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Address reprint requests to Marc Licker, Dept. of Acute Medicine, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland.
The infusion of glucose-insulin-potassium (GIK) has yielded conflicting results in terms of cardioprotective effects. We conducted a meta-analysis to examine the impact of perioperative GIK infusion in early outcome after cardiac surgery. Randomized controlled trials (RCTs) were eligible if they examined the efficacy of GIK infusion in adults undergoing cardiac surgery. The main study endpoint was postoperative myocardial infarction (MI) and secondary outcomes were hemodynamics, any complications and hospital resources utilization. Subgroup analyses explored the impact of the type of surgery, GIK composition and timing of administration. Odds ratio (OR) or mean difference (MD) with 95% confidence interval (CI) were calculated with a random-effects model. Fifty-three studies (n=6129) met the inclusion criteria. Perioperative GIK infusion was effective in reducing MI (k=32 OR 0.66[0.48, 0.89] P=0.0069), acute kidney injury (k=7 OR 0.57[0.4, 0.82] P=0.0023) and hospital length of stay (k=19 MD -0.89[-1.63, -0.16] days P=0.0175). Postoperatively, the GIK-treated group presented higher cardiac index (k=14 MD 0.43[0.29, 0.57] L/min P<0.0001) and lesser hyperglycemia (k=20 MD -30[-47, -13] mg/dL P=0.0005) than in the usual care group. The GIK-associated protection for MI was effective when insulin infusion rate exceeded 2 mUI/kg/min and after coronary artery bypass surgery. Certainty of evidence was low given imprecision of the effect estimate, heterogeneity in outcome definition and risk of bias. Perioperative GIK infusion is associated with improved early outcome and reduced hospital resource utilization after cardiac surgery. Supporting evidence is heterogenous and further research is needed to standardize the optimal timing and composition of GIK solutions.
The infusion of glucose-insulin-potassium lowers the risk of myocardial infarction while enhancing hemodynamics in patients undergoing on-pump cardiac surgery.
Perspective Statement
This updated meta-analysis of 53 studies including over 6′000 patients, found that, compared with usual care, the infusion of GIK was associated with fewer postoperative myocardial infarctions and atrial fibrillation along with faster discharge from the ICU and the hospital. Therefore, perioperative GIK treatment could be recommended in association with current cardioprotective techniques to improve clinical outcome in cardiac surgical patients.
INTRODUCTION
Each year, cardiac surgery is performed worldwide in ∼1.5 million individuals with ischemic, congenital and valvular disorders.
Over time, outcomes after cardiac surgery have improved along with better preoperative patient preparation, progress in surgical and anesthetic management as well as cardioprotective protocols.
Perioperative ischemia-reperfusion injuries and the release of free radicals and inflammatory mediators are incriminated in causing ventricular dysfunction that either resolves spontaneously or requires cardiovascular drug support and occasionally circulatory assistance.
Importantly, cardiac complications such as postoperative myocardial infarction (MI) and heart failure are known predictors of increasing medical costs, poor survival and decreased quality of life.
Decreasing prevalence but increasing importance of left ventricular dysfunction and reoperative surgery in prediction of mortality in coronary artery bypass surgery: Trends over 18 years.
Among various cardioprotective protocols, the infusion of glucose-insulin-potassium (GIK) has been studied extensively. In animal models, GIK has been shown effective in reducing the extent of MI and the occurrence of ventricular arrhythmias while preserving ventricular function.
These cardioprotective effects are mediated by pleiotropic glucose-dependent and -independent mechanisms of insulin involving preferential high-energy substrate production from glucose metabolism as well as upregulation of the reperfusion injury salvage kinase pathway.
Effects of an intravenous infusion of a potassium-glucose-insulin solution on the electrocardiographic signs of myocardial infarction. A preliminary clinical report.
GIK has failed to show conclusive clinical cardioprotective effects following percutaneous coronary intervention whereas favorable results have been reported after cardiac surgery.
Effect of perioperative glucose-insulin-potassium infusions on mortality and atrial fibrillation after coronary artery bypass grafting: A systematic review and meta-analysis.
the interactions between GIK therapy and confounding factors (eg, diabetes mellitus, type of surgery, glycemia or timing and composition of GIK infusion) have not been examined. Hence, our meta-analysis addresses these issues and provides an up-to-date review of the impact of GIK on early postoperative outcome.
