Effects of high-dose glucose-insulin-potassium on acute coronary syndrome patients undergoing reperfusion therapy: a meta-analysis

Effects of high-dose glucose-insulin-potassium on acute coronary syndrome patients undergoing reperfusion therapy: a meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of high-dose glucose-insulin-potassium on acute coronary syndrome patients undergoing reperfusion therapy: a meta-analysis Huiruo Liu, Rugang Liu, Hang Yin, Feng Xu, Yuguo Chen, Chuanbao Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1727509/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Normal glucose-insulin-potassium (GIK) did not improve clinical outcomes in ACS patients in today’s reperfusion era; however, whether high-dose GIK appeared any cardioprotective function remains uncertain. This meta-analysis aimed to assess the efficacy of high-dose GIK on clinical outcomes in acute coronary syndrome (ACS) patients undergoing reperfusion therapy. Methods : We searched PubMed, Web of science, MEDLINE, Embase and Cochrane Library databases from inception until April 26, 2022 for randomized controlled trials (RCTs) that compared high-dose GIK and placebos in ACS patients receiving reperfusion therapy. The primary endpoint was major adverse cardiovascular events (MACEs), and the secondary endpoints were all-cause mortality, left ventricular ejection fraction (LVEF), heart failure, reinfarction, phlebitis, hyperglycemia, hyperkalemia, hypoglycemia, secondary reperfusion, serum glucose and potassium, activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT). Results : Eleven RCTs with 884 patients were eventually included. Compared with placebos, high-dose GIK markedly reduced MACEs (RR 0.57, 95%CI 0.35 to 0.94, p<0.05) and the risk of heart failure (RR 0.48, 95%CI 0.25 to 0.95, p <0.05), also improved LVEF (MD 2.12, 95%CI 0.32 to 3.92, p<0.05) at 6 months. However, no difference was observed in occurring all-cause mortality at 30 days (RR 0.90, 95%CI 0.35 to 2.28, p=0.82) or 1 year (RR 0.57 95%CI 0.22 to 1.51, p=0.26). Additionally, high-dose GIK was significantly associated with higher occurrence of phlebitis (RR 4.78, 95%CI 1.36 to 16.76, p<0.05), hyperglycemia (RR 9.06, 95%CI 1.74 to 47.29, p<0.01) and hypoglycemia (RR 6.50, 95%CI 1.28 to 33.01, p<0.05), but not reinfarction (RR 0.74, 95%CI 0.36 to 1.50, p =0.40), hyperkalemia (RR 5.99, 95%CI 0.79 to 45.27, p=0.08) or secondary reperfusion (RR 0.91, 95%CI 0.72 to 1.14, p=0.41). As for oxidative stress-lowering function, high-dose GIK markedly reduced SOD activity (SMD -0.77, 95%CI -1.28 to -0.26, p<0.05), but not activity of GSH-Px (SMD 0.34, 95%CI -0.16 to 0.83, p=0.18) or CAT (SMD 0.35, 95%CI -0.14 to 0.84, p=0.16). Conclusions: Patients with ACS receiving reperfusion therapy showed reduction in MACEs and heart failure, improvement of LVEF, as well as good oxidative stress-lowering efficacy in response to high-dose GIK. Simultaneously, higher occurrence of several complications such as phlebitis, hyperglycemia and hypoglycemia accompanied, also a trend to an increase in serum potassium appeared. Furthermore, patients’ all-cause mortality did not modulate any benefits associated with exposure to high-dose GIK. More trails with long-term follow-up are stilled demanded to further verify its efficacy and security to provide powerful evidences for clinical practice. acute coronary syndrome high-dose glucose-insulin-potassium reperfusion therapy meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction GIK solution is extensively used in clinical practice as a metabolic and adjuvant therapy for ACS and, theoretically, plays cardioprotective roles due to a resultant reduction in cardiac FFA metabolism during ischemia [1,2] . International guidelines once recommended GIK infusion as a cardioprotective strategy to mitigate adverse outcomes in patients with ACS [3] , approved by improving composite ischemic results showed in some older trials in the pre-reperfusion era [4] . Recently, intravenous GIK for ACS becomes controversial again in today’s reperfusion-therapy era. No apparent cardiac benefits or larger mortality reductions of GIK were found from recent meta-analyses in ACS patients with reperfusion treatments [5,6] . Nevertheless, ECLA study [7,8] using high-dose GIK reported an enhanced clinical benefit in patients with ACS who received reperfusion therapy. A large amount of RCTs have analyzed the effects of GIK on clinical outcomes in patients with ACS at high-dosages. A quantitative analysis [9] published in 2006 comparing high-dose and low-dose GIK for ST-segment elevation myocardial infarction (STEMI) (combined patients with and without reperfusion therapy) from 16 RCTs reported no significantly beneficial or detrimental effect of high-dose GIK, versus low-dose. Currently, several additional RCTs about high-dose GIK have been published in the reperfusion era since then, and remarkably varying results were showed. Deserve to be mentioned, most of trials are placebo-controlled, studies compared high-dose GIK with low-dose GIK are still relatively absent [10] . Except for efficacy in the treatment of total ACS population, we are more concerned about its roles in those ACS patients who received reperfusion therapy. It is unclear whether high-dose shows benefits in today reperfusion therapy era. Herein, we collected randomized controlled trials relevant to high-dose GIK therapy in ACS patients with reperfusion treatments and performed this meta-analysis to better evaluate whether high-dose GIK can improve clinical benefits for ACS patients receiving reperfusion treatments, so as to provide a more reliable basis for adjuvant therapy for ACS in the reperfusion era. Methods Protocol and guidance This meta-analysis was performed in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [11] . Search strategies A systematic search of PubMed, Web of science, MEDLINE, Embase and Cochrane Library databases was performed by two independent investigators to identify eligible studies concerning “the effects of high-dose GIK intervention on outcomes in ACS patients treated with reperfusion therapy” published until April 26, 2022, without language restriction. The complete term strategy was: (“glucose insulin potassium cardioplegic solution” OR “polarized liquid” OR “glucose-insulin-potassium substrate” OR “GIK solution” OR “GIKCS” OR “GIK”) AND (“acute coronary syndrome” OR “heart infarction” OR “unstable angina pectoris” OR “infarction, myocardial” OR “infarctions, myocardial” OR “acute myocardial infarctions” OR “acute cardiovascular stroke” OR “acute cardiovascular strokes” OR “stroke, cardiovascular” OR “strokes, cardiovascular” OR “acute myocardial infarct” OR “infarct, myocardial” OR “infarcts, myocardial” OR “acute myocardial infarcts” OR “acute heart attack” OR “acute heart attacks” OR “anterior wall myocardial infarction” OR “inferior wall myocardial infarction” OR “minoca” OR “non-st elevated myocardial infarction” OR “shock, cardiogenic” OR “st elevation myocardial infarction” OR “acute coronary syndromes” OR “coronary syndrome, acute” OR “coronary syndromes, acute” OR “syndrome, acute coronary” OR “syndromes, acute coronary” OR “angina, unstable” OR “anginas, unstable” OR “unstable anginas” OR “angina pectoris, unstable” OR “angina pectori, unstable” OR “unstable angina pectori” OR “unstable angina pectoris” OR “unstable angina” OR “angina at rest” OR “angina, preinfarction” OR “anginas, preinfarction” OR “preinfarction angina” OR “preinfarction anginas” OR “myocardial preinfarction syndrome” OR “myocardial preinfarction syndromes” OR “preinfarction syndrome, myocardial” OR “preinfarction syndromes, myocardial” OR “syndrome, myocardial preinfarction”). Each term component included MESH terms and keywords. Articles were also identified from references of relevant original researches and reviews to avert possible omissions of eligible researches. Selection criteria PICOS framework was used to define the inclusion criteria. Published full-text papers in English fulfilling the following criteria were included: (a) patients: patients diagnosed with ACS treated with reperfusion therapy, (b) intervention: patients in experimental group received high-dose GIK therapy defined as an intravenous infusion of GIK in a dose equal to or higher than 30% glucose, 50IU/L regular insulin and 80 mM potassium given by an infusion rate at 1.5 ml/kg/h over 24 h [12] , (c) control: patients in control group received normal saline or any other liquids without glucose nor insulin, (d) outcomes: MACEs (the primary outcome) and all-cause mortality, LVEF, heart failure, reinfarction, phlebitis, hyperglycemia, hyperkalemia, hypoglycemia, secondary reperfusion, serum glucose and potassium, activity of SOD, GSH-Px and CAT post-PCI (the secondary outcomes), (e) study design: randomized controlled trials. Exclusion criteria were ongoing studies, papers unavailable for full-text and not in English. Study endpoints In this study, we evaluated adverse event outcomes and cardiac function-improving outcomes of high-dose GIK by comparing them with placebo which contains no glucose nor insulin. The primary endpoint was MACEs, which was defined as a composite of cardiac death, recurrent ischemia, malignant arrhythmias (ventricular fibrillation or tachycardia) and severe heart failure. Secondary endpoints were all-cause mortality, LVEF, heart failure, reinfarction, phlebitis, hyperglycemia, hyperkalemia, hypoglycemia, secondary reperfusion, serum glucose and potassium, activity of SOD, GSH-Px and CAT post-PCI. Data abstraction and extraction After the removal of duplicates, two investigators screened and cross-checked independently for initial output in terms of titles and abstracts, and obviously irrelevant studies were excluded. Remaining studies were evaluated through full-text scanning, and articles eligible for selection criteria were selected and included. In each step, further discussion or third reviewer was needed in case of disagreement to reach a final consensus. Two independent reviewers extracted data from included studies using a standardized extraction tool concerning trail or first author name, publication year, country of origin, study design, main characteristics of study populations, GIK concentrations, infusion rate and time of GIK solution, controls, initial reperfusion therapy, the proportion of patients with diabetes, baseline blood glucose, ACS subtypes, symptom to balloon time, postangioplasty thrombolysis in myocardial infarction grade (TIMI)-3 flow after reperfusion therapy, and initiation order between GIK and reperfusion therapy. Study quality assessment We adopted checklists in the Cochrane handbook for systematic reviews of interventions to examine the risk of bias for RCTs included in this meta-analysis. This tool mainly evaluates possible bias from the following aspects: selection bias (including random sequence generation and allocation concealment), performance bias, detection bias, attrition bias, reporting bias and other bias that is not mentioned above. Each assessment of bias is showed as low, high or unclear risk. Supplemental Fig. S1 showed the risk of bias. Statistical analysis Data was extracted from included studies, and Review Manager