A randomized controlled trial of intravenous magnesium sulphate as an adjunct to standard therapy in atrial fibrillation

Atrial fibrillation is one of the common arrhythmia, reported in hemodynamically unstable patients. The loss of atrial contraction and the sequential atrioventricular contraction decrease of overall cardiac output results in a severe inadequate tissue perfusion. Drugs such as verapamil, diltiazem, amiodarone, and beta blockers compromise the patient’s cardiac output by their negative inotropic effect [1,2,3]. Digoxin has a slow onset of action and is significantly less effective in states of increased sympathetic tone [4,5,6]. It also results in adverse effects with chronic dosing.

As per the American College of Emergency 2015, ventricular rate control is the primary therapeutic objective in atrial fibrillation [7].

Magnesium sulphate (MgSO₄) and its analgesic effect has been shown in animal models and humans. MgSO₄ competes with calcium ions in synaptic junctions and prevents the release of presynaptic acetylcholine, prolonging the effects of neuromuscular blocker agents [8, 9, 10, 11]. It has been proposed as an effective and safe adjunct in the treatment of acute asthma [12]. Magnesium had an inherent physiological association because of its effects on membrane potentials and ion transport [13]. In a meta-analysis of 5 randomized trials (n=380), the patients who had received magnesium had 3 times more likely to reach a heart rate of <100 bpm compared to digoxin [14].

However, studies were scarce in India on the safety and efficacy of magnesium sulphate infusion in atrial fibrillation.

Hence, this study aimed to analyse the safety and efficacy of magnesium sulphate infusion in addition to conventional treatment modalities in patients with atrial fibrillation. The outcome of this study is to achieve a heart rate of <100bpm, and a conversion to sinus rhythm throughout the period of infusion of magnesium sulphate.

Study Design: Prospective, randomized, double-blinded, and placebo-controlled trial.

Materials: Patients of adult age >18 years presenting with atrial fibrillation to the Emer gen cy Department, Sri Ramachandra Medical College and Research Institute, Chennai, India were considered for enrolment.

The study was performed between Nov 2007 to Nov 2008.

Patients of age >18 years presenting to ED with atrial fibrillation and a ventricular response rate of >120 beats/min were included. The exclusion criteria were a requirement for cardioversion, a systolic blood pressure of <90 mm Hg, symptomatic hypotension, a history of atrioventricular node disease, patients on permanent pacemakers, an acute myocardial infarction eligible for thrombolysis.

Ethics statement

This study followed the tenets of the Helsinki declaration and the protocol was approved by the Institutional Ethical Committee. All the included patients and their relatives were informed about the procedures and their conditions. Informed consent was obtained from the patients (those that were able to provide it) or from their relatives if the patients’ physi cal condition prevented them from signing it.

Randomization and Treatment Protocol

On arrival in the emergency room, a detailed history was taken, and a clinical examination was performed to rule out any associated illness. An informed consent was obtained from the patient’s relatives.

After the enrolment the patients were randomly allocated to one of the two groups viz the MgSO₄ tratment group and the placebo group.

The inclusion criteria for both groups were similar. We used random number tables for the randomization. The individual random numbers were kept in separate envelopes so that the concealment could be maintained until the patient was included in the assigned group. The treatment group received MgSO₄ and the control group received 0.9% sodium chloride in a double-blind fashion. The solutions were prepared by the coordinator of the study and the ED physician in charge of the patients during the treatment was unaware of the study medication.

Treatment group: The treatment group patients were given 40 mEq (5 g, 20 mmol) of Magne sium sulphate in 100 mL of Normal saline [NS] 20 mEq (2.5 g, 10 mmol) was given intravenously diluted in 100ml NS over a 20-minute period followed by 20 mEq (2.5 g, 10 mmol) intravenously diluted in 100ml NS over the next 2 hours. The patients were monitored with half-hourly pulse rate, oxygen saturation, and blood pressure.

