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DOI: 10.1111/1755-5922.12198

ORIGINAL RESEARCH ARTICLE

A double-­blind randomized clinical trial comparing different

doses of magnesium in cardioplegic solution for prevention of
atrial fibrillation after coronary artery bypass graft surgery

Afshin Gholipour Baradari1 | Amir Emami Zeydi2,3 | Rahman Ghafari4 | 

Mohsen Aarabi5 | Mahboubeh Jafari6

1
Department of Anesthesiology and
Critical Care Medicine, Faculty of Summary
Medicine, Mazandaran University of Medical Aims: This study aims to compare different doses of magnesium administered via
Sciences, Sari, Iran
2
cardioplegic solutions to prevent atrial fibrillation (AF) after coronary artery bypass
Student Research Committee, Department
of Medical-Surgical Nursing, School of graft (CABG) surgery.
Nursing and Midwifery, Mashhad University
Methods: A total of 120 patients who were scheduled for elective CABG surgery
of Medical Sciences, Mashhad, Iran
3 using cardiopulmonary bypass were enrolled in this double-blind, randomized clini-
Department of Nursing, Faculty of Nursing
and Midwifery, Mazandaran University of cal trial. After fulfilling the inclusion criteria, they were randomly allocated into
Medical Sciences, Sari, Iran
three groups (A, B, and C). Patients in groups A, B, and C received 60, 80, and
4
Department of Cardiac Surgery, Faculty of
Medicine, Mazandaran University of Medical 100  mg/kg of magnesium sulfate via cardioplegic solutions during aortic cross-­
Sciences, Sari, Iran clamp, respectively. Postoperative AF was assessed by continuous ECG monitoring
5
Department of Epidemiology, Health during 3  days after surgery. Also serum magnesium, potassium, and calcium levels
Sciences Research Center, Mazandaran
University of Medical Sciences, Sari, Iran were assessed during the study period.
6
Faculty of Medicine, Mazandaran University Results: The findings revealed significant differences in four point measurements
of Medical Sciences, Sari, Iran
of serum magnesium level after surgery (P<.001). In particular, it was observed

Correspondence
Rahman Ghafari, Mazandaran Heart
Center, Artesh Boulevard, Sari, Mazandaran
Province, Iran.
Email: contactroute@yahoo.com
that 10 (26.3%) patients in group A, 4 (10%) patients in group B, and 2 (5.4%)
patients in group C had AF after surgery. This indicates patients receiving mag-
nesium at doses of 80 and 100  mg/kg had lower rates of AF occurrence than
those receiving 60  mg/kg dose of magnesium (P=.02). Additionally, no significant
difference was found in serum calcium and potassium concentration between the
three groups throughout the study period.
Conclusion: Magnesium administration via the cardioplegic solution during aortic
cross-­clamping at doses of 80 and 100  mg/kg can reduce the risk of AF occur-
rence after CABG compared to the dose of 60  mg/kg. Considering the lower rate
of AF incidence and shorter length of ICU stay in patients receiving 100  mg/kg
of magnesium, it seems reasonable to administer 100  mg/kg magnesium during
aortic cross-­clamp to prevent postoperative AF.

KEYWORDS
Atrial fibrillation, Cardioplegic solutions, Coronary artery bypass, Magnesium sulfate

276  |  © 2016 John Wiley & Sons Ltd wileyonlinelibrary.com/cdr Cardiovascular Therapeutics 2016; 34: 276–282

