REPORTS ON THERAPY

Prospective Randomized Trial of Glucose-Insulin-Potassium In Acute Myocardial Infarction Effects on Myocardial Hemodynamics, Substrates and Rhythm

WILLIAM J. ROGERS, MD, FACC PETER H. SEGALL, MD, FACC HUEY G. MCDANIEL, MD JOHN A. MANTLE, MD. FACC RICHARD 0. RUSSELL, Jr., MD, FACC CHARLES E. RACKLEY, MD, FACC

Birmingham, Alabama

From the Division of Cardiology, Department of Medicine, and the Veterans Administration Hospital, University of Alabama Medical Center, University Station, Birmingham, Alabama. This research was supported in part by the National Heart, Lung, and Blood Institute (Specialized Center of Research for lschemic Heart Disease, Contract 5P50HL17667-04. Program Project Grant HL 11310, and the Clinical Research Unit Grant MO-RROOO-13, General Clinical Research Centers Program, Division of Research Resources) of the National Institutes of Health, Bethesda, Maryland. Address for reprints: William J. Rogers, MD, Division of Cardiology, Department of Medicine, University of Alabama Medical Center, Birmingham, Alabama 35294.

Fifty consecutive patients admitted within 12 hours of the onset of symptoms of acute myocardial infarction were randomly assigned to treatment with intravenous glucose-insulin-potassium infusion (23 patients) or to a control group (0.5 N sodium chloride infusion) (27 patients). The glucose-insulin-potassium infusion consisted of 30 g glucose, 50 U regular insulin and 80 mEq KCI per liter infused at 1.5 ml/kg per hour for 2 days. Serial measurements were made of pulmonary arterial end-diastolic pressure, cardiac indei, daily fluid intake and output, serum glucose, potassium, urea nitrogen, free fatty acids, osmolarity, creatine kinase-MB isoenzyme and cardiac rhythm. Although all patients admltted comatose died (three glucose-insulin-potassium recipients, one control subject), hospital mortality in patients admitted noncomatose was 0 percent (0 of 20) in glucose-insulin-potassium recipients versus 12 percent (3 of 28) in the control group (three deaths secondary to late pump failure). Glucose-insulin-potassium recipients experienced 4.9 f 1.3 hours of three or more premature ventricular complexes/min compared with 11.1 f 1.9 hours for control subjects (P was administered intravenously at a rate of 20 to 50 pg/kg per min to patients having six or more premature ventricular complexeslmin, premature ventricular contractions occurring in salvos of two or more, ventricular tachycardia. or ventricular fibrillation. Once the ventricular arrhythmia had been completely suppressed for 3 to 4 hours, the lidocaine infusion rate was rapidly tapered to 0. Digoxin was administered only for treatment of supraventricular tachycardia with rapid ventricular response. No patient was given hyaluronidase, nitroprusside, corticosteroids or propranolol during the study period.

Assay Techniques Hemodynamic measurements: Pulmonary arterial pressure and thermodilution cardiac index were determined with use of’ a previously described ctimputerized patient monitoring system.” Chemical determinations: Processing of serial blood samples for creatine kinase MB extraction and calculation of creatine kinase MB idfarct size (or accumulated Creatine kinase MB release) wereperformed exactly as recently described in work from our lahortitory.” Serum glucose and potassium and blood urea nitrogen were measured using standardized automated techniques on Technicon model 1260 and model AA II auto analyzers. Free fatty acids were analyzed according to the method of Itaya and Ui.“:{ Osmolarity was determined by freezing-point depression with an Ostiette Precision Osmometer, model no. 2007 (Precision Systems, Sudbury, Massachusetts). Rhythm analysis: Cardiac rhythm was monitored continuously during the study period by both a trained monitor technician and a computerized electrocardiographic recording

GLUCOSE-INSULIN-POTASSIUM

system.‘4 The technician

mounted in a diary those rhythm strips showing the occurrence of atria1 or ventricular arrhythmias, or both, conduction disturbances or other significant electrical events. In addition, regardless of the cardiac rhythm, the technician preserved a 15 second rhythm strip obtained every 4 hours, on the hour. The computerized system recorded all normal and abnormal electrical events. From a random I5 min/hour “window” of computerized data and from the technician’s diary, it was established whether three or more premature ventricular complexes/min had occurred during each hour. Each episode of ventricular tachycardia (defined as three or more consecutive ventricular complexes at a rate of 150/min or greater) was tabulated. Ventricular arrhythmias were thus expressed as (1) hours of three or more premature ventricular complexes/min, and (2) episodes of ventricular tachycardia per patient.

Statistics: (Continuous data are reported as mean f standard error of the mean. The nonpaired t test and chi-square test were used to assess paired data.

differences

between

groups

of non-

IN MYOCARDIAL

INFARCTION-ROGERS

ET AL.

(INFUSION (GlK 0r Placebo)/

2

T

IT A ’

I

cGlK (N.23) *--CONTROL (N.27)

I

@L I-DAY I-+ I-DAY 2-I cDAY 3-I I-DAY 4-! FIGURE 2. Pulmonary arterial end-diastolic pressure (PAEDP) during the study period. The baseline (BSL) pressure was elevated in both the glucose-insulin-potassium (GIK) and the control groups, but decreased proportionately in both groups during the 4 day study period. This variable did not differ significantly in the two groups. N = number of subjects.

