(Circulation. 1998;98:2227-2234.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Metabolic Modulation of Acute Myocardial Infarction
The ECLA Glucose-Insulin-Potassium Pilot Trial
From the Department of Cardiology, Instituto Cardiovascular de Rosario, Rosario, Argentina (R.D., E.A.P., G.R.); Instituto Dante Pazzanese de Cardiologia, Sao Paulo, Brasil (L.S.P.); Critical Care Unit, Sanatorio de la Providencia, Buenos Aires, Argentina (C.D.T.); Catheterization Laboratory, Instituto Nacional de Cardiología `Ignacio Chavez,' México DF, México (M.G.M.); Department of Cardiovascular Diseases, Hospital Clínico, Universidad Católica de Chile, Santiago, Chile (R.C.); and the Critical Care Unit, Hospital Dr Domingo Luciani, Caracas, Venezuela (J.E.I.).
Correspondence to Rafael Diaz, MD, ECLA Estudios Cardiológicos Latinoamérica, Bv Oroño 500. 2000 Rosario, Argentina. E-mail ecla{at}satlink.com
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Abstract |
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Background—Several trials have been performed in the past using glucose, insulin, and potassium infusion (GIK) for the treatment of acute myocardial infarction (AMI). Because of continuing uncertainty about the potential role of this therapeutic intervention, we conducted a randomized trial to evaluate the impact of a GIK solution during the first hours of AMI.
Methods and Results—Four hundred seven patients with suspected AMI admitted within 24 hours of symptoms onset were enrolled. In a ratio of 2:1, 268 patients were allocated to receive GIK (high- or low-dose) and 139 to receive control. Phlebitis and serum changes in the plasma concentration of glucose or potassium were observed more often with GIK. A trend toward a nonsignificant reduction in major and minor in-hospital events was observed in patients allocated to GIK. In 252 patients (61.9%) treated with reperfusion strategies, a statistically significant reduction in mortality (relative risk [RR] 0.34; 95% CI: 0.15 to 0.78; 2P=0.008) and a consistent trend toward fewer in-hospital events in the GIK group were observed.
Conclusions—Our results confirm that a metabolic modulation strategy in the first hours of an AMI is feasible, applicable worldwide, and has mild side effects. The statistically significant mortality reduction in patients who underwent a reperfusion strategy might have important implications for the management of AMI patients. It is now essential to perform a large-scale trial to reliably determine the magnitude of benefit.
Key Words: myocardial infarction • ischemia • glucose • insulin • potassium • coronary disease
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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The pathophysiological mechanism of acute myocardial infarction (AMI) is the rupture of an atherosclerotic plaque in an epicardial coronary artery, exposing subendothelial tissue to a subsequent thrombogenic response and leading to a complete obstruction of the vessel.1 2 Strategies directed toward achieving early and sustained reperfusion of the infarct-related artery have reduced mortality;3 4 5 6 7 thrombolytics, aspirin, and, in selected centers, primary angioplasty are used as routine treatment during the early hours of AMI. The concept of metabolic protection of the ischemic myocardium hinges on the fact that glucose can be metabolized anaerobically and can thereby provide glycolytic ATP in the cytosolic compartment.8 Because glucose uptake is promoted by insulin, infusions of glucose and insulin with potassium (GIK) were initially evaluated in AMI by Sodi Pallares in 1962.9
Because the potential role of this intervention is still uncertain, we conducted a pilot clinical trial to evaluate the feasibility of GIK administration in contemporary practice and to assess its effect on clinical end points to develop a rationale for performing a large-scale trial of GIK infusion during the acute phase of myocardial infarction.
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Methods |
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Recruitment of Patients
To encourage recruitment, the trial was kept simple and eligibility was broad. Patients with a suspected AMI within 24 hours of symptom onset were eligible regardless of age or ECG findings. There were no restrictions on ancillary treatments. Overall coordination was performed by the ECLA (Estudios Cardiológicos Latinoamérica) Coordinating Center in Rosario, Argentina.