Gholipour Baradari et al.
1 | INTRODUCTION
One of the most prevalent arrhythmia after coronary artery bypass
1
graft (CABG) surgery is atrial fibrillation (AF). It has been reported
that the rate of AF occurrence after CABG ranges from 3% to 50%.
AF does not increase the risk of mortality within 30  days after
CABG, and it is generally considered as a benign condition. How-
ever, concerns remain regarding its complications, including hemo-
dynamic disturbances, palpitation, thromboembolism, and post-
surgical stroke.2,3 Complications can lead to longer postoperative
stay period that will ultimately increase hospital costs.4,5 As such,
numerous attempts have been made to diminish postoperative AF
(POAF) occurrence.6 There is no clear etiology attributed to POAF
prevalence after cardiac surgery.1 However, several factors such as
a history of AF, advanced age, concurrent coronary and valve sur-
gery, history of congestive heart failure, chronic obstructive pulmo-
nary disease (COPD), and duration of cross-­clamp are believed to
increase the risk.7–9
Hypomagnesaemia is one of the well-­documented POAF risk fac-
tors. Since more than three decades ago, evidence has shown that
during cardiac surgery with cardiopulmonary bypass (CPB), the total
serum magnesium concentration decreases.10–12 Besides, there
is a reduction in total serum level of magnesium in more than 80%
of patients undergoing CABG. Thus, administering magnesium to
patients who have undergone cardiac surgery can lead to not only
reducing POAF occurrence, but also producing a better myocardial
outcome.4,13
Generally, magnesium is administered intravenously during
perioperative period to prevent POAF.13–16 Routine intravenous
administration of magnesium has been shown to have no signifi-
cant effect on serum magnesium concentration and occurrence of
perioperative arrhythmia after CABG surgery.17 In contrast, using
magnesium-­free cardioplegia might result in postoperative low
serum magnesium concentration which has been found as a risk
factor for the development of a new POAF.18 Therefore, adding
magnesium to the cardioplegic solution could be helpful in such
cases.18–20
A recent meta-­analysis has revealed that magnesium-­
supplemented cardioplegia can lead to a marginal reduction in the
21
occurrence of new-­onset POAF. It has been suggested that fur-
ther studies are necessary to determine the role of magnesium-­
supplemented cardioplegia in minimizing atrial arrhythmia occurrence
after CABG surgery.19 Moreover, it has been proposed applying a
higher concentrated magnesium cardioplegic solution can bring about
greater benefits in reducing perioperative arrhythmia occurrence in
patients.20 However, as shown in the extant literature, cardioplegia
supplemented with either low-­ or high-­concentration magnesium
does not decrease the frequency of POAF in patients undergoing
CABG.18
Given the paucity of research evidence in this regard, and the
contradictory findings of prior studies, this study aims to compare the
effectiveness of the different doses of magnesium in cardioplegic solu-
tion to prevent AF after CABG surgery.
17555922, 2016, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1755-5922.12198 by Nat Prov Indonesia, Wiley Online Library on [21/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
  |  277
2 | MATERIAL AND METHODS
An approval was first obtained from the Ethics Committee along
with an informed written consent from patients. Among the adult
patients who were scheduled for elective CABG surgery using
CPB, a total of 120 including male and female from the age group
of 35–75  years old, were considered for the double-­blind, rand-
omized clinical trial.
The following exclusion criteria were considered: (1) history of previ-
ous cardiac surgery, (2) prior treatment with antiarrhythmic medications
(except beta blockers), (3) history of heart failure with ejection fraction
(EF) <30%, (4) need for more than four grafts, (5) renal failure (serum
creatinine >1.5 on two consecutive tests), (6) liver dysfunction (hepatic
enzymes elevated over 1.5 times the normal value), (7) history of COPD,
(8) hyperthyroidism, (9) myocardial infarction (MI) after surgery, (10)
grade II to III atrioventricular (AV) block, and (11) serum pH <7.25 or
>7.55. Additionally, patients who required pacemaker, and re-­operation
for any reasons, as well as those who had hemodynamic instability
(MAP<60 and heart rate <50 or >110) were excluded from the study.
After fulfilling the inclusion criteria of the study, patients were ran-
domly assigned to three groups (A, B, or C) using a sealed envelope
technique. To allocate patients to the groups, a nurse who was blind to
the study used a computer generated numbering system to randomly
assign patients to each specific group. There were 40 patients in each
group.
In all patients, anesthesia induction was achieved with combina-
tions of midazolam, sufentanil, and pancuronium bromide. The trachea
was intubated and mechanically ventilated with oxygen. Anesthesia
maintenance was based on moderate doses of sufentanil and mid-
azolam supplemented with propofol (25–100 μg/min). Muscle relax-
ation was maintained with cisatracurium. Median sternotomy was
performed in all patients, and CPB was instituted through cannulation
of the ascending aorta and the right atrium. Heparin was given at an
initial dose of 300 IU/kg to achieve an activated clotting time (ACT)
of >480  seconds, and at the end of CPB it was reversed with a full
dose of protamine chloride to achieve an ACT of <120 seconds. Non-
pulsatile CPB was performed using a membrane oxygenator, an open
cardiotomy reservoir, and uncoated tubing systems. Colloid (Voluven)
without any blood product was used as the priming solution. During
CPB, the minimum and maximum allowed Hct levels were 20% and
24%, respectively. Moderate hypothermia (32°C) was used during
CPB. Mean arterial blood pressure was maintained between 60 and
80  mm  Hg. α-­Stat acid–base management was used for all patients.
The doses of 60, 80, and 100 mg/kg magnesium sulfate diluted to a
total volume of 20 cc with normal saline were used to treat patients
in the A, B, and C groups, respectively. Magnesium was infused via
cardioplegic solutions during aortic cross-clamp. The patients in all the
three groups were carefully and constantly monitored after remov-
ing the aortic cross-­clamp as well as postoperatively during the ICU
stay and after being transferred to coronary care unit. In case of any
dysrrhythmia, which could be detected visually by the head nurse,
was printed for accurate diagnosis by two intensive care nurse prac-
titioners/attending physicians. In this study, POAF was identified

