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Very early administration of glucose-insulin-potassium by emergency medical service for acute coronary syndromes: Biological mechanisms for benefit in the IMMEDIATE Trial.

ABSTRACT: AIMS:In the IMMEDIATE Trial, intravenous glucose-insulin-potassium (GIK) was started as early as possible for patients with suspected acute coronary syndrome by ambulance paramedics in communities. In the IMMEDIATE Biological Mechanism Cohort substudy, reported here, we investigated potential modes of GIK action on specific circulating metabolic components. Specific attention was given to suppression of circulating oxygen-wasting free fatty acids (FFAs) that had been posed as part of the early GIK action related to averting cardiac arrest. METHODS:We analyzed the changes in plasma levels of FFA, glucose, C-peptide, and the homeostasis model assessment (HOMA) index. RESULTS:With GIK, there was rapid suppression of FFA levels with estimated levels for GIK and placebo groups after 2 hours of treatment of 480 and 781 ?mol/L (P<.0001), even while patterns of FFA saturation remained unchanged. There were no significant changes in the HOMA index in the GIK or placebo groups (HOMA index: placebo 10.93, GIK 12.99; P = .07), suggesting that GIK infusions were not countered by insulin resistance. Also, neither placebo nor GIK altered endogenous insulin secretion as reflected by unchanging C-peptide levels. CONCLUSION:These mechanistic observations support the potential role of FFA suppression in very early cardioprotection by GIK. They also suggest that the IMMEDIATE Trial GIK formula is balanced with respect to its insulin and glucose composition, as it induced no endogenous insulin secretion.

SUBMITTER: Selker HP

PROVIDER: S-EPMC6390847 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Very early administration of glucose-insulin-potassium by emergency medical service for acute coronary syndromes: Biological mechanisms for benefit in the IMMEDIATE Trial.

Selker Harry P HP Harris William S WS Rackley Charles E CE Marsh Julian B JB Ruthazer Robin R Beshansky Joni R JR Rashba Eric J EJ Peter Inga I Opie Lionel H LH

American heart journal 20160602

<h4>Aims</h4>In the IMMEDIATE Trial, intravenous glucose-insulin-potassium (GIK) was started as early as possible for patients with suspected acute coronary syndrome by ambulance paramedics in communities. In the IMMEDIATE Biological Mechanism Cohort substudy, reported here, we investigated potential modes of GIK action on specific circulating metabolic components. Specific attention was given to suppression of circulating oxygen-wasting free fatty acids (FFAs) that had been posed as part of the ...[more]

PMID: 27502865

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Project description:ContextLaboratory studies suggest that in the setting of cardiac ischemia, immediate intravenous glucose-insulin-potassium (GIK) reduces ischemia-related arrhythmias and myocardial injury. Clinical trials have not consistently shown these benefits, possibly due to delayed administration.ObjectiveTo test out-of hospital emergency medical service (EMS) administration of GIK in the first hours of suspected acute coronary syndromes (ACS).Design, setting, and participantsRandomized, placebo-controlled, double-blind effectiveness trial in 13 US cities (36 EMS agencies), from December 2006 through July 31, 2011, in which paramedics, aided by electrocardiograph (ECG)-based decision support, randomized 911 (871 enrolled) patients (mean age, 63.6 years; 71.0% men) with high probability of ACS.InterventionIntravenous GIK solution (n = 411) or identical-appearing 5% glucose placebo (n = 460) administered by paramedics in the out-of-hospital setting and continued for 12 hours.Main outcome measuresThe prespecified primary end point was progression of ACS to myocardial infarction (MI) within 24 hours, as assessed by biomarkers and ECG evidence. Prespecified secondary end points included survival at 30 days and a composite of prehospital or in-hospital cardiac arrest or in-hospital mortality, analyzed by intent-to-treat and by presentation with ST-segment elevation.ResultsThere was no significant difference in the rate of progression to MI among patients who received GIK (n = 200; 48.7%) vs those who received placebo (n = 242; 52.6%) (odds ratio [OR], 0.88; 95% CI, 0.66-1.13; P = .28). Thirty-day mortality was 4.4% with GIK vs 6.1% with placebo (hazard ratio [HR], 0.72; 95% CI, 0.40-1.29; P = .27). The composite of cardiac arrest or in-hospital mortality occurred in 4.4% with GIK vs 8.7% with placebo (OR, 0.48; 95% CI, 0.27-0.85; P = .01). Among patients with ST-segment elevation (163 with GIK and 194 with placebo), progression to MI was 85.3% with GIK vs 88.7% with placebo (OR, 0.74; 95% CI, 0.40-1.38; P = .34); 30-day mortality was 4.9% with GIK vs 7.7% with placebo (HR, 0.63; 95% CI, 0.27-1.49; P = .29). The composite outcome of cardiac arrest or in-hospital mortality was 6.1% with GIK vs 14.4% with placebo (OR, 0.39; 95% CI, 0.18-0.82; P = .01). Serious adverse events occurred in 6.8% (n = 28) with GIK vs 8.9% (n = 41) with placebo (P = .26).ConclusionsAmong patients with suspected ACS, out-of-hospital administration of intravenous GIK, compared with glucose placebo, did not reduce progression to MI. Compared with placebo, GIK administration was not associated with improvement in 30-day survival but was associated with lower rates of the composite outcome of cardiac arrest or in-hospital mortality.Trial registrationclinicaltrials.gov Identifier: NCT00091507.