The absolute contraindications to GIK infusion were severe renal impairment or hyperkalemia. No other contraindications were specified by the protocol but instead were left to the discretion of the responsible physician. Patients were to be entered in the trial only once.
Randomization
Eligible patients were randomized in each participating center
by a central telephone randomization system located at the ECLA
Coordinating Center, except for patients in Brazil where, because of
language differences, randomization was done using sequentially
numbered sealed envelopes prepared centrally.
Informed consent was obtained from individual patients according to the requirements of local ethics committees, which approved the study.
Active treatment (GIK infusion) and control (usual care) were allocated within each center in a ratio of 2:1.
Treatment
Two GIK solutions concentrations were used. High-dose GIK (HD
GIK) has been advocated to suppress FFA
levels.10
HD GIK consisted of 25% glucose, 50 IU soluble insulin (either human or not human) per liter and 80 mmol KCl per liter at an infusion rate of 1.5 mL/(kg · h) over 24 hours. Low-dose GIK (LD GIK) was a mixture of 10% glucose, 20 IU soluble insulin (either human or not human) per liter and 40 mmol KCl per liter at an infusion rate of 1.0 mL · kg-1 · h-1 over 24 hours. GIK infusion was initiated immediately after randomization and interrupted only if it was thought by the attending physician to be clearly indicated. Physicians were free to use whatever additional therapy they considered necessary, including the method of reperfusion (thrombolytics or primary PTCA).
Data Recorded
After discharge, a clinical record form was sent to the ECLA
Coordinating Center. Serial plasma concentrations of glucose and
potassium were collected and recorded at randomization, and at 6,
24, and 48 hours after randomization.
The protocol stated that the population would be analyzed based on the treatment groups to which patients were randomized (HD GIK, LD GIK, and control), both GIK groups versus control, and both GIK groups versus control stratifying the population into those receiving and those not receiving a reperfusion strategy. All analyses were done on an intention-to-treat basis. The statistical analyses for continuous variables were done using ANOVA, and the comparisons for categorical variables were expressed as the relative risk (RR) with corresponding 95% CI. Probability values are 2-sided throughout and 2P>0.05 was considered not significant.
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Results |
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In 29 hospitals in 6 Latin American countries, 407 patients with a diagnosis of suspected AMI were randomized over 14 months. They were randomized as follows: 135 (33.2%) patients to HD GIK, 133 (32.7%) to LD GIK, and 139 (34.2%) to the control group. GIK infusion (HD or LD) was not started in 2 patients (0.7%) and was completed in 238 (88.8%) of the patients allocated to GIK. Among the 252 (61.9%) patients treated with a reperfusion strategy, 95% received lytic therapy and 5% were treated with primary angioplasty.
The mean infused volume was 2422 mL per 24 hours for HD GIK and 1795 mL/24 h for LD GIK in patients who received the infusion in accordance with the protocol (24-hour infusion). In 384 (94.3%) patients, myocardial infarction was enzymatically confirmed.
Tables 1
and 2 show the baseline characteristics of
the randomized population. A family history of coronary heart
disease and smoking were more frequently observed in the GIK group. All
other variables were well matched and did not differ
significantly.
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Because of a lack of significant differences in the rate of adverse
effects and the impossibility of detecting any difference in benefit
between the 2 dose regimens , owing to the small number of patients
(Table 3), the results are reported as a
comparison of the combination of both GIK regimens versus control.
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Adverse Effects
The hospital length of stay, an indirect measurement of morbidity,
did not differ in the treatments groups (9.8 days GIK versus 10.5 days
control). Most of the population received a peripheral line
(83%) ; phlebitis was reported in 45 (16.8%) patients allocated to
GIK, although only 5 were identified as severe (1.9%). In no case did
phlebitis cause an excess rate of morbidity (eg, sepsis) or any other
complication.
Signs and symptoms of fluid overload were not different among the
treatment groups. As shown in Table 4,
the incidence of severe heart failure (Killip class>2) was not
significantly different between the GIK and control groups, and a
nonsignificant trend toward a reduction in the incidence of severe
heart failure was observed in the GIK group.