   | 
278
according to the European Society of Cardiology guidelines as any dys-
rhythmia that represents the ECG characteristics of AF, lasting at least
30 seconds on a rhythm strip or 12 lead ECG.22 In continuous ECG
monitoring, suspicious rhythms were double-­checked and confirmed
by attending physician. The occurrence of AF during the first 96 hours
after CABG surgery was considered the primary endpoint of the study.
In addition, prior to, immediately after, and on days 1, 2, and 3 after
the surgery (at 8:00  am), venous blood samples were taken from all
the patients to assess their blood pH, serum total magnesium, potas-
sium, and calcium concentration. Along with the mentioned data,
other information was recorded in data collection forms. This infor-
mation includes age, sex, body mass index, EF before surgery, history
of MI, diabetes, right coronary artery involvement, duration of cross-­
clamping, duration of CPB, duration of mechanical ventilation, and
amount of blood received during surgery.
It is worth noting that protocols for anesthesia, the CPB, and sur-
gery were identical for all the three groups’ patients. As the study was
double-­blinded, patients were not aware of their categorization to
groups A, B, or C. Furthermore, the drug doses were numbered 1, 2,
or 3 with the same volume in syringes. Therefore, the categorization
of patients remained anonymous to the surgeon and perfusionists.
This study has been registered in the Iranian clinical trial database
(IRCT201211124365N15).
2.1 | Statistical analysis
To analyze the data, mean and standard deviation (SD) or number
(%) of the independent variables were described and compared
17555922, 2016, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1755-5922.12198 by Nat Prov Indonesia, Wiley Online Library on [21/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Gholipour Baradari et al.
over different intervention groups using suitable univariate analysis
methods. The main outcome (AF incidence) was described based
on intervention groups and analyzed using univariate and multivari-
ate logistic regression analysis (backward method, critical P-­value=.2).
To examine the mediation role of several variables such as changes
in serum magnesium, calcium, potassium, and pH, repeated measure
analysis of variance across four time points and over intervention
groups was applied. The analysis was also repeated for the out-
come groups. P values <.05 were considered significant.
3 | RESULTS
During the study period, screening was performed for a total
number of 141 patients who were scheduled for elective CABG
surgery. Among these patients, 14 of them did not meet the inclu-
sion criteria and seven others declined to participate in the study.
The remaining 120 patients were randomly categorized into three
groups of A, B, and C. Of the 120 patients, five of them dropped
out of the study. Overall, the data from 115 patients who com-
pleted this study were analyzed (Figure  1).
As illustrated in Table 1, the mean and SD of the patients’ age were
60.6 (6.3), 61.5 (7.9), and 59.8 (8.3) for groups A, B, and C, respec-
tively. Further demographic and clinical characteristics of patients are
presented in the table below.
The total frequencies of AF occurrence after removing the aortic
cross-­clamp as well as post surgical period were found as 10 (26.3%)
patients in group A, 4 (10%) patients in group B, and 2 (5.4%) patients

