Implication of Major Adverse Postoperative Events and Myocardial Injury on Disability and Survival: A Planned Subanalysis of the ENIGMA-II Trial.

BACKGROUND: Globally, >300 million patients have surgery annually, and ≤20% experience adverse postoperative events. We studied the impact of both cardiac and noncardiac adverse events on 1-year disability-free survival after noncardiac surgery. METHODS: We used the study cohort from the Evaluation of Nitrous oxide in Gas Mixture of Anesthesia (ENIGMA-II) trial, an international randomized trial of 6992 noncardiac surgical patients. All were ≥45 years of age and had moderate to high cardiac risk. The primary outcome was mortality within 1 postoperative year. We defined 4 separate types of postoperative adverse events. Major adverse cardiac events (MACEs) included myocardial infarction (MI), cardiac arrest, and myocardial revascularization with or without troponin elevation. MI was defined using the third Universal Definition and was blindly adjudicated. A second cohort consisted of patients with isolated troponin increases who did not meet the definition for MI. We also considered a cohort of patients who experienced major adverse postoperative events (MAPEs), including unplanned admission to intensive care, prolonged mechanical ventilation, wound infection, pulmonary embolism, and stroke. From this cohort, we identified a group without troponin elevation and another with troponin elevation that was not judged to be an MI. Multivariable Cox proportional hazard models for death at 1 year and assessments of proportionality of hazard functions were performed and expressed as an adjusted hazard ratio (aHR) and 95% confidence intervals (CIs). RESULTS: MACEs were observed in 469 patients, and another 754 patients had isolated troponin increases. MAPEs were observed in 631 patients. Compared with control patients, patients with a MACE were at increased risk of mortality (aHR, 3.36 [95% CI, 2.55-4.46]), similar to patients who suffered a MAPE without troponin elevation (n = 501) (aHR, 2.98 [95% CI, 2.26-3.92]). Patients who suffered a MAPE with troponin elevation but without MI had the highest risk of death (n = 116) (aHR, 4.29 [95% CI, 2.89-6.36]). These 4 types of adverse events similarly affected 1-year disability-free survival. CONCLUSIONS: MACEs and MAPEs occur at similar frequencies and affect survival to a similar degree. All 3 types of postoperative troponin elevation in this analysis were associated, to varying degrees, with increased risk of death and disability.

Effect of Insulin Therapy using Hyper-insulinemic Normoglycemic Clamp on Inflammatory Response in Brain Dead Organ Donors.

BACKGROUND: Brain death is a major stress that is associated with a massive inflammatory response and systemic hyperglycemia. Severe inflammation leads to increased graft immunogenicity and risk of graft dysfunction; while acute hyperglycemia aggravates the inflammatory response and increases the risk of morbidity and mortality. Insulin therapy not only controls hyperglycemia but also suppresses inflammation. The present study is to investigate the anti-inflammatory properties and the normoglycemia maintenance of high dose insulin on brain dead organ donors. DESIGN: 15 brain dead organ donors were divided into 2 groups, insulin treated (n=6) and controls (n=9). Insulin was provided for a minimum of 6 h using the hyperinsulinemic normoglycemic clamp technique. The changes of serum cytokines, including IL-6, IL-10, IL-1ß, IL-8, TNFα, TGFα and MCP-1, were measured by suspension bead array immunoassay and glucose by a glucose monitor. RESULTS: Compared to controls, insulin treated donors had a significant lower blood glucose 4.8 (4-6.9) vs. 9 (5.6-11.7) mmol/L, p<0.01); the net decreases of pro-inflammatory cytokines, such as IL-6 and MCP-1, and the net increase of anti-inflammatory cytokine, such as IL-10, reached significant level in insulin treated donors compared with those in controls. CONCLUSION: High dose insulin therapy decreases the concentrations of inflammatory cytokines in brain dead donors and preserves normoglycemia. High dose of insulin may have anti-inflammatory effects in brain dead organ donors and therefore, improve the quality of donor organs and potentially improve outcomes.

Randomized clinical trial of the impact of insulin therapy on liver function in patients undergoing major liver resection.

