Intravenous Magnesium Sulphate and Its Combination with Oral Vitamin C for AF Prophylaxis in Patients Undergoing Coronary Artery Bypass Surgery: A Randomized Double Blind Controlled Trial

Atrial fibrillation (AF) is one of the most commonly encountered complications following coronary artery bypass grafting, whose treatment modalities are still not definite. In this prospective randomized double blind controlled trial we evaluated the adjuvant role of oral vitamin C with intravenous magnesium sulphate for the prevention of postoperative AF among the patients who underwent CABG under cardiopulmonary bypass. Group M (n=90) received4gm of intravenous magnesium sulphate just after anesthesia induction followed by 2gm daily till the 3rd postoperative day. Group MC (n=91) received a similar dose of magnesium sulphate along with oral vitamin C 2gm on the night before surgery and their after 1 gm daily till the 3rd postoperative day. We noticed a significant number of patients from Group M suffered from AF while compared to Group MC (25.56% vs 13.9%,p=0.035).Moreover, the onset of this incidence was earlier in the former group (27.92±3.65 vs 30.55±3.24 hr, p=0.04) and lasted for a longer duration. More patients from Group M while compared with Group MC (21.11% vs 7.60%, p=0.01) needed rescue drug therapy for AF management. The incidence of AF was found to be more in male sex (71.42% vs 28.58, p=0.05), diabetic patients (28.06% vs 41.71%, p=0.02), patients with ventricular dysfunction (p=0.003) and those with poor sized vessels (p=0.004).The patients with AF had a longer duration of hospital stay (p=0.01) indicating a load on hospital resources. We conclude with an appropriate dosage and regime of intravenous magnesium, incidence of AF following CABG can be reduced but its administration alone may not be sufficient for the prophylaxis. Vitamin C as an adjuvant therapy is effective in reducing the incidence of AF.


Introduction
Atrial fibrillation (AF) is a frequent postoperative complication seen early after coronary artery bypass grafting (CABG) with a reported incidence of 20% to 50% [1]. Its onset is usually between 24 and 96 hours after surgery, with a peak incidence on the second to third postoperative day [1,2]. Atrial fibrillation potentially leads to prolonged hospitalization and significant morbidity, particularly hemodynamic deterioration and is an important risk factor for perioperative cerebrovascular accidents and perioperative myocardial infarction [3]. This subsequently leads to increase health care cost. The frequency of AF has not decreased despite recent developments in cardiac surgical technique, anesthetic management and myocardial management; hence search for an AF prophylaxis agent is important [4]. The mechanism of development of AF in these groups of patients has not been clearly defined. Possibly it is multi factorial, and factors like advanced age, withdrawal of β blockers, inadequate atrial protection, right coronary artery disease and electrolyte imbalance particularly hypomagnesaemia have been consistently associated with postoperative AF [2,5,6]. Hypo magnesia has been reported after cardiopulmonary bypass due to hemodilution, increased urinary loss and elevated catecholamine level [7]. Recently the role of inflammation and oxidative stress for generation of AF with free radical is under scanner [8,9]. Substance modulating inflammatory pathways and those with antioxidant properties has gain importance. Ascorbic acid with its potent antioxidant properties has found to decrease the incidence of AF in postoperative patients [10]. Several pharmacologic agents have been used to prevent postoperative atrial fibrillation with varying degrees of success. Among them only β blockers and amiodarone have been shown to decrease the incidence of this event [11,12]. However these are contraindicated in many patients, needs discontinuation in many because of side effects and also their cost effectiveness has not been proved. Magnesium sulphate has been used in prophylaxis of AF, although conflicting evidence exists [13,14]. Keeping the above facts in thought we formulated this study to assess the effect and potential efficacy of oral ascorbic acid as an adjunct to magnesium in reduction of the incidence of AF in patients undergoing CABG.