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F I G U R E   1   Changes in serum magnesium at the end of surgery and after surgery

 17555922, 2016, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1755-5922.12198 by Nat Prov Indonesia, Wiley Online Library on [21/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Gholipour Baradari et al.   |  279

T A B L E   1   Demographic and clinical characteristics of patients in T A B L E   2   Logistic regression analysis for AF occurrence over
the three study groups intervention groups (receiving 60 mg/kg was considered as the
baseline and other potential confounders were controlled)
Variables P-­value
P-­value OR
Baseline variables
Age A 60.6 (6.30) .63 Group(A) – 1
Mean(SD) B 61.5 (7.98) Group(B) .014 .157
C 59.8 (8.35)
EF A 47.2 (8.73) .46 Group(C) .008 .095
Mean(SD) B 49.3 (7.44) Blood .016 2.342
C 47.9 (6.92
Beta blocker .082 4.356
Magnesium (Mg) level A 2.0 (0.33) .24
(Baseline) B 2.1 (0.36) Diabetes .461 1.606
Mean(SD) C 1.9 (0.38)
Potassium (K) level (Baseline) A 3.8 (0.58) .62
Mean(SD) B 3.8 (0.65)
C 3.7 (0.35) respectively, compared to those patients receiving 60 mg/kg magne-
Calcium (Ca) level (Baseline) A 3.9 (0.42) .20 sium. In particular, the crude odds ratio of AF in patients receiving
Mean(SD) B 3.8 (0.53) 60 mg/kg magnesium was 6.25 times more often than patients treated
C 3.7 (0.76)
with 100 mg/kg magnesium (P=.025) and 1.94 times more often than
pH (Baseline) A 7.4 (0.10) .72
Mean(SD) B 7.4 (0.05) patients treated with 80 mg/kg magnesium (P=.459).
C 7.4 (0.10) This study later controlled for potential confounders such as blood
BMI A 27.1 (4.15) .71 transfusion, beta blocker, and history of diabetes in multivariable logis-
Mean(SD) B 26.7 (5.27)
tic regression. The results revealed that the odds ratio of AF in patients
C 26.3 (3.90)
receiving 80 mg/kg and 100 mg/kg magnesium changed to 0.157 and
Male A 21 (55.3) .68
N (%) B 19 (47.5) 0.095 times less often than patients receiving 60 mg/kg magnesium,
C 17 (45.9) respectively (P=.014, .008). Table  2 presents the results of logistic
Diabetes A 13 (34.2) .08 regression analysis.
N (%) B 16 (40.0)
Table 3 illustrates the changes in serum levels of magnesium at dif-
C 15 (40.5)
MI history A 10 (26.3) .09 ferent points throughout the study. There was no significant difference
N (%) B 6 (15.0) found in the serum magnesium levels of patients in the three groups
C 8 (21.6) prior to surgery. As shown in Table  3 and Figure  2, patients’ serum
Treatment with beta blocker A 20 (52.6) .73
magnesium was changed significantly over four points measurement
before surgery B 23 (57.5)
N (%) C 18 (48.6) (F2.6,291.4=276.7, P<.0001). The trend was statistically significant after

