ARTICLE
Auteur(s) : Wojciech
Dabrowski1, Ziemowit Rzecki1, Małgorzata
Sztanke2, Józef Visconti3, Piotr
Wacinski4, Kazimierz Pasternak2
1Department of Anaesthesiology
and Intensive Therapy, Medical University of Lublin,
Poland
2Department of Medicinal Chemistry, Medical
University of Lublin, Poland
3Department of Histology and Embryology,
Medical University of Lublin, Poland
4Department of Cardiology, Medical University
of Lublin, Poland
Magnesium (Mg) is one of the most important intracellular
cations, which plays a crucial role in many physiological
functions. Its physiological level in blood serum ranges from 0.8
to 1.2 mmol/L - 24% combined with proteins, 10% in complexes and
65% in the ionized form; 60% of Mg is found in bones and 40% in
erythrocytes, muscles, liver and connective tissues [1]. It is well
known that changes in Mg are likely to cause intracellular
disorders, which lead to cell dysfunction. Therefore,
hypomagnesaemia results in multi organ dysfunction, such as cardiac
arrhythmias, neuropsychological disorders, neurosis, paraesthesias,
muscular trembling, vascular cramps, impaired coagulation,
digestive disorders and others [1-3]. There are two kinds of
hypomagnesaemia: a clinically visible and an asymptomatic form. The
former is characterized by specific clinical disorders and occurs
in patients with overall Mg lower than 20% of the normal value.
During asymptomatic hypomagnesaemia, the serum Mg concentrations
are within normal limits yet tissue levels are low. Such disorders
can be diagnosed only by the Mg loading test, which is based on
analysis of differences between Mg supplementation and urine Mg
concentrations. In healthy individuals, the entire dose of Mg
supplementation is excreted in the urine; in asymptomatic
hypomagnesaemia, Mg is partly assimilated by cells [1]. Both types
of hypomagnesaemia may develop in patients undergoing
extracorporeal circulation (ECC) with normovolemic haemodilution
(NH) [1, 2, 4, 5]. Several studies have shown that ECC procedures
decreased serum total Mg concentrations (Mgt) [3-5].
Such disorders may be very important in patients undergoing
coronary artery bypass grafting (CABG), because many intra- and
postoperative pathologies result from hypomagnesaemia. Atrial
fibrillation is one of them [3]. Atrial fibrillation (AF) is a
serious problem in patients after CABG with ECC. Its aetiology has
not been fully explained; however several studies identified a
variety of independent predictors of such arrhythmias [3, 7-9],
including sex, preoperative hypertension, diabetes mellitus,
hypercholesterolemia, previous myocardial infarction, left
ventricular dysfunctions, number of grafts, duration of aortic
crossclamping, duration of ECC. AF episodes occur in 10 to 40% of
such patients and their frequency increases with age. AF
potentially leads to many serious complications such as
thromboembolism in its worst forms – neurological disorders,
haemodynamic disturbances, shock and higher early and late
postoperative mortality [7-10]. Several authors have described
different methods of treatment, most of them underlined the crucial
role of magnesium (Mg) [11-15]. Mg is a promising option for
reducing the incidence of supraventricular arrhythmias,
particularly AF, through multiple mechanisms. Mg plays an essential
role in cell membrane stabilization, modulates the function of
L-type calcium channels, is a cofactor for the activation of many
enzymatic reactions including the turnover of ATP (adenosine
triphosphate) [1, 3]. Moreover, Mg is used for the prevention of
coronary artery spasm, supra- and ventricular arrhythmias,
regulation of the cardiac stimulus-transmitting system and
myocardium contractility. Thus, many authors consider Mg
supplementation the gold standard for prevention of AF [10-13,
15-21]. Most of them have reported beneficial effects of intra- and
postoperative Mg infusions on the incidence of AF, yet did not
compare different forms of such a treatment. Furthermore, there are
no data which demonstrate the preoperative effects of long-term Mg
supplementation on the incidence of AF in the early postoperative
period in patients after ECC. Therefore, the purpose of the present
study was to assess the effect of various forms of magnesium
supplementation on its serum concentrations and on the incidence of
atrial fibrillation in patients after coronary artery bypass
grafting.