BACKGROUND: Postoperative liver dysfunction is the major source of morbidity and mortality in patients undergoing partial hepatectomy. This study tested the benefits of a metabolic support protocol based on insulin infusion, for reducing liver dysfunction following hepatic resection. METHODS: Consecutive consenting patients scheduled for liver resection were randomized to receive preoperative dextrose infusion followed by insulin therapy using the hyperinsulinaemic normoglycaemic clamp protocol (n = 29) or standard therapy (control group, n = 27). Patients in the insulin therapy group followed a strict dietary regimen for 24 h before surgery. Intravenous dextrose was started at 2 mg per kg per min the night before and continued until surgery. Hyperinsulinaemic therapy for a total of 24 h was initiated at 2 munits per kg per min at induction of anaesthesia, and continued at 1 munit per kg per min after surgery. Normoglycaemia was maintained (3.5-6.0 mmol/l). Control subjects received no additional dietary supplement and a conventional insulin sliding scale during fasting. All patients were tested serially to evaluate liver function using the Schindl score. Liver tissue samples were collected at two time points during surgery to measure glycogen levels. RESULTS: Demographics were similar in the two groups. More liver dysfunction occurred in the control cohort (liver dysfunction score range 0-8 versus 0-4 with insulin therapy; P = 0.031). Median (interquartile range) liver glycogen content was 278 (153-312) and 431 (334-459) µmol/g respectively (P = 0.011). The number of complications rose with increasing severity of postoperative liver dysfunction (P = 0.032) CONCLUSION: The glucose-insulin protocol reduced postoperative liver dysfunction and improved liver glycogen content. REGISTRATION NUMBER: NCT00774098 (http://www.clinicaltrials.gov).

Glucose and insulin administration while maintaining normoglycemia: the GIN concept.

The benefits of tight glucose control in critically ill and surgical patients remains a subject of debate. While some studies demonstrated a survival benefit associated with intensive insulin therapy, more recent studies have failed to demonstrate this correlation. On the contrary, the difficulty in achieving normoglycemia with the conventional insulin sliding scale protocols and a rising concern for severe hypoglycemic episodes associated with this strategy keep many clinicians skeptical. This article examines the use of hyperinsulinemic-normoglycemic clamping, or glucose-insulin-normoglycemia (GIN) therapy, a novel approach to achieve normoglycemia in the perioperative period. If properly applied, this therapy potentially reduces the morbidity and mortality associated with hyperglycemia and confers the pharmacological advantages of hyperinsulinemia. Further understanding of the underlying molecular mechanisms, as well as the development of a continuous intravenous glucose monitoring device would facilitate the routine clinical use of GIN therapy.

["Fast-Track" for laparoscopic-assisted rectum resection--what can be achieved? First results of a feasibility study]. / "Fast-Track" bei laparoskopisch assistierter Rektumresektion--was kann erreicht werden? Erste Ergebnisse einer Machbarkeitsstudie.

AIM: "Fast-track" multimodal rehabilitation is increasingly entering the perioperative management strategies in colon surgery aiming at minimized perioperative morbidity and accelerated recovery. So far little is known about the complementary effects of minimally invasive surgery along with "fast-track" rehabilitation in the treatment of rectal cancer. The aim of this pilot study was to investigate the influence of "fast-track" perioperative management on morbidity, recovery and length of hospital stay in laparoscopically-assisted rectum resections and to compare those data to earlier results. METHODS: An interdiciplinary "fast-track" multimodal rehabilitation strategy with avoidance of mechanical bowel cleansing, with a restrictive intravenous intra- and postoperative fluid regimen, forced mobilisation, and early enteral nutrition was introduced into clinical practice and applied in 16 laparoscopically-assisted rectum resections. Data were collected in the course af a prospective analysis. The mean patient age was 62 (42-79) years. RESULTS: Mean time of surgery was 245 (SD 46) min, and the mean intraoperative infusion rate was 11.2 (SD 2.6) ml/kg/BW. On day 2, 14 of the 16 patients tolerated solid food and 12 patients had had bowel movements. All patients returned to their initial body weight by day 4. The median postoperative hospital stay was 7.5 days (6-20), 12 patients were discharged between day 6 and 8. Two patients were readmitted for intestinal atony, one patient developed an anastomotic leakage. CONCLUSIONS: "Fast-track" rehabilitation is feasible in rectum surgery and seems to complement the beneficial effects of minimally invasive surgery without increasing the complication rate.

