George Carvalho

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.

High-Dose Insulin Therapy Attenuates Systemic Inflammatory Response in Coronary Artery Bypass Grafting Patients

BACKGROUND Cardiac surgery with cardiopulmonary bypass (CPB) induces an acute phase reaction that is implicated in the pathogenesis of several postoperative complications. Studies have shown that proinflammatory cytokines are increased by acute hyperglycemia. Recent evidence suggests that insulin has antiinflammatory properties. Therefore, we hypothesized that high-dose insulin therapy would attenuate the systemic inflammatory response to cardiopulmonary bypass and surgery in coronary artery bypass patients while maintaining normoglycemia. METHODS A total of 52 patients who presented for elective coronary artery bypass were randomized to receive intraoperative intravenous insulin infusion, titrated to maintain blood glucose concentrations less than 180 mg/dL (group I, n = 25), or receive intraoperative fixed high dose of intravenous insulin infusion (5 mU/kg/min) with dextrose 20% infused separately to maintain a blood glucose level between 70 and 110 mg/dL (group II, n = 27). Blood samples were collected at different time points to determine tumor necrosis factor alpha (TNFalpha), interleukin 6 and 8 (IL6 and IL8), and complement factor 3 and 4 (C3 and C4). RESULTS Patients in both groups had similar preoperative characteristics. Patients in the high-dose insulin group had higher blood insulin concentrations and tighter blood glucose control. There were lower levels of IL6 (150 pg/dL vs 245 pg/dL, p = 0.03), IL-8 (49 pg/dL vs 74 pg/dL, p = 0.05), and TNFalpha (2.2 pg/dL vs 3.0 pg/dL, p = 0.04) in group II in the early postoperative period. CONCLUSIONS High-dose insulin therapy blunts the early postoperative surge in inflammatory response to CPB as reflected by decreased levels of IL6, IL8, and TNFalpha.

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.

Type 2 diabetes mellitus and the catabolic response to surgery.

Background:The authors tested the hypothesis that the catabolic responses to colorectal surgery are amplified in the presence of type 2 diabetes mellitus. Methods:Seven nondiabetic and seven diabetic patients underwent a 6-h stable isotope infusion study (3 h fasted, 3-h glucose infusion at 4 mg · kg−1 · min−1) on the second postoperative day. Leucine rate of appearance (Ra), leucine oxidation, nonoxidative leucine disposal, and glucose Ra were assessed by L-[1-13C]leucine and [6,6-2H2]glucose. Circulating concentrations of glucose, lactate, insulin, glucagon, and cortisol also were determined. Results:Diabetic patients had a higher leucine oxidation than nondiabetic patients (P = 0.0003), whereas leucine Ra and nonoxidative leucine disposal were not different. Administration of glucose did not affect leucine kinetics regardless of whether patients were diabetic. In diabetic patients, glucose Ra was greater than in the nondiabetic group (P = 0.0032). Glucose infusion suppressed the endogenous glucose Ra to a lesser extent in diabetic than in nondiabetic patients (P = 0.0048). Plasma glucose concentrations were higher in diabetic than in nondiabetic patients (P = 0.0203), both in the postabsorptive and the fed state. Circulating concentrations of glucagon were higher (P = 0.0065) and concentrations of insulin were lower (P = 0.0146) in the presence of diabetes, resulting in a lower insulin/glucagon ratio (P = 0.0002). In diabetic patients, the insulin/glucagon ratio increased during glucose infusion to a lesser extent than in the nondiabetic group (P = 0.0014). Conclusion:Protein catabolism after colorectal surgery is increased in patients with type 2 diabetes mellitus as reflected by an increased oxidative protein loss.

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).

Fasting blood glucose levels in patients presenting for elective surgery

OBJECTIVE The incidence of diabetes mellitus (DM) is increasing worldwide; however, its diagnosis is often delayed. Identifying patients with abnormal fasting blood glucose (FBG) levels preoperatively may have important implications for immediate and long-term outcomes. The aim of the present study was to determine the prevalence of impaired fasting glucose (IFG) and provisional diagnosis of DM (PDD) with potential risk factors in patients presenting for elective surgery. METHODS We measured FBG in consecutive adult patients undergoing elective non-cardiac surgery from September 2006 to August 2007. Patient age, sex, body mass index, and FBG were collected in the morning of their scheduled intervention. FBG was classified according to the World Health Organization categorization. Patients with a history of DM were excluded from the final analysis. The prevalence of IFG and PDD and odds ratio for risk factors were calculated. RESULTS Four hundred ninety-three patients without a prior diagnosis of DM were sampled; 19.3% (95 of 493) had IFG and 6.5% (32 of 493) had PDD. Male subjects had a greater risk of PDD than female subjects (odds ratio 2.5, 95% confidence interval 1.2-5.5, P = 0.017). Increased body mass index was not a risk factor for IFG or PDD. The prevalence of IFG but not of PDD had a tendency to increase with age after 40 y. CONCLUSION More than 25% of patients without a prior diagnosis of DM presenting for elective surgery had increased FBG levels. Obtaining this information may initiate not only an earlier detection of DM in some patients but also affect acute perioperative management and outcomes.

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 patients 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 patients 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-[1-13C]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: &Dgr;leucine balance = 19.1 − (0.20 × age [years]) − (0.58) × leucine balancepreOP). Conclusions:We demonstrate a significant association between the degree of preoperative catabolism, the patients age, and the anabolic effect of hypocaloric nutrition (ClinicalTrials.gov registration ID: NCT01414946).

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.