Ralph Lattermann

The Association of Preoperative Glycemic Control, Intraoperative Insulin Sensitivity, and Outcomes after Cardiac Surgery

CONTEXT The impairment of insulin sensitivity, a marker of surgical stress, is important for outcomes. OBJECTIVE The aim was to assess the association between the quality of preoperative glycemic control, intraoperative insulin sensitivity, and adverse events after cardiac surgery. DESIGN AND SETTING We conducted a prospective cohort study at a tertiary care hospital. SUBJECTS Nondiabetic and diabetic patients scheduled for elective cardiac surgery were included in the study. Based on their glycosylated hemoglobin A (HbA(1c)), diabetic patients were allocated to a group with good (HbA(1c) <6.5%) or poor (HbA(1c) >6.5%) glycemic control. INTERVENTION We used the hyperinsulinemic-normoglycemic clamp technique. MAIN OUTCOME MEASURES The primary outcome was insulin sensitivity measurement. Secondary outcomes were major complications within 30 d after surgery including mortality, myocardial failure, stroke, dialysis, and severe infection (severe sepsis, pneumonia, deep sternal wound infection). Other outcomes included minor infections, blood product transfusions, and the length of intensive care unit and hospital stay. RESULTS A total of 143 nondiabetic and 130 diabetic patients were studied. In diabetic patients, a negative correlation (r = -0.527; P < 0.001) was observed between HbA(1c) and intraoperative insulin sensitivity. Diabetic patients with poor glycemic control had a greater incidence of major complications (P = 0.010) and minor infections (P = 0.006). They received more blood products and spent more time in the intensive care unit (P = 0.030) and the hospital (P < 0.001) than nondiabetic patients. For each 1 mg x kg(-1) x min(-1) decrease in insulin sensitivity, the incidence of major complications increased (P = 0.004). CONCLUSIONS In diabetic patients, HbA(1c) levels predict insulin sensitivity during surgery and possibly outcome. Intraoperative insulin resistance is associated with an increased risk of complications, independent of the patients diabetic state.

Epidural blockade modifies perioperative glucose production without affecting protein catabolism

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 &mgr;mol·kg−1·min−1, P < 0.05; postoperative, epidural blockade 8.5 ± 1.8 vs. control 10.5 ± 1.2 &mgr;mol·kg−1·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.

Propofol/sufentanil anesthesia suppresses the metabolic and endocrine response during, not after, lower abdominal surgery.

We investigated the influence of propofol/sufentanil anesthesia on metabolic and endocrine responses during, and immediately after, lower abdominal surgery. Twenty otherwise healthy patients undergoing abdominal hysterectomy for benign myoma received either continuous infusions of propofol supplemented with sufentanil (0.01 &mgr;g · kg−1 · min−1, n = 10) or enflurane anesthesia (enflurane, n = 10). Plasma concentrations of glucose, lactate, free fatty acids, triglycerides, insulin, glucagon, cortisol, epinephrine, and norepinephrine were measured before, during, and 2 h after surgery. Pre- and postoperative endogenous glucose production (Ra glucose) was analyzed by an isotope dilution technique by using [6,6-2H2] glucose. Propofol/sufentanil anesthesia prevented the increase in plasma cortisol and catecholamine concentrations and attenuated the hyperglycemic response during surgery without showing any difference after the operation. Mediated through a higher glucagon/insulin quotient (propofol/sufentanil 15 ± 7 versus enflurane 8 ± 4 pg/&mgr;U, P < 0.05), the Ra glucose postoperatively increased more in the propofol/sufentanil than in the enflurane group (propofol/sufentanil 15.6 ± 2.0 versus enflurane 13.4 ± 2.2 &mgr;mol · kg−1 · min−1, P < 0.05). Implications The concept of stress-free anesthesia using propofol combined with sufentanil is valid only during surgery. The metabolic endocrine stress response 2 h after the operation is more pronounced than after inhaled anesthesia.