Version 5.4 was used for statistical analysis. Publication bias was assessed graphically by visual inspection using the funnel plots and further verified by Egger's regression interception test using Stata SE 15.0 software. Overall effects of dichotomous variables were calculated by pooled risk ratio (RR) with 95% confidence intervals (CI) while the pooled mean difference and 95% CI was used for continuous data. Standard mean difference with 95% CI was used for continuous variables in cases of inconsistent units or different measurements. Symmetrical shape of funnel plots and a greater p value than 0.05 of Egger's test indicated no significant risk of publication bias. Fixed-effects-model or random-effects model was determined by the heterogeneity between studies included. In this study, we assessed heterogeneity using the Chi-square statistic and the I 2 . Heterogeneity was considered statistically significant when p value 50% was regarded as high levels of heterogeneity. Data extracted from studies were pooled using a random-effects model when the high degree of heterogeneity was assigned, otherwise a fixed-effects model was applied. The inspection level was set at two-tailed, 0.05 for hypothesis tests while at 0.05 for heterogeneity tests. Results Search results A total of potentially relevant 1036 studies were retrieved from initial research. As the PRISMA selection flowchart presents in Figure 1, 49 studies were identified for full-text scanning, after duplicates removing and initial screening by titles and abstracts. After a full-text reviewing, 11 studies according with eligibility were finally included. Study characteristics 11 RCTs [13-23] combined enrolled 884 patients with ACS who received reperfusion therapy through thrombolytic drugs, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) were eventually included, among 468 in the high-dose GIK arm and 416 in the placebo arm. Main characteristics of included studies were listed in Table 1. These studies were published between 2002 and 2010. Excepting for an unavailability for age and gender information of Zeynab study [18] , the mean age of study population from the remaining 10 [13-17,19-23] ranged from 49 to 67 years and the percentage of male was 58-100%. Data from four trials [13,16,19,22] showed that 142 participants had a successful angiographic reperfusion showing a final TIMI-3 flow. Mean time from symptom to balloon ranged from 1.3 to 5.8 hours in the high-dose GIK group and 1.3 to 6.1 hours in controls according to data provided by six RCTs [16,17,19,21-23] . Eight of eleven studies [13-19,22] initiated GIK infusion before reperfusion therapy. History of diabetes was presented in 15.6% (65/416) of patients in the control group while 15.0% (70/468) in the high-dose GIKs. Furthermore, five trials [14-16,19,22] underwent a GIK solution at a dose equal to or higher than the solution consisting of 30% glucose and 50IU/L insulin, five trials [13,17,18,20,21] underwent a GIK solution consisting 25% glucose and 50IU/L insulin, while another one [23] received a dose at 20% glucose and 40IU/L insulin.\ Table 1 Baseline characteristics of included RCTs. Study (Country of origin) Publication year Study Design No. of patients Age (years) Male (%) Killip I (%) Treatment Total C HD GIK C HD GIK C HD GIK C HD GIK C HD GIK Glucose (%) Insulin (IU/L) Potassium (mEq/L) Infusion rate (ml/kg/h) and time (h) Guillermo (Chile) 2002 RCT 20 10 10 55 54 10 (100) 8 (80) 7 (70) 9 (90) Normal saline 30 50 80 1.5 (>24) Pablo (Chile) 2003 RCT 37 19 18 55.2 55 15 (79) 13 (72) 15 (78) 14 (77) Normal saline 30 50 80 1.5 (>24) REVIVAL (Germany) 2004 RCT 312 157 155 64.1 60.8 114 (73) 111 (72) 109 (69.4) 105 (67.7) Normal saline 20 40 64 1.8 (>24) Mustafa (Turkey) 2005 RCT 52 25 27 59 60 19 (76) 19 (70) N/A N/A Normal saline 30 300 60 1.5 (>24) Gordana (Turkey) 2005 RCT 118 40 78 56.7 56.6 29 (73) 52 (67) 31 (78) 70 (90) Normal saline 25 50 80 1 (>24) Zhang (China) 2005 RCT 74 39 35 60.8 64.1 25 (64) 22 (63) 23 (59) 19 (54) N/A 25 50 80 1.5 (>24) Chiara (Italy) 2006 RCT 73 33 40 57 60 26 (79) 34 (85) 31 (94) 36 (90) Normal saline 30 50 80 1.5 (>24) CREATE-ECLA (America) 2007 RCT 25 12 13 49 58 10 (80) 11 (85) N/A N/A Normal saline 25 50 80 1.5 (>24) Sabri (Turkey) 2008 RCT 47 19 28 58.9 61.4 15 (79) 22 (79) N/A N/A Normal saline 30 300 60 1.5 (>24) Li (China) 2010 RCT 26 12 14 63 67 7 (58) 9 (64) N/A N/A N/A 25 50 80 1.5 (>24) Zeynab (Iran) 2010 RCT 100 50 50 N/A N/A N/A N/A 25 (50) 25 (50) Normal saline 25 50 80 1 (>24) Reperfusion therapy Diabetes (%) Baseline glucose (mg/dl) ACS Subtype (%) Symptom to balloon time (hrs) GIK falls behind reperfusion therapy or not Postangioplasty TIMI-3 flow, n (%) C HD GIK C HD GIK C HD GIK C HD GIK C HD GIK C HD GIK Thrombolytic medicine (%) PCI (%) CABG (%) Thrombolytic medicine (%) PCI (%) CABG (%) AMI UA AMI UA 0 (0) 10 (100) 0 (0) 0 (0) 10 (100) 0 (0) 1 (10) 0 (0) N/A N/A 10 (100) 0 (0) 10 (100) 0 (0) 3.5 1.9 No 10 (100) 9 (90) 0 (0) 19 (100) 0 (0) 0 (0) 18 (100) 0 (0) 1 (5) 3 (17) N/A N/A 19 (100) 0 (0) 18 (100) 0 (0) 4.3 3.6 No 17 (89) 16 (89) 11 (7) 142 (90.4) 2 (1.3) 12 (7.7) 137 (88.5) 3 (1.9) 37 (23.6) 35 (22.6) N/A N/A 157 (100) 0 (0) 155 (100) 0 (0) 1.3 1.3 N/A N/A N/A 0 (0) 25 (100) 0 (0) 0 (0) 27 (100) 0 (0) 0 (0) 0 (0) 93 90 N/A N/A N/A N/A N/A N/A No N/A N/A 40 (100) 0 (0) 0 (0) 78 (100) 0 (0) 0 (0) 7 (17) 13 (17) N/A N/A 40 (100) 0 (0) 78 (100) 0 (0) 3.2 3.1 No N/A N/A 0 (0) 39 (100) 0 (0) 0 (0) 35 (100) 0 (0) 8 (21) 7 (20) N/A N/A 39 (100) 0 (0) 35 (100) 0 (0) 5 5.8 Yes N/A N/A 0 (0) 33 (100) 0 (0) 0 (0) 40 (100) 2 (5) 6 (18) 8 (20) N/A N/A N/A N/A N/A N/A 6.1 5.2 No 30 (91) 35 (87.5) 0 (0) 12 (100) 0 (0) 1 (8) 12 (92) 0 (0) 5 (40) 4 (30) N/A N/A 12 (100) 0 (0) 13 (100) 0 (0) N/A N/A No 12 (12) 13 (13) 0 (0) 19 (100) 0 (0) 0 (0) 28 (100) 0 (0) N/A N/A 118.2 112 N/A N/A N/A N/A N/A N/A No N/A N/A 0 (0) 12 (100) N/A 0 (0) 13 (93) N/A N/A N/A 222 157 12 (100) 0 (0) 14 (100) 0 (0) N/A N/A N/A N/A N/A 50 (100) 19 (38) 8 (16) 50 (100) 13 (26) 7 (14) 0 (0) 0 (0) N/A N/A 50 (100) 0 (0) 50 (100) 0 (0) N/A N/A No N/A N/A C: control; HD GIK: high-dose glucose-insulin-potassium; RCT: randomized controlled trial; N/A: not applicable; ACS: acute coronary syndrome; TIMI: thrombolysis in myocardial infarction grade; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; AMI: acute myocardial infarction; UA: unstable angina. Clinical endpoints MACEs Overall, four [17-20] of the eleven studies provided data on MACEs in both high-dose GIK group and controls. During the follow-up, MACEs occurred in 13.1% of included patients (21/160) in the high-dose GIK group and 21.5% (26/121) in the control group. Quantitative synthesis confirmed that high-dose GIK infusion was associated with a significant reduction in the risk of MACEs (RR 0.57, 95%CI 0.35 to 0.94, p <0.05) in comparison with placebo in ACS patients with reperfusion treatments. No statistically significant heterogeneity was examined between these studies ( p =0.06, I 2 =64%) (Fig. 2). Adverse cardiovascular events The effects of high-dose GIK on independent adverse cardiovascular events of ACS patients receiving reperfusion therapy was shown in Fig.3. Compared to controls, results indicated high-dose GIK had no marked prevention of recurrent MI (RR 0.74, 95%CI 0.36 to 1.50, p =0.40) and secondary reperfusion (RR 0.91, 95%CI 0.72 to 1.14, p =0.41). While high-dose group showed a significant reduction in the incidence of heart failure (RR 0.48, 95%CI 0.25 to 0.95, p <0.05). No obvious heterogeneities were observed among the pooled estimates of all mentioned events (Fig. 3). All-cause mortality A total count of four RCTs [17-19,23] provided data on the incidence of all-cause mortality. In summary, 30-day all-cause mortality was mentioned in two trials [18,23] , occurring in 8 of 205 (3.9%) patients from high-dose GIK group while 9 of 207 (4.3%) patients from controls, with no statistically significant change (RR 0.90, 95%CI 0.35 to 2.28, p =0.82). Among, three studies [17-19] showed data regarding 1-year all-cause mortality and results showed that high-dose GIK was not superior in the prevention of all-cause mortality at 1 year (RR 0.57 95%CI 0.22 to 1.51, p =0.26). No significant heterogeneities were observed between above concerned studies. (Fig. 4) Change of 6-month LVEF Two RCTs [16,20] were included in the analysis, with no significant heterogeneity shown ( p =0.48, I 2 =0%). In Fig. 5, there was a significant efficacy in improving LVEF in ACS patients receiving reperfusion treatments subjected to intravenous high-dose GIK (MD 2.12, 95%CI 0.32 to 3.92, p <0.05) from baseline to 6 months, compared with placebos. (Fig. 5) Adverse effects Four [16,17,19,23] of the eleven trials provided data on the occurrence of phlebitis, reporting 4.5% (13/291) of studied populations in the high-dose GIK group and 0.8% (2/249) in the control group during the follow-up period (RR 4.78, 95%CI 1.36 to 16.76, p <0.05). Quantitative analyses of relevant studies [15,17,20] showed high-dose GIK infusion resulted in an obvious increase in serum potassium concentrations (MD 0.29, 95%CI 0.17 to 0.40, p <0.00001). Whereas no significant effect of high-dose GIK on the incidence of hyperkalemia was observed versus controls (RR 5.99, 95%CI 0.79 to 45.27, p =0.08). Despite obvious increases in both hyperglycemia (RR 9.06, 95%CI 1.74 to 47.29, p <0.01) and hypoglycemia (RR 6.50, 95%CI 1.28 to 33.01, p <0.05), the mean concentration of serum glucose after intravenous GIK did not show any significant change between the high-dose GIKs and control groups (MD 4.52, 95%CI -7.53 to 16.56, p =0.46). No significant heterogeneity was examined among all studies (Fig. 6). Changes of oxidative stress parameters A total of 67 patients were enrolled in two RCTs [15,22] . As shown in Fig. 7, high-dose GIK presented a marked reduction in SOD activity post-PCI when compared with controls (SMD -0.77, 95%CI -1.28 to -0.26, p <0.05). However, there was no statistically significant difference in GSH-Px activity (SMD 0.34, 95%CI -0.16 to 0.83, p =0.18) and CAT activity (SMD 0.35, 95%CI -0.14 to 0.84, p =0.16) after PCI between GIK and control groups. No severe heterogeneity was observed among all concerned studies (Fig. 7). Publication bias No significant asymmetry of the funnel plot for included RCTs was observed via visual inspection (Fig. 8), also no statistical publication bias was showed from Egger’s test (t = 0.16, p=0.586). Discussion This meta-analysis evaluated study data from eleven RCTs [13-23] relevant to the high-dose GIK applications for ACS patients following reperfusion therapy. Limited evidence, based on included trials, indicated that high-dose GIK was associated with better myocardial protection and higher occurrence of certain complications. Contrast to our beneficial findings on MACEs of high-dose GIK infusion in patients diagnosed with ACS undergoing reperfusion therapy, results of combined analysis of the OASIS-6 and CREATE-ECLA [24-26] , two largest RCTs regarding high-dose GIK treatments in acute myocardial infarction (AMI) patients, demonstrated that infusion of high-dose GIK provided no net clinical benefits while even an early harm was caused. There are several feasible accounts for this