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Figure 1 shows the mean plasma levels of
glucose and potassium at prerandomization and 6, 24, and 48 hours after
randomization. No significant differences were observed in the glucose
levels between the GIK and control groups, and significantly higher
potassium levels were observed 24 hours (GIK 4.25 mmol/L versus
control 4.04 mmol/L, P=0.0001) and 48 hours (GIK
4.24 mmol/L versus control 4.08 mmol/L, P=0.0027)
after randomization in the GIK group.
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In-Hospital Events
Table 4
shows the in-hospital events stratified by treatment
group. The overall mortality rate during the hospital phase was 8.35%
(95% CI 5.66 to 11.04). A trend toward a non–statistically
significant reduction of major and minor in-hospital events was
observed in patients allocated to GIK (Figure 2a). The reported incidence of
electromechanical dissociation was higher in the control group (5.8%
versus 1.5%, 2P=0.016).
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The baseline characteristics of 252 (61.9%) patients treated with a
reperfusion strategy are shown in Table 2. A higher prevalence of men
and smokers was observed in the GIK group; all other variables were
well matched. As shown in Table 4, a significant reduction in mortality
(RR 0.34; 95% CI 0.15 to 0.78; 2P=0.008) and
electromechanical dissociation (RR 0.18; 95% CI 0.036 to 0.909;
2P=0.02) as well as a nonsignificant trend toward fewer
in-hospital events was observed in the GIK treatment group (Figure 2b).
Using a more specific analysis of the data and focusing on hard
events, we stratified the end points of death, severe heart failure,
and ventricular fibrillation in reperfused and
nonreperfused patients. A 47% nonsignificant reduction in mortality
for any death was observed (2P=0.10); using the 99%
CI, the lower limit for mortality reduction in the reperfused patients
was still below the unit (odds ratio 0.27; 99% CI 0.08 to
0.96). Interestingly, the heterogeneity test was
significant, (
2=4.68,
P=0.03), probably reinforcing the concept that GIK
produces different effects in patients who do or do not undergo a
reperfusion strategy. A 30% nonsignificant reduction of any severe
heart failure was observed, which was more pronounced in reperfused
patients; and a striking 56% borderline-significant
(P=0.07) reduction in any ventricular
fibrillation was observed both in reperfused and nonreperfused patients
(Figure 3).
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A significant reduction in the composite end point of death, nonfatal
severe heart failure (Killip class >2), and nonfatal
ventricular fibrillation was observed for both the overall
and reperfused patients (Table 4, Figure 2).
We observed a nonsignificant trend toward more frequent use of invasive procedures during the in-hospital phase (CABG/nonprimary PTCA) in the GIK group (RR 1.36; 95% CI 0.61 to 3.00), and this trend was more pronounced in the reperfusion group (RR 2.28; 95% CI 0.68 to 7.66).
Although we have not done post hoc analyses due to the risk of true or false-positive or -negative results, we found a strong relation between the time from symptom onset and the impact of the infusion. A significant reduction in mortality was observed in patients treated within 12 hours of symptom onset (RR 0.43; 95% CI 0.2 to 0.9; P=0.02) both for the overall population and for patients who underwent a reperfusion strategy.
Among patients in whom the infusion was completed, we observed a
significant reduction in mortality in the overall GIK group (RR 0.44;
95% CI 0.21 to 0.90) and in those patients who underwent any
reperfusion strategy (RR 0.21; 95% CI 0.08 to 0.58) (Figure 4).
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The 1-year follow-up Kaplan-Meier curves show a dilution of the
treatment effect in both the overall and reperfused populations. A
nonsignificant mortality reduction of 19% and 33% for the overall and
reperfused patients, respectively, was observed. Although this
attenuation of the treatment effect, when analyzing each of the
treatment arms, a consistent statistically significant
reduction in mortality was still present for the HD GIK group in
reperfused patients (RR 0.37, 95% CI 0.14 to 1.00; log-rank test
0.046) (Figure 5).
