Role of Magnesium Alone or in Combination with Diltiazem and/or Amiodarone in prevention of Atrial Fibrillation following Off-Pump Coronary Artery Bypass Grafting

ABSTRACT

Objectives:

In this study the authors have tried to examine the role of magnesium alone or in combination with diltiazem and / or amiodarone in prevention of atrial fibrillation (AF) following off-pump coronary artery bypass grafting (CABG).

Background:

AF after CABG is common and contributes to morbidity and mortality. Various pharmacological preventive measures including magnesium, amiodarone, diltiazem, and combination therapy among others have been tried to lower the incidence of AF. Most of the studies have been performed in patients undergoing conventional on-pump CABG. In this uncontrolled trial, efficacy of magnesium alone or in combination with amiodarone and / or diltiazem has been studied in patients undergoing off-pump CABG.

Methods:

One hundred and fifty patients undergoing off-pump CABG were divided into 3 groups, Group M (n=21) received intraoperative magnesium infusion at 30mg/ kg over 1 hour after midline sternotomy; Group MD (n=78) received magnesium infusion in similar manner with diltiazem infusion at 0.05 μg/kg/hr throughout the intraoperative period; Group AMD (n=51) received preoperative oral amiodarone at a dose of 200 mg three times a day for 3 days followed by 200 mg twice daily for another 3 days followed by 200 mg once daily till the day of surgery along with magnesium and diltiazem infusion as in other groups. AF lasting more than 10 min or requiring medical intervention was considered as AF.

Results:

The overall incidence of postoperative AF was 12.6% with 11.7% in group AMD, 19% in group M, and 11.5% in group MD, which was not statistically significant.

Conclusions:

It is concluded that the use of amiodarone and/or diltiazem in addition to magnesium did not result in additional benefit of lowering the incidence of AF.

INTRODUCTION

Coronary artery bypass grafting (CABG) is a commonly performed cardiac surgical procedure. Atrial fibrillation (AF) is a frequently encountered complication following CABG with an incidence of 15%-33%.[1,2] The occurrence of AF increases the morbidity by causing hemodynamic deterioration, increasing incidence of thromboembolism, postoperative stroke, and the hospital length of stay.

Whereas, multiple risk factors can be attributed to the occurrence of AF, the definitive etiology remains unclear. Various pharmacologic strategies have been employed to prevent AF. Serum magnesium has been attributed as an important factor, and magnesium supplementation has been used as a potential prophylaxis.[3,4] Amiodarone, one of the most effective therapeutic agents for control of AF, has also been investigated alone or in combination with magnesium as a prophylactic agent for prevention of postoperative AF. Intraoperative use of diltiazem infusion has been shown to reduce vasospasm of arterial grafts and increasing grafts flow.[5,6] It was also demonstrated that intraoperative use of diltiazem reduces the incidence of ischemia and supraventricular tachycardia.[7]

Although various strategies and pharmacologic agents have been used to prevent post-CABG AF, the effect of each or in combination is still controversial. Most of the studies have been performed in patients undergoing conventional on-pump CABG with a limited number in patients undergoing off-pump CABG (OPCAB). The aim of this study was to compare the effect of magnesium alone, magnesium with preoperative amiodarone, and magnesium with preoperative amiodarone and intraoperative diltiazem infusion for prevention of post-OPCAB atrial fibrillation.

MATERIALS AND METHODS

Study population

The study was approved by the Institutional Ethics committee and a written informed consent was obtained from each patient. One hundred and fifty patients were included in this prospective single-blinded uncontrolled trial undergoing OPCAB. The use of arterial grafts, technique of surgery, and preoperative amiodarone was at the discretion of the surgeon. As per the institutional protocol, all patients received beta blocker (metoprolol) till the day prior to surgery. All patients aged more than 18 years undergoing OPCAB were considered eligible for the study. However, patients with heart rate less than 50 beats per minute, previous history of cardiac surgery, current use of antiarrhythmic medication (except amiodarone), implanted pacemaker, ejection fraction less than 30%, pregnancy, renal failure, hepatic dysfunction, severe lung disease, and severe pulmonary artery hypertension (mean pulmonary artery pressure >50 mmHg) were excluded from the study. During surgery, magnesium was administered to all the patients and diltiazem was administered to those who received arterial grafts.