divergence, and the main reason may be the essential distinctions between reperfusion or not. Populations included in our study all accepted at least one reperfusion treatment, while only about 80% patients in OASIS-6 and CREATE-ECLA combined analysis received reperfusion therapy. GIK may fail to reach severely ischemic myocardium and consequently function in cases without reperfusion because of the occlusion of coronary [27,28] . Besides, eight of eleven RCTs specifically clarified high-dose GIK was initiated before the onset of reperfusion therapy that signified the solution could get to ischemia area once criminal vascular was opened. An additional consideration for this difference might be relevant to a higher proportion of AMI in both OASIS-6 and CREATE-ECLA trials compared with our study, which represented a severe pathophysiological change and indicated a reduced tolerance for elevated glucose, potassium and net fluid infusion maybe [29,30] . Despite of early harmful effects showed in combined analysis of the OASIS-6 and CREATE-ECLA, a neutral overall effect on 30-day outcomes indicated that high-dose GIK therapy may have delayed benefits which neutralized its early harms. Similarly, studies reviewed in this meta-analysis demonstrated a consistent trend toward chronic cardiac function improvement, as LVEF at 6 months showed a statistical increase in patients receiving high-dose GIK infusion. Academically, myocardial infarction evokes excessive acquittal of catecholamines [31] and subsequently generated stressed reduction in insulin secretion and increase in FFAs [32-34] . These made myocardium converts from anaerobic glycolysis to anaerobic FFAs oxidation during ischemia, which lead to the deposition of toxic intermediates of FFAs depressing myocardial mechanical activity and contraction [35-37] . Regarded as a metabolic modulation strategy, GIK had several possible mechanisms for improving cardiac function [38,39] . Our analysis demonstrated that high-dose GIK could provide marked SOD activity reduction in ACS patients undergoing reperfusion therapy, which indicated a good oxidative stress-lowering function, reinforcing the concept that high-dose GIK improving LVEF by an inhibitory effect on fatty toxicity. Additionally, our meta-analysis did not show any benefit on mortality from high-dose GIK regimens; this is contrary to the results reported in a prior meta-analysis including eight trials (high- and low- combined) performed in pre-reperfusion era which confirmed a 28% proportional hospital mortality reduction [4] . The wicked effects of secondary hyperglycemia might give a considerable explanation for this discrepancy [40] . With an original intention with strengthening metabolic strategy of high-dose GIK infusion [41] , however, this oversupply of glucose can contribute to a higher occurrence of hyperglycemia. The ACC/AHA guideline has recommended the great necessity of glucose control in patients with ACS, and linked stress hyperglycemia to a poor prognosis of AMI [42] . Mild hyperglycemia in ACS was originally thought to be a self-defense behavior, but uncontrollable hyperglycemia would increase adverse clinical outcomes by increasing oxidative stress and amplifying inflammatory response [43] . Although no significant changes of serum glucose concentrations were found after high-dose GIK infusion in our analysis, the increased incidence of hypoglycemia as well as hyperglycemia indicated a possibility of drastic fluctuation of blood sugar, which was also associated with worse outcomes in ACS. Several prior meta-analyses confirmed that GIK (high- and low- dose combined) showed no beneficial effect on mortality of ACS in today's reperfusion era [6,44] . One theory as to “ceiling effect” of reperfusion therapy in this difference was that the therapeutic benefits of GIK were concealed by reperfusion treatments. Moreover, a recent meta-analysis reported a possible reduction in mortality if a high-dose GIK was used as an adjunct to reperfusion therapy in patients diagnosed with STEMI [45] . Known as the most serious type of ACS, AMI might gain greater benefits from GIK. While a quantitative analysis of GIK in patients with STEMI did not show a beneficial or detrimental effect of high-dose GIK on 30-day mortality, compared with low-dose [9] . Furthermore, a higher occurrence of complications such as phlebitis, hyperglycemia and hypoglycemia, and an incline to increase serum potassium following high-dose GIK administration are showed by limited evidence, compared with controls. Therefore, the application of high-dose GIK in clinical practice may be cautious for high-risk patients with metabolic disturbances, history of uncontrolled diabetes or renal insufficiency. Serum glucose and potassium should be monitored closely in case of detrimental clinical sequels. There are several limitations in this meta-analysis. Firstly, our analysis restricted to literatures published in English language, which may lead to a potential publication bias. Secondly, our meta-analysis showed that all trials included related to high-dose GIK were placebo-controlled while the low-dose-controlled were still very limited. The low-dose GIK infusion strategy is now often used as an adjuvant treatment of reperfusion therapy in clinical practice, so the comparison between high-dose GIK and placebos cannot directly reflect whether intravenous high-dose GIK has better or worse effects than the existing treatments. Thirdly, due to different background ACS subtype, possible selection bias may occur. Our research showed that study population in nine of eleven studies were all participants with AMI while information on the proportion of respective subtype of ACS of another two RCTs was not available for this analysis. Then, the sample size was small, and the duration of follow-up for each trail was short which might affect the reliability of the conclusion to some extent. Besides, there are five of eleven included studies conducted a standard high-dose GIK infusion consisting of 30% glucose, 50IU/L insulin and 80mM potassium, while the dose of GIK solution has been appropriately adjusted to a lower dosage in other six studies, so the potential benefits of high concentrations of glucose and insulin infusion might be diluted. Next, through the strict selecting, studies after 2010 were absent, which might lead to a deviation for the difference in clinical conditions. Finally, although high-dose GIK group showed higher serum potassium concentration after GIK infusion, our results demonstrated that high-dose GIK did not increase the occurrence of hyperkalemia. Further well-designed large-scaled RCTs with long-term follow-up, comparing high- and low- dose GIK are urgently warranted to confirm the efficacy and security of intravenous high-dose GIK in patients diagnosed with ACS in this reperfusion era. Conclusion In patients with ACS undergoing reperfusion therapy, this meta-analysis demonstrated that high-dose GIK presented a good oxidative stress-lowering effect and were effective in reducing the risk of MACEs and heart failure, as well as improving LVEF, as compared with placebos. Meanwhile, a significant trend to higher occurrence of hyperglycemia and hypoglycemia, also an increase in serum potassium was associated with high-dose GIK. As an adjuvant therapy for reperfusion treatment, high-dose GIK solution is efficient and economical for patients. Therefore, large-scaled clinical trials with long-term follow-up assessing high-dose GIK and low-dose GIK are urgently required. Abbreviations GIK: Glucose-insulin-potassium; FFAs: Free fat acids; ACS: Acute coronary syndrome; RCT Randomized controlled trial; MACE: Major adverse cardiovascular event; LVEF: Left ventricular ejection fraction; SOD: Super oxide dismutase; GSH-Px: Glutathione peroxidase; CAT: Catalase; RR: Risk ratio; MD: Mean difference; SMD: Standardized mean difference; STEMI: ST-segment elevation myocardial infarction; AMI: Acute myocardial infarction; PRISMA: Preferred reporting items for systematic reviews and meta-analysis; TIMI: Thrombolysis in myocardial infarction grade; CI: Confidence intervals; PCI: Percutaneous coronary intervention; CABG: Coronary artery bypass grafting. Declarations Acknowledgements The authors thank all members of the Emergency Department of Qilu Hospital of Shandong University for their valuable comments on the manuscript. Authors’ contributions HRL contributed to the literature review, data curation and writing. RGL contributed to investigation, writing and risk of bias assessment. HY performed data curation and analysis. FX contributed to review of all and final revisions. YGC hold the study design. CBL provided resources, performed statistical analysis and cerate figures and tables. All authors read and approved the final manuscript. Funding This study was supported by the National Natural Science Foundation of China (82070388 and 82170442), Taishan Pandeng Scholar Program of Shandong Province (tspd20181220), National Natural Science Foundation of Shandong Province (ZR2020MH035). Availability of data and materials All data generated or analyzed can be acquired from this published article and its additional information files. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Author details 1 Department of Emergency Medicine and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, Shandong, China. 2 Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, Shandong, China. 3 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China. References Opie L. Myocardial infarct size. Part 2. Comparison of anti-infarct effects of beta-blockade, glucose-insulin-potassium, nitrates, and hyaluronidase. American heart journal . 1980;100(4):531-52. doi:10.1016/0002-8703(80)90669-9 Thompson J, Husband D, Thai A, Alberti K. 