Advertisement

Cardioprotective Effects of Glucose-Insulin-Potassium Infusion in Patients Undergoing Cardiac Surgery: A Systematic Review and Meta-Analysis

Open AccessPublished:November 07, 2022DOI:https://doi.org/10.1053/j.semtcvs.2022.11.002
      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.

      Graphical abstract

      Keywords

      Abbreviations:

      95%CI (ninety-five percent confidence interval), AF (atrial fibrillation), AKI (acute kidney injury), AXC (aortic cross-clamping), CABG (coronary artery bypass grafting), CPB (cardiopulmonary bypass), GIK (glucose-insulin-potassium), ICU (intensive care unit), IQR (interquartile range 25%-75%), k (model sample count), MD (mean difference), MI (myocardial infarction (postoperative)), n (count (events or participants)), OR (odds ratio), RCT (randomized controlled trial)
      Unlabelled image
      GIK enhances recovery after cardiac surgery: a meta-analysis since inception.
      Central Message
      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.
      • Vervoort D
      • Meuris B
      • Meyns B
      • et al.
      Global cardiac surgery: Access to cardiac surgical care around the world.
      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.
      • Hausenloy DJ
      • Boston-Griffiths E
      • Yellon DM
      Cardioprotection during cardiac surgery.
      • Bonanni A
      • Signori A
      • Alicino C
      • et al.
      Volatile anesthetics versus propofol for cardiac surgery with cardiopulmonary bypass: Meta-analysis of randomized trials.
      • Weisse AB
      Cardiac surgery: A century of progress.
      • Adelborg K
      • Horváth-Puhó E
      • Schmidt M
      • et al.
      Thirty-year mortality after coronary artery bypass graft surgery: A danish nationwide population-based cohort study.
      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.
      • Ellenberger C
      • Sologashvili T
      • Cikirikcioglu M
      • et al.
      Risk factors of postcardiotomy ventricular dysfunction in moderate-to-high risk patients undergoing open-heart surgery.
      • Jarral OA
      • Saso S
      • Harling L
      • et al.
      Organ dysfunction in patients with left ventricular impairment: What is the effect of cardiopulmonary bypass?.
      • Anselmi A
      • Abbate A
      • Girola F
      • et al.
      Myocardial ischemia, stunning, inflammation, and apoptosis during cardiac surgery: A review of evidence.
      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.
      • Algarni KD
      • Elhenawy AM
      • Maganti M
      • et al.
      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.
      ,
      • Croal BL
      • Hillis GS
      • Gibson PH
      • et al.
      Relationship between postoperative cardiac troponin I levels and outcome of cardiac surgery.
      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.
      • Klein LJ
      • Visser FC
      The effect of insulin on the heart: Part 1: Effects on metabolism and 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.
      • Ng KW
      • Allen ML
      • Desai A
      • et al.
      Cardioprotective effects of insulin: How intensive insulin therapy may benefit cardiac surgery patients.
      Since its introduction in 1962,
      • Sodi-Pallares D
      • Testelli MR
      • Fishleder BL
      • et al.
      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.
      • Ng KW
      • Allen ML
      • Desai A
      • et al.
      Cardioprotective effects of insulin: How intensive insulin therapy may benefit cardiac surgery patients.
      ,
      • Maroko PR
      • Braunwald E
      Effects of metabolic and pharmacologic interventions on myocardial infarct size following coronary occlusion.
      In previous systematic reviews,
      • Fan Y
      • Zhang A-M
      • Xiao Y-B
      • et al.
      Glucose-Insulin-Potassium therapy in adult patients undergoing cardiac surgery: A meta-analysis.
      • Ali-Hassan-Sayegh S
      • Mirhosseini SJ
      • Zeriouh M
      • et al.
      Safety and efficacy of glucose-insulin-potassium treatment in coronary artery bypass graft surgery and percutaneous coronary intervention.
      • Li Q
      • Yang J
      • Zhang J
      • et al.
      Effect of perioperative glucose-insulin-potassium therapy in patients undergoing on-pump cardiac surgery: A meta-analysis.
      • Rabi DM
      • Clement FM
      • McAlister FA
      • et al.
      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).
      • Shamseer L
      • Moher D
      • Clarke M
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: Elaboration and explanation.
      ,
      • Cumpston M
      • Li T
      • Page MJ
      • et al.
      Updated guidance for trusted systematic reviews: A new edition of the cochrane handbook for systematic reviews of interventions.
      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.
      • Cumpston M
      • Li T
      • Page MJ
      • et al.
      Updated guidance for trusted systematic reviews: A new edition of the cochrane handbook for systematic reviews of interventions.
      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.
      • Savovic J
      • Turner RM
      • Mawdsley D
      • et al.
      Association between risk-of-bias assessments and results of randomized trials in cochrane reviews: The ROBES meta-epidemiologic study.
      Studies that did not detail allocation concealment, blinding of participants and personnel or random sequence generation were graded as unclear.
      The certainty of evidence was assessed using GRADE: the grading of recommendations assessment, development, and evaluation framework.
      • Guyatt GH
      • Oxman AD
      • Vist GE
      • et al.
      GRADE: An emerging consensus on rating quality of evidence and strength of recommendations.

      Statistical Analysis

      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.
      • Higgins J
      • Thomas J
      • Chandler J
      • et al.
      Cochrane Handbook for Systematic Reviews of Interventions Version 6.2.
      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”.
      R Core Team
      R: A Language and Environment for Statistical Computing.
      ,
      • Balduzzi S
      • Rücker G
      • Schwarzer G
      How to perform a meta-analysis with R: A practical tutorial.
      Analysis of the primary outcome was stratified by GIK timing, composition, insulin infusion rate (cutoff 2 mUI/kg/min),
      • Klein LJ
      • Visser FC
      The effect of insulin on the heart: Part 1: Effects on metabolism and function.
      ,
      • McDaniel HG
      • Papapietro SE
      • Rogers WJ
      • et al.
      Glucose-insulin-potassium induced alterations in individual plasma free fatty acids in patients with acute myocardial infarction.
      ,
      • Jaswal JS
      • Keung W
      • Wang W
      • et al.
      Targeting fatty acid and carbohydrate oxidation–a novel therapeutic intervention in the ischemic and failing heart.
      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.
      • Duval S
      • Tweedie R
      Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.

      RESULTS

      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).
      • Ellenberger C
      • Sologashvili T
      • Cikirikcioglu M
      • et al.
      Risk factors of postcardiotomy ventricular dysfunction in moderate-to-high risk patients undergoing open-heart surgery.
      ,
      • Coleman GM
      • Gradinac S
      • Taegtmeyer H
      • et al.
      Efficacy of metabolic support with glucose-insulin-potassium for left ventricular pump failure after aortocoronary bypass surgery.
      • Gradinac S
      • Coleman GM
      • Taegtmeyer H
      • et al.
      Improved cardiac function with glucose-insulin-potassium after aortocoronary bypass grafting.
      • Rudez I
      • Sutlić Z
      • Husedzinović I
      • et al.
      The importance of glucose-insulin-potassium with cardiopulmonary bypass prior to cardioplegic arrest in open-heart surgery.
      • Cimochowski GE
      • Harostock MD
      • Foldes PJ
      Minimal operative mortality in patients undergoing coronary artery bypass with significant left ventricular dysfunction by maximization of metabolic and mechanical support.
      • Jeppsson A
      • Ekroth R
      • Kirnö K
      • et al.
      Insulin and amino acid infusion after cardiac operations: Effects on systemic and renal perfusion.
      • Lindholm Lena
      • Nilsson Boris
      • Klaus
      Is skeletal muscle luxury perfusion the main hemodynamic effect of high-dose insulin in cardiac surgery?.
      • Díaz R
      • Goyal A
      • Mehta SR
      • et al.
      Glucose-insulin-potassium therapy in patients with ST-segment elevation myocardial infarction.
      • Zhao K
      • Fu F
      • Zhang Y
      • et al.
      Glucose-insulin-potassium improves cardiac performance via inhibiting hexosamine biosynthesis in patients undergoing cardiopulmonary bypass.
      • Licker M
      • Diaper J
      • Sologashvili T
      • et al.
      Glucose-insulin-potassium improves left ventricular performances after aortic valve replacement: A secondary analysis of a randomized controlled trial.
      • Ranasinghe AM
      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.
      • Duncan AE
      • Kateby Kashy B
      • Sarwar S
      • et al.
      Hyperinsulinemic normoglycemia does not meaningfully improve myocardial performance during cardiac surgery: A randomized trial.
      • Duncan AE
      • Sessler DI
      • Sato H
      • et al.
      Hyperinsulinemic normoglycemia during cardiac surgery reduces a composite of 30-day mortality and serious in-hospital complications: a randomized clinical trial.
      • Ellenberger C
      • Sologashvili T
      • Kreienbühl L
      • et al.
      Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
      • Un Roh G
      • Shim JK
      • Song JW
      • et al.
      Effect of glucoseInsulinPotassium on hyperlactataemia in patients undergoing valvular heart surgery: A randomised controlled study.
      • Jovic M
      • Gradinac S
      • Lausevic-Vuk L
      • et al.
      Preconditioning with glucose-insulin-potassium solution and restoration of myocardial function during coronary surgery.
      • Shim YH
      • Kweon TD
      • Lee JH
      • et al.
      Intravenous glucose?Insulin?Potassium during off-pump coronary artery bypass surgery does not reduce myocardial injury.
      • Shim J-K
      • Yang S-Y
      • Yoo Y-C
      • et al.
      Myocardial protection by glucose-Insulin-Potassium in acute coronary syndrome patients undergoing urgent multivessel off-pump coronary artery bypass surgery.
