Full text of DOI:10.1177/147323000303100306

The Journal of International Medical Research
003; 31: 202 – 209
2
Magnesium-flush Infusion into the Aortic
Root Just Before Reperfusion Reduces the
Requirement for Internal Defibrillation
and Early Post-perfusion Arrhythmias
.
.
Y BES¸OG˘UL, B TÜNERIR, C ÖZDEMIR AND R ASLAN
Department of Cardiovascular Surgery, Osmangazi University Medical School and
Research Hospital, Eski s¸ ehir, Turkey
Pre- and post-operative administration
of magnesium has beneficial effects on
post-operative ischaemia and reperfusion
arrhythmias, but few studies have
examined whether intra-operatively
administered magnesium can prevent the
effects of intra-operative arrhythmias.
The aim of this randomized, double-blind
study was to compare the effects of
intra-operative magnesium or placebo on
intra-operative arrhythmias in patients
undergoing coronary bypass grafting.
Patients received a flush infusion of
magnesium or placebo into the aortic root
before cross-clamp removal. The results
showed that rate of spontaneous
resumption of a cardiac rhythm was
significantly higher, and number of shocks
for defibrillation, energy requirement for
defibrillation and rate of intra-operative
ventricular tachyarrhythmias were signifi-
cantly lower in the magnesium group,
compared with the placebo group. The
differences in need for temporary pacing,
and in serum magnesium levels, were
not significant. Intra-operative admin-
istration of magnesium has beneficial
effects on the outcome of surgery. Larger,
multicentre clinical investigations should
now be undertaken.
KEY WORDS: CORONARY ARTERY BYPASS GRAFTING; CARDIOPULMONARY BYPASS;
ARRHYTHMIAS; MAGNESIUM
ventricular tachyarrhythmias, ventricular
Introduction
The most common complications of cardio-
pulmonary bypass (CPB) surgery are
bradyarrhythmias, atrial fibrillation, atrial
flutter and paroxysmal atrial tachycardia.3
Magnesium is often administered after
surgery as prophylaxis or treatment for
cardiac arrhythmias. Many reports show the
beneficial effects of pre- and post-operatively
administered magnesium for patients
undergoing CABG,4,5 and administration of
magnesium in the cardioplegic solution
1
ischaemic reperfusion injury and reperfusion-
2
induced arrhythmias. Ventricular and atrial
arrhythmias have been recognized as
common post-operative complications since
the advent of coronary bypass grafting
(
CABG). Such complications include
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Y Be s¸ o g˘ ul, B Tünerir, C Özdemir et al.
Benefits of magnesium-flush infusion
before CPB can decrease the incidence of
post-operative arrhythmias.6 Magnesium
post-operative outcomes, and serum
magnesium levels in patients undergoing
CABG.
administered post-operatively by infusion also
significantly reduced the incidence of atrial
fibrillation in patients undergoing CABG.7 – 10
Patients and methods
Potassium crystalloid cardioplegic solutions
elevate intracellular calcium levels. Potassium
cardioplegic infusion is, in part, associated
with opening of adenosine triphosphate-
Patients recruited to the study were
functional class III or IV, according to the
New York Heart Association (NYHA)
guidelines, and were undergoing an aortic
coronary bypass operation because of
coronary artery disease. The hospital ethics
committee approved the study, and all
patients gave informed consent. Patients
were randomly divided into two groups:
magnesium and placebo. The patients’
clinical characteristics are shown in Table 1.
Exclusion criteria were: additional
valvular heart disease; renal and hepatic
dysfunction; repeat operation; patients
in NYHA classes I or II; uncontrollable
diabetes mellitus; and pre-operative hypo-
magnesaemia (< 1.5 mg/dl), hypocalcaemia
+
activated potassium channels (K ATP channels)
and calcium accumulation in coronary
vascular smooth muscle.11,12 Magnesium
blocks the L-type calcium channels, reduces
calcium loading and energy demands, and
preserves myocardial metabolites.
Hypomagnesaemia increases the rate of
ventricular and atrial arrhythmias and
prolongs mechanical ventilatory support.13,14
Intravenous administration of magnesium is
thought to be beneficial because it decreases
the incidence of ventricular arrhythmias and
improves cardiac function in patients after
CABG.15 Magnesium administration also
reduces the incidence of heart failure and
mortality in patients after acute myocardial
infarction (MI).16
(< 8.5 mg/dl) or hypokalaemia (< 3.5 mEq/l).