Project description:BackgroundExperimental studies suggest that metabolic myocardial support by intravenous (IV) glucose, insulin, and potassium (GIK) reduces ischemia-induced arrhythmias, cardiac arrest, mortality, progression from unstable angina pectoris to acute myocardial infarction (AMI), and myocardial infarction size. However, trials of hospital administration of IV GIK to patients with ST-elevation myocardial infarction (STEMI) have generally not shown favorable effects possibly because of the GIK intervention taking place many hours after ischemic symptom onset. A trial of GIK used in the very first hours of ischemia has been needed, consistent with the timing of benefit seen in experimental studies.ObjectiveThe IMMEDIATE Trial tested whether, if given very early, GIK could have the impact seen in experimental studies. Accordingly, distinct from prior trials, IMMEDIATE tested the impact of GIK (1) in patients with acute coronary syndromes (ACS), rather than only AMI or STEMI, and (2) administered in prehospital emergency medical service settings, rather than later, in hospitals, after emergency department evaluation.DesignThe IMMEDIATE Trial was an emergency medical service-based randomized placebo-controlled clinical effectiveness trial conducted in 13 cities across the United States that enrolled 911 participants. Eligible were patients 30 years or older for whom a paramedic performed a 12-lead electrocardiogram to evaluate chest pain or other symptoms suggestive of ACS for whom electrocardiograph-based acute cardiac ischemia time-insensitive predictive instrument indicated a ≥75% probability of ACS, and/or the thrombolytic predictive instrument indicated the presence of a STEMI, or if local criteria for STEMI notification of receiving hospitals were met. Prehospital IV GIK or placebo was started immediately. Prespecified were the primary end point of progression of ACS to infarction and, as major secondary end points, the composite of cardiac arrest or in-hospital mortality, 30-day mortality, and the composite of cardiac arrest, 30-day mortality, or hospitalization for heart failure. Analyses were planned on an intent-to-treat basis, on a modified intent-to-treat group who were confirmed in emergency departments to have ACS, and for participants presenting with STEMI.ConclusionThe IMMEDIATE Trial tested whether GIK, when administered as early as possible in the course of ACS by paramedics using acute cardiac ischemia time-insensitive predictive instrument and thrombolytic predictive instrument decision support, would reduce progression to AMI, mortality, cardiac arrest, and heart failure. It also tested whether it would provide clinical and pathophysiologic information on GIK's biological mechanisms.