      • Sato H
      • Hatzakorzian R
      • Carvalho G
      • et al.
      High-dose insulin administration improves left ventricular function after coronary artery bypass graft surgery.
      As reported in Table 1, studies were published between 1977 and 2021, were conducted in 21 countries and included CABG surgery: (39 RCTs),
      • Jovic M
      • Gradinac S
      • Lausevic-Vuk L
      • et al.
      Preconditioning with glucose-insulin-potassium solution and restoration of myocardial function during coronary surgery.
      • Shim YH
      • Kweon TD
      • Lee JH
      • et al.
      Intravenous glucose?Insulin?Potassium during off-pump coronary artery bypass surgery does not reduce myocardial injury.
      • Shim J-K
      • Yang S-Y
      • Yoo Y-C
      • et al.
      Myocardial protection by glucose-Insulin-Potassium in acute coronary syndrome patients undergoing urgent multivessel off-pump coronary artery bypass surgery.
      • Sato H
      • Hatzakorzian R
      • Carvalho G
      • et al.
      High-dose insulin administration improves left ventricular function after coronary artery bypass graft surgery.
      • Lolley DM
      Preservation of human cardiac contractility during anoxic arrest with glucose-containing cardioplegia.
      • Andĕl M
      • Táborský J
      • Martínek J
      • et al.
      Cardioprotective conditioning with glucose and insulin prior to cardiac surgery involving ischaemic cold arrest.
      • Wistbacka M
      • Kaukoranta PK
      • Nuutinen LS
      Prebypass glucose-insulin-potassium infusion in elective nondiabetic coronary artery surgery patients.
      • Boldt J
      • Knothe C
      • Zickmann B
      • et al.
      Influence of different glucose-insulin-potassium regimes on glucose homeostasis and hormonal response in cardiac surgery patients.
      • Brodin LA
      • Dahlgren G
      • Ekeström S
      • et al.
      Influence of glucose-insulin-potassium on left ventricular function during coronary artery bypass grafting.
      • Kjellman UW
      • Björk K
      • Dahlin A
      • et al.
      Insulin(GIK) improves myocardial metabolism in patients during blood cardioplegia.
      • Szabó Z
      • Arnqvist H
      • Håkanson E
      • et al.
      Effects of high-dose glucose-insulin-potassium on myocardial metabolism after coronary surgery in patients with Type II diabetes.
      • Bruemmer-Smith S
      • Avidan MS
      • Harris B
      • et al.
      Glucose, insulin and potassium for heart protection during cardiac surgery.
      • Lell WA
      • Nielsen VG
      • McGiffin DC
      • et al.
      Glucose-insulin-potassium infusion for myocardial protection during off-pump coronary artery surgery.
      • Visser L
      • Zuurbier CJ
      • Hoek FJ
      • et al.
      Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
      • Quinn DW
      • Pagano D
      • Bonser RS
      • et al.
      Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: A randomized controlled trial.
      • de Barcellos C da S
      • Wender OCB
      • de Azambuja PC
      Glicose insulina e potássio (GIK) na revascularização do miocárdio de pacientes diabéticos: Ensaio clínico randomizado.
      • Zuurbier CJ
      • Hoek FJ
      • van Dijk J
      • et al.
      Perioperative hyperinsulinaemic normoglycaemic clamp causes hypolipidaemia after coronary artery surgery this article is accompanied by editorial I.
      • Laiq N
      • Khan S
      • Ahmed H
      • et al.
      The effects of glycaemic control in cardiac patients undergoing CABG surgery.
      • Ahmad S
      • Altaf Ahmad R
      • Ahsan Qureshi B
      • et al.
      Myocardial protection with Glucose-Insulin-Potassium infusion during adult cardiac surgery.
      • Girard C
      • Quentin P
      • Bouvier H
      • et al.
      Glucose and insulin supply before cardiopulmonary bypass in cardiac surgery: A double-blind study.
      • Lazar HL
      • Philippides G
      • Fitzgerald C
      • et al.
      Glucose-insulin-potassium solutions enhance recovery after urgent coronary artery bypass grafting.
      • Lazar HL
      • Chipkin S
      • Philippides G
      • et al.
      Glucose-insulin-potassium solutions improve outcomes in diabetics who have coronary artery operations.
      • Lazar HL
      • Chipkin SR
      • Fitzgerald CA
      • et al.
      Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.
      • Celkan M
      • Kazaz H
      • Daglar B
      • et al.
      Effects of glucose-insulin-potassium solution on cardiac cytokines and enzymes.
      • Koskenkari JK
      • Kaukoranta PK
      • Rimpiläinen J
      • et al.
      Anti-inflammatory effect of high-dose insulin treatment after urgent coronary revascularization surgery.
      • Ranasinghe AM
      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.
      • Smith A
      • Grattan A
      • Harper M
      • et al.
      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.
      • Foroughi M
      • Rahimian H
      • Dabbagh A
      • et al.
      Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
      • Tsang MW
      • Davidoff R
      • Korach A
      • et al.
      Diastolic dysfunction after coronary artery bypass grafting?The effect of glucose-insulin-potassium infusion.
      • Straus S
      • Gerc V
      • Kacila M
      • et al.
      Glucosa-Insulin-Potassium (GIK) solution used with diabetic patients provides better recovery after coronary bypass operations.
      • Seied-Hosseini SM
      • Pourmoghadas A
      • Aghadavoudi O
      • et al.
      Efficacy of glucose-insulin-potassium infusion on left ventricular performance in type II diabetic patients undergoing elective coronary artery bypass Graft.Dy.
      • Wistbacka JO
      • Nuutinen LS
      • Lepojärvi MV
      • et al.
      Perioperative glucose-insulin-potassium infusion in elective coronary surgery: Minor benefit in connection with blood cardioplegia?.
      • Turkoz A
      • Toprak H
      • Sari S
      • et al.
      Glucose-insulin-potassium solution before cardiopulmonary bypass in coronary artery surgery.
      • Ray JF
      • Tewksbury DA
      • Myers WO
      • et al.
      Can the frequency of myocardial infarction be reduced during coronary artery operations.
      • Lolley DM
      • Ray JF
      • Myers WO
      • et al.
      Reduction of intraoperative myocardial infarction by means of exogenous anaerobic substrate enhancement: Prospective randomized study.
      • Salerno TA
      • Wasan SM
      • Charrette EJ
      Glucose substrate in myocardial protection.
      • Svensson S
      • Ekroth R
      • Nilsson F
      • et al.
      Insulin as a vasodilating agent in the first hour after cardiopulmonary bypass.
      • Hallhagen S
      • Svedjeholm R
      • Ekroth R
      • et al.
      Effects of insulin on myocardial uptake of branched chain amino acids soon after cardiac operations.
      • Albacker TB
      • Carvalho G
      • Schricker T
      • et al.
      Myocardial protection during elective coronary artery bypass grafting using high-dose insulin therapy.
      valve surgery (4 RCTs)
      • Haider W
      • Benzer H
      • Schütz W
      • et al.
      Improvement of cardiac preservation by preoperative high insulin supply.
      • Oldfield GS
      • Commerford PJ
      • Opie LH
      Effects of preoperative glucose-insulin-potassium on myocardial glycogen levels and on complications of mitral valve replacement.
      • Tünerir B
      • Aslan R
      • Isiksoy S
      • et al.
      Benefits of glucose-insulin-potassium before mitral valve replacement.
      • Besogul Y
      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.
      and combined procedures (10 RCTs).
      • Duncan AE
      • Kateby Kashy B
      • Sarwar S
      • et al.
      Hyperinsulinemic normoglycemia does not meaningfully improve myocardial performance during cardiac surgery: A randomized trial.
      • Duncan AE
      • Sessler DI
      • Sato H
      • et al.
      Hyperinsulinemic normoglycemia during cardiac surgery reduces a composite of 30-day mortality and serious in-hospital complications: a randomized clinical trial.
      • Ellenberger C
      • Sologashvili T
      • Kreienbühl L
      • et al.
      Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
      • Un Roh G
      • Shim JK
      • Song JW
      • et al.
      Effect of glucoseInsulinPotassium on hyperlactataemia in patients undergoing valvular heart surgery: A randomised controlled study.
      ,
      • Bengtsson Lindholm V Anders
      Insulin (GIK) improves central mixed and hepatic venous oxygenation in clinical cardiac surgery.
      • Wallin M
      • Barr G
      • Öwall A
      • et al.
      The influence of glucose-insulin-potassium (GIK) on the GH/IGF-1/IGFBP-1 axis during elective coronary artery bypass surgery.
      • Howell NJ
      • Ashrafian H
      • Drury NE
      • et al.
      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.
      • Rujirojindakul P
      • Liabsuetrakul T
      • Mcneil E
      • et al.
      Safety and efficacy of intensive intraoperative glycaemic control in cardiopulmonary bypass surgery: A randomised trial: Safety and efficacy of glycaemic control.
      • Zhao K
      • Zhang Y
      • Li J
      • et al.
      Modified glucose-insulin-potassium regimen provides cardioprotection with improved tissue perfusion in patients undergoing cardiopulmonary bypass surgery.
      • Nilsson FN
      • Berglin EE
      • Ekroth R
      • et al.
      Effects of graded insulin infusions on plasma levels of free fatty acids, adrenaline and noradrenaline directly after open heart surgery.
      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,
      • Ellenberger C
      • Sologashvili T
      • Kreienbühl L
      • et al.
      Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
      ,
      • Un Roh G
      • Shim JK
      • Song JW
      • et al.
      Effect of glucoseInsulinPotassium on hyperlactataemia in patients undergoing valvular heart surgery: A randomised controlled study.
      ,
      • Quinn DW
      • Pagano D
      • Bonser RS
      • et al.
      Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: A randomized controlled trial.
      ,
      • de Barcellos C da S
      • Wender OCB
      • de Azambuja PC
      Glicose insulina e potássio (GIK) na revascularização do miocárdio de pacientes diabéticos: Ensaio clínico randomizado.
      ,
      • Ranasinghe AM
      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.
      ,
      • Howell NJ
      • Ashrafian H
      • Drury NE
      • et al.
      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.
      • Rujirojindakul P
      • Liabsuetrakul T
      • Mcneil E
      • et al.
      Safety and efficacy of intensive intraoperative glycaemic control in cardiopulmonary bypass surgery: A randomised trial: Safety and efficacy of glycaemic control.
      • Zhao K
      • Zhang Y
      • Li J
      • et al.
      Modified glucose-insulin-potassium regimen provides cardioprotection with improved tissue perfusion in patients undergoing cardiopulmonary bypass surgery.
      5 with unclear risk
      • Shim J-K
      • Yang S-Y
      • Yoo Y-C
      • et al.
      Myocardial protection by glucose-Insulin-Potassium in acute coronary syndrome patients undergoing urgent multivessel off-pump coronary artery bypass surgery.
      ,
      • Girard C
      • Quentin P
      • Bouvier H
      • et al.
      Glucose and insulin supply before cardiopulmonary bypass in cardiac surgery: A double-blind study.
      ,
      • Celkan M
      • Kazaz H
      • Daglar B
      • et al.
      Effects of glucose-insulin-potassium solution on cardiac cytokines and enzymes.
      ,
      • Smith A
      • Grattan A
      • Harper M
      • et al.
      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.
      ,
      • Foroughi M
      • Rahimian H
      • Dabbagh A
      • et al.
      Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
      and 40 trials at high risk of bias.
      • Duncan AE
      • Kateby Kashy B
      • Sarwar S
      • et al.
      Hyperinsulinemic normoglycemia does not meaningfully improve myocardial performance during cardiac surgery: A randomized trial.
      ,
      • Duncan AE
      • Sessler DI
      • Sato H
      • et al.
      Hyperinsulinemic normoglycemia during cardiac surgery reduces a composite of 30-day mortality and serious in-hospital complications: a randomized clinical trial.
      ,
      • Jovic M
      • Gradinac S
      • Lausevic-Vuk L
      • et al.
      Preconditioning with glucose-insulin-potassium solution and restoration of myocardial function during coronary surgery.
      ,
      • Shim YH
      • Kweon TD
      • Lee JH
      • et al.
      Intravenous glucose?Insulin?Potassium during off-pump coronary artery bypass surgery does not reduce myocardial injury.
      ,
      • Sato H
      • Hatzakorzian R
      • Carvalho G
      • et al.
      High-dose insulin administration improves left ventricular function after coronary artery bypass graft surgery.
      • Lolley DM
      Preservation of human cardiac contractility during anoxic arrest with glucose-containing cardioplegia.
      • Andĕl M
      • Táborský J
      • Martínek J
      • et al.
      Cardioprotective conditioning with glucose and insulin prior to cardiac surgery involving ischaemic cold arrest.
      • Wistbacka M
      • Kaukoranta PK
      • Nuutinen LS
      Prebypass glucose-insulin-potassium infusion in elective nondiabetic coronary artery surgery patients.
      • Boldt J
      • Knothe C
      • Zickmann B
      • et al.
      Influence of different glucose-insulin-potassium regimes on glucose homeostasis and hormonal response in cardiac surgery patients.
      • Brodin LA
      • Dahlgren G
      • Ekeström S
      • et al.
      Influence of glucose-insulin-potassium on left ventricular function during coronary artery bypass grafting.
      • Kjellman UW
      • Björk K
      • Dahlin A
      • et al.
      Insulin(GIK) improves myocardial metabolism in patients during blood cardioplegia.
      • Szabó Z
      • Arnqvist H
      • Håkanson E
      • et al.
      Effects of high-dose glucose-insulin-potassium on myocardial metabolism after coronary surgery in patients with Type II diabetes.
      • Bruemmer-Smith S
      • Avidan MS
      • Harris B
      • et al.
      Glucose, insulin and potassium for heart protection during cardiac surgery.
      • Lell WA
      • Nielsen VG
      • McGiffin DC
      • et al.
      Glucose-insulin-potassium infusion for myocardial protection during off-pump coronary artery surgery.
      • Visser L
      • Zuurbier CJ
      • Hoek FJ
      • et al.
      Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
      ,
      • Zuurbier CJ
      • Hoek FJ
      • van Dijk J
      • et al.
      Perioperative hyperinsulinaemic normoglycaemic clamp causes hypolipidaemia after coronary artery surgery this article is accompanied by editorial I.
      • Laiq N
      • Khan S
      • Ahmed H
      • et al.
      The effects of glycaemic control in cardiac patients undergoing CABG surgery.
      • Ahmad S
      • Altaf Ahmad R
      • Ahsan Qureshi B
      • et al.
      Myocardial protection with Glucose-Insulin-Potassium infusion during adult cardiac surgery.
      ,
      • Lazar HL
      • Philippides G
      • Fitzgerald C
      • et al.
      Glucose-insulin-potassium solutions enhance recovery after urgent coronary artery bypass grafting.
      • Lazar HL
      • Chipkin S
      • Philippides G
      • et al.
      Glucose-insulin-potassium solutions improve outcomes in diabetics who have coronary artery operations.
      • Lazar HL
      • Chipkin SR
      • Fitzgerald CA
      • et al.
      Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.
      ,
      • Koskenkari JK
      • Kaukoranta PK
      • Rimpiläinen J
      • et al.
      Anti-inflammatory effect of high-dose insulin treatment after urgent coronary revascularization surgery.
      ,
      • Tsang MW
      • Davidoff R
      • Korach A
      • et al.
      Diastolic dysfunction after coronary artery bypass grafting?The effect of glucose-insulin-potassium infusion.
      • Straus S
      • Gerc V
      • Kacila M
      • et al.
      Glucosa-Insulin-Potassium (GIK) solution used with diabetic patients provides better recovery after coronary bypass operations.
      • Seied-Hosseini SM
      • Pourmoghadas A
      • Aghadavoudi O
      • et al.
      Efficacy of glucose-insulin-potassium infusion on left ventricular performance in type II diabetic patients undergoing elective coronary artery bypass Graft.Dy.
      • Wistbacka JO
      • Nuutinen LS
      • Lepojärvi MV
      • et al.
      Perioperative glucose-insulin-potassium infusion in elective coronary surgery: Minor benefit in connection with blood cardioplegia?.
      • Turkoz A
      • Toprak H
      • Sari S
      • et al.
      Glucose-insulin-potassium solution before cardiopulmonary bypass in coronary artery surgery.
      • Ray JF
      • Tewksbury DA
      • Myers WO
      • et al.
      Can the frequency of myocardial infarction be reduced during coronary artery operations.
      • Lolley DM
      • Ray JF
      • Myers WO
      • et al.
      Reduction of intraoperative myocardial infarction by means of exogenous anaerobic substrate enhancement: Prospective randomized study.
      • Salerno TA
      • Wasan SM
      • Charrette EJ
      Glucose substrate in myocardial protection.
      • Svensson S
      • Ekroth R
      • Nilsson F
      • et al.
      Insulin as a vasodilating agent in the first hour after cardiopulmonary bypass.
      • Hallhagen S
      • Svedjeholm R
      • Ekroth R
      • et al.
      Effects of insulin on myocardial uptake of branched chain amino acids soon after cardiac operations.
      • Albacker TB
      • Carvalho G
      • Schricker T
      • et al.
      Myocardial protection during elective coronary artery bypass grafting using high-dose insulin therapy.
      • Haider W
      • Benzer H
      • Schütz W
      • et al.
      Improvement of cardiac preservation by preoperative high insulin supply.
      • Oldfield GS
      • Commerford PJ
      • Opie LH
      Effects of preoperative glucose-insulin-potassium on myocardial glycogen levels and on complications of mitral valve replacement.
      • Tünerir B
      • Aslan R
      • Isiksoy S
      • et al.
      Benefits of glucose-insulin-potassium before mitral valve replacement.
      • Besogul Y
      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.
      • Bengtsson Lindholm V Anders
      Insulin (GIK) improves central mixed and hepatic venous oxygenation in clinical cardiac surgery.
      • Wallin M
      • Barr G
      • Öwall A
      • et al.
      The influence of glucose-insulin-potassium (GIK) on the GH/IGF-1/IGFBP-1 axis during elective coronary artery bypass surgery.
      ,
      • Nilsson FN
      • Berglin EE
      • Ekroth R
      • et al.
      Effects of graded insulin infusions on plasma levels of free fatty acids, adrenaline and noradrenaline directly after open heart surgery.
      The risks of bias assessment are summarized in Figure 2 and detailed in a supplementary file (S4).