ANAESTHESIA AND OPERATIVE
TECHNIQUES
Addition of magnesium to intermittent
warm blood cardioplegia resulted in a lower
incidence of intra- and post-operative
arrhythmias in patients undergoing urgent
CABG for unstable angina.6 Optimum
method, dose and timing of magnesium
All operations were performed under
fentanyl anaesthesia (1.5 mg/h fentanyl by
infusion and 1% inhaled isoflurane) and
neuromuscular blockade was achieved using
0.15 mg/kg pancuronium bromide. Intra-
venous heparin (300 IU/kg) was administered
immediately before cannulation for CPB and
additional doses were given to maintain an
activated clotting time of 480 s or faster.
Cannulation of the aorta and insertion of a
single two-stage cannula into the right
atrium was used to initiate CPB. Non-pulsatile
prophylaxis
has
not
been
clearly
determined, however. These findings led us
to hypothesize that flush administration of
magnesium into the aortic root before cross-
clamp removal may preserve myocardial
metabolites and reduce intra-operative
arrhythmias after ischaemic reperfusion.
This prospective, randomized, double-
blind clinical study was designed to evaluate
the effects of intra-operative flush
administered magnesium on intra-operative
reperfusion-induced arrhythmias, early
2
flow rates of 2.4 l/min per m and moderate
hypothermia (28 – 32°C) were used. Cold
crystalloid cardioplegia containing 16 mmol
magnesium (+4 °C; Plegisol®, Abbott
Laboratories, Abbott Park, IL, USA) was used
for myocardial protection. Magnesium (10 ml
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Y Be s¸ o g˘ ul, B Tünerir, C Özdemir et al.
Benefits of magnesium-flush infusion
TABLE 1:
Clinical characteristics of the magnesium and control study groups
Magnesium group
Placebo group
a
a
Characteristic
(n = 50 )
(n = 50 )
Age (years)
64 ± 2.7
61 ± 3.2
Women/men
7/43
6/44
Body mass index
25.8 ± 2.7
26.1 ± 3.2
Bivascular disease
5
7
Trivascular disease
45
43
Number of grafts per patient
Mean ejection fraction
Poor ejection fraction (< 35%)
Unstable angina
2.8 ± 0.9
2 9 ± 0.6
0.4 ± 1.9
0.4 ± 1.7
10
3
12
4
Peri-operative myocardial infarction
Previous myocardial infarction
New York Heart Association Class
III
0
0
18
14
37
13
35
15
IV
Euro-score
0.7 ± 1.3
12
0.8 ± 1.6
14
Diabetes
Chronic obstructive pulmonary disease
15
13
Serum magnesium levels before surgery (mg/dl)
2.3 ± 0.2
2.1 ± 0.3
aThere were no statistically significant differences in the clinical characteristics between the two groups.
of 1.5 nmol/ml magnesium sulphate), or POST-OPERATIVE MANAGEMENT
placebo (10 ml saline solution), was infused AND DATA COLLECTION
into the aortic root over a 30-s period, after
distal anastomosis completion, and 5 min
before cross-clamp removal. The membrane
oxygenator and standard synthetic circuits
were used for CPB.
Post-operative ventilation was achieved
with 60% oxygen by volume-controlled
ventilation and a tidal volume of 10 ml/kg
with 5 cm H O positive end expiratory
2
pressure, in the intensive care unit (ICU).
Extubation criteria were: haemodynamic
stability; no excessive bleeding (< 70 ml/h);
normothermia; and consciousness.
Revascularization was achieved by
grafting the internal mammary artery and
saphenous veins. Distal anastomosis was
completed under cross-clamping and cardiac
stand still. All proximal anastomoses were
performed using a partial side clamping of
the aorta during CPB.
Haemodynamic measurements were
made by standard radial, central venous
catheterization. Serial plasma magnesium
concentrations were recorded before surgery
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Y Be s¸ o g˘ ul, B Tünerir, C Özdemir et al.
Benefits of magnesium-flush infusion
and at 6 h and 24 h after the operation.
poor ventricular ejection fraction and
previous occurrence of MI or MI after surgery.
Measures of effectiveness are shown in
Table 2. Comparison of the findings between
the two groups showed that the rate of
spontaneous resumption of cardiac rhythm
or spontaneous defibrillation was higher in
the magnesium group than the control
group (P < 0.05). The number of shocks
for defibrillation, energy required for
defibrillation and post-CPB ventricular
tachyarrhythmias were lower in the
magnesium-treatment group than in the
control group (P < 0.05). No significant
difference was found between the two groups
for temporary pacing requirement, total
blood loss, re-operation for bleeding,
intubation time, length of ICU stay and
length of hospital stay. At the time of cross-
clamp removal, mean oesophageal probe
Post-CPB inotropic agents, peri-operative
MI, intra-aortic balloon pump usage and the
need for temporary pacing were recorded.