[Catabolic stress response during and after abdominal surgery. Comparison between two anaesthesia procedures]. / Katabole Stressantwort während und nach abdominalchirurgischen Eingriffen. Ein Vergleich zwischen zwei Anästhesieverfahren.

BACKGROUND: The purpose of the study was to investigate the effect of modified neuroleptanesthesia (NLA) with fentanyl/midazolam on the catabolic responses during and after abdominal surgery. METHODS: A total of 13 patients undergoing cystoprostatectomy received either modified NLA ( n=7) or inhaled anesthesia with isoflurane (ISO, n=6). Glucose and urea production rates were assessed before, during and 1 day after the operation. Plasma concentrations of glucose, urea, lactate, insulin, glucagon and cortisol were also determined. RESULTS: In contrast to isoflurane anesthesia, modified NLA prevented an increase in plasma glucose concentration and glucose production during ( P<0.05), but not after surgery. There were no differences in perioperative urea production rates or plasma concentrations of urea, insulin, glucagon and lactate between the two groups. Modified NLA suppressed the intraoperative increase in plasma cortisol concentration as observed in the ISO group ( P<0.05). CONCLUSION: Modified NLA inhibits the increase in plasma glucose concentration and glucose production as seen during isoflurane anesthesia. However, NLA does not influence the catabolic response on the first postoperative day.

Sevoflurane versus isoflurane--anaesthesia for lower abdominal surgery. Effects on perioperative glucose metabolism.

BACKGROUND: The aim of this study was to determine the impact of sevoflurane anaesthesia on metabolic and endocrine responses to lower abdominal surgery. METHODS: A prospective randomized controlled study in 20 patients undergoing abdominal hysterectomy. Patients were randomly assigned to receive either sevoflurane (S) or isoflurane anaesthesia (I). Using a stable isotope dilution technique, endogenous glucose production (EGP) and plasma glucose clearance (GC) were determined pre- and postoperatively (6,6-2H2-glucose). Plasma concentrations of glucose, insulin, cortisol, epinephrine and norepinephrine were measured preoperatively, 5 min after induction of anaesthesia, during surgery and 2 h after the operation. RESULTS: EGP increased in both groups with no intergroup differences (preop. S 12.2 +/- 1.6, I 12.4 +/- 1.6; postop. S 16.3 +/- 1.9*, I 19.0 +/- 3.1* micromol kg(-1) min(-1), all values are means +/- SD, *P < 0.05 vs. preop.). Plasma glucose concentration increased and GC decreased in both groups. There were no differences between groups. (Glucose conc. mmol l(-1) preop.: S 4.1 +/- 0.3, I 3.9 +/- 0.5; 5 AI S 5.1 +/- 0.6*, I 5.1 +/- 1.0*, postop. S 7.0 +/- 1.0*, I 7.1 +/- 1.4*; * = P < 0.05 vs. preop.; GC ml kg(-1)min(-1) preop. S 3.0 +/- 0.4, I 3.2 +/- 0.4; postop. S 2.4 +/- 0.3*, I 2.7 +/- 0.3*; *=P < 0.05 vs. preop.) Insulin plasma concentrations were unchanged. Cortisol plasma concentrations increased intra- and postoperatively with no changes between the groups. Norepinephrine plasma concentration increased in the S group after induction of anaesthesia. I group norepinephrine was increased 2 h after operation and showed no intergroup differences. CONCLUSION: Sevoflurane, as well as isoflurane, does not prevent the metabolic endocrine responses to surgery.

Epidural analgesia and postoperative lipid metabolism: stable isotope studies during a fasted/fed state.