Understanding the mechanisms by which isoflurane modifies the hyperglycemic response to surgery.

We studied the effect of anesthesia on the kinetics of perioperative glucose metabolism by using stable isotope tracers. Twenty-three patients undergoing cystoprostatectomy were randomly assigned to receive epidural analgesia combined with general anesthesia (n = 8), fentanyl and midazolam anesthesia (n = 8), or inhaled anesthesia with isoflurane (n = 7). Whole-body glucose production and glucose clearance were measured before and during surgery. Glucose clearance significantly decreased during surgery independent of the type of anesthesia. Epidural analgesia caused a significant decrease in glucose production from 10.2 ± 0.4 to 9.0 ± 0.4 &mgr;mol · kg−1 · min−1 (P < 0.05), whereas the plasma glucose concentration was not altered (before surgery, 5.0 ± 0.2 mmol/L; during surgery, 5.2 ± 0.1 mmol/L). Glucose production did not significantly change during fentanyl/midazolam anesthesia (before surgery, 10.5 ± 0.5 &mgr;mol · kg−1 · min−1; during surgery, 10.1 ± 0.5 &mgr;mol · kg−1 · min−1), but plasma glucose concentration significantly increased from 4.8 ± 0.1 mmol/L to 5.3 ± 0.2 mmol/L during surgery (P < 0.05). Isoflurane anesthesia caused a significant increase in plasma glucose concentration (from 5.2 ± 0.1 mmol/L to 7.2 ± 0.5 mmol/L) and glucose production (from 10.8 ± 0.5 &mgr;mol · kg−1 · min−1 to 12.4 ± 1.0 &mgr;mol · kg−1 · min−1) (P < 0.05). Epidural analgesia prevented the hyperglycemic response to surgery by a decrease in glucose production. The increased glucose plasma concentration during fentanyl/midazolam anesthesia was caused by a decrease in whole-body glucose clearance. The hyperglycemic response observed during isoflurane anesthesia was a consequence of both impaired glucose clearance and increased glucose production.

Perioperative glucose infusion and the catabolic response to surgery: the effect of epidural block.

Although the nitrogen-sparing properties of epidural block and i.v. glucose on the days after surgical trauma have been well established, their metabolic effects during the acute phase of the stress response remain unclear. Therefore, in this study we investigated the effect of epidural block on glucose and protein kinetics during and immediately after surgery in patients receiving i.v. glucose at 2 mg x kg(-1) x min(-1). Sixteen patients undergoing colorectal surgery received either general anesthesia with epidural block with bupivacaine (EDA; n = 8) or general anesthesia alone (control; n = 8). Glucose and protein kinetics were determined during and 2 h after the operation by stable isotope tracers [6,6-(2)H(2)]glucose and L-[1-(13)C]leucine. Plasma concentrations of glucose, insulin, cortisol, and glucagon were also determined. Epidural block attenuated the perioperative increase in plasma glucose concentration (P < 0.05). The rate of appearance of glucose (R(a) glucose) and endogenous glucose production (EGP) were slower in the EDA group than in control subjects during (R(a) glucose, EDA 13.2 +/- 1.0 versus control 15.3 +/- 1.8 micromol x kg(-1) x min(-1); P < 0.05; EGP, EDA 1.2 +/- 1.2 versus control 3.8 +/- 1.7 micromol x kg(-1) x min(-1); P < 0.05) and after the operation (P > 0.05). Whereas protein breakdown and amino acid oxidation decreased in both groups (P < 0.05), whole-body protein synthesis remained unchanged. Insulin levels increased with both anesthetic techniques (P < 0.05). Intraoperative plasma concentrations of cortisol and glucagon were smaller in the EDA group (P < 0.05). The intraoperative suppression of EGP by exogenous glucose was more pronounced in the presence of epidural block. However, epidural block failed to exert a protein-sparing effect during the acute phase of the stress response in patients receiving i.v. glucose.