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Discussion |
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This pilot trial demonstrates that GIK infusion is feasible and could have worldwide applicability. It requires neither human nor technological resources that could limit its wide use, has few side effects (which are easily managed), and does not produce major morbidity or mortality in AMI patients (compared with treatments of proven benefit but life-threatening side effects).
Direction of the Effect
Important clinical events such as mortality, severe heart failure,
ventricular fibrillation, and electromechanical
dissociation (Figure 2a and 2b), which could be influenced by the GIK
infusion (infarct size limitation or protection of
ischemic/viable myocardium and incidence of
arrhythmias), demonstrated a consistent trend toward
benefit. This effect was more impressive and reached statistical
significance in patients who underwent reperfusion strategies. When
examining only patients who were actually treated (not on an
intention-to-treat basis), which is a useful approach for in-depth
analysis in pilot studies, the reduction in events was in the
same direction, more pronounced, and it reached statistical
significance for mortality in the overall population as well as in
patients who underwent a reperfusion strategy (Figure 4).
The only end point that went in the opposite direction was the use of in-hospital invasive procedures (CABG/nonprimary PTCA). Although we cannot draw any conclusion about this observation, we can speculate that patients who received GIK, especially those with reperfusion therapy, have a larger amount of viable myocardium leading to a higher demand for revascularization procedures.
Regarding the impact of GIK in patients within 12 hours of symptom onset (a post hoc analysis), the explanation could be that the earlier the solution is infused, the more evident is the effect obtained. Although this hypothesis agrees with experimental data, confounding factors actually modify this interpretation, because most patients (72%) studied before 12 hours from the onset of symptoms received a reperfusion strategy.
Magnitude of the Effect
The impressive magnitude of the reduction in mortality in patients
who underwent reperfusion (Figure 2b) deserves cautious interpretation
mainly because most treatments in AMI produce only moderate effects on
major outcomes such as mortality (eg, 15% to
20%),11 and much larger numbers of patients are
needed for clinical trials to yield a reliable estimate of the
magnitude of the treatment effect.12
However, experimental data support the concept that GIK infusion in the context of ischemic/reperfused myocardium produces an impressive impact on the evolution of the injured but viable myocardium when added early during the ischemic period.13 Thus, as shown in our trial, an important impact of GIK on the reperfused myocardium cannot be excluded.
The surprising high mortality rates for control patients who underwent any reperfusion strategy is difficult to explain. The only plausible explanation is the small number of patients in that group, 79, and the high number of fatal events, 12, perhaps reflecting the play of chance. Although the mortality rate in this group was 15.2%, the 95% CI was 7.22 to 23.14. The same explanation could be applied to the low mortality rate of the reperfused patients in the GIK group, with a mortality of 5.2% and a 95% CI between 1.89 and 8.51; one could, therefore, expect a lower magnitude of effect in a larger trial. An alternative explanation of the high death rates of the control-reperfused patients could be a selection bias (sicker patients underwent reperfusion therapy), because reperfusion therapy was not randomized.
Reinforcing the concepts that GIK mainly induces beneficial effects in
the subgroup of reperfused patients and that HD GIK appears to be
superior to LD GIK, the 1-year follow-up in HD GIK –reperfused
patients showed a statistically significant reduction in
mortality (Figure 5).
Our pilot study was similar in size to or larger than most trials conducted to test the efficacy of early primary angioplasty for the treatment of AMI before the GUSTO II substudy.14 15 16 17 18 19 The impressive magnitude of benefit of these early small studies led to the incorporation of such a strategy as routine care of AMI patients in some selected centers.
Our study is, however, the largest trial with GIK published in the thrombolytic era. Our findings of an impressive impact on clinical events and few, manageable side effects could be of great importance for the clinical management of AMI patients.