Anesthesia technique

All patients were premedicated with intramuscular morphine sulphate (0.1-0.2 mg/kg) and promethazine (0.5 mg/kg) 1-2 hours before surgery. General anesthesia was induced with fentanyl 5-10 μg/kg, thiopentone 50-100 mg, and midazolam 0.05 mg/kg with pancuronium bromide 0.15 mg/kg used as a muscle relaxant. Anesthesia was maintained with oxygen and nitrous oxide (fractional inspired oxygen concentration 0.5) with sevoflurane and intermittent boluses of pancuronium and fentanyl. Monitoring included pulmonary artery pressure, invasive arterial pressure, electrocardiogram, urine output, temperature and intermittent cardiac output, and arterial blood gases. Serum magnesium levels were obtained one day prior to surgery and on the first postoperative day in addition to other routine investigations.

Study groups

Patients were divided into three groups based on the type of medicines they received. As per the Institutional protocol, all patients received magnesium and all patients in whom arterial grafts were used received diltiazem. In addition, a particular surgeon had a practice of administering preoperative amiodarone. In this manner, some patients fell in group M (those receiving magnesium), others in group MD (those receiving magnesium and diltiazem), and the remaining fell in group AMD (those receiving magnesium, diltiazem, and amiodarone). Therefore, patients belonging to AMD group were operated by a single surgeon, whereas patients in the other two groups were operated by all the surgeons (total 4). Magnesium was administered as an infusion at 30mg/kg over 1 hour after midline sternotomy; likewise, diltiazem was administered as an infusion at 0.05 μg/kg/hr throughout the intraoperative period; and amiodarone was administered preoperatively in oral form at the dose of 200 mg three times a day for 3 days followed by 200 mg twice daily for another 3 days followed by 200 mg once daily till the day of surgery.

Postoperative management

All the patients were electively ventilated postoperatively with adequate sedation until the criteria for weaning and extubation were met. All these patients were kept in the intensive care unit (ICU) for 4 postoperative days with continuous electrocardiogram monitoring. Potassium infusion was administered (if necessary) to maintain serum potassium levels more than 4 mmol/L. The patients were managed as per the institutional ICU protocol. Daily routine investigations including complete blood counts, liver function, and renal function tests were performed. The study end point was occurrence of AF or discharge of patient from the ICU, whichever was earlier. AF was defined as absence of P waves, the presence of low amplitude, high-frequency atrial fibrillatory waves (f waves) with an irregularly irregular ventricular rhythm, and often a ventricular rate in the range of 120 to 180 beats/min. Presence of AF lasting more than 10 minutes or requiring medical intervention before 10 minutes was considered as AF. Patients with AF showing hemodynamic compromise were generally treated at the discretion of clinician.

Measured parameters

Preoperative demographics including age, weight, gender, comorbidities, previous history of major adverse cardiac event, ejection fraction, coronary angiographic findings (coronary vessel involvement), hemodynamic parameters (HR, systolic and diastolic arterial pressures), and laboratory parameters (hemoglobin, preoperative magnesium levels) were noted.

Intraoperative parameters observed were technique of surgery, number of grafts, time for distal anastomosis, inotropic requirement, mean blood loss, and intraoperative occurrence of AF.

Postoperative parameters observed were occurrence of AF, duration of mechanical ventilation, hospital length of stay, ICU length of stay, and new major neurological event (transient ischemic attack or cerebrovascular event).

Outcomes

As per 2011 guidelines published by the American College of Cardiology, American Heart Association, and European Society of Cardiology, with the collaboration of the Heart Rhythm Society an episode of AF is defined as an event lasting more than 30 seconds in duration. However, from a clinical standpoint, an episode of AF will initiate treatment not before 10 minutes, unless there is hemodynamic compromise. Therefore, presence of AF lasting more than 10 minutes or requiring medical intervention was considered as AF (primary outcome).