Patients and methods
This study was approved by the Committee of Bioethics of the
Medical University of Lublin and informed consent was obtained from
all patients. Patients scheduled for elective CABG due to stable
angina pectoris were examined. The exclusion criteria were:
neurological diseases, any chronic respiratory disease, serious
endocrine diseases, unstable angina pectoris, abdominal surgery
history, chronic renal insufficiency, chronic diarrhea and
EuroScore higher than 8.
Anaesthesia and surgery
One day before surgery all patients received oral lorazepam
(Lorafen, Polfa, Poland) – 2 mg. One hour before anaesthesia
induction all of them received oral lorazepam – 2 mg and
intramuscular morphine hydrochloride (Morphicum hydrochloricum,
Polfa, Warsaw, Poland) – 0.1 mg/kg body wt. with midazolam
(Sopodorm, Polfa, Rzeszow, Poland) – 0.01 mg/kg body wt. The
induction of anaesthesia was performed with fentanyl (Fentanyl,
Polfa, Warsaw, Pl) at the dose of 0.01 - 0.02 mg/kg body wt.,
midazolam: 0.05-0.1 mg/kg body wt. and etomidate (Etomidate, Braun,
Melsungen, Germany): 0.1-0.5 mg/kg. Muscle relaxation was obtained
with single dose (0.08-0.1 mg/kg body wt.) of pancuronium bromide
(Pancuronium, Jelfa, Jelenia Gora, Poland). After tracheal
intubation, mechanical ventilation with a mixture of air and oxygen
(60 and 40%, respectively) was provided. All the patients were
ventilated using intermittent positive pressure ventilation (IPPV)
with the following ventilation parameters: tidal volume
6-7 mL/kg body wt and respiratory rate-9/min. The parameters
were adjusted to maintain normocapnia, controlled by blood gas
analysis. The anaesthesia was maintained throughout the procedure
using the midazolam - fentanyl infusion and inhaled forane
(Isoflurane, Baxter, Guyayama, USA) - 0.5-1 vol%. Before ECC,
heparinum sulfuricum (Heparin, Polfa, Warsaw, Poland) was used at
the initial dose of 3 mg/kg body wt. Additional doses of 25-50 mg
were used to maintain activated clotting time at the level of at
least 400 s. For ECC, standard cannulation of the ascending
aorta and vena cava inferior through the right atrium was
performed. During ECC, circulation and ventilation were maintained
with the heart - lung machine S III (Stöckert, Munich, Germany).
The priming fluid consisted of: 1000 ml of Ringer’s solution
(Ringer, Baxter, Sabinanico, Spain), 500 ml of a 6% solution of
hydroxyethylated starch (Voluven, Fresenius-Kabi, Kutno, Poland),
250 ml of 20% mannitol (Mannitol, Fresenius-Kabi, Kutno, Poland),
20 mL of sodium hydroxycarbonate (Natrium bicarbonatum,
Polfarma, Stargard Gdanski, Poland) and 75 mg of heparinum
sulfuricum. Cardiopulmonary bypass was instituted with pulsatile
flow of 2.4 L/min/m2 of body surface area (BSA).
After typical aorta clamping, myocardial viability was preserved
with antegrade hyperkalemic blood cardioplegia (6 g of KCl and 2 g
of MgSO4). During ECC, mean arterial pressure,
haematocrit, gasometry parameters, lactate, sodium and potassium
levels were measured.
After the completion of ECC, several patients received an
infusion of dopamine hydrochloride (Dopaminum, Polfa, Warsaw,
Poland) or dobutaminum hydrochloride (Dobutamin, Hexal, Wassenburg,
Germany) in doses adjusted to their clinical condition (3-15
μg/kg/min or 3-9 μg/kg/min, respectively). The effect of heparin
was reversed by an adequate dose of protamini sulfurici (Biomed,
Warsaw, Poland).