Proposed Mechanism of Action of GIK
Major metabolic changes occur during the early hours
of AMI20 ; these include increased secretion of
catecholamines,21 increased
concentration of circulating free fatty acids
(FFA),22 and glucose
intolerance.23 Each of these abnormalities might
adversely influence the outcome of AMI, either by provoking
arrhythmias or by compromising the survival of ischemic
tissue.24 25
Under normal conditions, myocardium depends on aerobic metabolism, and the preferred fuels for myocardial oxidative metabolism are FFA.26 The high concentration of FFA during the early stages of AMI, a consequence of high sympathetic activity,21 could be deleterious, increasing the incidence of potentially malignant arrhythmias22 and adversely influencing the outcome of ischemic but viable tissue.24 25
A detailed review of the mechanism of action of GIK has recently been written by Apstein and Taegtmeyer.13 A meta-analysis of all properly randomized trials27 of GIK in AMI that involves about 2000 patients and 350 deaths showed a consistent reduction in mortality of 28% (95% CI 14 to 83, P=0.004). Our findings concur with those results, although the suggested benefit was more pronounced in our pilot study, reaching statistical significance in patients who underwent a reperfusion strategy. The trials included in the meta-analysis were conducted in the prethrombolytic era, which could explain the differences in the magnitude of the effect. When we add our HD GIK data to the 4 trials in the meta-analysis that used HD GIK, those results become clearer, with an odds reduction of 43% (SD: 22), 2P=0.05.
Supporting the concept that long-term metabolic control in diabetic patients is of critical importance in preventing vascular complications, one clinical trial, the Digami trial,28 found 1-year mortality of diabetic patients with AMI to be reduced significantly with an in-hospital glucose-insulin infusion followed by multidose subcutaneous insulin.
Limitations of Our Study
The lack of a blinded design introduced a potential bias in end
point assessment or ancillary care that may have affected patient
outcomes. The large volume of fluid that had to be administered made
blinding difficult, because the blinding procedure would probably have
been detrimental to the control group.
We also were unable to explore the mechanistic action of the GIK infusion, mainly because we did not measure plasma FFA or insulin levels.
Conclusions
The results of our pilot clinical trial confirm that a
metabolic modulating strategy is feasible in the first
hours of an AMI with a GIK infusion. Such a strategy is also applicable
worldwide and is associated with mild side effects that do not lead to
an increase in morbidity or mortality. The impressive magnitude of the
benefit in terms of mortality reduction and other in-hospital clinical
events is in agreement with other data and could have a major impact on
the clinical management of AMI patients.
Because of the provocative results of this clinical trial in contemporary practice and the consistency of the evidence between the meta-analysis and our study, we have designed and started a full-scale clinical trial to definitively confirm the convenience of incorporating this simple and inexpensive therapy for the routine care of AMI patients.
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Acknowledgments |
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We are indebted to patients who took part in this study, the investigators and nurses who collaborated wholeheartedly with the national coordinators in each country and Prof Robert Califf (Duke University) for useful comments on the early draft of the manuscript and Penny Hodgson for her helpful assistance in the correction of the manuscript.
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Footnotes |
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1 Investigators who collaborated in this trial are listed in the Appendix.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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The following centers and investigators collaborated in the performance of this study (values in parentheses denote the number of patients enrolled).
ECLA Steering Committee: Ernesto Paolasso (Chairman), Rafael Díaz, Leopoldo S. Piegas, Carlos Tajer, Andres Orlandini.
ECLA Coordinating Center: Graciela Romero, María Inés Genisans, Jorgelina Cirasa, Andrea Pascual, Mirta Abraham, Daniel Wojdyla, Cristina Cuesta.
Argentina: Norberto Nordaby, Hospital Frances (38), Buenos Aires; David Ryba, Hospital Santojanni (1), Buenos Aires; Luis Guzman, Sanatorio Allende (7), Cordoba; Osvaldo Perrino, Hospital Italiano (25), La Plata; Victor Arregui, Instituto Medico Platense (1), La Plata; Gustavo Irusta, Hospital Lagomaggiore (20), Mendoza; Roberto Balado, Clinica Maria Auxiliadora (4), Olavarria; Fernando Colombo Berra, Sanatorio Quilmes (15), Quilmes; Miguel Cartia, Hospital De Emergencias (37), Rosario; Ariel Dogliotti, Instituto Cardiovascular de Rosario (11), Rosario; Alberto Navarro Zaval, Instituto de Cardiologia (2), Tucuman.