Study population
The study was designed as a prospective, randomized double blind, controlled trial to determine the role of intravenous magnesium, as well as adjuvant role of oral ascorbic acid in AF prophylaxis following CABG. A total of 181 consecutive patients scheduled for elective, isolated, first time coronary artery bypass grafting between the periods of May 2008 to December 2010 were included in the study. The exclusion criteria's for the eligibility were, patients with AF, those with history of second or third degree heart block, sufferer of obstructive sleep apnoea, severe pulmonary disease, end stage renal disease, hepatic failure or ventricular dysfunction, enlarged left atrium on preoperative echocardiography, patients with pacemaker or on medication with antiarrhythmic drug therapy or with digoxin and those who had to undergo emergency CABG. The study was approved by the hospital ethics committee, and informed consent was obtained from all patients or their authorized representative.

Study design
Based on previous retrospective data from our institute patients, the incidence of AF in CABG patients treated with 2gm of magnesium sulphate during the intra opertive period and their after till the second postoperative day was found to be 25%. Anticipating a 15% less incidence in patients treated with a combination of intravenous magnesium and oral ascorbic acid compared with those treated only with the former agent, with 5%level of significance and 80% power, estimated sample size was 226 patients (113 patients in each group). However, due to time constraint we could able to enroll a total number of 181 patient in the present study. All the patients underwent the routine investigations including coronary angiography and 2-D echocardiography before the enrolment. Patients were randomly allocated to two groups by using a computer generated random number table. Patients in magnesium group (M) received 4 gram of intravenous (iv) magnesium sulphate just after anesthesia induction followed by 2 grams of this drug everyday for 3 days. Patients in the ascorbic acid group (MA) were given 2 grams of effervescent vitamin C tablets on the night before surgery, followed by 1 gm daily for 3 days after surgery in addition to magnesium therapy like group M. All the drugs were administered by a resident or a staff nurse who were not the part of monitoring or data analysis.

Anesthetic management
All the patients were managed by a single surgical, anesthetic and perfusion team. All the patients were premedicated with oral diazepam 10 mg night before and 5mg morning on the day of surgery along with intravenous morphine sulphate 0.2 mgm/ kg body weight and intramuscular phenergan 25mg one hour before anesthesia induction. All of them were induced with intravenous thiopentone sodium 3-5mg/kg, fentanyl 5µgm/kg and rocuronium bromide 0.6 mg/kg body weight. The anesthesia was maintained with intermittent dose of fentanyl, midazolam and pancuronium bromide. Mechanical ventilation was achieved with a mixture of O 2 : air (50:50) via Aestiva 5 (Datex-Ohmeda,UK) anesthesia machine. The tidal volume and respiratory rates were adjusted to maintain normocarbia.

Surgical procedure and postoperative period
Patients underwent CABG on standard cardiopulmonary bypass (CPB) technique with ascending aortic and right atrial double staged cannulation. Cardiac arrest was obtained and maintained by intermittent antegrade hyperkalemic blood cardioplegia. Left internal mammary artery, radial artery and reverse saphenous vein graft were used as deemed appropriate. All distal anastomoses were performed during total aortic cross clamping and proximal anastomoses were constructed with partial clamping of aorta during rewarming. The hemoglobin was maintained between 9-10 gm/dl throughout CPB and >11gm/ dl during the study period. After surgery, all the patients were transferred to cardiac surgery intensive care unit (ICU).Post operative pain management was done with intravenous fentanyl till extubation and oral tramadol or ketorolac thereafter. Weaning from mechanical ventilation and catecholamine infusion was guided by institute protocol. Patients were discharged from the ICU to the nursing ward as soon as their hemodynamic and respiratory condition was stable. Continuous monitoring of vital parameters

Journal of Pharmacology & Clinical Research
and 5 lead ECG was done by using Simens 7000 bed side monitor (Siemens, Danvers, USA) during their ICU stay and thereafter continuously during the hospital stay along with a standard 12 lead ECG examination was carried out twice daily till the time of discharge. All the patients were monitored for any new onset of atrial fibrillation starting from the onset of magnesium therapy till 7 th postoperative day. AF was considered to be significant if it persisted for greater than 15 minutes and or required treatment because of hemodynamic compromise. If it occurred, the prophylaxis was considered to have failed and patient was treated as appropriate. Throughout the study duration serum potassium level of both the groups was maintained at a level of 4-4.5 meq/L. Intraoperatevely adequate death of anesthesia was maintained with the help of bispectral index monitoring and any evidence of pain was adequately treated throughout the study period.