Project description:A challenge for emergency medical service (EMS) is accurate identification of acute coronary syndromes (ACS) and ST-segment elevation myocardial infarction (STEMI) for immediate treatment and transport. The electrocardiograph-based acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI) and the thrombolytic predictive instrument (TPI) have been shown to improve diagnosis and treatment in emergency departments (EDs), but their use by paramedics in the community has been less studied.To identify candidates for participation in the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care (IMMEDIATE) Trial, we implemented EMS use of the ACI-TIPI and the TPI in out-of-hospital electrocardiographs and evaluated its impact on paramedic on-site identification of ACS and STEMI as a community-based approach to improving emergency cardiac care.Ambulances in the study municipalities were outfitted with electrocardiographs with ACI-TIPI and TPI software. Using a before-after quasi-experimental design, in Phase 1, for seven months, paramedics were provided with the ACI-TIPI/TPI continuous 0-100% predictions automatically printed on electrocardiogram (ECG) text headers to supplement their identification of ACS; in Phase 2, for 11 months, paramedics were told to identify ACS based on an ACI-TIPI cutoff probability of ACS ? 75% and/or TPI detection of STEMI. In Phase 3, this cutoff approach was used in seven additional municipalities. Confirmed diagnoses of ACS, acute myocardial infarction (AMI), and STEMI were made by blinded physician review for 100% of patients.In Phase 1, paramedics identified 107 patients as having ACS; in Phase 2, 104. In Phase 1, 45.8% (49) of patients so identified had ACS confirmed, which increased to 76.0% (79) in Phase 2 (p < 0.001). Of those with ACS, 59.2% (29) had AMI in Phase 1 versus 84.8% (67) with AMI in Phase 2 (p < 0.01), and STEMI was confirmed in 40.8% (20) versus 68.4% (54), respectively (p < 0.01). In Phase 3, of 226 patients identified by paramedics as having ACS, 74.3% (168) had ACS confirmed, of whom 81.0% (136) had AMI and 65.5% (110) had STEMI. Among patients with ACS, the proportion who received percutaneous coronary intervention (PCI) was 30.6% (15) in Phase 1, increasing to 57.0% (45) in Phase 2 (p < 0.004) and 50.6% (85) in Phase 3, and the proportions of patients with STEMI receiving PCI rose from 75.0% (15) to 83.3% (45) (p < 0.4) and 82.7% (91).In a wide range of EMS systems, use of electrocardiographs with ACI-TIPI and TPI decision support using a 75% ACI-TIPI cutoff improves paramedic diagnostic performance for ACS, AMI, and STEMI and increases the proportions of patients who receive PCI.

Project description:BackgroundPrevious studies examining sex-related differences in the treatment of coronary artery disease have focused on patients in hospital. We sought to examine sex-related differences at an earlier point in care--presentation to the emergency department.MethodsWe collected data on ambulatory care and hospital admissions for 54,134 patients (44% women) who presented to an emergency department in Alberta between July 1998 and March 2001 because of acute myocardial infarction, unstable angina, stable angina or chest pain. We used logistic regression and Cox regression analyses to determine sex-specific associations between the likelihood of discharge from the emergency department or coronary revascularization within 1 year and 1-year mortality after adjusting for age, comorbidities and socioeconomic factors.ResultsFollowing the emergency department visit, 91.3% of patients with acute myocardial infarction, 87.4% of those with unstable angina, 40.7% of those with stable angina and 19.8% of those with chest pain were admitted to hospital. Women were more likely than men to be discharged from the emergency department: adjusted odds ratio (and 95% confidence interval [CI]) 2.25 (1.75-2.90) for acute myocardial infarction, 1.71 (1.45-2.01) for unstable angina, 1.33 (1.15-1.53) for stable angina and 1.46 (1.36-1.57) for chest pain. Women were less likely than men to undergo coronary revascularization within 1 year: adjusted odds ratio (and 95% CI) 0.65 (0.57-0.73) for myocardial infarction, 0.39 (0.35-0.44) for unstable angina, 0.35 (0.29-0.42) for stable angina and 0.32 (0.27-0.37) for chest pain. Female sex had no impact on 1-year mortality among patients with acute myocardial infarction; it was associated with a decreased 1-year mortality among patients with unstable angina, stable angina and chest pain: adjusted hazard ratio (and 95% CI) 0.60 (0.46-0.78), 0.60 (0.46-0.78) and 0.74 (0.63-0.87) respectively.InterpretationWomen presenting to the emergency department with coronary syndromes are less likely than men to be admitted to an acute care hospital and to receive coronary revascularization procedures. These differences do not translate into worse outcomes for women in terms of 1-year mortality.

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Very early administration of glucose-insulin-potassium by emergency medical service for acute coronary syndromes: Biological mechanisms for benefit in the IMMEDIATE Trial.

Publications

Very early administration of glucose-insulin-potassium by emergency medical service for acute coronary syndromes: Biological mechanisms for benefit in the IMMEDIATE Trial.

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