The administration of the Magnesium sulphate solution started in addition to the Amiodarone infusion as the standard therapy at ED. However, there were no guidelines that amiodarone was recommended, but amiodarone is acceptable. All the patients were given efficient anticoagulant prior. Dose administered as per American college of cardiology protocol, and dose given to all patient presented to ED after counselling and consent.

Placebo: 0.9% sodium chloride+ standard therapy. In placebo, the administration of 0.9% sodium chloride solution as placebo was added to the standard therapy as Amiodarone infusion at the emergency department.

Assessment of Response: Ventricular response rate control (the pulse rate of <100 beats/ min), mean changes in the heart rate, the conversion to sinus rhythm, and major (hypotension and bradycardia) or minor adverse events.

ECG was taken before and after the infusion. Blood was drawn for a magnesium level estimation before the infusion. The patients were monitored and the rhythm was analyzed at the end of the infusion. The patients were followed up during their course of stay in the hospital, their ECG was repeated, and their heart rates were monitored continuously after the ₄ MgSOinfusion.

ECHO cardiograph was performed within ED and the patients were treated accordingly with a standard treatment. Transesophageal echocardiogram (TEE) was not done.

The patients discharged from the ED were instructed to continue their regular medications.

The statistical analysis was performed using Pearson’s chi-square and Fischer's Tests. The effect of MgSO₄ on pulse rate measured at various points was analyzed by the analysis of variance-ANOVA (with a random intercept and slope for each subject), with contrasts to test the research hypotheses. The effect of treatment on the binary outcomes ‘‘any pulse rate of <100bpm,’’ the conversion to sinus rhythm, and any adverse effects were analyzed using the chi-square test. The statistics package SPSS ver 18.0 was used for analyses (SPSS Inc, US).

Magnesium is an important electrolyte in cardiovascular physiology. Magnesium sulphate is capable of increasing the conduction time and refractoriness at the atrium and the atrioven tricular nodal level while suppressing atrial automaticity. It has been found to be useful for treating various atrial tachyarrhythmias^15-18 but there are few if any data on its use in paroxysmal atrial fibrillation. Our study showed that magnesium sulphate used in conjunction with other agents results in 86.4% of the patients achieving a heart rate of less than 100 beats/min compared with the placebo. The current study demonstrated that magnesium sulphate increases the rate of conversion from atrial fibrillation to sinus rhythm when added to standard therapies.

Thirteen of the 41 patients in MgSO₄ treated group were on antiarrthymic drugs at the time of the admission [77%], two of the fourteen patients in the Placebo group were on anti-arrthymic drugs at the time of the admission [23%]. This indicates most of the patients presented to ED were new onset atrial fibrillation patients who were not on any medication.

Out of total patients presenting to the emergency department, most of the patients were having heart rates ranging from 150-170bpm, of which the least heart rate at the presentation was 127 bpm & the maximum heart rate was 210 bpm. At the end of 150 minutes MgSO₄ infusion 31 [70%] patients [of a total of 41] attained a heart rate of < 100bpm and in the Placebo infusion, two [14%] patients [of the total of 14] attained the heart rate of < 100bpm.

These patients were followed for the next 24hrs and their heart rate and rhythm were recorded, which was not done in previous studies. Analyses at 30 min, 60 min, 90 min, and 150 min revealed mean pulse rate differences of -12.60, -12.60, -23.85, and 27.94 beats/min respectively. This shows the heart rate started to decrease once the MgSO4 infusion was started and at the end of 150 min about 31 subjects attained a heart rate of <100bpm, which proves its efficacy in atrial fibrillation patients.

In the MgSO₄ treated group, 35 out of 41 patients (84.5%) achieved a heart rate less than 100beats /min and 25 of 35 patients [65%] attained normal sinus rhythm. In the placebo group, 2 of 14 patients [12.28%] achieved a heart rate less than 100beats /min and no patient attained normal sinus rhythm, 87.72% were continued to be in atrial fibrillation at the end of 24 hours. This proves the effectiveness of MgSO₄ in reducing heart rate and attaining rhythm control at the end of 24hrs in conjunction with antiarrhythmic drugs when compared to the placebo.