MATERIAL AND METHODS
Search Strategy
This review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and the Cochrane methodology as well as in agreement with a preregistered protocol (PROSPERO CRD 42022120746).
Ethical review board approval was waived due to the absence of new data collection. Minor deviations from the protocol are reported in a Supplemental file (S1). Three investigators (R.S., A.H. and A.P.) independently searched MEDLINE, EMBASE and the Cochrane Central Register of Clinical Trials from inception to September 19th, 2022. The search strategy aimed to select RCTs with the following terms: glucose-insulin-potassium, GIK, cardiac surgery, cardiopulmonary bypass, CPB, coronary artery bypass surgery, CABG, valve (S2). Additional articles were identified by manual review of the references of included studies.
Study Selection
Search results were examined at the abstract level and the full-text version was retrieved if relevant. Eligibility criteria were defined following the PICOS approach: (P) adult patients scheduled for elective or emergent cardiac surgery with or without cardio-pulmonary bypass (CPB); (I) use of GIK in the perioperative period; (C) usual care or placebo, (O) MI and (S) RCT. Exclusion criteria were inclusion of pediatric cases, studies with overlapping population or irrelevant study endpoints. Four authors (A.H, R.S, A.P., and G.K-B.) independently made the final assessment for inclusion into the analysis and disagreements were resolved through consensus or by third party adjudication (M.L.). If documents did not contain MI data or were unavailable as full-texts, the corresponding authors were contacted for further information. No language restriction was imposed.
Data Abstraction
The relevant information was extracted from each selected study by a single author (R.S.) and checked by 2 others (A.P. and G.K-B.), disagreements being resolved by a fourth author (A.H.). Sources of clinical heterogeneity were also extracted according to the same process (ie, study design, clinical setting, inclusion/exclusion criteria. Study characteristics were collected regarding demographic data, the type of surgery, the duration of surgery as well as GIK composition (dose of insulin and glucose) and timing of administration (before, during or/and after CPB). The primary outcome was postoperative MI and secondary outcomes were in-hospital mortality, the postoperative occurrence of stroke, acute kidney injury (AKI), atrial fibrillation (AF), ventricular fibrillation (VF), any infections, postoperative gylcemia, cardiac index, the need for pharmacological or mechanical circulatory support as well as the duration of mechanical ventilation, intensive care unit (ICU) and hospital stay.
Quality Assessment
Two authors (R.S. and A.P.) independently assessed the internal validity of included trials according to the Cochrane Collaboration methodology (risk of bias 1 tool), namely: risk of bias associated to the random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, completeness of outcome data, selective reporting and other biases.
Studies were rated as low, unclear, or high risk of bias. Included trials were rated as low risk of bias when 5 or more evaluation domains were judged as low risk of bias.
Odds ratio (OR) or mean difference (MD) with 95% confidence intervals (95%CI) were reported. Random effects models were used in all cases. Between-study variance for binary analyses was assessed using the Paule-Mandel estimator since the DerSimonian-Laird estimator is known to be unreliable with sparse data.
Continuous models used the DerSimonian-Laird estimator. Prediction intervals were computed for all models. Heterogeneity was assessed using Cochrane's Q and the I² value. All models used a continuity correction of 0.5 at each step, except for Peto models. The analysis was performed using R 4.0.4 with package “meta”.
presence of diabetes mellitus and type of surgical procedure (coronary artery bypass, valve or combined surgery). Sensitivity assessments were performed using both fixed and random effects models for continuous meta-analyses, while Peto models were used for binary meta-analyses. Small-study effect for the primary outcome was investigated by the trim-and-fill method.
After removing 3659 duplicates and adding 7 studies through manual search 2,647 citations were identified, of which 2,576 abstracts and 11 full-text articles were considered ineligible (S3).
Minimal operative mortality in patients undergoing coronary artery bypass with significant left ventricular dysfunction by maximization of metabolic and mechanical support.
Glucose-insulin-potassium improves left ventricular performances after aortic valve replacement: A secondary analysis of a randomized controlled trial.
How does glucose insulin potassium improve hemodynamic performance?: Evidence for altered expression of beta-adrenoreceptor and calcium handling genes.
A total of 53 RCTs involving 6129 participants were included in the meta-analysis (Figure 1). Additional information was obtained from corresponding authors regarding 8 RCTs.
Hyperinsulinemic normoglycemia during cardiac surgery reduces a composite of 30-day mortality and serious in-hospital complications: a randomized clinical trial.
Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.
