular glycogen content and glycogen synthase activity were not altered. The AMPK activity remained unchanged during ischemia in the GIN group, whereas it increased in the control group (P < 0.05). Enhanced AKT phosphorylation before ischemia was observed (P < 0.05) in the presence of GIN. However, there was no evidence for AKT-dependent AMPK inhibition. CONCLUSIONS: GIN therapy protects the myocardium and inhibits ischemia-induced AMPK activation.