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Oct 29 1977;2(8044):890-2. doi:10.1016/s0140-6736(77)90830-3 Rogers WJ, Stanley AW, Jr., Breinig JB, et al. Reduction of hospital mortality rate of acute myocardial infarction with glucose-insulin-potassium infusion. Am Heart J . Oct 1976;92(4):441-54. doi:10.1016/s0002-8703(76)80043-9 Doorey AJ, Barry WH. The effects of inhibition of oxidative phosphorylation and glycolysis on contractility and high-energy phosphate content in cultured chick heart cells. Circ Res . Aug 1983;53(2):192-201. doi:10.1161/01.res.53.2.192 Valori C, Thomas M, Shillingford J. Free noradrenaline and adrenaline excretion in relation to clinical syndromes following myocardial infarction. Am J Cardiol . Nov 1967;20(5):605-17. doi:10.1016/0002-9149(67)90001-x Gupta DK, Jewitt DE, Young R, Hartog M, Opie LH. Increased plasma-free-fatty-acid concentrations and their significance in patients with acute myocardial infarction. Lancet . Dec 6 1969;2(7632):1209-13. doi:10.1016/s0140-6736(69)90749-1 Cinquegrani G, Spigoni V, Fantuzzi F, Bonadonna RC, Dei Cas A. Empagliflozin does not reverse lipotoxicity-induced impairment in human myeloid angiogenic cell bioenergetics. Cardiovasc Diabetol . Feb 17 2022;21(1):27. doi:10.1186/s12933-022-01461-4 Kurien VA, Oliver MF. Serum-free-fatty-acids after acute myocardial infarction and cerebral vascular occlusion. Lancet . Jul 16 1966;2(7455):122-7. doi:10.1016/s0140-6736(66)92420-2 Opie LH. Metabolism of free fatty acids, glucose and catecholamines in acute myocardial infarction. Relation to myocardial ischemia and infarct size. Am J Cardiol . Dec 1975;36(7):938-53. doi:10.1016/0002-9149(75)90086-7 Vanoverschelde JL, Janier MF, Bakke JE, Marshall DR, Bergmann SR. Rate of glycolysis during ischemia determines extent of ischemic injury and functional recovery after reperfusion. Am J Physiol . Nov 1994;267(5 Pt 2):H1785-94. doi:10.1152/ajpheart.1994.267.5.H1785 Liu N, Sheng J, Wang Y. Effect of stress hyperglycaemia on monocyte chemoattractant protein-1 levels and the short-term prognosis of patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Exp Ther Med . May 2019;17(5):3823-3829. doi:10.3892/etm.2019.7338 Cave AC, Ingwall JS, Friedrich J, et al. ATP synthesis during low-flow ischemia: influence of increased glycolytic substrate. Circulation . May 2 2000;101(17):2090-6. doi:10.1161/01.cir.101.17.2090 Kosiborod M, Inzucchi SE, Krumholz HM, et al. Glucometrics in patients hospitalized with acute myocardial infarction: defining the optimal outcomes-based measure of risk. Circulation . Feb 26 2008;117(8):1018-27. doi:10.1161/circulationaha.107.740498 Pan Y, Cai X, Jing J, et al. Stress Hyperglycemia and Prognosis of Minor Ischemic Stroke and Transient Ischemic Attack: The CHANCE Study (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events). Stroke . Nov 2017;48(11):3006-3011. doi:10.1161/strokeaha.117.019081 Jin PY, Zhang HS, Guo XY, Liang WF, Han QF. Glucose-insulin-potassium therapy in patients with acute coronary syndrome: a meta-analysis of randomized controlled trials. BMC Cardiovasc Disord . Nov 25 2014;14:169. doi:10.1186/1471-2261-14-169 Timmer JR, van der Horst IC, Ottervanger JP, et al. Glucose-insulin-potassium infusion as adjunctive therapy in myocardial infarction: current evidence and potential mechanisms. Ital Heart J . Oct 2004;5(10):727-31. Additional Declarations No competing interests reported. Supplementary Files FigureS1.tif Risk of bias assessment. 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2","display":"","copyAsset":false,"role":"figure","size":165648,"visible":true,"origin":"","legend":"\u003cp\u003eEffects of high-dose GIK on major adverse cardiac events (MACEs) compared with placebos.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-1727509/v1/4b9614fab9711f89d1d0689b.png"},{"id":22594915,"identity":"c0d8652b-7311-4e67-b6a7-8b8ceeafd1cf","added_by":"auto","created_at":"2022-06-13 18:36:11","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":476440,"visible":true,"origin":"","legend":"\u003cp\u003eEffects of high-dose GIK on the risk of recurrent myocardial infarction, secondary reperfusion and heart failure compared with placebos.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-1727509/v1/908ad98a6d2ce0f2b12aa3a5.png"},{"id":22595074,"identity":"cd403780-d3f4-463d-bde2-59a1a4a3abce","added_by":"auto","created_at":"2022-06-13 18:41:11","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":295985,"visible":true,"origin":"","legend":"\u003cp\u003eEffects of high-dose GIK on all-cause mortality at 1 year and 30 days.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-1727509/v1/87841238ad6b84284a63d64e.png"},{"id":22594917,"identity":"3eea4e29-d329-414c-aa64-f5dee9d52fc8","added_by":"auto","created_at":"2022-06-13 18:36:11","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":136864,"visible":true,"origin":"","legend":"\u003cp\u003eEffects of high-dose GIK on LVEF at 6 months.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-1727509/v1/b1f5d247dc187d9ba1b52406.png"},{"id":22595174,"identity":"0ddc8b26-3283-475b-bdbe-63d8dec67753","added_by":"auto","created_at":"2022-06-13 18:46:11","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":962568,"visible":true,"origin":"","legend":"\u003cp\u003eEffects of high-dose GIK on the occurrence of phlebitis, hyperkalemia, hyperglycemia, hypoglycemia, and the concentrations of serum potassium and glucose.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-1727509/v1/6e9e0471272e9c9776b92fb5.png"},{"id":22594920,"identity":"8270195d-4038-48c7-a67b-831d46e6954c","added_by":"auto","created_at":"2022-06-13 18:36:11","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":405849,"visible":true,"origin":"","legend":"\u003cp\u003eEffects of high-dose GIK on activity of super oxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT).\u003c/p\u003e","description":"","filename":"Figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-1727509/v1/31c238d34a4af53ff9c43cba.png"},{"id":22595073,"identity":"5d4f5749-b993-49c4-a1de-48375ff0faa0","added_by":"auto","created_at":"2022-06-13 18:41:11","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":66954,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot of publication bias.\u003c/p\u003e","description":"","filename":"Figure8.png","url":"https://assets-eu.researchsquare.com/files/rs-1727509/v1/bc934790ea1848c9cb451375.png"},{"id":22595191,"identity":"9004ddb3-01aa-4067-8608-e009daf4e1ce","added_by":"auto","created_at":"2022-06-13 18:46:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1165813,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1727509/v1/12cc1ff8-a7ae-4b64-9949-49d2e336e803.pdf"},{"id":22595173,"identity":"1e109f5f-c9ea-4ac9-8158-6f71a509412b","added_by":"auto","created_at":"2022-06-13 18:46:11","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":641196,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias assessment.\u003c/p\u003e","description":"","filename":"FigureS1.tif","url":"https://assets-eu.researchsquare.com/files/rs-1727509/v1/07421a30abf091da7436b36e.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of high-dose glucose-insulin-potassium on acute coronary syndrome patients undergoing reperfusion therapy: a meta-analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGIK solution is extensively used in clinical practice as a metabolic and adjuvant therapy for ACS and, theoretically, plays cardioprotective roles due to a resultant reduction in cardiac FFA metabolism during ischemia\u0026nbsp;\u003csup\u003e[1,2]\u003c/sup\u003e. International guidelines once recommended GIK infusion as a cardioprotective strategy to mitigate adverse outcomes in patients with ACS\u0026nbsp;\u003csup\u003e[3]\u003c/sup\u003e, approved by improving composite ischemic results showed in some older trials in the pre-reperfusion era\u0026nbsp;\u003csup\u003e[4]\u003c/sup\u003e. Recently, intravenous GIK for ACS becomes controversial again in today\u0026rsquo;s reperfusion-therapy era. No apparent cardiac benefits or larger mortality reductions of GIK were found from recent meta-analyses in ACS patients with reperfusion treatments\u0026nbsp;\u003csup\u003e[5,6]\u003c/sup\u003e. Nevertheless, ECLA study\u0026nbsp;\u003csup\u003e[7,8]\u003c/sup\u003e using high-dose GIK reported an enhanced clinical benefit in patients with ACS who received reperfusion therapy.\u003c/p\u003e\n\u003cp\u003eA large amount of RCTs have analyzed the effects of GIK on clinical outcomes in patients with ACS at high-dosages. A quantitative analysis\u0026nbsp;\u003csup\u003e[9]\u003c/sup\u003e published in 2006 comparing high-dose and low-dose GIK for ST-segment elevation myocardial infarction (STEMI) (combined patients with and without reperfusion therapy) from 16 RCTs reported no significantly beneficial or detrimental effect of high-dose GIK, versus low-dose.\u0026nbsp;Currently, several additional RCTs about high-dose GIK have been published in the reperfusion era since then, and remarkably varying results were showed. Deserve to be mentioned, most of trials are placebo-controlled, studies compared high-dose GIK with low-dose GIK are still relatively absent\u0026nbsp;\u003csup\u003e[10]\u003c/sup\u003e. Except for efficacy in the treatment of total ACS population, we are more concerned about its roles in those ACS patients who received reperfusion therapy. It is unclear whether high-dose shows benefits in today reperfusion therapy era. Herein, we collected randomized controlled trials relevant to high-dose GIK therapy in ACS patients with reperfusion treatments and performed this meta-analysis to better evaluate whether high-dose GIK can improve clinical benefits for ACS patients receiving reperfusion treatments, so as to provide a more reliable basis for adjuvant therapy for ACS in the reperfusion era.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eProtocol and guidance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis meta-analysis was performed in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)\u0026nbsp;\u003csup\u003e[11]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSearch strategies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA systematic search of PubMed, Web of science, MEDLINE, Embase and Cochrane Library databases was performed by two independent investigators to identify eligible studies concerning \u0026ldquo;the effects of high-dose GIK intervention on outcomes in ACS patients treated with reperfusion therapy\u0026rdquo; published until April 26, 2022, without language restriction. The complete term strategy was: (\u0026ldquo;glucose insulin potassium cardioplegic solution\u0026rdquo; OR \u0026ldquo;polarized liquid\u0026rdquo; OR \u0026ldquo;glucose-insulin-potassium substrate\u0026rdquo; OR \u0026ldquo;GIK solution\u0026rdquo; OR \u0026ldquo;GIKCS\u0026rdquo; OR \u0026ldquo;GIK\u0026rdquo;) AND (\u0026ldquo;acute coronary syndrome\u0026rdquo; OR \u0026ldquo;heart infarction\u0026rdquo; OR \u0026ldquo;unstable angina pectoris\u0026rdquo; OR \u0026ldquo;infarction, myocardial\u0026rdquo; OR \u0026ldquo;infarctions, myocardial\u0026rdquo; OR \u0026ldquo;acute myocardial infarctions\u0026rdquo; OR \u0026ldquo;acute cardiovascular stroke\u0026rdquo; OR \u0026ldquo;acute cardiovascular strokes\u0026rdquo; OR \u0026ldquo;stroke, cardiovascular\u0026rdquo; OR \u0026ldquo;strokes, cardiovascular\u0026rdquo; OR \u0026ldquo;acute myocardial infarct\u0026rdquo; OR \u0026ldquo;infarct, myocardial\u0026rdquo; OR \u0026ldquo;infarcts, myocardial\u0026rdquo; OR \u0026ldquo;acute myocardial infarcts\u0026rdquo; OR \u0026ldquo;acute heart attack\u0026rdquo; OR \u0026ldquo;acute heart attacks\u0026rdquo; OR \u0026ldquo;anterior wall myocardial infarction\u0026rdquo; OR \u0026ldquo;inferior wall myocardial infarction\u0026rdquo; OR \u0026ldquo;minoca\u0026rdquo; OR \u0026ldquo;non-st elevated myocardial infarction\u0026rdquo; OR \u0026ldquo;shock, cardiogenic\u0026rdquo; OR \u0026ldquo;st elevation myocardial infarction\u0026rdquo; OR \u0026ldquo;acute coronary syndromes\u0026rdquo; OR \u0026ldquo;coronary syndrome, acute\u0026rdquo; OR \u0026ldquo;coronary syndromes, acute\u0026rdquo; OR \u0026ldquo;syndrome, acute coronary\u0026rdquo; OR \u0026ldquo;syndromes, acute coronary\u0026rdquo; OR \u0026ldquo;angina, unstable\u0026rdquo; OR \u0026ldquo;anginas, unstable\u0026rdquo; OR \u0026ldquo;unstable anginas\u0026rdquo; OR \u0026ldquo;angina pectoris, unstable\u0026rdquo; OR \u0026ldquo;angina pectori, unstable\u0026rdquo; OR \u0026ldquo;unstable angina pectori\u0026rdquo; OR \u0026ldquo;unstable angina pectoris\u0026rdquo; OR \u0026ldquo;unstable angina\u0026rdquo; OR \u0026ldquo;angina at rest\u0026rdquo; OR \u0026ldquo;angina, preinfarction\u0026rdquo; OR \u0026ldquo;anginas, preinfarction\u0026rdquo; OR \u0026ldquo;preinfarction angina\u0026rdquo; OR \u0026ldquo;preinfarction anginas\u0026rdquo; OR \u0026ldquo;myocardial preinfarction syndrome\u0026rdquo; OR \u0026ldquo;myocardial preinfarction syndromes\u0026rdquo; OR \u0026ldquo;preinfarction syndrome, myocardial\u0026rdquo; OR \u0026ldquo;preinfarction syndromes, myocardial\u0026rdquo; OR \u0026ldquo;syndrome, myocardial preinfarction\u0026rdquo;). Each term component included MESH terms and keywords. Articles were also identified from references of relevant original researches and reviews to avert possible omissions of eligible researches.