Hyperinsulinemic Normoglycemia during Cardiac Surgery Reduces a Composite of 30-day Mortality and Serious In-hospital Complications: A Randomized Clinical Trial.

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; or (2) standard glycemic management, low-dose insulin infusion targeting glucose greater than 150 mg · dl. 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 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) 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.

Body mass index predicts insulin sensitivity during cardiac surgery: a prospective observational study.

PURPOSE: Taking into account the previously described link between body weight and diabetes mellitus (DM) in non-surgical patients, and the understanding that the degree of intraoperative insulin resistance is a predictor of adverse clinical outcomes, we investigated the relationship between body mass index (BMI) and insulin sensitivity during cardiac surgery. METHODS: We prospectively enrolled 400 patients scheduled for elective cardiac surgery and divided them into groups based on the presence or absence of type-2 DM. They were further categorized into four subgroups based on their BMI: group 1- normal weight, BMI 18.5-24.9 kg·m-2; group 2 - overweight, BMI 25-29.9 kg·m-2; group 3 - obese, BMI 30-34.9 kg·m-2; group 4 - morbidly obese, BMI ≥ 35 kg·m-2. Insulin sensitivity was assessed using the hyperinsulinemic-normoglycemic clamp technique during surgery. We also analyzed the association of BMI, quality of postoperative glycemic control, and postoperative outcomes. RESULTS: A linear negative relationship between BMI and insulin sensitivity (r = 0.42, P < 0.001) was observed, independent of the patients' diabetic state. There was also a positive correlation between BMI and postoperative glycemia (r = 0.30, P < 0.001) though the relationship between BMI and major and infectious complication was not significant (P = 0.56, P = 0.10, respectively). CONCLUSIONS: Patient BMI may be used as a simple predictor of insulin sensitivity during cardiac surgery and as a predictor of the quality of postoperative glycemic control. A larger cohort will be necessary to evaluate the association of BMI, perioperative insulin resistance, and clinical outcomes.

Hyperinsulinemic-normoglycemic clamp administered together with amino acids induces anabolism after cardiac surgery.

Cardiac surgery triggers an inflammatory stress response, leading to protein catabolism, a process that even high-dose insulin therapy alone cannot reverse. To determine whether hyperinsulinemic-normoglycemic clamp and perioperative amino acid (AA) supplementation improves whole body protein balance, 20 patients scheduled for elective coronary artery bypass grafting surgery were randomly assigned to have intra- and postoperative hyperinsulinemic-normoglycemic clamp, with or without intravenous AA supplementation. Primed continuous infusions of [6,6-2H2]glucose and l-[1-13C]leucine were used to quantify whole body protein and glucose metabolism before and after surgery. Adipose tissue and serum cytokines were also analyzed to measure their responsiveness to the anabolic effect of AA administration. During hyperinsulinemic-normoglycemic clamp, AA supplementation successfully stimulated whole body protein synthesis, resulting in a positive whole body protein balance after surgery (insulin: -13.6 ± 4.5 vs. insulin + AA: 2.1 ± 5.4 µmol·kg-1·h-1, P < 0.001). Endogenous glucose production was equally suppressed in both groups (insulin: 0.0 ± 3.8 vs. insulin + AA 1.6 ± 1.6 µmol·kg-1·min-1, P = 0.230). AA supplementation led to significant changes in serum and tissue IL-6 (insulin: 246.6 ± 111.2 vs. insulin + AA: 124.5 ± 79.3 pg/ml, P = 0.011). In conclusion, hyperinsulinemic-normoglycemic clamp technique, together with AA supplementation, can induce an anabolic state after open-heart surgery, as quantified by a positive whole body protein balance.

Poor preoperative left ventricular function is associated with decreased insulin sensitivity during cardiac surgery.

OBJECTIVE: To investigate the association between preoperative left ventricular ejection function (LVEF) and whole-body insulin sensitivity during cardiac surgery. DESIGN: A prospective, non-randomized trial. SETTING: A tertiary care hospital setting. PARTICIPANTS: Patients undergoing elective cardiac surgery. INTERVENTIONS: Consenting, non-diabetic patients scheduled for elective cardiac surgery requiring cardiopulmonary bypass (CPB) were assigned either to a group with normal LVEF (EF≥55%) or one with low LVEF (EF≤45%) as assessed by coronary angiography. Insulin sensitivity was assessed by the hyperinsulinemic-normoglycemic clamp technique before and towards the end of CPB. The association between LVEF and insulin sensitivity was tested using Student t-test. RESULTS: One hundred forty patients were studied, with 48 patients in the low and 92 patients in the normal LVEF group. Patient demographics were similar in both groups except for preoperative LVEF (p<0.001). Before CPB, patients with normal LVEF showed higher insulin sensitivity when compared to patients with low LVEF (p = 0.04). Insulin sensitivity decreased towards the end of CPB (p<0.001) in both groups, resulting in similar values. CONCLUSIONS: Poor preoperative left ventricular function is associated with reduced insulin sensitivity before the onset of CPB in cardiac surgery.