      Table 1Characteristics of the Included Population
      AuthorsCountryAge [y]M/FDiabetes mellitusLVEF [%]AXC [min]SurgeryGIK FormulaGIK Timing
      Ahmad et al. 2017Pakistan55(8)/54(10)(69/11)/(72/8)No53(9)/ 52(10)64(17)/62(18)CABGS0.5 mUI/kg/min insulin, 5% dextrose, K 70 mEq/Lpreop
      Albacker et al. 2007Canada59(3)/65(2)(20/2)/(16/6)Mixed49(3)/47(3)65(5)/71(5)CABGS5 mUI/kg/min insulin, 20% dextrose, K NApreop, cpb, postop
      Andel et al. 1990Czechoslovakia56(NA)/51(NA)NANoNA57(NA)/54 (NA)CABGS1.5 mUI/kg/min rapid insulin, 40% glucose, K 60 mEq/Lpreop
      Barcellos et al. 2007Brazil60(9)/59(6)(7/5)/(8/4)Yes60(14)/ 54(16)89(29)/87(22)CABGS1.2 mUI/kg/min regular insulin, 5% glucose, K 80 mEq/Lpreop, postop
      Besogul et al. 1999Turkey38(NA)/35(NA)(4/11)/(3/12)Mixed55(NA)/ 52 (NA)76(NA)/73 (NA)Valve0.2 mUI/kg/min insulin, 20% glucose, K 45 mEq/Lpreop
      Boldt et al. 1993Germany62(7)/63(7)NANo63(9)/64(7)45(8)/44(11)CABGS35.7 mUI/kg/min regular insulin, glucose, K 70 mEq/Lpreop
      Boldt et al. 1993Germany61(6)/63(7)NANo66(6)/64(7)48(8)/44(11)CABGS17.9 mUI/kg/min regular insulin, glucose, K 70 mEq/Lpreop
      Brodin et al. 1993Sweden60(NA)/57(NA)(7/0)/ (4/3)MixedNA81(40)/55(21)CABGS22.5 mUI/kg/min insulin, 30% glucose, K 2000 mEq/Lpreop
      Bruemmer et al. 2002UK64(10)/66(10)(19/0)/ (15/5)NoNA51(14)/45(12)CABGS2.5 mUI/kg/min insulin, 50% glucose, K 160 mEq/Lpreop, cpb, postop
      Celkan et al. 2006Turkey58(11)/56(11)NANoNA70(15)/64(22)CABGS3.3 mUI/kg/min insulin, 30% dextrose, K 160 mEq/Lpreop, postop
      Duncan et al. 2015USA70(9)/70(11)(36/13)/(31/17)mixed59(15)/ 64(9)NACombined5 mUI/kg/min insulin, 20% dextrose, K 40 mEq/L, PO 120 mEq/Lpreop, cpb, postop
      Duncan et al. 2018USA66(11)/66(11)(520/189/(546/184)mixedNA80(33)/81(31)Combined5 mUI/kg/min insulin, 20% dextrose, K 40 mEq/LNA
      Ellenberger et al. 2018Switzerland71(11)/72(11)(73/80)/ (37/32)mixed43(10)/ 47(9)79(36)/76(33)Combined4.8 mUI/kg/min rapid insulin, 40% glucose, K 10 mEq/Lpreop
      Foroughi et al. 2012Iran61(1)/59(1)(21/15)/(17/13)NoNA62(19)/65(14)CABGS1.3 mUI/kg/min regular insulin, 10% dextrose, K 80 mEq/L,preop, cpb
      Girard et al. 1992France58(9)/56(10)(27/13)/(29/11)mixedNA48(16)/45(16)CABGSinsulin, 30% glucose, K 70 mEq/Lpreop
      Haider et al. 1984Austria58(NA)/52(NA)NAmixedNA35(NA)/39(NA)Valve16.7 mUI/kg/min rapid insulin, 33% glucose, K 70 mEq/Lpreop
      Hallhagen et al. 1992Sweden57(3)/56(4)NANoNA61(6)/66(8)CABGS22.7 mUI/kg/min rapid insulin, 40% glucose, K 100 mEq/Lpostop
      Howell et al. 2011UK70(10)/70(7)(67/43)/ (77/30)NoNANACombinedNANA
      Jovic et al. 2009SerbiaNANAmixedNA44(NA)/39(NA)CABGS1.1 mUI/kg/min insulin, 20% glucose, K 80 mEq/Lpreop, postop
      Jovic et al. 2009SerbiaNANAmixedNA47(NA)/39(NA)CABGS0.3 mUI/kg/min insulin, 10% glucose, K 80 mEq/Lpreop, postop
      Kjellman et al. 2000Sweden64(3)/63(2)(14/0)/(14/0)No47(4)/ 42(6)64(3)/64(3)CABGS66.7 mUI/kg/min insulin, 30% glucose, K 40 mEq/Lcpb
      Koskenkari et al. 2006Finland67(8)/67(8)(13/6)/(15/5)NoNA93(22)/84(13)CABGS16.7 mUI/kg/min rapid insulin, 30% glucose, K 20 mEq/Lcpb, postop
      Laiq et al. 2015PakistanNANAYesNA48(2)/45(1)CABGS1.5 mUI/kg/min regular insulin, 5% dextrose, K 80 mEq/Lpreop, cpb, postop
      Lazar et al. 1997USA60(NA)/65(NA)(11/4)/(10/5)NoNA44(3)/41(2)CABGSregular insulin, 30% dextrose, K 80 mEq/Lpreop, postop
      Lazar et al. 2000USA65(9)/65(11)(10/10)/(11/9)Yes41(10) /40(10)47(12)/42(11)CABGS1.1 mUI/kg/min regular insulin, 5% dextrose, K 80 mEq/Lpreop, postop
      Lazar et al. 2004USA64(1)/64(2)(42/46)/(30/23)Yes42(1)/ 41(2)48(2)/44(1)CABGS1.1 mUI/kg/min regular insulin, 5% dextrose, K 80 mEq/Lpreop, postop
      Lell et al. 2002USA62(9)/57(10)(11/10)/(13/7)mixed50(12)/ 41(16)34(13)/31(14)CABGSOff-pumpregular insulin, 25% glucose, K 80 mEq/Lpreop, cpb, postop
      Lindholm et al. 2001Sweden72(8)/74(7)(8/8)/(5/9)mixed57(12)/ 57(15)84(32)/114(45)Combined285.7 mUI/kg/min rapid insulin, 30% glucose, no Kpostop
      Lolley et al. 1978USA56(NA)/54(NA)(84/30)/(126/31)mixedNA48(16)/44(15)CABGS5.7 mUI/kg/min regular insulin, 5% dextrose, K 22.5 mEq/Lcpb
      Lolley et al. 1985USA56(1)/54(1)(40/13)/(40/9)mixed62(2)/ 64(2)47(2)/42(2)CABGS4.8 mUI/kg/min regular insulin, 5% glucose, K 20 mEq/Lcpb
      Nilsson et al. 1987Sweden52(NA)/64(NA)(5/1)/(5/3)NoNA68(10)/78(7)Combined2.5 mUI/kg/min rapid insulin, 40% glucose, K 100 mEq/L, PO 120 mEq/Lpostop
      Nilsson et al. 1987Sweden56(NA)/64(NA)(4/2)/(5/3)NoNA87(7)/78(7)Combined5 mUI/kg/min rapid insulin, 40% glucose, K 100 mEq/L, PO 120 mEq/Lpostop
      Nilsson et al. 1987Sweden60(NA)/64(NA)(8/0)/(5/3)NoNA80(7)/78(7)Combined16.7 mUI/kg/min rapid insulin, 40% glucose, K 100 mEq/L, PO 120 mEq/Lpostop
      Oldfield et al. 1986South Africa38(27)/41(19)(6/14)/(8/15)mixedNA67(8)/63(6)Valve0.2 mUI/kg/min insulin, 20% glucose, K 45 mEq/Lpreop
      Quinn et al. 2006UK64(9)/64(9)NANoNA49(16)/48(18)CABGS2.1 mUI/kg/min rapid insulin, 40% dextrose, K 80 mEq/Lpreop, cpb, postop
      Ranasinghe et al. 2006UK64(9)/64(9)(137/20)/(132/28)NoNA49(15)/47(18)CABGS0.9 mUI/kg/min rapid insulin, 40% dextrose, K 80 mEq/Lpreop, cpb, postop
      Ray et al. 1977USANANAmixedNANACABGS700 mUI/kg/min insulin, 10% glucose, K 120 mEq/Lcpb
      Roh et al. 2015Korea61(11)/64(11)(27/26)/(24/29)mixed62(10)/ 62(11)96(41)/95(35)Combined1.7 mUI/kg/min insulin, 30% glucose, K 80 mEq/Lpreop
      Rujirojindakul et al.2014Thailand52(19)/55(15)(55/44)/(57/43)mixedNA62(24)/60(23)Combined5 mUI/kg/min insulin, 25% glucose, K 400 mEq/Lpreop, cpb, postop
      Salerno et al. 1980CanadaNANANoNA48(NA)/45(NA)CABGS0.3 mUI/kg/min insulin, 10% dextrose, K 40 mEq/Lpreop
      Sato et al. 2011Canada64(8)/65(11)(14/6)/(15/5)mixed54(8)/ 55(8)84(29)/82(30)CABGS5 mUI/kg/min insulin, 20% glucose, K NA, PO 120 mEq/LNA
      Seied et al. 2010Iran58(10)/61(8)(9/16)/(14/6)Yes51(8)/ 50(12)60(15)/61(17)CABGS1.1 mUI/kg/min regular insulin, 5% dextrose, K 80 mEq/Lpreop, cpb, postop
      Shim et al. 2006Korea64(9)/59(10)(12/31)/(11/28)Mixed59(13)/ 62(12)NACABGS3.1 mUI/kg/min regular insulin, 50% dextrose, K 160 mEq/Lpreop, cpb, postop
      Shim et al. 2013Korea63(NA)/55(NA)(20/13)/(23/10)Mixed35(11)/ 39(9)NACABGSOff-pump3.3 mUI/kg/min regular insulin, 50% glucose, K 160 mEq/Lpreop, cpb, postop
      Smith et al. 2002UK64(8)/68(8)(9/2)/(10/2)MixedNA45(14)/40(16)CABGSOff-pump0.8 mUI/kg/min rapid insulin, 50% dextrose, K 250 mEq/Lpreop, cpb, postop
      Straus et al. 2013Bosnia62(8)/61(7)(35/15)/(29/21)Yes50(NA)/45(NA)42(NA)/39(NA)CABGSNAcpb
      Svensson et al. 1989Sweden61(4)/58(2)NAMixed50(7)/ 58(4)65(7)/57(6)CABGS251.7 mUI/kg/min rapid insulin, 40% glucose, K 100 mEq/L, PO 120 mEq/Lcpb, postop
      Szabo et al. 2001Sweden58(6)/56(9)(9/1)/(7/3)YesNA45(22)/46(16)CABGS16.7 mUI/kg/min rapid insulin, 30% glucose, no K, PO 160 mEq/Lmmol/Lpostop
      Tsang et al. 2007USA64(9)/67(7)(12/2)/(15/2)Mixed61(11)/ 58(14)43(8)/42(9)CABGS0.8 mUI/kg/min regular insulin, 30% dextrose, K 80 mEq/Lpreop, postop
      Tunerir et al. 1998Turkey38(NA)/35(NA)(4/11)/(3/12)Mixed55(NA)/52(NA)76(NA)/73(NA)Valve0.2 mUI/kg/min insulin, 20% glucose, K 45 mEq/Lpreop
      Turkoz et al. 2000Turkey64(2)/60(2)(10/5)/(13/3)No40(3)/ 41(1)63(5)/63(6)CABGS2.3 mUI/kg/min insulin, 30% dextrose, K 160 mEq/Lpreop
      Visser et al. 2005Netherlands63(NA)/62(NA)(8/2)/(10/1)NoNA57(34)/57(17)CABGS1.7 mUI/kg/min rapid insulin, 30% glucose, K 80 mEq/L, PO 240 mEq/Lpreop, cpb, postop
      Wallin et al. 2003Sweden66(9)/63(9)(8/1)/(7/2)NoNA87(24)/87(24)Combined9.2 mUI/kg/min insulin, glucose, K 140 mEq/Lpreop, cpb, postop
      Wistbacka et al. 1992Finland56(7)/55(8)(13/3)/(14/2)No56(5)/ 59(7)104(31)/93 (27)CABGS2 mUI/kg/min rapid insulin, 17% glucose, K 16.8 mEq/Lpreop