Brazil: Joao B. Lopes Loures, S.C. Mis. Juiz De Fora (12), Juiz De Fora; Luis M. Fragomeni, H.S. Vicente De Apulo (15), Passo Fundo; Rui Fernando Ramos, Inst. Dante Pazzanese (18), San Pablo; Luiz Gomes Da Silva, Sancor (15), Santos.
Chile: Ramon Corbalan, Hospital PTS Universidad Catolica (9), Santiago; Eduardo Chavez, Asistencia Publica (2), Santiago.
Mexico: Juan Carlos Ramirez, Hospital Miguel Hidalgo (12), Aguascalientes; Sergio Gonzalez, Hospital General De Durango (6), Durango; Isaac Medina Godinez, Hospital Civil De Guadalajara (40), Guadalajara; Jesus Zuñiga Sedan, Hospital Del Carmen (8), Guadalajara; Manuel Barrera Bustil, Clinica De Merida (1), Merida; Lauro Carrillo, Hospital Español (9), Mexico DF; Jesus Martinez Sanche, Hospital Ingles Abc (8), Mexico DF; Jorge Bahema Cuevas, Hospital Universitario (2), Monterrey.
Uruguay: Gabriel Vanerio, Hospital Britanico (6), Montevideo.
Venezuela: Jesus Isea, Félix Sanchez, Hospital Domingo Luciani (70), Caracas; Leonardo Madrid, Centro Clínico Orinoco (13), Ciudad Bolivar.
Received March 3, 1998; revision received May 28, 1998; accepted July 24, 1998.
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L. H. Opie Glucose-Insulin-Potassium Therapy in Patients With STEMI JAMA, May 28, 2008; 299(20): 2385 - 2386. [Full Text] [PDF]
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 R. A. Kloner and R. W. Nesto Glucose-Insulin-Potassium for Acute Myocardial Infarction: Continuing Controversy Over Cardioprotection Circulation, May 13, 2008; 117(19): 2523 - 2533. [Full Text] [PDF]
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 R. D. Evans and Y. Niu Hypolipidaemic effects of high-dose insulin therapy Br. J. Anaesth., April 1, 2008; 100(4): 429 - 433. [Full Text] [PDF]
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R. W. Nesto and R. M. Lago Glucose: A Biomarker in Acute Myocardial Infarction Ready for Prime Time? Circulation, February 26, 2008; 117(8): 990 - 992. [Full Text] [PDF]
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 H. Su, X. Sun, H. Ma, H.-F. Zhang, Q.-J. Yu, C. Huang, X.-M. Wang, R.-H. Luan, G.-L. Jia, H.-C. Wang, et al. Acute hyperglycemia exacerbates myocardial ischemia/reperfusion injury and blunts cardioprotective effect of GIK Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E629 - E635. [Abstract] [Full Text] [PDF]
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 Authors/Task Force Members, L. Ryden, E. Standl, M. Bartnik, G. V. d. Berghe, J. Betteridge, M.-J. de Boer, F. Cosentino, B. Jonsson, M. Laakso, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: full text: The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD) Eur. Heart J. Suppl., June 1, 2007; 9(suppl_C): C3 - C74. [Full Text] [PDF]
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M. T. Dirksen, G. J. Laarman, M. L. Simoons, and D. J.G.M. Duncker Reperfusion injury in humans: A review of clinical trials on reperfusion injury inhibitory strategies Cardiovasc Res, June 1, 2007; 74(3): 343 - 355. [Abstract] [Full Text] [PDF]
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 M.F. Oliver Sudden cardiac death: the lost fatty acid hypothesis QJM, October 1, 2006; 99(10): 701 - 709. [Abstract] [Full Text] [PDF]
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G. Li, I. S. Ali, and R. W. Currie Insulin induces myocardial protection and Hsp70 localization to plasma membranes in rat hearts Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1709 - H1721. [Abstract] [Full Text] [PDF]
