Modified Glucose-Insulin-Potassium Regimen Provides Cardioprotection With Improved Tissue Perfusion in Patients Undergoing Cardiopulmonary Bypass Surgery

Abstract

Background Laboratory studies demonstrate glucose-insulin-potassium (GIK) as a potent cardioprotective intervention, but clinical trials have yielded mixed results, likely because of varying formulas and timing of GIK treatment and different clinical settings. This study sought to evaluate the effects of modified GIK regimen given perioperatively with an insulin-glucose ratio of 1:3 in patients undergoing cardiopulmonary bypass surgery. Methods and Results In this prospective, randomized, double-blinded trial with 930 patients referred for cardiac surgery with cardiopulmonary bypass, GIK (200 g/L glucose, 66.7 U/L insulin, and 80 mmol/L KCl) or placebo treatment was administered intravenously at 1 mL/kg per hour 10 minutes before anesthesia and continuously for 12.5 hours. The primary outcome was the incidence of in-hospital major adverse cardiac events including all-cause death, low cardiac output syndrome, acute myocardial infarction, cardiac arrest with successful resuscitation, congestive heart failure, and arrhythmia. GIK therapy reduced the incidence of major adverse cardiac events and enhanced cardiac function recovery without increasing perioperative blood glucose compared with the control group. Mechanistically, this treatment resulted in increased glucose uptake and less lactate excretion calculated by the differences between arterial and coronary sinus, and increased phosphorylation of insulin receptor substrate-1 and protein kinase B in the hearts of GIK-treated patients. Systemic blood lactate was also reduced in GIK-treated patients during cardiopulmonary bypass surgery. Conclusions A modified GIK regimen administered perioperatively reduces the incidence of in-hospital major adverse cardiac events in patients undergoing cardiopulmonary bypass surgery. These benefits are likely a result of enhanced systemic tissue perfusion and improved myocardial metabolism via activation of insulin signaling by GIK. Clinical Trial Registration URL: clinicaltrials.gov. Identifier: NCT01516138.

Keywords: cardiac surgery; cardiopulmonary bypass; insulin; tissue perfusion.

Figures

Figure 1

Number of patients assessed, enrolled, and randomized in the trial. CPB indicates cardiopulmonary bypass; GIK, glucose‐insulin‐potassium; LVEF, left ventricular ejection fraction.

Figure 2

Regulation of glucose metabolism by GIK. Blood glucose (A) and lactate levels (B) between the GIK and control arms before the surgery (baseline), 5 minutes after commencing CPB, 5 minutes afterACC), 5 minutes after ACC removal and 1, 6, 12, 24, and 48 hours after surgery. Values are mean±SD for all the patients in both arms. **P<0.01 vs control. Percentage of myocardial extraction/excretion of glucose (C), lactate (D), and oxygen (E) immediately before ACC and 5 minutes after ACC removal. Positive value indicates myocardial extraction, whereas negative indicates myocardial excretion. Values are mean±SD for 16 patients in the GIK arm and 20 patients in the control arm. (F) Glycogen abundance in cardiac biopsies performed 15 minutes after ACC removal by transmission electron micrograph. ACC indicates aortic cross clamp; CPB, cardiopulmonary bypass; GIK, glucose‐insulin‐potassium.

Figure 3

Activation of insulin signaling in the hearts of GIK‐treated patients. Representative western blots and quantification of IRS‐1, Tyr phosphorylated IRS‐1, Akt, Ser473 phosphorylated Akt in cardiac biopsies. Each bar denotes mean±SD intensities quantified by densitometric analysis of the immunoblots. n=10 per group. Akt indicates protein kinase 1; GAPDH, glyceraldehyde 3‐phosphate dehydrogenase; GIK, glucose‐insulin‐potassium; IRS‐1, insulin receptor substrate 1; p‐Akt, phospho‐Akt; p‐IRS‐1, phospho‐IRS‐1.