      Wistbacka et al. 1994Finland55(10)/57(9)(16/4)/(16/4)No58(13)/ 57(11)100(36)/102(23)CABGS1.2 mUI/kg/min rapid insulin, 20% glucose, K 147 mEq/L, PO 94 mEq/Lpreop, cpb, postop
      Zhao et al. 2020China42(14)/42(14)(199/266)/(206/25)NoNA51(30)/52(31)Combined + Congenital1.1 mUI/kg/min regular insulin, 20% glucose, K 80 mEq/Lpreop, cpb, postop
      Zuurbier et al. 2008Netherlands63(NA)/64(NA)(18/5)/(18/3)NoNA62(29)/56(17)CABGS1.7 mUI/kg/min rapid insulin, 30% glucose, K 80 mEq/L, PO 240 mEq/Lpreop, cpb, postop
      AXC, aortic cross clamping; CABGS, coronary artery bypass graft surgery; CPB, cardiopulmonary bypass; LVEF, left ventricular ejection fraction; M/F, male/female
      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%).
      • Ellenberger C
      • Sologashvili T
      • Kreienbühl L
      • et al.
      Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
      ,
      • Un Roh G
      • Shim JK
      • Song JW
      • et al.
      Effect of glucoseInsulinPotassium on hyperlactataemia in patients undergoing valvular heart surgery: A randomised controlled study.
      ,
      • Shim J-K
      • Yang S-Y
      • Yoo Y-C
      • et al.
      Myocardial protection by glucose-Insulin-Potassium in acute coronary syndrome patients undergoing urgent multivessel off-pump coronary artery bypass surgery.
      ,
      • Lolley DM
      Preservation of human cardiac contractility during anoxic arrest with glucose-containing cardioplegia.
      ,
      • Wistbacka M
      • Kaukoranta PK
      • Nuutinen LS
      Prebypass glucose-insulin-potassium infusion in elective nondiabetic coronary artery surgery patients.
      ,
      • Brodin LA
      • Dahlgren G
      • Ekeström S
      • et al.
      Influence of glucose-insulin-potassium on left ventricular function during coronary artery bypass grafting.
      ,
      • Bruemmer-Smith S
      • Avidan MS
      • Harris B
      • et al.
      Glucose, insulin and potassium for heart protection during cardiac surgery.
      • Lell WA
      • Nielsen VG
      • McGiffin DC
      • et al.
      Glucose-insulin-potassium infusion for myocardial protection during off-pump coronary artery surgery.
      • Visser L
      • Zuurbier CJ
      • Hoek FJ
      • et al.
      Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
      • Quinn DW
      • Pagano D
      • Bonser RS
      • et al.
      Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: A randomized controlled trial.
      • de Barcellos C da S
      • Wender OCB
      • de Azambuja PC
      Glicose insulina e potássio (GIK) na revascularização do miocárdio de pacientes diabéticos: Ensaio clínico randomizado.
      ,
      • Ahmad S
      • Altaf Ahmad R
      • Ahsan Qureshi B
      • et al.
      Myocardial protection with Glucose-Insulin-Potassium infusion during adult cardiac surgery.
      ,
      • Lazar HL
      • Philippides G
      • Fitzgerald C
      • et al.
      Glucose-insulin-potassium solutions enhance recovery after urgent coronary artery bypass grafting.
      ,
      • Lazar HL
      • Chipkin SR
      • Fitzgerald CA
      • et al.
      Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.
      ,
      • Koskenkari JK
      • Kaukoranta PK
      • Rimpiläinen J
      • et al.
      Anti-inflammatory effect of high-dose insulin treatment after urgent coronary revascularization surgery.
      • Ranasinghe AM
      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.
      • Smith A
      • Grattan A
      • Harper M
      • et al.
      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.
      • Foroughi M
      • Rahimian H
      • Dabbagh A
      • et al.
      Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
      • Tsang MW
      • Davidoff R
      • Korach A
      • et al.
      Diastolic dysfunction after coronary artery bypass grafting?The effect of glucose-insulin-potassium infusion.
      ,
      • Turkoz A
      • Toprak H
      • Sari S
      • et al.
      Glucose-insulin-potassium solution before cardiopulmonary bypass in coronary artery surgery.
      • Ray JF
      • Tewksbury DA
      • Myers WO
      • et al.
      Can the frequency of myocardial infarction be reduced during coronary artery operations.
      • Lolley DM
      • Ray JF
      • Myers WO
      • et al.
      Reduction of intraoperative myocardial infarction by means of exogenous anaerobic substrate enhancement: Prospective randomized study.
      • Salerno TA
      • Wasan SM
      • Charrette EJ
      Glucose substrate in myocardial protection.
      • Svensson S
      • Ekroth R
      • Nilsson F
      • et al.
      Insulin as a vasodilating agent in the first hour after cardiopulmonary bypass.
      • Hallhagen S
      • Svedjeholm R
      • Ekroth R
      • et al.
      Effects of insulin on myocardial uptake of branched chain amino acids soon after cardiac operations.
      • Albacker TB
      • Carvalho G
      • Schricker T
      • et al.
      Myocardial protection during elective coronary artery bypass grafting using high-dose insulin therapy.
      ,
      • Oldfield GS
      • Commerford PJ
      • Opie LH
      Effects of preoperative glucose-insulin-potassium on myocardial glycogen levels and on complications of mitral valve replacement.
      ,
      • Howell NJ
      • Ashrafian H
      • Drury NE
      • et al.
      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.
      ,
      • Zhao K
      • Zhang Y
      • Li J
      • et al.
      Modified glucose-insulin-potassium regimen provides cardioprotection with improved tissue perfusion in patients undergoing cardiopulmonary bypass surgery.
      ,
      • Nilsson FN
      • Berglin EE
      • Ekroth R
      • et al.
      Effects of graded insulin infusions on plasma levels of free fatty acids, adrenaline and noradrenaline directly after open heart surgery.
      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%).
      • Ellenberger C
      • Sologashvili T
      • Kreienbühl L
      • et al.
      Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
      ,
      • Un Roh G
      • Shim JK
      • Song JW
      • et al.
      Effect of glucoseInsulinPotassium on hyperlactataemia in patients undergoing valvular heart surgery: A randomised controlled study.
      ,
      • Quinn DW
      • Pagano D
      • Bonser RS
      • et al.
      Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: A randomized controlled trial.
      ,
      • de Barcellos C da S
      • Wender OCB
      • de Azambuja PC
      Glicose insulina e potássio (GIK) na revascularização do miocárdio de pacientes diabéticos: Ensaio clínico randomizado.
      ,
      • Ranasinghe AM
      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.
      ,
      • Howell NJ
      • Ashrafian H
      • Drury NE
      • et al.
      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.
      ,
      • Zhao K
      • Zhang Y
      • Li J
      • et al.
      Modified glucose-insulin-potassium regimen provides cardioprotection with improved tissue perfusion in patients undergoing cardiopulmonary bypass surgery.
      Figure 3
      Figure 3forest plot and funnel plot for the main outcome (postoperative myocardial infarction).
      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]),
      • Shim J-K
      • Yang S-Y
      • Yoo Y-C
      • et al.
      Myocardial protection by glucose-Insulin-Potassium in acute coronary syndrome patients undergoing urgent multivessel off-pump coronary artery bypass surgery.
      ,
      • Lolley DM
      Preservation of human cardiac contractility during anoxic arrest with glucose-containing cardioplegia.
      ,
      • Wistbacka M
      • Kaukoranta PK
      • Nuutinen LS
      Prebypass glucose-insulin-potassium infusion in elective nondiabetic coronary artery surgery patients.