BACKGROUND AND OBJECTIVES: Although previous studies have reported an inhibitory effect of epidural block and glucose feeding on plasma concentrations of glycerol and free fatty acids (FFA), it remains unclear how epidural analgesia modifies the postoperative production and uptake of lipid metabolites. This can be achieved by determining the rate of lipolysis during a feeding state with dextrose. METHODS: Twelve patients with or without postoperative epidural analgesia were studied 48 hours after surgery. They underwent a 6-hour stable isotope infusion study using [1,1,2,3,3,-(2)H(5)] glycerol; 3 hours of fasting, and 3 hours of dextrose infusion (4 mg/kg/min). The rate of glycerol appearance (R(a) glycerol) i.e., rate of lipolysis, and plasma concentrations of glycerol, FFA, glucose, lactate, insulin, glucagon, and cortisol were measured during the fasted and the fed states. RESULTS: The rates of lipolysis were similar in both groups during the fasted state and were not modified by dextrose infusion. In contrast, plasma concentrations of glycerol and FFA were decreased significantly during the fed state (P <.01). Glycerol clearance (ratio between R(a) glycerol and plasma glycerol concentration) increased significantly in both groups (P <.05) with feeding. Similarly, plasma concentrations of glucose and insulin increased significantly following feeding with dextrose in both groups. CONCLUSIONS: The elevated rates of lipolysis associated with surgery cannot be suppressed by either epidural analgesia or dextrose feeding implying that the sustained stress response continues in the postoperative period and is the most important factor responsible for the increased release of glycerol.

Integrated analysis of protein and glucose metabolism during surgery: effects of anesthesia.

The aim of this study was to assess dynamic changes in protein and glucose metabolism during surgery. Twelve patients undergoing colorectal surgery received either intravenous propofol anesthesia (n = 6) or inhalational anesthesia with desflurane (n = 6). Pre- and intraoperative protein and glucose kinetics were analyzed by an isotope dilution technique using L-[1-(13)C]leucine and [6,6-(2)H(2)]glucose. Plasma concentrations of glucose, lactate, free fatty acids, insulin, glucagon, and cortisol were measured before and after 2 h of surgery. The rates of appearance of leucine and glucose, leucine oxidation, protein synthesis, and glucose clearance decreased during surgery, independent of the type of anesthesia (P < 0.05). A correlation between the rate of appearance of leucine and glucose was observed (r = 0.755, P < 0.001). Intraoperative plasma cortisol and glucose concentrations increased (P < 0.05), whereas plasma concentrations of lactate, free fatty acids, insulin, and glucagon did not change. Surgery causes a depression of whole body protein and glucose metabolism, independent of the anesthetic technique. There is a correlation between perioperative glucose production and protein breakdown.

Intraoperative epidural blockade prevents the increase in protein breakdown after abdominal surgery.

BACKGROUND: The aim of this study was to investigate the effect of epidural blockade with bupivacaine, restricted to the intraoperative period, on protein catabolism after major abdominal surgery. METHODS: Fourteen patients undergoing cystoprostatectomy were randomly assigned to receive either general anaesthesia with isoflurane (control group, n=7) or a combination of general anaesthesia and epidural blockade with bupivacaine from segment T4 to S5 (epidural group, n=7). Rates of urea (Ra urea) and glucose production (Ra glucose) were measured three days before and three days after the operation using stable isotope tracers ([15N2]urea, [6,6-2H2]glucose). Protein breakdown was calculated from the urea production rate. Plasma concentrations of metabolic substrates (urea, glucose, lactate, glycerol, amino acids) and hormones (insulin, glucagon, cortisol, adrenaline, noradrenaline) were also determined. RESULTS: Protein breakdown significantly increased after surgery in the control group (P<0.05), while it remained unaltered in the epidural group (control; 66 (54-76), epidural; 43 (29-58) mg x kg(-1) x h(-1), P<0.05, median (range)). Glucose plasma concentration and Ra glucose increased in both groups to a similar extent (P<0.05). Plasma concentration of branched chain amino acids decreased after epidural analgesia to a value significantly lower than in the control group (P<0.05). Glutamine plasma concentration decreased in the control group (P<0.05), but did not change in the epidural group. There were no differences in plasma concentrations of insulin, cortisol and catecholamines between the two groups. Glucagon plasma concentration in the epidural group was significantly lower than in the control group (P<0.05). CONCLUSION: Intraoperative epidural blockade inhibits the increase in protein breakdown after abdominal surgery.

Laparoscopic-assisted vaginal hysterectomy and the hyperglycemic response to surgery: an observational study.