Statistical analysis
Statistical analysis was carried out by using Stata 9.0 (College Statins,Texas, USA). Data were presented as number (%) or mean ± SD as appropriate. The univariate association between qualitative variable was evaluated using Chi square test and student t test was used for continuous variables. Bivariate, univariate and multivariate logistic regression was carried out to find the predictors of AF.The results for this were reported as odds ratio (95% confidence interval). In each of the analysis a p value of <0.05 was considered to be significant.

Results
We evaluated 181 patients undergoing CABG, with 90 patients receiving iv magnesium and the other 91 patients got both iv magnesium and oral ascorbic acid as AF prophylaxis. The first part of the study was dedicated to record the incidence of the development of atrial fibrillation at any point of time from the beginning of the case till the time of discharge of the patient and the importance of vitamin C and magnesium combination as AF prophylaxis; whereas the second part examined the predictors of AF in these group of patients, need of additional therapy for treatment of this episode and duration of ICU and hospital stay; and thereby an indirect assessment of the health care cost. Both the groups were comparable regarding their demographic profile and preoperative characteristics ( Table 1). The clinical parameters and perioperative variables of the patients appear in Table 2 did not reveal any statistical between the groups. While studying the overall incidence of atrial fibrillation , the authors noted a significant number of cases from Group

Journal of Pharmacology & Clinical Research Discussion
The incidence of AF after CABG varies between 10-40% and it remains as a drain on hospital resources [1][2][3][4]. Incidence of AF in our study with the use of magnesium is 25.56% which is comparable to few of the reports in literature those used magnesium as prophylaxis. However there has been conflicting evidence regarding the prophylaxis role of magnesium in decreasing the incidence of AF after CABG. Various studies show incidence ranging from 0% to 34.5% [13,[15][16][17][18]. Kohno et al. [13] in their retrospective study of 200 patients showed that postoperative 3 day magnesium infusion reduced the incidence of AF (16%) as compared to 35% in untreated group. Kaplan et al. [14] treated their patients with 3gm of magnesium sulphate during the preoperative period, day of surgery, and thereafter till the 3 rd postoperative day. They noticed a 15% incidence AF in the treated group and 16% among the unnoticed ones. Fanning et al. [16] in their prospective study showed that prophylactic magnesium not only decreases the incidence, but also reduces the severity of AF after CABG. Toraman et al. [17] gave magnesium preoperatively, intraoperatively, as well as postoperatively for 4 days. Hey found that magnesium infusion dramatically decreases the incidence of AF after CABG, not only in hypomagnesemic patients, but also in patients with normal magnesium levels. The mean hour of onset of AF in their group of patients was 49.4±16.8 hour postoperatively in contrast to our result. However, Treggire-Venzi et al. and Parikka [3,18] and associates did not find any benefit from intravenous magnesium sulphate as prophylaxis on AF after CABG. A number of reasons account for this wide variation of results. Dosing and riming of magnesium administration is an important aspect. As the onset of AF after CABG is usually between 1 st postoperative day to 3 rd postoperative day, and hypomagnesaemia was demonstrable during this time, magnesium administration has to be such that it covers this period [5,6]. So our protocol was to administer magnesium intraoperatively and continue it till the 3 rd postoperative day. Secondly, the criteria used to define the post operative AF and type of monitoring varies widely. Various studies have included arrhythmias with shorter durations, which are of no clinical significance and prophylaxis is not warranted. In our study patients were considered to be in AF,only when it is more than 15 minutes or when they develop symptoms or hemodynamic compromise to warrant treatment, thus representing the true load of patients requiring prophylaxis. In spite of so many proven reports considering the role of magnesium for postoperative arrhythmia prophylaxis, some studies had a query regarding the role of magnesium alone for the same [12,18]. This is because of the fact that post operative AF is multifactorial in origin. Oxidative stress due to surgical intervention and ischemia/reperfusion injury occurring in the myocardial tissue contributes to the development of tissue remodeling which in turn thought to be responsible for functional cardiac impairment and development of postoperative arrhythmia [19]. Vitamin C is an essential element in human body, a co factor for various enzymatic functions necessary for metabolic reactions. It is a powerful antioxidant that protects against oxidative stress produced by peroxide and free radicals [20]. The requirement of this element increases during trauma or tissue injury, reflecting an increase in