      ,
      • Brodin LA
      • Dahlgren G
      • Ekeström S
      • et al.
      Influence of glucose-insulin-potassium on left ventricular function during coronary artery bypass grafting.
      ,
      • Bruemmer-Smith S
      • Avidan MS
      • Harris B
      • et al.
      Glucose, insulin and potassium for heart protection during cardiac surgery.
      • Lell WA
      • Nielsen VG
      • McGiffin DC
      • et al.
      Glucose-insulin-potassium infusion for myocardial protection during off-pump coronary artery surgery.
      • Visser L
      • Zuurbier CJ
      • Hoek FJ
      • et al.
      Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
      • Quinn DW
      • Pagano D
      • Bonser RS
      • et al.
      Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: A randomized controlled trial.
      • de Barcellos C da S
      • Wender OCB
      • de Azambuja PC
      Glicose insulina e potássio (GIK) na revascularização do miocárdio de pacientes diabéticos: Ensaio clínico randomizado.
      ,
      • Ahmad S
      • Altaf Ahmad R
      • Ahsan Qureshi B
      • et al.
      Myocardial protection with Glucose-Insulin-Potassium infusion during adult cardiac surgery.
      ,
      • Lazar HL
      • Philippides G
      • Fitzgerald C
      • et al.
      Glucose-insulin-potassium solutions enhance recovery after urgent coronary artery bypass grafting.
      ,
      • Lazar HL
      • Chipkin SR
      • Fitzgerald CA
      • et al.
      Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.
      ,
      • Koskenkari JK
      • Kaukoranta PK
      • Rimpiläinen J
      • et al.
      Anti-inflammatory effect of high-dose insulin treatment after urgent coronary revascularization surgery.
      • Ranasinghe AM
      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.
      • Smith A
      • Grattan A
      • Harper M
      • et al.
      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.
      • Foroughi M
      • Rahimian H
      • Dabbagh A
      • et al.
      Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
      • Tsang MW
      • Davidoff R
      • Korach A
      • et al.
      Diastolic dysfunction after coronary artery bypass grafting?The effect of glucose-insulin-potassium infusion.
      ,
      • Turkoz A
      • Toprak H
      • Sari S
      • et al.
      Glucose-insulin-potassium solution before cardiopulmonary bypass in coronary artery surgery.
      • Ray JF
      • Tewksbury DA
      • Myers WO
      • et al.
      Can the frequency of myocardial infarction be reduced during coronary artery operations.
      • Lolley DM
      • Ray JF
      • Myers WO
      • et al.
      Reduction of intraoperative myocardial infarction by means of exogenous anaerobic substrate enhancement: Prospective randomized study.
      • Salerno TA
      • Wasan SM
      • Charrette EJ
      Glucose substrate in myocardial protection.
      • Svensson S
      • Ekroth R
      • Nilsson F
      • et al.
      Insulin as a vasodilating agent in the first hour after cardiopulmonary bypass.
      • Hallhagen S
      • Svedjeholm R
      • Ekroth R
      • et al.
      Effects of insulin on myocardial uptake of branched chain amino acids soon after cardiac operations.
      • Albacker TB
      • Carvalho G
      • Schricker T
      • et al.
      Myocardial protection during elective coronary artery bypass grafting using high-dose insulin therapy.
      with no difference between on-pump
      • Ellenberger C
      • Sologashvili T
      • Kreienbühl L
      • et al.
      Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
      ,
      • Un Roh G
      • Shim JK
      • Song JW
      • et al.
      Effect of glucoseInsulinPotassium on hyperlactataemia in patients undergoing valvular heart surgery: A randomised controlled study.
      ,
      • Lolley DM
      Preservation of human cardiac contractility during anoxic arrest with glucose-containing cardioplegia.
      ,
      • Wistbacka M
      • Kaukoranta PK
      • Nuutinen LS
      Prebypass glucose-insulin-potassium infusion in elective nondiabetic coronary artery surgery patients.
      ,
      • Brodin LA
      • Dahlgren G
      • Ekeström S
      • et al.
      Influence of glucose-insulin-potassium on left ventricular function during coronary artery bypass grafting.
      ,
      • Bruemmer-Smith S
      • Avidan MS
      • Harris B
      • et al.
      Glucose, insulin and potassium for heart protection during cardiac surgery.
      ,
      • Visser L
      • Zuurbier CJ
      • Hoek FJ
      • et al.
      Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
      • Quinn DW
      • Pagano D
      • Bonser RS
      • et al.
      Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: A randomized controlled trial.
      • de Barcellos C da S
      • Wender OCB
      • de Azambuja PC
      Glicose insulina e potássio (GIK) na revascularização do miocárdio de pacientes diabéticos: Ensaio clínico randomizado.
      ,
      • Ahmad S
      • Altaf Ahmad R
      • Ahsan Qureshi B
      • et al.
      Myocardial protection with Glucose-Insulin-Potassium infusion during adult cardiac surgery.
      ,
      • Lazar HL
      • Philippides G
      • Fitzgerald C
      • et al.
      Glucose-insulin-potassium solutions enhance recovery after urgent coronary artery bypass grafting.
      ,
      • Lazar HL
      • Chipkin SR
      • Fitzgerald CA
      • et al.
      Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.
      ,
      • Koskenkari JK
      • Kaukoranta PK
      • Rimpiläinen J
      • et al.
      Anti-inflammatory effect of high-dose insulin treatment after urgent coronary revascularization surgery.
      • Ranasinghe AM
      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.
      • Smith A
      • Grattan A
      • Harper M
      • et al.
      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.
      • Foroughi M
      • Rahimian H
      • Dabbagh A
      • et al.
      Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
      • Tsang MW
      • Davidoff R
      • Korach A
      • et al.
      Diastolic dysfunction after coronary artery bypass grafting?The effect of glucose-insulin-potassium infusion.
      ,
      • Turkoz A
      • Toprak H
      • Sari S
      • et al.
      Glucose-insulin-potassium solution before cardiopulmonary bypass in coronary artery surgery.
      • Ray JF
      • Tewksbury DA
      • Myers WO
      • et al.
      Can the frequency of myocardial infarction be reduced during coronary artery operations.
      • Lolley DM
      • Ray JF
      • Myers WO
      • et al.
      Reduction of intraoperative myocardial infarction by means of exogenous anaerobic substrate enhancement: Prospective randomized study.
      • Salerno TA
      • Wasan SM
      • Charrette EJ
      Glucose substrate in myocardial protection.
      • Svensson S
      • Ekroth R
      • Nilsson F
      • et al.
      Insulin as a vasodilating agent in the first hour after cardiopulmonary bypass.
      • Hallhagen S
      • Svedjeholm R
      • Ekroth R
      • et al.
      Effects of insulin on myocardial uptake of branched chain amino acids soon after cardiac operations.
      • Albacker TB
      • Carvalho G
      • Schricker T
      • et al.
      Myocardial protection during elective coronary artery bypass grafting using high-dose insulin therapy.
      ,
      • Oldfield GS
      • Commerford PJ
      • Opie LH
      Effects of preoperative glucose-insulin-potassium on myocardial glycogen levels and on complications of mitral valve replacement.
      ,
      • Howell NJ
      • Ashrafian H
      • Drury NE
      • et al.
      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.
      ,
      • Zhao K
      • Zhang Y
      • Li J
      • et al.
      Modified glucose-insulin-potassium regimen provides cardioprotection with improved tissue perfusion in patients undergoing cardiopulmonary bypass surgery.
      ,
      • Nilsson FN
      • Berglin EE
      • Ekroth R
      • et al.
      Effects of graded insulin infusions on plasma levels of free fatty acids, adrenaline and noradrenaline directly after open heart surgery.
      and off-pump subgroups (Q=0.23 P=0.6343).
      • Shim J-K
      • Yang S-Y
      • Yoo Y-C
      • et al.
      Myocardial protection by glucose-Insulin-Potassium in acute coronary syndrome patients undergoing urgent multivessel off-pump coronary artery bypass surgery.
      ,
      • Lell WA
      • Nielsen VG
      • McGiffin DC
      • et al.
      Glucose-insulin-potassium infusion for myocardial protection during off-pump coronary artery surgery.
      After combined surgery, there was a trend to support the cardioprotective efficacy of GIK (k=5 OR 0.84[0.48, 1.17]),
      • Ellenberger C
      • Sologashvili T
      • Kreienbühl L
      • et al.
      Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
      ,
      • Un Roh G
      • Shim JK
      • Song JW
      • et al.
      Effect of glucoseInsulinPotassium on hyperlactataemia in patients undergoing valvular heart surgery: A randomised controlled study.
      ,
      • Howell NJ
      • Ashrafian H
      • Drury NE
      • et al.
      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.
      ,
      • Zhao K
      • Zhang Y
      • Li J
      • et al.
      Modified glucose-insulin-potassium regimen provides cardioprotection with improved tissue perfusion in patients undergoing cardiopulmonary bypass surgery.
      ,
      • Nilsson FN
      • Berglin EE
      • Ekroth R
      • et al.
      Effects of graded insulin infusions on plasma levels of free fatty acids, adrenaline and noradrenaline directly after open heart surgery.
      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])
      • Ellenberger C
      • Sologashvili T
      • Kreienbühl L
      • et al.
      Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
      ,
      • Shim J-K
      • Yang S-Y
      • Yoo Y-C
      • et al.
      Myocardial protection by glucose-Insulin-Potassium in acute coronary syndrome patients undergoing urgent multivessel off-pump coronary artery bypass surgery.
      ,
      • Lolley DM
      Preservation of human cardiac contractility during anoxic arrest with glucose-containing cardioplegia.
      ,
      • Wistbacka M
      • Kaukoranta PK
      • Nuutinen LS
      Prebypass glucose-insulin-potassium infusion in elective nondiabetic coronary artery surgery patients.