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSelection criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePICOS framework was used to define the inclusion criteria. Published full-text papers in English fulfilling the following criteria were included: (a) patients: patients diagnosed with ACS treated with reperfusion therapy, (b) intervention: patients in experimental group received high-dose GIK therapy defined as an intravenous infusion of GIK in a dose equal to or higher than 30% glucose, 50IU/L regular insulin and 80 mM potassium given by an infusion rate at 1.5 ml/kg/h over 24 h\u0026nbsp;\u003csup\u003e[12]\u003c/sup\u003e, (c) control: patients in control group received normal saline or any other liquids without glucose nor insulin, (d) outcomes:\u0026nbsp;MACEs (the primary outcome) and all-cause mortality, LVEF, heart failure,\u0026nbsp;reinfarction, phlebitis, hyperglycemia, hyperkalemia, hypoglycemia, secondary reperfusion, serum glucose and potassium, activity of SOD, GSH-Px and CAT post-PCI (the secondary outcomes), (e) study design: randomized controlled trials.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExclusion criteria were ongoing studies, papers unavailable for full-text and not in English.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy endpoints\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, we evaluated adverse event outcomes and cardiac function-improving outcomes of high-dose GIK by comparing them with placebo which contains no glucose nor insulin. The primary endpoint was MACEs, which was defined as a composite of cardiac death, recurrent ischemia, malignant arrhythmias (ventricular fibrillation or tachycardia) and severe heart failure. Secondary endpoints were all-cause mortality, LVEF, heart failure,\u0026nbsp;reinfarction, phlebitis, hyperglycemia, hyperkalemia, hypoglycemia, secondary reperfusion, serum glucose and potassium, activity of SOD, GSH-Px and CAT post-PCI.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData abstraction and extraction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter the removal of duplicates, two investigators screened and cross-checked independently for initial output in terms of titles and abstracts, and obviously irrelevant studies were excluded. Remaining studies were evaluated through full-text scanning, and articles eligible for selection criteria were selected and included. In each step, further discussion or third reviewer was needed in case of disagreement to reach a final consensus.\u003c/p\u003e\n\u003cp\u003eTwo independent reviewers extracted data from included studies using a standardized extraction tool concerning trail or first author name, publication year, country of origin, study design, main characteristics of study populations, GIK concentrations, infusion rate and time of GIK solution, controls, initial reperfusion therapy, the proportion of patients with diabetes, baseline blood glucose, ACS subtypes, symptom to balloon time, postangioplasty thrombolysis in myocardial infarction grade (TIMI)-3 flow after reperfusion therapy, and initiation order between GIK and reperfusion therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy quality assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe adopted checklists in the Cochrane handbook for systematic reviews of interventions to examine the risk of bias for RCTs included in this meta-analysis. This tool mainly evaluates possible bias from the following aspects: selection bias (including random sequence generation and allocation concealment), performance bias, detection bias, attrition bias, reporting bias and other bias that is not mentioned above. Each assessment of bias is showed as low, high or unclear risk. Supplemental Fig. S1 showed the risk of bias.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData was extracted from included studies, and Review Manager Version 5.4 was used for statistical analysis. Publication bias was assessed graphically by visual inspection using the funnel plots and further verified by Egger\u0026apos;s regression interception test using Stata SE 15.0 software. Overall effects of dichotomous variables were calculated by pooled risk ratio (RR) with 95% confidence intervals (CI) while the pooled mean difference and 95% CI was used for continuous data. Standard mean difference with 95% CI was used for continuous variables in cases of inconsistent units or different measurements. Symmetrical shape of funnel plots and a greater \u003cem\u003ep\u003c/em\u003e value than 0.05 of Egger\u0026apos;s test indicated no significant risk of publication bias.\u003c/p\u003e\n\u003cp\u003eFixed-effects-model or random-effects model was determined by the heterogeneity between studies included. In this study, we assessed heterogeneity using the Chi-square statistic and the I\u003csup\u003e2\u003c/sup\u003e. Heterogeneity was considered statistically significant when \u003cem\u003ep\u003c/em\u003e value \u0026lt; 0.05, and I\u003csup\u003e2\u003c/sup\u003e statistic with a value \u0026gt; 50% was regarded as high levels of heterogeneity. Data extracted from studies were pooled using a random-effects model when the high degree of heterogeneity was assigned, otherwise a fixed-effects model was applied. The inspection level was set at two-tailed, 0.05 for hypothesis tests while at 0.05 for heterogeneity tests.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eSearch results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of potentially relevant 1036 studies were retrieved from initial research. As the PRISMA selection flowchart presents in Figure 1, 49 studies were identified for full-text scanning, after duplicates removing and initial screening by titles and abstracts. After a full-text reviewing, 11 studies according with eligibility were finally included.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e11 RCTs \u003csup\u003e[13-23]\u003c/sup\u003e combined enrolled 884 patients with ACS who received reperfusion therapy through thrombolytic drugs, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) were eventually included, among 468 in the high-dose GIK arm and 416 in the placebo arm. Main characteristics of included studies were listed in Table 1. These studies were published between 2002 and 2010. Excepting for an unavailability for age and gender information of Zeynab study \u003csup\u003e[18]\u003c/sup\u003e, the mean age of study population from the remaining 10 \u003csup\u003e[13-17,19-23]\u003c/sup\u003e ranged from 49 to 67 years and the percentage of male was 58-100%. Data from four trials \u003csup\u003e[13,16,19,22]\u003c/sup\u003e showed that 142 participants had a successful angiographic reperfusion showing a final TIMI-3 flow. Mean time from symptom to balloon ranged from 1.3 to 5.8 hours in the high-dose GIK group and 1.3 to 6.1 hours in controls according to data provided by six RCTs \u003csup\u003e[16,17,19,21-23]\u003c/sup\u003e. Eight of eleven studies \u003csup\u003e[13-19,22]\u003c/sup\u003e initiated GIK infusion before reperfusion therapy. History of diabetes was presented in 15.6% (65/416) of patients in the control group while 15.0% (70/468) in the high-dose GIKs. Furthermore, five trials \u003csup\u003e[14-16,19,22]\u003c/sup\u003e underwent a GIK solution at a dose equal to or higher than the solution consisting of 30% glucose and 50IU/L insulin, five trials \u003csup\u003e[13,17,18,20,21]\u003c/sup\u003e underwent a GIK solution consisting 25% glucose and 50IU/L insulin, while another one \u003csup\u003e[23]\u003c/sup\u003e received a dose at 20% glucose and 40IU/L insulin.\\\u003c/p\u003e\n\u003ctable align=\"left\" border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"17\" width=\"100%\"\u003e\n \u003cp style=\"text-align: center;\"\u003eTable 1\u003c/p\u003e\n \u003cp style=\"text-align: center;\"\u003e\u0026nbsp;Baseline characteristics of included RCTs.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" width=\"5.882352941176471%\"\u003e\n \u003cp\u003eStudy (Country of origin)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" width=\"5.882352941176471%\"\u003e\n \u003cp\u003ePublication year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" width=\"5.882352941176471%\"\u003e\n \u003cp\u003eStudy Design\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" width=\"17.647058823529413%\"\u003e\n \u003cp\u003eNo. of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"11.764705882352942%\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"11.764705882352942%\"\u003e\n \u003cp\u003eMale (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"11.764705882352942%\"\u003e\n \u003cp\u003eKillip I (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" width=\"29.41176470588235%\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" width=\"7.142857142857143%\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"7.142857142857143%\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"7.142857142857143%\"\u003e\n \u003cp\u003eHD GIK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"7.142857142857143%\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"7.142857142857143%\"\u003e\n \u003cp\u003eHD GIK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"7.142857142857143%\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"7.142857142857143%\"\u003e\n \u003cp\u003eHD GIK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"7.142857142857143%\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"7.142857142857143%\"\u003e\n \u003cp\u003eHD GIK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"7.142857142857143%\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" width=\"28.571428571428573%\"\u003e\n \u003cp\u003eHD GIK\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eGlucose (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eInsulin (IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003ePotassium (mEq/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\"\u003e\n \u003cp\u003eInfusion rate (ml/kg/h) and time (h)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eGuillermo (Chile)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e2002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e10 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e8 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e7 (70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e9 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eNormal saline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e1.5 (\u0026gt;24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003ePablo (Chile)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e2003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e55.