Operative mortality was defined as any
death that occurred within 30 days of the
operation. Ventilatory failure was defined as
requiring mechanical ventilation for more
than 48 h. Post-operative blood loss was
measured as total volume retrieved through
the chest drain, starting immediately after
closure of the chest in the operating theatre.
The following were recorded to evaluate
the effects of intra-operatively administered
magnesium versus placebo: spontaneous
resumption of cardiac rhythm or spon-
taneous defibrillation; number of shocks
for defibrillation; energy required for
defibrillation; ventricular tachyarrhythmias;
and temporary pacing required for
bradyarrhythmias after completion of CPB.
Heart rate and rhythm were continuously
temperature was 35
± 0.2 °C in the
magnesium group and 35 ± 0.6°C in the
control group.
®
monitored and displayed (Artema , Diascope
Traveller, Albertslund, Denmark) during
surgery and the first 24 h after surgery. Twelve-
lead electrocardiograph recordings were
performed before surgery, 1 h after surgery, and
daily thereafter during the early post-operative
days.
In the control group, one patient died
because of low cardiac output syndrome and
multiorgan failure.
Serum levels of magnesium were in
normal range (1.5 – 2.6 mg/dl) in all
patients before the operation. The mean
magnesium levels measured in the ICU are
given in Table 2. According to these
measurements, administration of 1.5 mmol
magnesium before cross-clamp removal did
not affect post-operative plasma magnesium
levels as compared with the control group.
STATISTICAL ANALYSIS
Data were expressed as mean
± SD.
Categorical variables were analysed using
either the χ2 test or Fisher’s exact test.
Continuous variables were compared using
the unpaired Student’s t-test. P-values < 0.05
were considered significant.
Discussion
Post-perfusion arrhythmias are the most
common complications of CPB in patients
Results
2
A total of 100 patients were enrolled in the
study, with 50 randomized to each group.
The clinical characteristics of the two groups
were similar (see Table 1), and there was no
difference in mean age, body mass index,
undergoing CABG. They increase morbidity
because of post-operative haemodynamic
instability, ventricular dysrhythmias and
iatrogenic complications associated with
treatment. Magnesium, like several other
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Y Be s¸ o g˘ ul, B Tünerir, C Özdemir et al.
Benefits of magnesium-flush infusion
TABLE 2:
Intra- and post-operative data for the magnesium and control groups showing the
effectiveness of the treatment
Magnesium group
Control group
Variable
(n = 50)
(n = 50)
P-value
< 0.05
< 0.05
< 0.05
< 0.05
NS
Spontaneous resumption of a
cardiac rhythm
42 (84%)
0.32 ± 0.6
2.6 ± 0.7
1 (2%)
2 (4%)
0
14 (28%)
1.4 ± 0.8
17.4 ± 2.5
14 (28%)
3 (6%)
Number of shocks for defibrillation
per patient
Mean energy required for
defibrillation (J)
Post-cardiopulmonary bypass
ventricular tachyarrhythmias
Post-cardiopulmonary bypass atrial
fibrillation
Post-cardiopulmonary bypass
temporary pacing
1 (2%)
NS
Post-cardiopulmonary bypass
inotropic usage
29 (58%)
3 (6%)
32 (64%)
4 (8%)
NS
NS
NS
Intra-aortic balloon pump support
Cross-clamp time (min)
40 ± 1.6
44.4 ± 1.1
Post-cardiopulmonary bypass
myocardial infarction
0
0
NS
NS
NS
NS
NS
NS
Total blood loss (mean) (ml)
Re-operation for bleeding
Intubation time (h)
850 ± 530
0
926 ± 480
1 (2%)
9.9 ± 4.4
1.3 ± 0.7
7.9 ± 2.6
10.8 ± 2.3
1.4 ± 0.6
8.0 ± 3.2
Intensive care unit stay (days)
Hospital stay (days)
Serum magnesium levels after
operation (mg/dl)
2.4 ± 0.4
2.5 ± 0.3
1.9 ± 0.7
2.0 ± 0.6
NS
NS
Serum magnesium levels 24 h after
operation (mg/dl)
Data are presented as number of observations with percentages in parentheses, or as mean ± SD.
NS, not significant.
pharmacological agents such as amiodarone
and sotalol, has been administered after
surgery for prophylaxis and treatment of
cardiac arrhythmias.9 Administration of
magnesium was shown to be beneficial in
both animal and human models of
ischaemic-reperfusion injury.17,18 The effect
that magnesium in chrystalloid cardioplegic
solutions has on post-operative arrhythmias
has predominantly been studied experi-
mentally and clinically in ischaemic-
reperfused hearts.13,19,20
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Y Be s¸ o g˘ ul, B Tünerir, C Özdemir et al.