Coronary revascularization: A procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study.
Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
Efficacy of glucose-insulin-potassium infusion on left ventricular performance in type II diabetic patients undergoing elective coronary artery bypass Graft.Dy.
Clinical, biochemical and histochemical assessment of pretreatment with glucoseInsulinPotassium for patients undergoing mitral valve replacement in the third and fourth functional groups of the New York Heart Association.
Hyperinsulinemic normoglycemia during cardiac surgery reduces a composite of 30-day mortality and serious in-hospital complications: a randomized clinical trial.
Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: Results from the hypertrophy, insulin, glucose, and electrolytes (HINGE) trial.
Safety and efficacy of intensive intraoperative glycaemic control in cardiopulmonary bypass surgery: A randomised trial: Safety and efficacy of glycaemic control.
The median of the mean times of CPB and aortic cross-clamping (AXC) were respectively 99 min (ranging from 47 to 167 min) and 59 min (ranging from 38 to 101 minutes). Patients with diabetes mellitus were enrolled in 31 RCTs. At the evaluation of risk of bias, 8 studies were rated at low risk,
Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.
Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: Results from the hypertrophy, insulin, glucose, and electrolytes (HINGE) trial.
Safety and efficacy of intensive intraoperative glycaemic control in cardiopulmonary bypass surgery: A randomised trial: Safety and efficacy of glycaemic control.
Coronary revascularization: A procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study.
Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
Hyperinsulinemic normoglycemia during cardiac surgery reduces a composite of 30-day mortality and serious in-hospital complications: a randomized clinical trial.
Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
Efficacy of glucose-insulin-potassium infusion on left ventricular performance in type II diabetic patients undergoing elective coronary artery bypass Graft.Dy.
Clinical, biochemical and histochemical assessment of pretreatment with glucoseInsulinPotassium for patients undergoing mitral valve replacement in the third and fourth functional groups of the New York Heart Association.
The proportion of participants with a MI was 5.3% and 8.2% in the GIK and control groups, respectively. As illustrated in Figure 3, the GIK infusion was associated with a decrease in MI (k=32 OR 0.66[0.48, 0.89] P=0.0069 I²=0%).
Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.
Coronary revascularization: A procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study.
Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: Results from the hypertrophy, insulin, glucose, and electrolytes (HINGE) trial.
The funnel plot for the primary analysis did not reveal a significant publication bias. A sensitivity cumulative meta-analysis with Peto OR yielded unchanged results (k=32 OR 0.58[0.42, 0.79] P=0.0007 I²=11%). Adjustment for small-study effect left results unchanged (k=32 OR 0.66[0.48, 0.89] P=0.0069 I²=0%) and subgroup analysis of low-risk of bias RCTs also supported the efficacy of GIK treatment (k=7 OR 0.67[0.45, 0.98] P=0.0396 I²=14%).
Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.
Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: Results from the hypertrophy, insulin, glucose, and electrolytes (HINGE) trial.
A sub-analysis by stratifying all RCTs into 2 time periods ascertained the effectiveness of GIK to reduce the incidence of MI in the early period (from 1977 to 2005; k=19 OR 0.45 [0.22, 0.86]) and in the last period (from 2006 to 2021; k=13 OR 0.67 [0.49, 0.91]).
The GIK infusion was associated with fewer MIs after CABG (k=24 OR 0.47[0.32, 0.68]),
Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.
Coronary revascularization: A procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study.
Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.
Coronary revascularization: A procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study.
Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: Results from the hypertrophy, insulin, glucose, and electrolytes (HINGE) trial.
Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: Results from the hypertrophy, insulin, glucose, and electrolytes (HINGE) trial.
whereas a single RCT including valve surgery, - although with favorable results-, did not allow further analysis. Importantly, stratification on the rate of insulin infusion indicated that an insulin infusion rate higher than 2 mUI/kg/min was protective against MI (k=17 OR 0.42[0.28, 0.62])
Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.
Coronary revascularization: A procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study.
Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
(Q=3.9 P=0.0482). The occurrence of postoperative MI was decreased regardless of the timing of GIK infusion either started before CPB (k=22 OR 0.65[0.47, 0.9]),
Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.
Coronary revascularization: A procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study.
Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: Results from the hypertrophy, insulin, glucose, and electrolytes (HINGE) trial.
Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.
Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: Results from the hypertrophy, insulin, glucose, and electrolytes (HINGE) trial.
Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
Coronary revascularization: A procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study.
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