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e15 (79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e13 (72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e15 (78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e14 (77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eNormal saline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e1.5 (\u0026gt;24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eREVIVAL (Germany)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e2004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e312\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e157\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e64.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e60.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e114 (73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e111 (72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e109 (69.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e105 (67.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eNormal saline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e1.8 (\u0026gt;24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eMustafa (Turkey)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e2005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e19 (76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e19 (70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eNormal saline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e1.5 (\u0026gt;24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eGordana (Turkey)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e2005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e56.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e56.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e29 (73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e52 (67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e31 (78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e70 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eNormal saline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e1 (\u0026gt;24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eZhang (China)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e2005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e60.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e64.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e25 (64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e22 (63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e23 (59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e19 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e1.5 (\u0026gt;24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eChiara (Italy)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e2006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e26 (79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e34 (85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e31 (94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e36 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eNormal saline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e1.5 (\u0026gt;24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eCREATE-ECLA (America)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e2007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e10 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e11 (85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eNormal saline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e1.5 (\u0026gt;24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eSabri (Turkey)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e2008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e58.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e61.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e15 (79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e22 (79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eNormal saline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e1.5 (\u0026gt;24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eLi (China)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e7 (58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e9 (64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e1.5 (\u0026gt;24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eZeynab (Iran)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e25 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e25 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003eNormal saline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.882352941176471%\"\u003e\n \u003cp\u003e1 (\u0026gt;24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n\u003c/table\u003e\n\u003ctable align=\"left\" border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" width=\"32.358674463937625%\"\u003e\n \u003cp\u003eReperfusion therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.428849902534113%\"\u003e\n \u003cp\u003eDiabetes (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.428849902534113%\"\u003e\n \u003cp\u003eBaseline glucose (mg/dl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" width=\"20.760233918128655%\"\u003e\n \u003cp\u003eACS Subtype (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.331384015594542%\"\u003e\n \u003cp\u003eSymptom to balloon time (hrs)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003eGIK falls behind reperfusion therapy or not\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.428849902534113%\"\u003e\n \u003cp\u003ePostangioplasty TIMI-3 flow, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"17.11340206185567%\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"17.11340206185567%\"\u003e\n \u003cp\u003eHD GIK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"5.463917525773196%\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"5.463917525773196%\"\u003e\n \u003cp\u003eHD GIK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"5.463917525773196%\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"5.463917525773196%\"\u003e\n \u003cp\u003eHD GIK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.927835051546392%\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.927835051546392%\"\u003e\n \u003cp\u003eHD GIK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"5.463917525773196%\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"5.463917525773196%\"\u003e\n \u003cp\u003eHD GIK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"5.56701030927835%\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" width=\"5.56701030927835%\"\u003e\n \u003cp\u003eHD GIK\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"10.885608856088561%\"\u003e\n \u003cp\u003eThrombolytic medicine (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.77859778597786%\"\u003e\n \u003cp\u003ePCI (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.77859778597786%\"\u003e\n \u003cp\u003eCABG (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.885608856088561%\"\u003e\n \u003cp\u003eThrombolytic medicine (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.77859778597786%\"\u003e\n \u003cp\u003ePCI (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.77859778597786%\"\u003e\n \u003cp\u003eCABG (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.77859778597786%\"\u003e\n \u003cp\u003eAMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.77859778597786%\"\u003e\n \u003cp\u003eUA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.77859778597786%\"\u003e\n \u003cp\u003eAMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"9.77859778597786%\"\u003e\n \u003cp\u003eUA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e10 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e10 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e10 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e10 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003e10 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003e9 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e19 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e18 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e1 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e3 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e19 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e18 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003e17 (89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003e16 (89)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e11 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e142 (90.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e2 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e12 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e137 (88.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e3 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e37 (23.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e35 (22.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e157 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e155 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e25 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e27 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e40 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e78 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e7 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e13 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e40 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e78 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e3.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e39 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e35 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e8 (21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e7 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e39 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e35 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e33 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e40 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e2 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e6 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e8 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e6.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e5.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003e30 (91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003e35 (87.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e12 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e12 (92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e5 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e4 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e12 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e13 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003e12 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003e13 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e19 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e28 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e118.