Secondary outcome measures were duration of mechanical ventilation, hospital length of stay, ICU length of stay, and new major neurological event (transient ischemic attack or cerebrovascular event).

Statistical analysis

Categorical variables are presented in number and percentage (%), and continuous variables are presented as mean ± SD and median. Normality of data was tested by Kolmogorov-Smirnov test. If the normality was rejected, then nonparametric test was used.

Sample size: By assuming an AF rate of 20% to 50% between the groups of comparison, a sample size of 38 is required in each arm with 80% power and 5% level of significance with equal allocation of subjects in each group. Sample size will be enhanced to 46 in each group after a possible attrition of cases due to loss to follow-up.

Statistical tests were applied as follows:

1. Quantitative variables were compared using independent t-test/Mann-Whitney test (when the datasets were not normally distributed) between the two groups and ANOVA/Kruskal-Wallis test was used for comparison between three groups.

2. Qualitative variables were compared using Chi-square test/Fisher’s exact test.

A P value of <.05 was considered statistically significant. The data were entered in MS EXCEL spreadsheet and analysis was performed using Statistical Package for Social Sciences (SPSS) version 21.0.

RESULTS

Of the 150 patients included in the study, 51 belonged to the AMD, 21 belonged to the M, and 78 belonged to the MD groups.

Preoperative patient demographics

Preoperative demographic data are shown in Table 1. The three groups did not differ except for a lower heart rate in the preoperative period in the AMD group as compared with the MD group, and percentage of patients in the AMD group having a history of myocardial infarction (MI) being higher as compared with the other two groups (P = 0.03). Mean preoperative magnesium levels among the three groups showed no significant difference. Triple vessel disease was the most common (76%) and left main disease was present in 26.67% patients.

Table 1.

Distribution of patient demographics, medical comorbidities, and cardiac parameters in the three groups

	Group AMD (n=51)	Group M (n=21)	Group MD (n=78)	Total	P
Age (years)	55.57±8.68	54.95±10.83	55.81±8.82	55.61±9.02	NS
Female	6 (11.76%)	3 (14.29%)	9 (11.54%)	18 (12%)	NS
Male	45 (88.24%)	18 (85.71%)	69 (88.46%)	132 (88%)	NS
Weight (in kg)	64.22±11	65.43±7.88	66.03±10.12	65.33±10.13	NS
Diabetes mellitus	10 (19.61%)	8 (38.10%)	14 (17.95%)	32 (21.33%)	NS
Hypertension	14 (27.45%)	8 (38.10%)	23 (29.49%)	45 (30%)	NS
Smokers	18 (35.29%)	9 (42.86%)	32 (41.03%)	59 (39.33%)	NS
Peripheral vascular disease	1 (1.96%)	0 (0%)	3 (3.85%)	4 (2.67%)	NS
Old MI	18 (35.29%)	1 (4.76%)	22 (28.21%)	41 (27.33%)	0.03
Ejection fraction (%)	48.75±9.68	44.52±9.86	47.05±10.27	47.27±10.04	NS
Hemoglobin (g/dL)	13.08±1.12	13.2±1.37	13.08±1.58	13.09±1.4	NS
Systolic blood pressure (mm Hg)	134.18±18.27	130.86±19.02	135.94±19.28	134.63±18.86	NS
Diastolic blood pressure (mm Hg)	76.94±11.79	78.62±14.15	79.97±12.03	78.75±12.26	NS
Heart rate (beats/min)	68.53±12.58	74.71±12.47	72.63±12.23	71.53±12.51	AMD vs. MD 0.046
Left main disease	14 (27.45%)	6 (28.57%)	20 (25.64%)	40 (26.67%)	NS
1 vessel disease	1 (1.96%)	0 (0%)	1 (1.28%)	2 (1.33%)	NS
2 vessel disease	11 (21.57%)	6 (28.57%)	17 (21.79%)	34 (22.67%)	NS
3 vessel disease	39 (76.47%)	15 (71.43%)	60 (76.92%)	114 (76%)	NS
Mean preoperative magnesium level (m Eq/L	1.95±0.22	2±0.21	2.01±0.2	1.99±0.21	NS