Parenteral amino acid supplementation with high-dose insulin prevents hypoaminoacidemia during cardiac surgery.

OBJECTIVES: Surgery triggers a stress response that produces insulin resistance and hyperglycemia. During cardiac surgery, the administration of high-dose insulin along with dextrose titration maintains normoglycemia, but dramatically decreases plasma amino acids (AAs) compared with preoperative fasting levels. Hypoaminoacidemia limits protein synthesis and prevents anabolic responses after surgery. We investigated whether parenteral infusion of AAs during and immediately after cardiac surgery would prevent hypoaminoacidemia in patients who receive high-dose insulin therapy. METHODS: Sixteen patients undergoing coronary artery bypass grafting surgery were randomly allocated to receive AAs with % kcal equivalent to either 20% (n = 8) or 35% (n = 8) of their measured resting energy expenditure (REE). Insulin was infused at a constant rate of 5 mU/(kg × min), whereas dextrose was titrated to maintain normoglycemia during and until 5 h after surgery. Plasma AA concentrations were measured at baseline before and after surgery. RESULTS: Compared with the 20% AA group after surgery, AA concentrations were significantly higher in the 35% AA group for 12 of 20 AAs (P < 0.032), including all branched-chain AAs. In the 20% AA group, total essential AAs decreased by 21% and nonessential AAs decreased by 14% after surgery compared with preoperative fasting levels. In contrast, giving 35% AAs prevented this unfavorable decrease in AAs, and in fact allowed for a 23% and 12% increase in essential and nonessential AAs, respectively. CONCLUSIONS: AA supplementation at 35% REE, but not 20% REE, can effectively prevent hypoaminoacidemia caused by high-dose insulin therapy during cardiac surgery.

Anesthesia in the Elderly Patient Undergoing Otolaryngology Head and Neck Surgery.

Geriatric patients undergoing surgery have a whole set of specific physiologic changes, perioperative needs, and postoperative complications. This review presents an overview of the basic concepts and the evolving challenges pertaining to the care of geriatric patients undergoing otolaryngologic procedures from the perspective of the anesthesiologist.

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.

Perioperative tight glucose control with hyperinsulinemic-normoglycemic clamp technique in cardiac surgery.

OBJECTIVE: Previous attempts to achieve tight glucose control in surgical patients were associated with a significant incidence of hypoglycemia. The purpose of this study was to evaluate the efficacy of perioperative glucose and insulin administration while maintaining normoglycemia using a hyperinsulinemic-normoglycemic clamp technique. METHODS: We studied 70 non-diabetic and 40 diabetic patients undergoing cardiac procedures. Before induction of anesthesia, insulin was administered at 5 mU·kg(-1)·min(-1). Blood glucose (BG) concentrations were determined every 15-30 min. Dextrose 20% was infused at a rate adjusted to maintain BG within 3.5-6.1 mmol/L. At the end of surgery, insulin infusion was decreased to 1 mU·kg(-1)·min(-1) and continued for 24h. The mean ± standard deviation of BG and the percentage of BG values within the target range were calculated perioperatively. Episodes of severe hypoglycemia, i.e., BG <2.2 mmol/L, were recorded. RESULTS: The mean BG remained within target at all times. Normoglycemia in non-diabetic patients was achieved in 92.8% of measurements during and in 83.2% after surgery. In diabetic patients 87.4% of values were within target intraoperatively and 76.7% after surgery. The rate of severe hypoglycemia was 2.7% (three patients). In non-diabetic patients the incidence of severe hypoglycemia was 0.2% of measurements during and 0.1% after surgery. Diabetic patients showed only one episode of severe hypoglycemia after surgery (0.1%). CONCLUSION: Perioperative use of a hyperinsulinemic-normoglycemic clamp technique established and maintained normoglycemia in patients undergoing cardiac surgery with little risk of hypoglycemia.