Tamaki Sato

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.

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).

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.

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 (β = −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 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.

High-dose insulin administration is associated with hypoaminoacidemia during cardiac surgery

Although the effects of insulin on glucose homeostasis are well recognized in surgical patients, its effect on perioperative protein metabolism has received little attention. The purpose of this study was to examine the effect of high-dose insulin therapy on the plasma concentrations of amino acids (AAs) in patients undergoing coronary artery bypass grafting surgery. We studied 20 nondiabetic patients scheduled for elective coronary artery bypass grafting surgery. Patients were randomly allocated to receive either standard metabolic care (target glycemia 6.0-10.0 mmol/L, control group, n = 10) or high-dose insulin therapy (insulin group, n = 10). Insulin was administered at 5 mU·kg(-1)·min(-1) beginning at skin incision. Simultaneously, 20% dextrose was infused at a variable rate adjusted to maintain glycemia between 4.0 and 6.0 mmol/L. Plasma AAs, glucose, cortisol, and insulin were measured immediately before surgery and at sternal closure. Differences in mean values were assessed by Student t test. Plasma concentrations of all AAs decreased in the insulin group, with 15 of 22 AAs, including all branched-chain AAs, being significantly lower at sternal closure when compared with the control group. At the end of surgery, plasma glucose concentration was significantly lower in the insulin group (4.2 ± 0.6 vs 7.3 ± 1.0 mmol/L, P = .0001), whereas plasma cortisol levels did not show any difference between groups. High-dose insulin therapy resulted in a significant reduction in plasma AAs, particularly branched-chain AAs, during cardiac surgery.

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 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.

Hyperinsulinemic Normoglycemia during Cardiac Surgery Reduces a Composite of 30-day Mortality and Serious In-hospital ComplicationsA 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–1; or (2) standard glycemic management, low-dose insulin infusion targeting glucose greater than 150 mg · dl–1. The primary outcome was a composite of 30-day mortality, mechanical circulatory support, infection, renal or neurologic morbidity. Interim analyses were planned at each 12.5% enrollment of a maximum 2,790 patients. Results: At the third interim analysis (n = 1,439; hyperinsulinemic normoglycemia, 709, standard glycemic management, 730; 52% of planned maximum), the efficacy boundary was crossed and study stopped per protocol. Time-weighted average glucose concentration (means ± SDs) with hyperinsulinemic normoglycemia was 108 ± 20 versus 150 ± 33 mg · dl–1 with standard glycemic management, P < 0.001. At least one component of the composite outcome occurred in 49 (6.9%) patients receiving hyperinsulinemic normoglycemia versus 82 (11.2%) receiving standard glucose management (P < efficacy boundary 0.0085); estimated relative risk (95% interim-adjusted CI) 0.62 (0.39 to 0.97), P = 0.0043. There was a treatment-by-site interaction (P = 0.063); relative risk for the composite outcome was 0.49 (0.26 to 0.91, P = 0.0007, n = 921) at Royal Victoria Hospital, but 0.96 (0.41 to 2.24, P = 0.89, n = 518) at the Cleveland Clinic. Severe hypoglycemia (less than 40 mg · dl–1) occurred in 6 (0.9%) patients. Conclusions: Intraoperative hyperinsulinemic normoglycemia reduced mortality and morbidity after cardiac surgery. Providing exogenous glucose while targeting normoglycemia may be preferable to simply normalizing glucose concentrations.

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.