AMD, amiodarone magnesium diltiazem; MD, magnesium diltiazem; M, magnesium

Intraoperative parameters

Intraoperative details are shown in Table 2. Technique of surgery, choice of conduits, and number of conduits were as per the surgeon’s preference. There was no statistically significant difference in the incidence of AF in the three groups. However, the number of grafts used were higher and hence, the total time for distal anastomosis was more in the AMD group (P <.001). There was no significant difference in the intraoperative need for inotropes. Mean blood loss among the three groups was similar.

Table 2.

Intraoperative parameters of patients in AMD, M, and MD groups

	AMD (n=51)	M (n=21)	MD (n=78)	Total	P
Mean Number of grafts	3.49±0.64	3.05±0.67	2.91±0.81	3.13±0.78	0.0001
Median Number of grafts	4 (3-4)	3 (3-3)	3 (2-3)	3 (3-4)	0.0001
Time for distal anastomosis (minutes)	79.8±17.76	66.67±28.63	56.45±21.6	65.82±3.87	<0.001
Intraoperative inotropes	11 (21.57%)	5 (23.81%)	12 (15.38%)	28 (18.67%)	NS
Intraoperative AF	4 (7.84%)	4 (19.05%)	4 (5.13%)	12 (8%)	NS
Mean blood loss (mL)	525.1±172.76	523.81±355.89	554.87±293.73	540.4±268.02	NS

AMD, amiodarone magnesium diltiazem; MD, magnesium diltiazem; M, magnesium

Postoperative details

Table 3 shows the postoperative details. The overall incidence of AF in all the patients was 12.67%; however, there was no statistically significant difference between the three groups [Figure 1]. There were no differences in other parameters such as duration of ICU stay, hospital stay, postoperative magnesium levels, and duration of ventilation. Likewise, the incidence of deranged renal, liver function tests, and sepsis were similar in the three groups. Three patients died during the study. There was sternal infection in one patient for which sternal debridement and rewiring was performed.

Table 3.

Postoperative parameters of patients in AMD, M, and MD groups

	AMD (n=51)	M (n=21)	MD (n=78)	Total	P
Postoperative AF	6 (11.76%)	4 (19.05%)	9 (11.54%)	19 (12.67%)	NS
Duration of ICU stay (days)	7.55±4.54	6±2.35	7.19±2.77	7.15±3.45	NS
Duration of hospital stay (days)	17.06±19.04	13.33±3.12	13.18±4.37	14.52±11.67	NS
Postoperative (day 1) magnesium (m Eq/L)	1.91±0.2	1.93±0.15	1.95±0.19	1.93±0.19	NS
Duration of ventilation (hours)	20.69±2.66	21±2.93	19.09±3.92	19.9±3.49	NS
Deranged renal function	3 (5.88%)	1 (4.76%)	5 (6.41%)	9 (6%)	NS
Deranged liver function	0 (0%)	0 (0%)	1 (1.28%)	1 (0.67%)	NS
Sepsis	3 (5.88%)	1 (4.76%)	4 (5.13%)	8 (5.33%)	NS
Sternal debridement and rewiring for sternal infection	1 (1.96%)	0 (0%)	0 (0%)	1 (0.67%)	NS
Mortality	3 (5.88%)	0 (0%)	0 (0%)	3 (2%)

AMD, amiodarone magnesium diltiazem; MD, magnesium diltiazem; M, magnesium

Figure 1.