The Anabolic Effect of Epidural Blockade Requires Energy and Substrate 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 · kg−1 · min−1 glucose) and amino acids (0.02 ml · kg−1 · min−1 Travasol™ 10%, equivalent to approximately 2.9 g · kg−1 · 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-[1-13C]leucine and [6,6-2H2]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 &mgr;mol · kg−1 · h−1) and by 4% in the patient-controlled analgesia group (from 90.0 ± 27.1 to 92.9 ± 14.8 &mgr;mol · kg−1 · h−1;P = 0.054). Conclusions Epidural blockade accentuates the stimulating effect of parenteral alimentation on whole body protein synthesis.

Postoperative Protein Sparing With Epidural Analgesia and Hypocaloric Dextrose

Objective:We examined the hypothesis that epidural analgesia prevents the increase in amino acid oxidation after elective colorectal surgery in patients receiving hypocaloric infusion of dextrose. Summary Background Data:Increased oxidative protein loss after surgery may adversely affect postoperative outcome. We have previously shown that effective segmental pain relief by epidural analgesia improves postoperative substrate utilization, resulting in less protein catabolism. Methods:We randomly allocated 10 patients to receive general anesthesia combined with epidural analgesia using bupivacaine/fentanyl and 10 to receive general anesthesia followed by patient-controlled analgesia with intravenous morphine. All patients received a peripheral 72-hour infusion of dextrose 10% from the day before until the second day after surgery. The dextrose infusion rate was adjusted to provide 50% of the patients’ resting energy expenditure. The primary end point was whole-body leucine oxidation as determined by a stable isotope tracer technique (l-[1-13C]leucine). Results:In the intravenous analgesia group, leucine oxidation increased from 19 ± 4 to 28 ± 6 &mgr;mol kg−1 h−1 after surgery. Epidural analgesia prevented this increase of leucine oxidation (preoperative 21 ± 6 &mgr;mol kg−1 h−1, postoperative 21 ± 5 &mgr;mol kg−1 h−1). This difference was statistically significant (P = 0.01; analysis of variance for repeated measures). Conclusion:Perioperative epidural analgesia and hypocaloric dextrose infusion suppress the postoperative increase in amino acid oxidation, thereby saving more than 100 g of lean body mass per day.

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.

The anticatabolic effect of neuraxial blockade after hip surgery

Although the protein-sparing effect of neuraxial blockade after abdominal surgery is well established, its metabolic effect after operations on the lower extremities remains unclear. In this study, we tested the hypothesis that combined spinal and epidural blockade (CSE) inhibits amino acid oxidation after hip surgery. Sixteen patients undergoing hip replacement surgery received either general anesthesia followed by IV patient-controlled analgesia with piritramide (control; n = 8) or CSE using bupivacaine 0.5% for spinal anesthesia and ropivacaine 0.2% with 0.5 &mgr;g/mL of sufentanil for postoperative epidural analgesia (CSE; n = 8). Glucose and protein kinetics were assessed by stable isotope tracer technique ([6,6-2H2]glucose, L-[1-13C]leucine) on the day before and one day after surgery. Plasma concentrations of glucose, lactate, free fatty acids, cortisol, glucagon, and insulin were also determined. CSE prevented the increase in plasma glucose concentration during and immediately after the operation (60 min after skin incision: CSE 4.9 ± 0.7 versus control 6.2 ± 0.7 mmol/L; P < 0.05; postanesthesia care unit: CSE 5.0 ± 0.9 versus control 7.3 ± 1.1 mmol/L; P < 0.05). Intraoperative cortisol plasma concentrations were smaller in the CSE group than in the control group. One day after the operation, however, glucose plasma concentration, glucose production, and glucose clearance were comparable in both groups. CSE inhibited the postoperative increase in leucine oxidation rate (CSE 30 ± 12 versus control 43 ± 8 &mgr;mol·kg−1·h−1; P < 0.05). There were no differences between the groups in protein breakdown, whole body protein synthesis, and plasma concentrations of lactate, free fatty acids, insulin, and glucagon. In conclusion, CSE prevents hyperglycemia during hip surgery and inhibits protein catabolism thereafter.