its metabolism. Trauma and reperfusion injury during open heart surgery promotes the accumulation of proinflammatory cytokines responsible for oxidative stress. This subsequently affects the electrophysiological property of atrial myocyte leading to genesis of arrhythmia [10,21]. Carnes et al [10] gave supplemental ascorbic acid to patients before, and five days following CABG. They found that patients receiving ascorbic acid had a 16.3% incidence of post operative AF compared to 34.9% in controlled subjects. Eslami et al. [15] noted that combination of oral ascorbic acid with beta blockers is more effective than beta blockers alone and according to their view vitamin C has got an adjuvant role in the prevention of AF after cardioversion. Papoulidis and team [22] observed a significant difference in the overall incidence of postoperative AF in patients who received vitamin C in comparison with control group. A much lower incidence in our patients might be due to the use of magnesium sulfate along with vitamin C. In another report, after one week following cardioversion AF reoccurred in 4.5% of patients in the vitamin C group compared to 36.3% in control group [22] in our study, the time of onset of AF was not consistent with that reported by previous authors [15,21]. The height onset was 1 st postoperative day (27.92±3.65hr and 28.82±3.69hr in Group M and MC respectively, we considered D-O as the day of surgery till 24 hour). While treated with antiarrhythmic group of drugs, more patients in Group MC restored back to the normal rhythm. Again more number of patients in Group M needed a rescue drug for AF management and regained back the rhythm later while compared with Group MC. These findings denotes a definite role of Vitamin C pertain to AF event. Unlike the previous reports, in none of our patients it was noted beyond 5 th postoperative day. This might be due to the fact that supplementation of magnesium in both the groups had a protective role. A delayed onset, less incidence, and shorter duration of AF episode in MC Group of patients support the beneficial effect of vitamin C described in literature. The duration of ICU stay (p=0.00) and hospital stay (p=0.01) was much longer in patients who had AF. This duration required additional expenses in term of hospital charges. Another finding in our study was, though the time for ICU stay was similar, the duration of hospital stay in MC Group was shorter by one day while compared to Group M. Even if this finding was not statistically significant it was important when factor cost was calculated. The predictors for postoperative AF have not been clearly defined. Numerous factors preoperative, operative as well as postoperative have been suggested by previous experimental and clinical observations. Among them advanced age, reduced LVEF and beta blocker withdrawal has been consistently shown as a risk factor for AF following CABG. In a study by Kohno et al. [13] mean age of patients who had AF was 69 years compared to 64 years who not experience AF. They also found that 60% patients who had AF were > 70 years. Our patients belong to a relatively younger group with mean age 58 years .This could explain the absence of age as a risk factor in our study. All the patients who had AF were on beta blockers preoperatively but this finding was not statistically significant. Since none of the patients who were not on beta blockers preoperatively had AF, beta blocker withdrawal can be taken a risk factor. Smoking by causing postoperative pulmonary ateletasis and dysfunction with resultant hypoxemia as found to be a risk factor by Adams et al was not noted in our patients [23]. Most of our patients with AF were males, had ventricular dysfunction like previous authors [21]. Our study showed a statistically significant direct relation of male sex, diabetes mellitus, poor quality vessel and ventricular dysfunction.

Limitations of the study
The lack of continuous Holter monitoring may have missed some patients with AF. Since our aim was to find out clinically significant AF this might not have affected our results. As all the patients who experienced AF had preoperative beta blocker therapy, beta blocker withdrawal as AF among the patients who received vitamin C. Thirdly we could not evaluated age as a risk factor as all of our patients were < 60 year old [13].fourthly serum magnesium and vitamin C level was never monitored at any point of time to rule out a preexisting nutritional deficiency. By monitoring serum magnesium level we could have made a differentiation among the patients who had AF due to hypermagnesemia or hypomagnesemia [16]. Finally, due to a limited time frame we could not able to enroll the desired number of patients which might affect the predictors and overall incidence of AF.

Conclusion
We conclude that with an appropriate dosage and regime of intravenous magnesium, incidence of AF following CABG can be reduced but its administration alone may not be sufficient for the prophylaxis. Vitamin C as an adjuvant therapy is inexpensive and effective regime and can be considered for the prevention of AF in patients who undergoes coronary artery bypass grafting.