Intraoperative variables
CPB time A 85.4 (11.7) .55
Mean(SD) B 84.5 (18.2)
C 88.2 (15.6)
Cross-­clamp time A 53.1 (15.7) .74
Mean(SD) B 52.9 (16.4)
C 55.4 (13.9)
Blood transfusion (unit) A 1.6 (0.7) .11
Mean(SD) B 1.9 (0.9)
C 1.8 (0.8)
Intubation Time A 6.9 (2.2) .42
Mean(SD) B 7.1 (2.3)
C 7.6 (2.2)
Length of ICU stay (days) A 2.6 (0.73) .02
B 2.4 (0.49)
C 2.2 (0.59)
EF, ejection fraction; BMI, body mass index; MI, myocardial infarction;
CPB, cardiopulmonary bypass.
in group C (P=.02). The findings revealed administration of magnesium
to patients at doses of 80 and 100 mg/kg, reducing the AF occurrence
compared to magnesium dose of 60 mg/kg (P=.02).
The crude odds ratio of AF in patients receiving 80  mg/kg and
100  mg/kg magnesium was 0.311 (P=.069) and 0.16 (P=.025),
including the study groups to the model. This indicates that there is a
mutual effect of drug dose and changes (F5.2,291.4=7.49, P<.0001). It is
noteworthy that the trend is linear (F2,112=14.4, P<.0001).
Figure  3 demonstrates the trend of serum calcium changes in
the three groups over four points of measurement after surgery. The
changes were found not to be statistically significant (F1.87,209.2=2.165,
P=.121). Likewise, the mutual impact with therapy groups was not
found to be significant (F3.74,291.4=2.308, P<.074).
As shown in Figure 4, there are nonsignificant changes in serum
potassium and pH during the study period and the treatment effect
(P>.05).
4 | DISCUSSION
This study compared the effectiveness of different doses of mag-
nesium in cardioplegic solution to prevent AF occurrence after
CABG surgery. The results revealed that POAF occurrence in patients
receiving magnesium sulfate at doses of 80 and 100  mg/kg
during cross-­clamping via cardioplegic solution was significantly lower
than those receiving magnesium sulfate at dose of 60  mg/kg.
Moreover, a significant difference was observed in the length of
 17555922, 2016, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1755-5922.12198 by Nat Prov Indonesia, Wiley Online Library on [21/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
   | 
280 Gholipour Baradari et al.

T A B L E   3   Changes in mean serum levels of magnesium before the study, after cross clamping, immediately after surgery, and on days 1, 2,
and 3 after surgery in the three groups (mean and standard deviation)

Group A (60 mg/kg) Group B (80 mg/kg) Group C (100 mg/kg) P value (among

Variables Mean (SD) Mean (SD) Mean (SD) three groups)

Serum Mg before surgery 2.05 (0.33) 2.12 (0.36) 1.98 (0.37) .240
Serum Mg immediately after surgery 3.13 (0.39) 3.22 (0.43) 3.50 (0.36) <.0001
Serum Mg on day 1 after surgery 2.56 (0.38) 2.71 (0.48) 2.85 (0.33) .010
Serum Mg on day 2 after surgery 2.47 (0.39) 2.63 (0.46) 2.67 (0.44) .118
Serum Mg on day 3 after surgery 2.35 (0.35) 2.46 (0.41) 2.28 (0.38) .147

need for internal defibrillation and temporary epicardial pacing in

F I G U R E   2   Changes in serum magnesium prior to, during, and
after surgery
patients. Besides, a lower plasma magnesium concentration was
found in POAF patients compared to patients without POAF.20 In
another study by Shakerinia et  al.19 which was aimed to evaluate
the effectiveness of magnesium-­supplemented cardioplegia in pre-
venting postoperative arrhythmias and perioperative ischemia, it
was revealed that complications in patients undergoing CABG surgery
were reduced by adding magnesium to the cardioplegic solution.
Additionally, Maruyama et  al.23 provided support for the correlation
between efficacy of postconditioning, which attenuates reperfusion
injury, and the magnesium concentration of the cardioplegic solu-
tion. Hayashi et  al.24 found that cardioplegia supplemented with
potassium and magnesium led to a significant reduction in POAF.
Furthermore, Caputo et  al.18 confirmed that cardiac injury was
reduced, although cardioplegia supplemented with either low-­ or
high-­concentration magnesium did not reduce the frequency of
POAF in patients undergoing CABG. Administration of magnesium
sulfate before the release of aortic cross-­clamp was found to
decrease the occurrence of postoperative ventricular fibrillation in
patients after CABG surgery.25
This study is distinct from the earlier studies because it used
magnesium sulfate during surgery and aortic cross-­clamping via the