Low dose clonidine premedication accentuates the hyperglycemic response to surgery.

PurposeTo investigate the influence of low dose clonidine premedication on perioperative glucose homeostasis.MethodsSixteen patients undergoing abdominal hysterectomy for benign uterine myoma were randomly assigned to receive eitheriv clonidine (1 μg·kg−1) 30 min before induction of general anesthesia (clonidine,n = 8) or saline (control,n = 8). Plasma concentrations of glucose, insulin, cortisol, epinephrine and norepinephrine were measured before, during and two hours after surgery. At the same time heart rate, mean arterial pressure and cardiac output were recorded.ResultsIn both groups, glucose concentrations significantly increased during and after surgery. Intraoperative glucose plasma concentration in the clonidine group was higher than in the control group (clonidine: 6.8 ± 0.6 mmol·L−1 vs control: 5.7 ± 0.8 mmol·L−1,P < 0.05). This was accompanied by a lower insulin plasma concentration (clonidine: 3.9 ± 1.9 μU·mL−1 vs control: 6.5 ± 2.8 μU·mL−1,P < 0.05). Heart rate, mean arterial pressure and cardiac output remained unchanged throughout the study period without any differences between the groups. While norepinephrine plasma concentrations increased in the control group only (P < 0.05), the plasma concentrations of epinephrine and cortisol increased in both groups (P < 0.05). Clonidine significantly attenuated the cortisol response as reflected by lower intra- and postoperative cortisol plasma concentrations than in the control group (P < 0.05).ConclusionPremedication with clonidine 1 μg·kg−1 accentuates the hyperglycemic response to lower abdominal surgery caused by the decrease in insulin plasma concentrations.RésuméObjectifExplorer l’influence d’une prémédication avec une faible dose de clonidine sur l’homéostase périopératoire du glucose.MéthodeSeize patientes devant subir une hystérectomie abdominale pour un myome utérin bénin ont été réparties au hasard et ont reçu de la clonidine iv (1 μg·kg−1) 30 min avant l’induction de l’anesthésie générale (groupe clonidine,n = 8) ou une solution salée (groupe témoin,n = 8 ). Les concentrations plasmatiques de glucose, d’insuline, de cortisol, d’épinéphrine et de norépinéphrine ont été mesurées pendant l’intervention et deux heures après. Au même moment, la fréquence cardiaque, la tension artérielle moyenne et le débit cardiaque ont été enregistrés.RésultatsDans les deux groupes, les concentrations de glucose ont significativement augmenté pendant et après l’opération. La concentration plasmatique peropératoire dans le groupe clonidine a été plus élevée que celle du groupe témoin (clonidine : 6,8 ± 0,6 mmol·L−1 vs témoin : 5,7 ± 0,8 mmol·L−1,P < 0,05). Ce changement s’est accompagné d’une concentration plus faible d’insuline plasmatique (clonidine : 3,9 ± 1,9 μU·mL−1 vs témoin : 6,5 ± 2,8 μU·mL−1,P < 0,05). La fréquence cardiaque, la tension artérielle moyenne et le débit cardiaque sont demeurés inchangés tout au long de l’étude et ce, sans différence intergroupe. Les concentrations plasmatiques de norépinéphrine ont augmenté chez les témoins seulement (P < 0,05) alors que celles de l’épinéphrine et du cortisol ont augmenté dans les deux groupes (P < 0,05). La clonidine a diminué de façon significative la réponse du cortisol comme l’indiquent les concentrations plasmatiques peropératoires et postopératoires plus faibles que dans le groupe témoin (P < 0,05).ConclusionLa prémédication avec 1 μg·kg−1 de clonidine augmente la réaction hyperglycémique à une hystérectomie abdominale causée par la baisse des concentrations plasmatiques d’insuline.