Benefits of magnesium-flush infusion
Hypomagnesaemia is common after
associated with derangements in coronary
vasomotor tone and contractility after
ischaemic cardioplegic infusion. Caputo
cardiac surgery, with an incidence of 70%
after CPB.20 Togashi et al.21 showed that
magnesium was transferred from the intra-
to the extracelluar compartment during and
after CPB. Hypomagnesaemia impairs
release of nitric oxide from the coronary
endothelium,22 whereas magnesium admin-
istration transiently increases release of
nitric oxide.23 Changes in magnesium levels
3
et al. demonstrated that supplementation of
blood cardioplegia with magnesium
prevented the metabolic derangements after
ischaemia and reduced the reperfusion
injury seen in the hearts of patients
undergoing CABG. The best method of
administration of magnesium has not
previously been determined, however, and
the dose and timing of magnesium
prophylaxis require clarification.
have
profound
effects
on
cellular
metabolism and bioenergetics: metabolic
pathways, mitochondrial ion transports,
calcium channel activities in the cell
One clinical trial suggested that
magnesium supplementation of intermittent
cold blood cardioplegia reduced the
incidence of ventricular tachyarrhythmias
but not the incidence of post-operative atrial
fibrillation.29 Yeatman et al.5 reported that
when magnesium was added to warm blood
cardioplegia during the ischaemic period of
CPB, there was a lower incidence of intra-
operative and post-operative arrhythmias in
patients undergoing urgent CABG for
unstable angina. In contrast, Hecker et al.30
reported that infusion of 0.25 – 0.375 mEq/kg
magnesium before CPB did not affect
membrane
and
reactions
requiring
adenosine triphosphate are all modified by
changes in magnesium concentration.24 It
has also been demonstrated that serum
magnesium concentration does not correlate
with myocardial magnesium, and myo-
cardial magnesium concentration was found
to be lower in patients with post-operative
arrhythmia than in those without.25
The
pathogenesis
and
underlying
mechanism of post-operative arrhythmias is
not completely understood, and our limited
knowledge has precluded development of
specific therapies to prevent their occurrence. A
variety of strategies have been proposed for
pharmacological26 and non-pharmacological
therapies.27 There are two goals of
pharmacological therapy: control of the heart
rate; and conversion to a sinus rhythm.
spontaneous resumption of
a
cardiac
rhythm. Caspi et al.,15 however, showed
that peri-operative administration of
magnesium contributed to better myocardial
recovery,
and
fewer
post-operative
These
ventricular
tachyarrhythmias.
The mechanism by which magnesium
reduces myocardial irritability and tachy-
arrhythmias is unknown. The cardio-
protective effects of magnesium during
ischaemia-reperfusion injury are mainly
thought to arise from blocking of L-type
calcium channels. This limits the influx of
intracellular calcium that occurs during
hyperkalaemic arrest and subsequent
reperfusion.28 Intracellular calcium accumu-
lation in coronary smooth muscle cells is
conflicting findings may be explained by
differences in: the dose of magnesium;
pre-operative serum magnesium levels; the
methods used; and the timing of magnesium
administration.
The effects of magnesium in cardioplegic
solutions have been extensively studied, but
few have examined the effects of direct flush
infusion of magnesium during the reperfusion
period. The findings of previous investigations
led us to hypothesize that direct flush infusion
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Y Be s¸ o g˘ ul, B Tünerir, C Özdemir et al.
Benefits of magnesium-flush infusion
of magnesium just before the reperfusion
for defibrillation, and ventricular tachy-
arrhythmias. This dosage of magnesium did
not significantly change the serum
magnesium levels during the early post-
operative period. Patients are likely to
benefit from further doses of magnesium,
administered later, and we believe that larger
serial studies are needed to investigate this.
period may be beneficial for early post-
perfusion arrhythmias during CPB surgery.
We have shown that intra-operative direct
flush infusion of magnesium into the aortic
root, just before reperfusion, reduced the
need for internal defibrillation, the number
of shocks for defibrillation, energy required
•
Received for publication 11 December 2002 • Accepted 17 January 2003
Copyright © 2003 Cambridge Medical Publications
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Address for correspondence
Dr Y Be s¸ o g˘ ul
Vi s¸ nelik Mahallesi Keskin Sokak, Tan Apt. No. 11/17, 26000 Eski s¸ ehir, Turkey.
E-mail: btunerir@ogu.edu.tr
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