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e112\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e12 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e13 (93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e222\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e157\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e12 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e14 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e50 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e19 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e8 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.772994129158513%\"\u003e\n \u003cp\u003e50 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e13 (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e7 (14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e50 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e50 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.185909980430528%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.283757338551859%\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"19\" valign=\"top\" width=\"100%\"\u003e\n \u003cp\u003eC: control; HD GIK: high-dose glucose-insulin-potassium; RCT: randomized controlled trial; N/A: not applicable; ACS: acute coronary syndrome; TIMI: thrombolysis in myocardial infarction grade; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; AMI: acute myocardial infarction; UA: unstable angina.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical endpoints\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMACEs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall, four\u0026nbsp;\u003csup\u003e[17-20]\u003c/sup\u003e of the eleven studies provided data on MACEs in both high-dose GIK group and controls. During the follow-up, MACEs occurred in 13.1% of included patients (21/160) in the high-dose GIK group and 21.5% (26/121) in the control group. Quantitative synthesis confirmed that high-dose GIK infusion was associated with a significant reduction in the risk of MACEs (RR 0.57, 95%CI 0.35 to 0.94, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05) in comparison with placebo in ACS patients with reperfusion treatments. No statistically significant heterogeneity was examined between these studies (\u003cem\u003ep\u003c/em\u003e=0.06, I\u003csup\u003e2\u003c/sup\u003e=64%) (Fig. 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse cardiovascular events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe effects of high-dose GIK on independent adverse cardiovascular events of ACS patients receiving reperfusion therapy was shown in Fig.3. Compared to controls, results indicated high-dose GIK had no marked prevention of recurrent MI (RR 0.74, 95%CI 0.36 to 1.50, \u003cem\u003ep\u003c/em\u003e =0.40) and secondary reperfusion (RR 0.91, 95%CI 0.72 to 1.14, \u003cem\u003ep\u003c/em\u003e=0.41). While high-dose group showed a significant reduction in the incidence of heart failure (RR 0.48, 95%CI 0.25 to 0.95, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05). No obvious heterogeneities were observed among the pooled estimates of all mentioned events (Fig. 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAll-cause mortality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total count of four RCTs\u0026nbsp;\u003csup\u003e[17-19,23]\u003c/sup\u003e provided data on the incidence of all-cause mortality. In summary, 30-day all-cause mortality was mentioned in two trials\u0026nbsp;\u003csup\u003e[18,23]\u003c/sup\u003e, occurring in 8 of 205 (3.9%) patients from high-dose GIK group while 9 of 207 (4.3%) patients from controls, with no statistically significant change (RR 0.90, 95%CI 0.35 to 2.28, \u003cem\u003ep\u003c/em\u003e=0.82). Among, three studies\u0026nbsp;\u003csup\u003e[17-19]\u003c/sup\u003e showed data regarding 1-year all-cause mortality and results showed that high-dose GIK was not superior in the prevention of all-cause mortality at 1 year (RR 0.57 95%CI 0.22 to 1.51, \u003cem\u003ep\u003c/em\u003e=0.26). No significant heterogeneities were observed between above concerned studies. (Fig. 4)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChange of 6-month LVEF\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo RCTs\u0026nbsp;\u003csup\u003e[16,20]\u003c/sup\u003e were included in the analysis, with no significant heterogeneity shown (\u003cem\u003ep\u003c/em\u003e=0.48, I\u003csup\u003e2\u003c/sup\u003e=0%). In Fig. 5, there was a significant efficacy in improving LVEF in ACS patients receiving reperfusion treatments subjected to intravenous high-dose GIK (MD 2.12, 95%CI 0.32 to 3.92, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05) from baseline to 6 months, compared with placebos. (Fig. 5)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse effects\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFour\u0026nbsp;\u003csup\u003e[16,17,19,23]\u003c/sup\u003e of the eleven trials provided data on the occurrence of phlebitis, reporting 4.5% (13/291) of studied populations in the high-dose GIK group and 0.8% (2/249) in the control group during the follow-up period (RR 4.78, 95%CI 1.36 to 16.76, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05). Quantitative analyses of relevant studies\u0026nbsp;\u003csup\u003e[15,17,20]\u003c/sup\u003e showed high-dose GIK infusion resulted in an obvious increase in serum potassium concentrations (MD 0.29, 95%CI 0.17 to 0.40, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.00001). Whereas no significant effect of high-dose GIK on the incidence of hyperkalemia was observed versus controls (RR 5.99, 95%CI 0.79 to 45.27, \u003cem\u003ep\u003c/em\u003e=0.08). Despite obvious increases in both hyperglycemia (RR 9.06, 95%CI 1.74 to 47.29, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.01) and hypoglycemia (RR 6.50, 95%CI 1.28 to 33.01, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05), the mean concentration of serum glucose after intravenous GIK did not show any significant change between the high-dose GIKs and control groups (MD 4.52, 95%CI -7.53 to 16.56, \u003cem\u003ep\u003c/em\u003e=0.46). No significant heterogeneity was examined among all studies (Fig. 6).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChanges of oxidative stress parameters\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 67 patients were enrolled in two RCTs\u0026nbsp;\u003csup\u003e[15,22]\u003c/sup\u003e. As shown in Fig. 7, high-dose GIK presented a marked reduction in SOD activity post-PCI when compared with controls (SMD -0.77, 95%CI -1.28 to -0.26, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05). However, there was no statistically significant difference in GSH-Px activity (SMD 0.34, 95%CI -0.16 to 0.83, \u003cem\u003ep\u003c/em\u003e=0.18) and CAT activity (SMD 0.35, 95%CI -0.14 to 0.84, \u003cem\u003ep\u003c/em\u003e=0.16) after PCI between GIK and control groups. No severe heterogeneity was observed among all concerned studies (Fig. 7).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication bias\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo significant asymmetry of the funnel plot for included RCTs was observed via visual inspection (Fig. 8), also no statistical publication bias was showed from Egger\u0026rsquo;s test (t = 0.16, p=0.586).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis meta-analysis evaluated study data from eleven RCTs\u0026nbsp;\u003csup\u003e[13-23]\u003c/sup\u003e relevant to the high-dose GIK applications for ACS patients following reperfusion therapy. Limited evidence, based on included trials, indicated that high-dose GIK was associated with better myocardial protection and higher occurrence of certain complications.\u003c/p\u003e\n\u003cp\u003eContrast to our beneficial findings on MACEs of high-dose GIK infusion in patients diagnosed with ACS undergoing reperfusion therapy, results of combined analysis of the OASIS-6 and CREATE-ECLA\u0026nbsp;\u003csup\u003e[24-26]\u003c/sup\u003e, two largest RCTs regarding high-dose GIK treatments in acute myocardial infarction (AMI) patients, demonstrated that infusion of high-dose GIK provided no net clinical benefits while even an early harm was caused. There are several feasible accounts for this divergence, and the main reason may be the essential distinctions between reperfusion or not. Populations included in our study all accepted at least one reperfusion treatment, while only about 80% patients in OASIS-6 and CREATE-ECLA combined analysis received reperfusion therapy. GIK may fail to reach severely ischemic myocardium and consequently function in cases without reperfusion because of the occlusion of coronary\u0026nbsp;\u003csup\u003e[27,28]\u003c/sup\u003e. Besides,\u0026nbsp;eight of eleven RCTs specifically clarified high-dose GIK was initiated before the onset of reperfusion therapy that signified the solution could get to ischemia area once criminal vascular was opened. An additional consideration for this difference might be relevant to a higher proportion of AMI in both OASIS-6 and CREATE-ECLA trials compared with our study, which represented a severe pathophysiological change and indicated a reduced tolerance for elevated glucose, potassium and net fluid infusion maybe\u0026nbsp;\u003csup\u003e[29,30]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDespite of early harmful effects showed in combined analysis of the OASIS-6 and CREATE-ECLA, a neutral overall effect on 30-day outcomes indicated that high-dose GIK therapy may have delayed benefits which neutralized its early harms. Similarly, studies reviewed in this meta-analysis demonstrated a consistent trend toward chronic cardiac function improvement, as LVEF at 6 months showed a statistical increase in patients receiving high-dose GIK infusion. Academically, myocardial infarction evokes excessive acquittal of catecholamines\u0026nbsp;\u003csup\u003e[31]\u003c/sup\u003e and subsequently generated stressed reduction in insulin secretion and increase in FFAs\u0026nbsp;\u003csup\u003e[32-34]\u003c/sup\u003e. These made myocardium converts from anaerobic glycolysis to anaerobic FFAs oxidation during ischemia, which lead to the deposition of toxic intermediates of FFAs depressing myocardial mechanical activity and contraction\u0026nbsp;\u003csup\u003e[35-37]\u003c/sup\u003e. Regarded as a metabolic modulation strategy, GIK had several possible mechanisms for improving cardiac function\u0026nbsp;\u003csup\u003e[38,39]\u003c/sup\u003e. Our analysis demonstrated that high-dose GIK could provide marked SOD activity reduction in ACS patients undergoing reperfusion therapy, which indicated a good oxidative stress-lowering function, reinforcing the concept that high-dose GIK improving LVEF by an inhibitory effect on fatty toxicity.