Results Clinical data: Of the 50 patients, 27 were randomly allocated to the control and 23 to the glucose-insulinpotassium infusion group (Table I). Mean age, sex distribution and incidence of prior myocardial infarction were similar in the two groups. Elapsed time from the first symptom of infarction until randomization was similar and averaged approximately 7 hours in the two groups. Ventricular fibrillation or cardiac arrest, or both, before randomization was documented in 28 percent of the patients (14 of 50). Four patients-one in the control group and three in the glucose-insulin-potassium group-had sustained a prolonged cardiac arrest and were deeply comatose on admission. In both groups, anterior infarcts were most common. Hemodynamics and degree of heart failure on admission were similar as assessed by the Killip classification,25 pulmonary arterial end-diastolic pressure and cardiac index. The overall hospital mortality rate for the 50 patients was 14 percent (7 of 50). It was 15 percent (4 of 27) in the control group and 13 percent (3 of 23) in glucose-insulin-potassium group (difference not significant). However, in the glucose-insulin-potassium group, all deaths occurred in patients who had sustained prolonged cerebral hypoxia and had been admitted comatose, had been respirator-dependent and had shown no evidence of neurologic recovery throughout their hospitalization. The four deaths in the control group occurred in one patient who had been admitted comatose and in three patients who had been admitted noncomatose but subsequently died of late cardiac pump failure 9 to 11 days after randomization. No complications attributable to glucose-insulinpotassium infusion were encountered. In five patients, serum glucose levels rose above 300 mg/lOO ml, requiring use of supplemental subcutaneous or intravenous regular insulin. Hemodynamic data: Left ventricular filling pressure, estimated from pulmonary arterial end-diastolic pressure’” (Fig. 2), was elevated on admission in both the glucose-insulin-potassium and control groups but fell proportionately in both groups during the study

period. At no time was pulmonary arterial end-diastolic pressure significantly different in the two groups. The dosage and frequency of administration of diuretic drugs, nitrates and dextran were also similar in the two groups (Table II). Cardiac index averaged 3.0 f 0.2 liters/min per m2 during the 48 hour treatment period and 3.6 f 0.2 liters/min per m2 during the second 48 hour period in the glucose-insulin-potassium group; the respective values were 3.4 f 0.2 and 3.8 f 0.2 liters/min per m”, in the control group (difference not significant).

TABLE I Clinical,

Hemodynamic

and Rhythm

Data on Admission* Control Group

Patients (no.) ;,9; (yr) Prior Ml Arrhythmia (before randomization) Cardiac arrest/V Fib Atrial fibrillation 2’ or 3’ A-V block Elapsed time until randomization (hr) Mental status Alert Comatose Ml Location by ECG Anterior Inferior Undetermined Killip classz5 PAEDP+ Cl’

z*

GIK Group

1 24M. 3F 8 (30%)

::*2 21M. 2F 11 (48%)

5 (19%) 3(11%)

9 (39%)

0 (0%) 6.8 f 0.3

26 (96%) 1(4%)

20 (87%) 3 (13%)

13 (48%) 8 (30%) 6 (22%) 1.9 f 0.2 20 f 2 3.1 f 0.2

13 (57%) 7 (30%) 3 (13%) .^ 1.8 f cl.2 21 f 2 2.9 f 0.2

* Data in control and glucose-insulin-potassium groups did not differ statistically. + Hemodynamic variables were measured immediately after Swan-Ganz catheter insertion and before volume manipulation. A-V = atrioventricular; Cl = cardiac index (liters/min per m*); ECG = electrocardiogram; GIK = glucose-insulin-potassium; Ml = myocardial infarction: PAEDP = pulmonary arterial enddiastolic pressure (mm Hg); 2O = second degree: 3’ = third degree: V Fib = ventricular fibrillation.

April 1979

The American Journal of CARDIOLOGY

Volume 43

803

GLUCOSE-INSULIN-POTASSIUMIN MYOCARDIAL INFARCTION-ROGERS ET AL

TABLE II Supplemental Drugs Employed During 48 Hour Treatment Period’ Control Group (no. = 27) Recipients Dosage/ Dosage/ Recipient Group (no.) Furosemide (mg) Sublingual isosorbide dinitrate (mg) Digoxin (mg) Morphine (mg) Dextran (ml) KCI (mEq)

9 16 0 14 10 9

111 f31 24 f 2 14:3

37f 14 14 f 3 0 7f2 113f33 18f6

305 f 42 54f 12

Recipients (no.) 1: 1: 10 5

GIK Group (no. = 23) Dosage/ Dosage/ Recipient Group 108 f 47 29 f 5 0.5 13f4 284 f 43 52f 15

41 f 23 f 0.02 f 6f2 123 f 11 f5

19 5 0.02 35

Distribution of recipients and dosages in control and glucose-insulin-potassium groups did not differ statistically. GIK = glucose-insulin-potassium; KCI = potassium chloride. l

Total fluid intake in the glucose-insulin-potassium group during the 48 hour treatment period averaged 8.5 f 0.2 liters compared with 4.9 f 0.3 liters in the control group (P