The subjects in the MgSO₄ treated group had [2.25] days of ICU stay compared to the place bo group [4.25] days. Hence, MgSO4 also reduces the duration of ICU stay, thereby reducing the cost factors and burden on the patients.

Seven patients in the magnesium sulphate treated group had minor side effects like flushing, headache, and nausea, which shows it is safe and effective in rate and rhythm control when used in conjunction with other antiarrhythmic agents in atrial fibrillation with fast ventricular rate.

In our study, the Antiarrhythmic drug used was Amiodarone and MgSO₄. ECG was taken after 24 hrs to detect the Rate Rhythm and ICU Stay has been studied.

Whereas a study by David Teubner, Michael John Davey used Antiarrhythmic Drug as Digoxin, Verapamil, & Beta-blocker. They measured ECG after 24 hrs., Rate Rhythm, but ICU stay has not been taken into their study.

Our study demonstrated that MgSO₄ produced a statistically significant reduction in ventricular response rates at all duration intervals up to 150 minutes. We showed that magnesium sulphate used in conjunction with other agents results in 56.4% of the patients achieving a pulse rate of less than 100 beats/min compared with the placebo. In the magnesium sulphate treated group, the majority of adverse effects were minor. Only 7 patients in the magnesium sulphate treatment group had minor side effects confirming its safety.

Numerous studies conducted on to use of intravenous magnesium injection to treat acute onset atrial fibrillation.

An event is successful cardioversion to sinus rhythm or the absence of atrial fibrillation on follow-up.

Ho KM et al., 2007, used intravenous magnesium injection and observed cardioversion or prevention; 42 events in 166 cases in Mgso4, 31 events in 161 cases in the placebo group, respectively [13].Chu et al., 2009, identified events of 2/24 in Mgso4, and 6/24 in placebo groups, respectively [19].

Cook et al., 2012, identified events of 465/595 in the Mgso4 and 457/595 in the placebo groups, respectively [20]. Sultan et al., 2012, identified events of 81/84 in the Mgso4 treated and 74/86 in the placebo groups, respectively [21]. Klinger et al., 2015, identified events of 107/186 in the MgSO₄ treated and 110/177 in the placebo groups, respectively [22].

Rajagopalan et al., add to the growing evidence base on this issue by performing a randomized, double-blind, placebo-controlled trial of intravenous magnesium before electric cardioversion of AF. A total of 261 patients were enrolled with normal magnesium levels at baseline (2.1±0.2 mg/dL; 0.86±0.08 mmol/L). Their key finding was that 1-hour conversion to sinus rhythm was similar in both the magnesium-treated patients and the placebo group (86.4% magnesium versus 86.0% placebo). They also found no difference in biphasic energy requirement, or the number of shocks needed in a ramping energy protocol. Rajagopalan et al., identified events of 114/132 in the MgSO₄ treated, and 111/129 in the placebo groups, respectively [23].

Literature related to the management of atrial fibrillation has analysed the evidence of the pharmacologic agents [1, 2, 3]. The literature recommends that calcium-channel blockers and b-blockers were considered as the first-line agents for rate control in patients with preserved left ventricular function.

The current study also believes that physicians can use digoxin even if it is a slow onset of effect due to uncertainty of the patients’ underlying cardiac status. The current study demonstrated that an infusion of magnesium sulphate marginally improved the early ventricular response rate control and increases the rates of conversion to sinus rhythm in rapid atrial fibrillation when added to a usual conventional pharmacological treatment.

The limitations include sample size is not adequate, the majority of patients who present to the ED with atrial fibrillation are elderly, and it is often difficult to rapidly confirm the reliability of medical history in this setting.

Magnesium sulphate showed a statistically significant reduction of ventricular response rates at all-time intervals up to 150 minutes. In summary, 2.5 g of IV magnesium sulfate administered along with a standard therapy in patients presenting to ED with atrial fibrillation causes improvement in the heart rate and conversion to sinus rhythm. Larger double-blind studies with this design should be done to find the potential benefits of IV MgSO₄ as additional treatment along with standard drugs.