Long term outcome after intravenous magnesium sulphate in suspected acute myocardial infarction

Kent L Woods, Susan Fletcher Lancet April 1994

Lancet June 1992

Introduction

Cardiovascular actions of Mg:

• coronary systemic vasodilatation
• platelet inhibition
• antiarrthymic effects
• protect myocardial tissue against ischemia and reperfusion injury

LIMIT-2 was designed to test the hypothesis that doubling serum Mg conc. in AMI would reduce the mortality

This strategy has been suggested by 3 evidences:

1. a significant mortality benefit is apparent in pooled analyses of all early small trails
2. Mg protects the myocardium from experimental ischemic-perfusion injury
3. Mg has potentially beneficial in human beings including coronary and systemic vasodilatation, platelet inhibition and antiarrthymic effects

Trail:

• randomised, double blind, placebo controlled study
• 2316 patients with suspected AMI
• conducted between Sept 1987 - Feb. 1992 in CCU of Leciester Royal Infirmary
• receive randomly either immediate IV loading injection (8 mmol) and 24 hr infusion of Mg sulphate (65 mmol) or equal volume of saline
• patient likely to have AMI (no ECG criteria specified) were included
• exclusion criteria : refuse consent, complete HB, Cr > 300 mmol/l
• 35% of patients receive thrombolytic (usually streptokinase) and 66% were given heparin
• for those who confirmed AMI 48% received a thrombolytic
• infusion of the thrombolytic was started immediately after the initial injection of the trial medication (Mg/saline)

RESULTS:

• Baseline characteristics were similar
• primary outcome (1992)

28 day mortality (ascertained in 99.3% of patients) relative reduction of 24%

incidence of left ventricular failure reduced by 25% (p=0.009)

• long term outcome (follow up 1.0-5.5 average 2.7 yr.)

mortality from IHD reduced by 21% (p=0.01)

all cause mortality reduced by 16% (p=0.03)

• only 11 case losses FU, so 99.5% of patients were included

DISCUSSION:

• left ventricular function after myocardial infarction is the strongest predicator of subsequent mortality
• the reduction of mortality likely to be due to the evidence that Mg protects myocardial contractile function in experimental models of ischemia-perfusion injury, mechanical impairment of the heart ("stunning") develops within the first minutes of reperfusion and is associated with an uncontrolled rise in intracellular Ca, depletion of high energy phosphates and contractile dysfunction
• these effects can be reversed by increasing the external concentration of Mg but the protection is confined to the first 1-2 min. of reperfusion
• on reperfusion, normal or high conc. of Mg promotes restoration of high energy phosphates and faster recovery from stunning
• reduction of reperfusion injury is likely to be the main mechanism of therapeutic action of Mg
• In ISIS-4 study, randomised comparison of the effects of Mg in 55,000 patients who were randomised to receive (or not) throbolytic therapy, captopril 6.25 orally, and mononitrate, the results, disclosed at Nov., 1993 AHA in Altanta show NO benefit for Mg suprisingly to the author of LIMIT-2. The dose was identical to that of the LIMIT-2.

• WHY???

1. uneven randomisation, cross over, inadequate FU, water hardness, geographical difference
2. ISIS-4 time from onset to randomisation averaged 8 hours (3 hr. in LIMIT-2 study) and thrombolytic given and lysis completed BEFORE giving Mg. (Mg shown to be beneficial more if given BEFORE reperfusion in animal models)
3. Mg has antithrombotic effect-- if given early, may have more beneficial effect
4. In ISIS-4 the late administration of Mg may cause infarct extension due to hypotension, as those who receive Mg had a somewhat greater incidence of hypotension than those who receive placebo

SIDE EFFECT OF Mg

• flushing is a common but not universal symptom and can be reduced if Mg is given over 10 min.
• blood pressure fall transiently by a mean of 8 mmHg sys and 5 mmHg diastolic
• no other important side effects were identified

WHAT SHOULD WE DO NOW???

Author's comment:

• give iv Mg to patients within 6 hours of AMI except those with hypotension, bradycardia or AV block or those with high Mg conc. (e.g. Antacids, CRF)
• give aspirin orally
• give streptokinase, nitrates, morphine, -blockers as indicated
• lignocaine for VT, frequent ventricular couplets, multifocal ventricular contractions
• +/- coronary angioplasty