PURPOSE: To test the hypothesis that laparoscopic-assisted vaginal hysterectomy (LAVH) attenuates the hyperglycemic response to surgery when compared to vaginal hysterectomy (VH). METHODS: Fourteen patients received either LAVH (n=7) or VH (n=7). Whole body glucose production was measured before and three hours after surgery using [6.6-2H2] glucose. Before, during and after the operation, plasma concentrations of glucose, insulin, glucagon, cortisol, epinephrine and norepinephrine were determined. RESULTS: Plasma glucose concentration increased in both groups during and after surgery showing a significantly higher value after VH than after LAVH (VH: 8.3 +/- 1.4 mmol x L(-1); LAVH: 6.6 +/- 0.9 mmol x L(-1), P <0.05). The postoperative increase in glucose production was comparable in both groups. While plasma concentrations of insulin and glucagon remained unchanged, intra- and postoperative plasma cortisol concentrations were significantly higher in the VH group than in the LAVH group. Plasma catecholamine concentrations significantly increased after both types of surgery to the same extent. CONCLUSION: In this observational study, LAVH appears to blunt the hyperglycemic and cortisol response to surgery when compared to VH.

Low dose clonidine premedication accentuates the hyperglycemic response to surgery.

PURPOSE: To investigate the influence of low dose clonidine premedication on perioperative glucose homeostasis. METHODS: Sixteen patients undergoing abdominal hysterectomy for benign uterine myoma were randomly assigned to receive either iv clonidine (1 microg x 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. RESULTS: In 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 x L(-1) vs control: 5.7 +/- 0.8 mmol x L(-1), P < 0.05). This was accompanied by a lower insulin plasma concentration (clonidine: 3.9 +/- 1.9 microU x mL(-1) vs control: 6.5 +/- 2.8 microU x 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). CONCLUSION: Premedication with clonidine 1 microg x kg(-1) accentuates the hyperglycemic response to lower abdominal surgery caused by the decrease in insulin plasma concentrations.

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

UNLABELLED: 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 micromol. 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 micromol. kg(-1). min(-1); during surgery, 10.1 +/- 0.5 micromol. 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 micromol. kg(-1). min(-1) to 12.4 +/- 1.0 micromol. 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. IMPLICATIONS: Epidural analgesia combined with general anesthesia prevented the hyperglycemic response to surgery by decreasing endogenous glucose production. The increased glucose plasma concentration in patients receiving fentanyl/midazolam anesthesia was caused by a decrease in whole-body glucose clearance. The hyperglycemic response observed during inhaled anesthesia with isoflurane was a consequence of both impaired glucose clearance and increased glucose production.

Glucose infusion does not suppress increased lipolysis after abdominal surgery.

The purpose of this study was to investigate the effect of glucose infusion on lipid metabolism after abdominal surgery. Patients (n = 6) with non-metastasized colorectal carcinoma were investigated on the second day after surgery and healthy volunteers were studied after an overnight fast. The rates of glycerol appearance (R(a) glycerol), i.e., lipolysis rates, were assessed by primed continuous infusion of [1,1,2,3,3,-5H2]glycerol before and after 3 h of glucose infusion (4 mg x kg(-1) x min(-1)). Plasma concentrations of glycerol, free fatty acids, glucose, lactate, insulin, and glucagon were determined. Fasting R(a) glycerol was higher in patients than in volunteers (7.7 +/- 1.8 versus 1.9 +/- 0.3 micromol x kg(-1) x min(-1), P < 0.05). Glucose infusion suppressed the R(a) glycerol in volunteers to 1.0 +/- 0.2 micromol x kg(-1) x min(-1) (P < 0.05), whereas lipolysis was not affected in patients. Plasma concentrations of glycerol and free fatty acids similarly decreased during glucose administration by 50% in both groups (P < 0.05). In contrast to the patients, a significant correlation (r = 0.78, P < 0.05) between the R(a) glycerol and plasma glycerol concentration was observed in normal subjects. The hyperglycemic response to glucose infusion was significantly more pronounced (P < 0.05) in patients (10.7 +/- 0.7 mmol/L) than in volunteers (7.1 +/- 0.4 mmol/L), whereas the plasma insulin increased to the same extent in the two groups (P < 0.001). In conclusion, lipolysis rates are increased after abdominal surgery and glucose administration, most likely due to insulin resistance, and fail to inhibit stimulated whole-body lipolysis.

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

UNLABELLED: 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 microg. 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 (R(a) glucose) was analyzed by an isotope dilution technique by using [6,6-(2)H(2)] 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/microU, P < 0.05), the R(a) 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 micromol. 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.