      ,
      • Brodin LA
      • Dahlgren G
      • Ekeström S
      • et al.
      Influence of glucose-insulin-potassium on left ventricular function during coronary artery bypass grafting.
      ,
      • Bruemmer-Smith S
      • Avidan MS
      • Harris B
      • et al.
      Glucose, insulin and potassium for heart protection during cardiac surgery.
      ,
      • Quinn DW
      • Pagano D
      • Bonser RS
      • et al.
      Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: A randomized controlled trial.
      ,
      • Koskenkari JK
      • Kaukoranta PK
      • Rimpiläinen J
      • et al.
      Anti-inflammatory effect of high-dose insulin treatment after urgent coronary revascularization surgery.
      ,
      • Turkoz A
      • Toprak H
      • Sari S
      • et al.
      Glucose-insulin-potassium solution before cardiopulmonary bypass in coronary artery surgery.
      • Ray JF
      • Tewksbury DA
      • Myers WO
      • et al.
      Can the frequency of myocardial infarction be reduced during coronary artery operations.
      • Lolley DM
      • Ray JF
      • Myers WO
      • et al.
      Reduction of intraoperative myocardial infarction by means of exogenous anaerobic substrate enhancement: Prospective randomized study.
      ,
      • Svensson S
      • Ekroth R
      • Nilsson F
      • et al.
      Insulin as a vasodilating agent in the first hour after cardiopulmonary bypass.
      • Hallhagen S
      • Svedjeholm R
      • Ekroth R
      • et al.
      Effects of insulin on myocardial uptake of branched chain amino acids soon after cardiac operations.
      • Albacker TB
      • Carvalho G
      • Schricker T
      • et al.
      Myocardial protection during elective coronary artery bypass grafting using high-dose insulin therapy.
      ,
      • Nilsson FN
      • Berglin EE
      • Ekroth R
      • et al.
      Effects of graded insulin infusions on plasma levels of free fatty acids, adrenaline and noradrenaline directly after open heart surgery.
      whereas an insulin infusion rate lower than 2 mUI/kg/min failed to provide beneficial effects (k=12 OR 0.79[0.48, 1.3]);
      • Un Roh G
      • Shim JK
      • Song JW
      • et al.
      Effect of glucoseInsulinPotassium on hyperlactataemia in patients undergoing valvular heart surgery: A randomised controlled study.
      ,
      • Visser L
      • Zuurbier CJ
      • Hoek FJ
      • et al.
      Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
      ,
      • de Barcellos C da S
      • Wender OCB
      • de Azambuja PC
      Glicose insulina e potássio (GIK) na revascularização do miocárdio de pacientes diabéticos: Ensaio clínico randomizado.
      ,
      • Ahmad S
      • Altaf Ahmad R
      • Ahsan Qureshi B
      • et al.
      Myocardial protection with Glucose-Insulin-Potassium infusion during adult cardiac surgery.
      ,
      • Lazar HL
      • Chipkin SR
      • Fitzgerald CA
      • et al.
      Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.
      ,
      • Ranasinghe AM
      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.
      • Smith A
      • Grattan A
      • Harper M
      • et al.
      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.
      • Foroughi M
      • Rahimian H
      • Dabbagh A
      • et al.
      Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
      • Tsang MW
      • Davidoff R
      • Korach A
      • et al.
      Diastolic dysfunction after coronary artery bypass grafting?The effect of glucose-insulin-potassium infusion.
      ,
      • Salerno TA
      • Wasan SM
      • Charrette EJ
      Glucose substrate in myocardial protection.
      ,
      • Oldfield GS
      • Commerford PJ
      • Opie LH
      Effects of preoperative glucose-insulin-potassium on myocardial glycogen levels and on complications of mitral valve replacement.
      ,
      • Zhao K
      • Zhang Y
      • Li J
      • et al.
      Modified glucose-insulin-potassium regimen provides cardioprotection with improved tissue perfusion in patients undergoing cardiopulmonary bypass surgery.
      (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]),
      • Ellenberger C
      • Sologashvili T
      • Kreienbühl L
      • et al.
      Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
      ,
      • Un Roh G
      • Shim JK
      • Song JW
      • et al.
      Effect of glucoseInsulinPotassium on hyperlactataemia in patients undergoing valvular heart surgery: A randomised controlled study.
      ,
      • Shim J-K
      • Yang S-Y
      • Yoo Y-C
      • et al.
      Myocardial protection by glucose-Insulin-Potassium in acute coronary syndrome patients undergoing urgent multivessel off-pump coronary artery bypass surgery.
      ,
      • Wistbacka M
      • Kaukoranta PK
      • Nuutinen LS
      Prebypass glucose-insulin-potassium infusion in elective nondiabetic coronary artery surgery patients.
      ,
      • Brodin LA
      • Dahlgren G
      • Ekeström S
      • et al.
      Influence of glucose-insulin-potassium on left ventricular function during coronary artery bypass grafting.
      ,
      • Bruemmer-Smith S
      • Avidan MS
      • Harris B
      • et al.
      Glucose, insulin and potassium for heart protection during cardiac surgery.
      • Lell WA
      • Nielsen VG
      • McGiffin DC
      • et al.
      Glucose-insulin-potassium infusion for myocardial protection during off-pump coronary artery surgery.
      • Visser L
      • Zuurbier CJ
      • Hoek FJ
      • et al.
      Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
      • Quinn DW
      • Pagano D
      • Bonser RS
      • et al.
      Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: A randomized controlled trial.
      • de Barcellos C da S
      • Wender OCB
      • de Azambuja PC
      Glicose insulina e potássio (GIK) na revascularização do miocárdio de pacientes diabéticos: Ensaio clínico randomizado.
      ,
      • Ahmad S
      • Altaf Ahmad R
      • Ahsan Qureshi B
      • et al.
      Myocardial protection with Glucose-Insulin-Potassium infusion during adult cardiac surgery.
      ,
      • Lazar HL
      • Philippides G
      • Fitzgerald C
      • et al.
      Glucose-insulin-potassium solutions enhance recovery after urgent coronary artery bypass grafting.
      ,
      • Lazar HL
      • Chipkin SR
      • Fitzgerald CA
      • et al.
      Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.
      ,
      • Ranasinghe AM
      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.
      • Smith A
      • Grattan A
      • Harper M
      • et al.
      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.
      • Foroughi M
      • Rahimian H
      • Dabbagh A
      • et al.
      Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
      • Tsang MW
      • Davidoff R
      • Korach A
      • et al.
      Diastolic dysfunction after coronary artery bypass grafting?The effect of glucose-insulin-potassium infusion.
      ,
      • Turkoz A
      • Toprak H
      • Sari S
      • et al.
      Glucose-insulin-potassium solution before cardiopulmonary bypass in coronary artery surgery.
      ,
      • Salerno TA
      • Wasan SM
      • Charrette EJ
      Glucose substrate in myocardial protection.
      ,
      • Albacker TB
      • Carvalho G
      • Schricker T
      • et al.
      Myocardial protection during elective coronary artery bypass grafting using high-dose insulin therapy.
      ,
      • Oldfield GS
      • Commerford PJ
      • Opie LH
      Effects of preoperative glucose-insulin-potassium on myocardial glycogen levels and on complications of mitral valve replacement.
      ,
      • Zhao K
      • Zhang Y
      • Li J
      • et al.
      Modified glucose-insulin-potassium regimen provides cardioprotection with improved tissue perfusion in patients undergoing cardiopulmonary bypass surgery.
      or during/after CPB (k=10 OR 0.38[0.17, 0.85],
      • Lolley DM
      Preservation of human cardiac contractility during anoxic arrest with glucose-containing cardioplegia.
      ,
      • Koskenkari JK
      • Kaukoranta PK
      • Rimpiläinen J
      • et al.
      Anti-inflammatory effect of high-dose insulin treatment after urgent coronary revascularization surgery.
      ,
      • Ray JF
      • Tewksbury DA
      • Myers WO
      • et al.
      Can the frequency of myocardial infarction be reduced during coronary artery operations.
      ,
      • Lolley DM
      • Ray JF
      • Myers WO
      • et al.
      Reduction of intraoperative myocardial infarction by means of exogenous anaerobic substrate enhancement: Prospective randomized study.
      ,
      • Svensson S
      • Ekroth R
      • Nilsson F
      • et al.
      Insulin as a vasodilating agent in the first hour after cardiopulmonary bypass.
      ,
      • Hallhagen S
      • Svedjeholm R
      • Ekroth R
      • et al.
      Effects of insulin on myocardial uptake of branched chain amino acids soon after cardiac operations.
      ,
      • Howell NJ
      • Ashrafian H
      • Drury NE
      • et al.
      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.
      ,
      • Nilsson FN
      • Berglin EE
      • Ekroth R
      • et al.
      Effects of graded insulin infusions on plasma levels of free fatty acids, adrenaline and noradrenaline directly after open heart surgery.
      Q=1.43 P=0.2319).
      No subgroup effects were found in trials including only non-diabetic patients (k=17 OR 0.55[0.36, 0.84]),
      • Wistbacka M
      • Kaukoranta PK
      • Nuutinen LS
      Prebypass glucose-insulin-potassium infusion in elective nondiabetic coronary artery surgery patients.
      ,
      • Bruemmer-Smith S
      • Avidan MS
      • Harris B
      • et al.
      Glucose, insulin and potassium for heart protection during cardiac surgery.
      ,
      • Visser L
      • Zuurbier CJ
      • Hoek FJ
      • et al.
      Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: Effects on inflammatory response during coronary artery surgery.
      ,
      • Quinn DW
      • Pagano D
      • Bonser RS
      • et al.
      Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: A randomized controlled trial.
      ,
      • Ahmad S
      • Altaf Ahmad R
      • Ahsan Qureshi B
      • et al.
      Myocardial protection with Glucose-Insulin-Potassium infusion during adult cardiac surgery.
      ,
      • Lazar HL
      • Philippides G
      • Fitzgerald C
      • et al.
      Glucose-insulin-potassium solutions enhance recovery after urgent coronary artery bypass grafting.
      ,
      • Koskenkari JK
      • Kaukoranta PK
      • Rimpiläinen J
      • et al.
      Anti-inflammatory effect of high-dose insulin treatment after urgent coronary revascularization surgery.
      ,
      • Ranasinghe AM
      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.
      ,
      • Foroughi M
      • Rahimian H
      • Dabbagh A
      • et al.
      Postoperative N-terminal proBrain natriuretic peptide level in coronary artery bypass surgery with ventricular dysfunction after perioperative glucose-insulin-potassium treatment.
      ,
      • Turkoz A
      • Toprak H
      • Sari S
      • et al.
      Glucose-insulin-potassium solution before cardiopulmonary bypass in coronary artery surgery.
      ,
      • Salerno TA
      • Wasan SM
      • Charrette EJ
      Glucose substrate in myocardial protection.
      ,
      • Hallhagen S
      • Svedjeholm R
      • Ekroth R
      • et al.
      Effects of insulin on myocardial uptake of branched chain amino acids soon after cardiac operations.
      ,
      • Howell NJ
      • Ashrafian H
      • Drury NE
      • et al.
      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.
      ,
      • Zhao K
      • Zhang Y
      • Li J
      • et al.
      Modified glucose-insulin-potassium regimen provides cardioprotection with improved tissue perfusion in patients undergoing cardiopulmonary bypass surgery.
      ,
      • Nilsson FN
      • Berglin EE
      • Ekroth R
      • et al.
      Effects of graded insulin infusions on plasma levels of free fatty acids, adrenaline and noradrenaline directly after open heart surgery.
      only diabetic patients (k=2 OR 0.35[0.05, 2.64])
      • de Barcellos C da S
      • Wender OCB
      • de Azambuja PC
      Glicose insulina e potássio (GIK) na revascularização do miocárdio de pacientes diabéticos: Ensaio clínico randomizado.
      ,
      • Lazar HL
      • Chipkin SR
      • Fitzgerald CA
      • et al.
      Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.
      or a mixed population (k=13 OR 0.55[0.3, 1.03])
      • Ellenberger C
      • Sologashvili T
      • Kreienbühl L
      • et al.
      Myocardial protection by glucoseinsulinpotassium in moderate- to high-risk patients undergoing elective on-pump cardiac surgery: A randomized controlled trial.
      ,
      • Un Roh G
      • Shim JK
      • Song JW
      • et al.
      Effect of glucoseInsulinPotassium on hyperlactataemia in patients undergoing valvular heart surgery: A randomised controlled study.
      ,
      • Shim J-K
      • Yang S-Y
      • Yoo Y-C
      • et al.
      Myocardial protection by glucose-Insulin-Potassium in acute coronary syndrome patients undergoing urgent multivessel off-pump coronary artery bypass surgery.
      ,
      • Lolley DM
      Preservation of human cardiac contractility during anoxic arrest with glucose-containing cardioplegia.
      ,
      • Brodin LA
      • Dahlgren G
      • Ekeström S
      • et al.
      Influence of glucose-insulin-potassium on left ventricular function during coronary artery bypass grafting.
      ,
      • Lell WA
      • Nielsen VG
      • McGiffin DC
      • et al.
      Glucose-insulin-potassium infusion for myocardial protection during off-pump coronary artery surgery.
      ,
      • Smith A
      • Grattan A
      • Harper M
      • et al.
      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.
      ,
      • Tsang MW
      • Davidoff R
      • Korach A
      • et al.
      Diastolic dysfunction after coronary artery bypass grafting?The effect of glucose-insulin-potassium infusion.
      ,
      • Ray JF
      • Tewksbury DA
      • Myers WO
      • et al.
      Can the frequency of myocardial infarction be reduced during coronary artery operations.
      ,
      • Lolley DM
      • Ray JF
      • Myers WO
      • et al.
      Reduction of intraoperative myocardial infarction by means of exogenous anaerobic substrate enhancement: Prospective randomized study.
      ,
      • Svensson S
      • Ekroth R
      • Nilsson F
      • et al.
      Insulin as a vasodilating agent in the first hour after cardiopulmonary bypass.
      ,
      • Albacker TB
      • Carvalho G
      • Schricker T
      • et al.
      Myocardial protection during elective coronary artery bypass grafting using high-dose insulin therapy.
      ,
      • Oldfield GS
      • Commerford PJ
      • Opie LH
      Effects of preoperative glucose-insulin-potassium on myocardial glycogen levels and on complications of mitral valve replacement.
      (non-diabetics vs diabetics: Q=0.19 P=0.9113; diabetics vs. mixed: Q=0.19 P=0.9113). A summary of the heterogeneity of GIK composition is reported in a supplemental file (S5).
      Meta-analyses of secondary endpoints are summarized in Table 2. Perioperative GIK infusion was associated with a reduction in postoperative AF (19.8% vs 24.8% in control groups) and in AKI (3.3% vs 5.7% in control groups), along with higher CI (3.16 vs 2.77 L/min/m2 in control groups), faster ventilatory weaning as well as shorter ICU and hospital length of stay. There was no evidence of an association between GIK and in-hospital mortality, cardiovascular drug support, ventricular arrhythmias, infection or stroke.
      Table 2Meta-Analyses of Secondary Endpoints
      N RCTs (N participants)ControlsGIKTE (95\%CI)I ² (P-value)
      In-hospital mortality38 (4,599)58/2,33836/2,261OR=0.71 (0.49- 1.04)0% (0.08)
      AKI7 (2,939)85/1,48149/1,458OR=0.57 (0.4-0.82)0% (0.002)
      Atrial fibrillation27 (4,664)587/2,366455/2,298OR=0.68 (0.5-0.92)52% (0.013)
      Cardiac index [L/min]14 (707)2.6(0.9)3.1(0.9)MD=0.43 (0.29- 0.57)79% (<0.001)
      Glycemia [mg]20 (2,024)182.4(66.5)152.5(46.8)MD=-29.84 (-46.63 to -13.06)99% (<0.001)
      Hospital LOS [d]19 (1,852)9(3.3)8.1(3.2)MD=-0.89 (-1.63 to -0.16)93% (0.018)
      ICU LOS [h]20 (4,023)29.8(23.8)24.6(24.4)MD=-5.17 (-7.35 to -2.99)99% (<0.001)
      Infection11 (3,201)139/1,613112/1,588OR=0.78 (0.5-1.23)41% (0.283)
      Mechanical ventilation16 (2,247)13.6(6.3)11.9(4.8)MD=-1.68 (-2.87 to -0.5)97% (0.005)
      Stroke8 (1,743)18/87517/868OR=0.96 (0.48-1.92)0% (0.916)
      Ventricular Fibrillation11 (1,758)210/903159/855OR=0.87 (0.56-1.35)0% (0.527)
      RCT, randomized control trial; N, participants count; GIK, insulin-glucose-potassium; TE, treatment effect (odds ratio [OR] or mean difference [MD]); 95%CI, 95% confidence interval; AKI, acute kidney injury; AF, atrial fibrillation; CI, cardiac index; LOS, length of stay; ICU, intensive care unit; MVT, mechanical ventilation time; VF, ventricular fibrillation.
      Postoperative glycemia was higher in control than in GIK-treated patients (mean[SD] 185[49] mg/dL vs 155[42] mg/dL, respectively; MD[95%CI] -30[-46.63 to -13.06] mg/dL, I²=99%).
      • Shim YH
      • Kweon TD
      • Lee JH
      • et al.
      Intravenous glucose?Insulin?Potassium during off-pump coronary artery bypass surgery does not reduce myocardial injury.
      ,
      • Shim J-K
      • Yang S-Y
      • Yoo Y-C
      • et al.
      Myocardial protection by glucose-Insulin-Potassium in acute coronary syndrome patients undergoing urgent multivessel off-pump coronary artery bypass surgery.
      ,
      • Boldt J
      • Knothe C
      • Zickmann B
      • et al.
      Influence of different glucose-insulin-potassium regimes on glucose homeostasis and hormonal response in cardiac surgery patients.
      ,
      • Kjellman UW
      • Björk K
      • Dahlin A
      • et al.
      Insulin(GIK) improves myocardial metabolism in patients during blood cardioplegia.
      ,
      • Szabó Z
      • Arnqvist H
      • Håkanson E
      • et al.
      Effects of high-dose glucose-insulin-potassium on myocardial metabolism after coronary surgery in patients with Type II diabetes.
      ,
      • Lell WA
      • Nielsen VG
      • McGiffin DC
      • et al.
      Glucose-insulin-potassium infusion for myocardial protection during off-pump coronary artery surgery.
      ,
      • Zuurbier CJ
      • Hoek FJ
      • van Dijk J
      • et al.
      Perioperative hyperinsulinaemic normoglycaemic clamp causes hypolipidaemia after coronary artery surgery this article is accompanied by editorial I.
      ,
      • Laiq N
      • Khan S
      • Ahmed H
      • et al.
      The effects of glycaemic control in cardiac patients undergoing CABG surgery.
      ,
      • Lazar HL
      • Chipkin S
      • Philippides G
      • et al.
      Glucose-insulin-potassium solutions improve outcomes in diabetics who have coronary artery operations.
      ,
      • Lazar HL
      • Chipkin SR
      • Fitzgerald CA
      • et al.
      Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.