Comparison of atrial fibrillation between the three groups. (AMD, amiodarone magnesium diltiazem; MD, magnesium diltiazem; M, magnesium)

DISCUSSION

The overall incidence of AF in the present study was 8% (12 patients) intraoperatively and 12.6% (19 patients) postoperatively with no statistically significant difference in the three groups. The incidence of AF in early postoperative period after CABG ranges from 15%-33% with no significant differences between conventional on-pump CABG and OPCAB.[1,2] The occurrence of postoperative AF carries significance, as it can lead to multiple complications such as hemodynamic derangement, congestive heart failure, stroke, renal and respiratory failure, and an increase in mortality.[8,9] The various proposed mechanisms for the occurrence of AF are atrial structural changes, postoperative inflammation, pericarditis, electrical remodelling, autonomic imbalance, electrolyte imbalance, perioperative ischemia, alterations in atrial oxidative stress, and inflammatory mediators.[8] Preoperative optimization, surgical technique, anesthetic management, and postoperative management play a complex role in determining occurrence of arrythmias. Although the predictors for postoperative AF following on-pump CABG and OPCAB are well studied, there are no clear guidelines regarding antiarrhythmic prophylaxis for preventing AF.[10,11] Among the various antiarrhythmic prophylaxis, magnesium has been widely used as hypomagnesemia is associated with arrhythmias. There are a few reports of the use of magnesium in combination with antiarrhythmic agents, especially in patients undergoing OPCAB. As amiodarone and diltiazem are widely used antiarrhythmics, the authors studied their combination with magnesium to decrease the incidence of AF.

The literature related to the prophylactic use of magnesium is controversial. While some large randomized controlled trials and a meta-analysis have failed to show the utility of magnesium, other studies and meta-analysis have shown that magnesium therapy was beneficial in decreasing the incidence of postoperative AF.[3,12-15] Most of these reports have included patients undergoing on-pump CABG.

Amiodarone and diltiazem are other agents that have been studied alone or in combination, but there are limited number of publications. The incidence of postoperative AF among high-risk patients can be significantly reduced by prophylactic amiodarone treatment. In a large trial of 601 patients undergoing cardiac surgery including valve replacement/repair and CABG, preoperative oral administration of amiodarone decreased the incidence of AF in coronary artery bypass surgery patients.[16] Use of amiodarone in addition to magnesium in patients undergoing CABG was studied by Tiryakioglu and coworkers; they found it to be effective for prevention of total arrythmias, although there was no difference in the prevention of supraventricular arrythmia.[17] Both these studies do not mention whether the patients underwent conventional CABG or OPCAB. A recent practice advisory by SCA/EACTA 2019 has given Class IIa recommendation for consideration of perioperative use of amiodarone to prevent AF after cardiac surgery. While amiodarone has been shown to be useful, AF still occurs and there is a need to further decrease the incidence so that the postoperative outcome is improved. The authors tried to find out if this is possible by combination therapy.

Diltiazem is commonly used to relieve graft spasm in arterial grafts and can be useful in reducing the perioperative ischemia and arrhythmias. In a meta-analysis of 27 studies by Hu, et al.[7] involving more than 1,600 patients undergoing both on-pump CABG and OPCAB, it was found that diltiazem had highest odds of preventing perioperative AF when compared with nitroglycerin or placebo. In another study by Dobrilovic et al.,[18] lower incidence of AF following CABG was observed among 287 patients treated prophylactically with diltiazem either orally in combination with intravenous or intravenous route alone. Mikroulis et al.[19] in their study on patients undergoing conventional CABG observed marginally significant decrease in AF when amiodarone or diltiazem was used. However, there was no significant difference when diltiazem was compared with amiodarone. The present study shows that magnesium in combination with amiodarone and/or diltiazem does not decrease the incidence of AF further in patients undergoing OPCAB.

The major strength of this study is that frequently used combinations of antiarrythmics are compared for prevention of perioperative AF following OPCAB. Although various studies have compared different pharmacological agents including beta blockers, amiodarone, magnesium, colchicine, etc., only limited number of trials have observed the effect of combination therapy, especially in patients undergoing OPCAB. There are some limitations to this study. This is an uncontrolled trial, which resulted in the AMD group patients being operated upon by a single surgeon, smaller number of patients in group M, and higher incidence of old MI in group AMD.

CONCLUSION

The use of amiodarone and/or diltiazem in addition to magnesium did not result in additional benefit of lowering the incidence of AF.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.