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 H. B. Van Wezel Glucose-insulin-potassium techniques in cardiac surgery: historical overview and future perspectives. Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2006; 10(3): 224 - 227. [Abstract] [PDF]
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 R. Tian and J. A. Balschi Interaction of Insulin and AMPK in the Ischemic Heart: Another Chapter in the Book of Metabolic Therapy? Circ. Res., July 7, 2006; 99(1): 3 - 5. [Full Text] [PDF]
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C. D.L. Folmes, A. S. Clanachan, and G. D. Lopaschuk Fatty Acids Attenuate Insulin Regulation of 5'-AMP-Activated Protein Kinase and Insulin Cardioprotection After Ischemia Circ. Res., July 7, 2006; 99(1): 61 - 68. [Abstract] [Full Text] [PDF]
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 J. R. Timmer, T. Svilaas, J. P. Ottervanger, J. P.S. Henriques, J.-H. E. Dambrink, S. A.J. van den Broek, I. C.C. van der Horst, and F. Zijlstra Glucose-Insulin-Potassium Infusion in Patients With Acute Myocardial Infarction Without Signs of Heart Failure: The Glucose-Insulin-Potassium Study (GIPS)-II J. Am. Coll. Cardiol., April 18, 2006; 47(8): 1730 - 1731. [Full Text] [PDF]
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 J. D. Schipke, R. Friebe, and E. Gams Forty years of glucose-insulin-potassium (GIK) in cardiac surgery: a review of randomized, controlled trials. Eur. J. Cardiothorac. Surg., April 1, 2006; 29(4): 479 - 485. [Abstract] [Full Text] [PDF]
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 N. W. Cheung, V. W. Wong, and M. McLean The Hyperglycemia: Intensive Insulin Infusion In Infarction (HI-5) Study: A randomized controlled trial of insulin infusion therapy for myocardial infarction Diabetes Care, April 1, 2006; 29(4): 765 - 770. [Abstract] [Full Text] [PDF]
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 A. G. Pittas, R. D. Siegel, and J. Lau Insulin Therapy and In-Hospital Mortality in Critically Ill Patients: Systematic Review and Meta-analysis of Randomized Controlled Trials JPEN J Parenter Enteral Nutr, March 1, 2006; 30(2): 164 - 172. [Abstract] [Full Text] [PDF]
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 S. S. Hamdulay, A. A. Khafaji, and H. Montgomery Glucose-Insulin and Potassium Infusions in Septic Shock Chest, March 1, 2006; 129(3): 800 - 804. [Abstract] [Full Text] [PDF]
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 A. Orlandini, R. Diaz, D. Wojdyla, K. Pieper, F. Van de Werf, C. B. Granger, R. A. Harrington, E. Boersma, R. M. Califf, P. Armstrong, et al. Outcomes of patients in clinical trials with ST-segment elevation myocardial infarction among countries with different gross national incomes Eur. Heart J., March 1, 2006; 27(5): 527 - 533. [Abstract] [Full Text] [PDF]
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 D. W. Quinn, D. Pagano, R. S. Bonser, S. J. Rooney, T. R. Graham, I. C. Wilson, B. E. Keogh, J. N. Townend, M. E. Lewis, P. Nightingale, et al. Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: A randomized controlled trial J. Thorac. Cardiovasc. Surg., January 1, 2006; 131(1): 34 - 42. [Abstract] [Full Text] [PDF]
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 R. Garg, A. Chaudhuri, F. Munschauer, and P. Dandona Hyperglycemia, Insulin, and Acute Ischemic Stroke: A Mechanistic Justification for a Trial of Insulin Infusion Therapy Stroke, January 1, 2006; 37(1): 267 - 273. [Abstract] [Full Text] [PDF]
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Y. Abdallah and C. Schafer Insulin: An overall cardiovascular protector? Cardiovasc Res, January 1, 2006; 69(1): 4 - 6. [Full Text] [PDF]
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