F I G U R E   3   Changes in serum calcium before, during, and after

surgery in the three groups

ICU stay among the patients of the three groups. Patients receiving
100  mg/kg magnesium stayed shorter in ICU in comparison with
those who received magnesium at different doses. Yetman et  al.
in a study provided evidence regarding magnesium-­supplemented
cardioplegia. Their study showed that magnesium-­supplemented F I G U R E   4   Changes in serum K and pH after surgery in the three
cardioplegia significantly reduced the occurrence of POAF and the groups

Gholipour Baradari et al.
cardioplegic solution at three different doses. It was found that all
patients had postoperative serum magnesium concentration higher
than their preoperative level, which was gradually diminished during
3 days after surgery (within normal range). This study provided empir-
ical evidence that there is a positive relationship between magnesium
dosage and its serum concentrations. Therefore, the greatest serum
magnesium level was resulted from a dose of 100  mg/kg. Greater
myocardial protection might be the consequence of a higher concen-
tration of magnesium in the cardioplegic solution.20 A study by Kurian
et al. on CABG patients demonstrated that administering 2 g magne-
sium sulfate before aortic cross-­clamping led to a hypomagnesaemia
rate of 9%, while this rate was 35% in control group (not receiving
magnesium). This indicates that magnesium supplementation has a
significant effect on serum magnesium level which also reduced AF
occurrence.26 There are several mechanisms involved in magnesium-­
supplemented cardioplegia to reduce postoperative arrhythmias. One
of the possible mechanism is magnesium-­supplemented cardioplegia
may limit the injury caused by calcium-­mediated ischemic-­reperfusion
18
and early partial postoperative hypomagnesemia prevention. Addi-
tionally, calcium ion entry into the cells can be caused by surgery-­
induced hyperkalemia. This can result in increasing myocardial tension
with a subsequent decrease in adenosine triphosphate (ATP). The
loss of ATP by antagonizing the calcium effect can be prevented by
magnesium-­supplemented cardioplegic solution.19 Another possible
mechanism is the role of magnesium as a free radical scavenger in pre-
venting reperfusion injury. This could play a part in the development of
post-­CABG complication. Magnesium supplementation can stabilize
the plasma membrane of myocardium before aortic cross-­clamp that
mediates the protective effect.25,27
This study is limited by its relatively small sample size. There is a
possibility that the small sample size in this study may have caused
insignificant differences among the three groups. As such, it is sug-
gested that future studies might need to consider a larger sample
sizes. Despite nullifying known confounding variables, we believe that
the unknown confounders still might be in effect. Another limitation is
lacking of control group in this trial, because we were not allowed to
withhold the routine treatment of giving magnesium sulfate via cardio-
plegic solutions during aortic cross-­clamp.
In conclusion, magnesium administration via the cardioplegic
solution during aortic cross-­clamping at doses of 80 and 100 mg/kg
can reduce the risk of AF occurrence after CABG compared to the
dose of 60 mg/kg. Considering the lower rate of AF incidence and
shorter length of ICU stay in patients receiving 100 mg/kg of mag-
nesium, it seems reasonable to administer 100  mg/kg magnesium
during aortic cross-­clamp to prevent POAF. However, further stud-
ies are required to determine the most effective therapy protocols.
ACKNOWLE DGME N TS
The authors would like to acknowledge the financial support pro-
vided by Research Deputy of Mazandaran University of Medical
Sciences. Additionally, the authors wish to thank all the study
participants for their kind cooperation and support.
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  |  281
ET HI C S
An approval was obtained from the Ethics Committee along with
an informed written consent from patients.
CO NFL I C T O F I NT ER ES T
The authors declare no conflict of interest.
AU T HO R CO NT R I B U T I O NS
AGB, AEZ, RG, and MA contributed to study concept and design.
MA contributed to statistical analysis and interpretation of data.
AGB, AEZ, RG, and MJ were involved in the drafting of the manu-
script. Critical revision of the manuscript for important intellectual
content was carried out by AGB, AEZ, RG, MA, and MJ
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