\u003c/p\u003e\n\u003cp\u003eAdditionally, our meta-analysis did not show any benefit on mortality from high-dose GIK regimens; this is contrary to the results reported in a prior meta-analysis including eight trials (high- and low- combined) performed in pre-reperfusion era which confirmed a 28% proportional hospital mortality reduction\u0026nbsp;\u003csup\u003e[4]\u003c/sup\u003e. The wicked effects of secondary hyperglycemia might give a considerable explanation for this discrepancy\u003csup\u003e[40]\u003c/sup\u003e. With an original intention with strengthening metabolic strategy of high-dose GIK infusion\u003csup\u003e[41]\u003c/sup\u003e, however, this oversupply of glucose can contribute to a higher occurrence of hyperglycemia. The ACC/AHA guideline has recommended the great necessity of glucose control in patients with ACS, and linked stress hyperglycemia to a poor prognosis of AMI\u0026nbsp;\u003csup\u003e[42]\u003c/sup\u003e. Mild hyperglycemia in ACS was originally thought to be a self-defense behavior, but uncontrollable hyperglycemia would increase adverse clinical outcomes by increasing oxidative stress and amplifying inflammatory response\u0026nbsp;\u003csup\u003e[43]\u003c/sup\u003e. Although no significant changes of serum glucose concentrations were found after high-dose GIK infusion in our analysis, the increased incidence of hypoglycemia as well as hyperglycemia indicated a possibility of drastic fluctuation of blood sugar, which was also associated with worse outcomes in ACS. Several prior meta-analyses confirmed that GIK (high- and low- dose combined) showed no beneficial effect on mortality of ACS in today\u0026apos;s reperfusion era\u0026nbsp;\u003csup\u003e[6,44]\u003c/sup\u003e. One theory as to \u0026ldquo;ceiling effect\u0026rdquo; of reperfusion therapy in this difference was that the therapeutic benefits of GIK were concealed by reperfusion treatments. Moreover, a recent meta-analysis reported a possible reduction in mortality if a high-dose GIK was used as an adjunct to reperfusion therapy in patients diagnosed with STEMI\u0026nbsp;\u003csup\u003e[45]\u003c/sup\u003e. Known as the most serious type of ACS, AMI might gain greater benefits from GIK. While a quantitative analysis of GIK in patients with STEMI did not show a beneficial or detrimental effect of high-dose GIK on 30-day mortality, compared with low-dose\u0026nbsp;\u003csup\u003e[9]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eFurthermore, a higher occurrence of complications such as phlebitis, hyperglycemia and hypoglycemia, and an incline to increase serum potassium following high-dose GIK administration are showed by limited evidence, compared with controls. Therefore, the application of high-dose GIK in clinical practice may be cautious for high-risk patients with metabolic disturbances, history of uncontrolled diabetes or renal insufficiency. Serum glucose and potassium should be monitored closely in case of detrimental clinical sequels.\u003c/p\u003e\n\u003cp\u003eThere are several limitations in this meta-analysis. Firstly, our analysis restricted to literatures published in English language, which may lead to a potential publication bias. Secondly, our meta-analysis showed that all trials included related to high-dose GIK were placebo-controlled while the low-dose-controlled were still very limited. The low-dose GIK infusion strategy is now often used as an adjuvant treatment of reperfusion therapy in clinical practice, so the comparison between high-dose GIK and placebos cannot directly reflect whether intravenous high-dose GIK has better or worse effects than the existing treatments. Thirdly, due to different background ACS subtype, possible selection bias may occur. Our research showed that study population in nine of eleven studies were all participants with AMI while information on the proportion of respective subtype of ACS of another two RCTs was not available for this analysis. Then, the sample size was small, and the duration of follow-up for each trail was short which might affect the reliability of the conclusion to some extent. Besides, there are five of eleven included studies conducted a standard high-dose GIK infusion consisting of 30% glucose, 50IU/L insulin and 80mM potassium, while the dose of GIK solution has been appropriately adjusted to a lower dosage in other six studies, so the potential benefits of high concentrations of glucose and insulin infusion might be diluted. Next, through the strict selecting, studies after 2010 were absent, which might lead to a deviation for the difference in clinical conditions. Finally, although high-dose GIK group showed higher serum potassium concentration after GIK infusion, our results demonstrated that high-dose GIK did not increase the occurrence of hyperkalemia. Further well-designed large-scaled RCTs with long-term follow-up, comparing high- and low- dose GIK are urgently warranted to confirm the efficacy and security of intravenous high-dose GIK in patients diagnosed with ACS in this reperfusion era.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn patients with ACS undergoing reperfusion therapy, this meta-analysis demonstrated that high-dose GIK presented a good oxidative stress-lowering effect and were effective in reducing the risk of MACEs and heart failure, as well as improving LVEF, as compared with placebos. Meanwhile, a significant trend to higher occurrence of hyperglycemia and hypoglycemia, also an increase in serum potassium was associated with high-dose GIK. As an adjuvant therapy for reperfusion treatment, high-dose GIK solution is efficient and economical for patients. Therefore, large-scaled clinical trials with long-term follow-up assessing high-dose GIK and low-dose GIK are urgently required.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eGIK: Glucose-insulin-potassium; FFAs: Free fat acids; ACS: Acute coronary syndrome; RCT Randomized controlled trial; MACE: Major adverse cardiovascular event; LVEF: Left ventricular ejection fraction; SOD: Super oxide dismutase; GSH-Px: Glutathione peroxidase; CAT: Catalase; RR: Risk ratio; MD: Mean difference; SMD: Standardized mean difference; STEMI: ST-segment elevation myocardial infarction; AMI: Acute myocardial infarction; PRISMA: Preferred reporting items for systematic reviews and meta-analysis; TIMI: Thrombolysis in myocardial infarction grade; CI: Confidence intervals; PCI: Percutaneous coronary intervention; CABG: Coronary artery bypass grafting.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all members of the Emergency Department of Qilu Hospital of Shandong University for their valuable comments on the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHRL contributed to the literature review, data curation and writing. RGL contributed to investigation, writing and risk of bias assessment. HY performed data curation and analysis. FX contributed to review of all and final revisions. YGC hold the study design. CBL provided resources, performed statistical analysis and cerate figures and tables. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Natural Science Foundation of China (82070388 and 82170442), Taishan Pandeng Scholar Program of Shandong Province (tspd20181220), National Natural Science Foundation of Shandong Province (ZR2020MH035).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed can be acquired from this published article and its additional information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Emergency Medicine and Chest Pain Center, Qilu Hospital of\u0026nbsp;Shandong University, Jinan, Shandong, China. \u003csup\u003e2\u003c/sup\u003eKey Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital of Shandong University, Jinan, Shandong, China.\u003csup\u003e3\u003c/sup\u003eThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eOpie L. 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Oct 2004;5(10):727-31. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"acute coronary syndrome, high-dose, glucose-insulin-potassium, reperfusion therapy, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-1727509/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1727509/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Normal glucose-insulin-potassium (GIK) did not improve clinical outcomes in ACS patients in today’s reperfusion era; however, whether high-dose GIK appeared any cardioprotective function remains uncertain. This meta-analysis aimed to assess the efficacy of high-dose GIK on clinical outcomes in acute coronary syndrome (ACS) patients undergoing reperfusion therapy.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We searched PubMed, Web of science, MEDLINE, Embase and Cochrane Library databases from inception until April 26, 2022 for randomized controlled trials (RCTs) that compared high-dose GIK and placebos in ACS patients receiving reperfusion therapy. The primary endpoint was major adverse cardiovascular events (MACEs), and the secondary endpoints were all-cause mortality, left ventricular ejection fraction (LVEF), heart failure, reinfarction, phlebitis, hyperglycemia, hyperkalemia, hypoglycemia, secondary reperfusion, serum glucose and potassium, activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Eleven RCTs with 884 patients were eventually included. Compared with placebos, high-dose GIK markedly reduced MACEs (RR 0.57, 95%CI 0.35 to 0.94, p\u0026lt;0.05) and the risk of heart failure (RR 0.48, 95%CI 0.25 to 0.95, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05), also improved LVEF (MD 2.12, 95%CI 0.32 to 3.92, p\u0026lt;0.05) at 6 months. However, no difference was observed in occurring all-cause mortality at 30 days (RR 0.90, 95%CI 0.35 to 2.28, p=0.82) or 1 year (RR 0.57 95%CI 0.22 to 1.51, p=0.26). Additionally, high-dose GIK was significantly associated with higher occurrence of phlebitis (RR 4.78, 95%CI 1.36 to 16.76, p\u0026lt;0.05), hyperglycemia (RR 9.06, 95%CI 1.74 to 47.29, p\u0026lt;0.01) and hypoglycemia (RR 6.50, 95%CI 1.28 to 33.01, p\u0026lt;0.05), but not reinfarction (RR 0.74, 95%CI 0.36 to 1.50, p =0.40), hyperkalemia (RR 5.99, 95%CI 0.79 to 45.27, p=0.08) or secondary reperfusion (RR 0.91, 95%CI 0.72 to 1.14, p=0.41). As for oxidative stress-lowering function, high-dose GIK markedly reduced SOD activity (SMD -0.77, 95%CI -1.28 to -0.26, p\u0026lt;0.05), but not activity of GSH-Px (SMD 0.34, 95%CI -0.16 to 0.83, p=0.18) or CAT (SMD 0.35, 95%CI -0.14 to 0.84, p=0.16).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Patients with ACS receiving reperfusion therapy showed reduction in MACEs and heart failure, improvement of LVEF, as well as good oxidative stress-lowering efficacy in response to high-dose GIK. Simultaneously, higher occurrence of several complications such as phlebitis, hyperglycemia and hypoglycemia accompanied, also a trend to an increase in serum potassium appeared. Furthermore, patients’ all-cause mortality did not modulate any benefits associated with exposure to high-dose GIK. More trails with long-term follow-up are stilled demanded to further verify its efficacy and security to provide powerful evidences for clinical practice.\u003c/p\u003e","manuscriptTitle":"Effects of high-dose glucose-insulin-potassium on acute coronary syndrome patients undergoing reperfusion therapy: a meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-06-13 18:36:08","doi":"10.21203/rs.3.rs-1727509/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3c41768e-d06d-4bee-9c30-94d7c74191bc","owner":[],"postedDate":"June 13th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-06-13T18:36:10+00:00","versionOfRecord":[],"versionCreatedAt":"2022-06-13 18:36:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1727509","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1727509","identity":"rs-1727509","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}