After surgery, the patients were transferred to the
Postoperative Intensive Care Unit. All of them were ventilated
using synchronized intermittent mandatory ventilation (SIMV) with
pressure support and evaluated for extubation until the sixth hour
after surgery.
Study protocol and division of patients
The serum Mgt concentrations were determined at five
time points: 1) 10 min before induction of anaesthesia; 2)
10 min after ECC; 3) 10 min after surgery; 4) in the
morning of postoperative day 1; 5) in the morning of postoperative
day 2. All patients received intravenous infusions of
MgSO4 during surgery and the early postoperative period
(during 18 postoperative hours). Moreover, some of them received
preoperative Mg supplementation. Therefore, according to the
different forms of Mg supplementation, the patients were divided
into six groups: A) patients receiving intravenous infusions of
MgSO4 at the dose of 3.33 mg/min; B) patients receiving
preoperative, oral Mg supplementation (OPS-Mg) and intravenous
infusion 3.33 mg/min of MgSO4; C) patients receiving
intravenous infusion of MgSO4 at the dose of 6.66
mg/min; D) patients receiving OPS-Mg and intravenous infusion of
MgSO4 at the dose of 6.66 mg/min; E) patients receiving
MgSO4 infusions at the dose 10 mg/min; F) patients
receiving OPS-Mg and intravenous infusion of MgSO4 at
the dose of 10 mg/min.
According to catecholamine infusions, all patients were divided
into three groups:
– O: patients, who did not receive dopamine or dobutamine
infusions;
– DOP: those receiving dopamine infusions at doses dependent on
their clinical state;
– DOB: those receiving dobutamine infusions at doses dependent
on their clinical state.
After the operation the heart rate was continuously monitored.
AF was diagnosed by 12-lead EKG when there were no P waves before
the QRS complex and an irregular ventricular rate was observed. In
all patients an intravenous infusion of amiodarone hydrochloride
(Cordarone, Sanofi – Winthrop, Ambares, France) or/and electrical
cardioversion were used for AF treatment. None of them received an
extra dose of Mg. The development of AF was analyzed in relation
to:
– changes in serum Mgt concentrations;
– different forms of Mg supplementation;
– catecholamine infusions.
The blood was sampled from the radial artery and immediately
centrifuged (2500 r/min); the obtained serum was frozen at -20°C;
the xylidine blue was added for each of refrozen probes. The serum
Mgt concentrations were determined by spectrophotometric
methods with ultraviolet (length of wave – 520 nm;
Spectrophotometer SPECORD M40 – Zeiss, Jena, Germany) [22].
Statistics
Means and standard deviations (SD) were calculated. The value at
time point 1 was regarded as baseline. The incidence of AF was
measured as a percentage of patients affected. Categorical
variables were compared using the χ2 and Fisher exact
test, χ2 with Yates’ correction were applicable. The
Student’s unpaired t-test was used for variables with normal
distribution. For variables with non-normal distribution the
Wilcoxon signed-rank, U-Mann-Whitney test, Kruskal-Wallis ANOVA
tests and post hoc Dunnett’s multiple comparison test were used.
Additionally, the Spearman’s rank correlation tests were used for
inter-point and overall comparisons. p < 0.05 was considered
significant.
Results
From January 2004 to December 2007 120 adult patients (41 women and
79 men) aged 42 to 80 (mean 65 ± 8) undergoing CABG with NH due to
I°, II° or III° coronary disease (according to CCS - Canadian
Cardiovascular Society) were examined. Firstly, patients were
divided into those receiving preoperative Mg supplementation and
those without preoperative Mg supplementation. Next, all patients
were randomized into groups receiving intravenous infusion of
MgSO4 at the doses: 3.33 mg/min, 6.66 mg/min or 10
mg/min, respectively. Thus, six examination groups were created. In
all patients, the mean time of anaesthesia was 260 min ±
35.23, of surgery - 203 min ± 28.7, ECC – 118 min ± 30.45 and
of aorta clamping 63 min ± 21.31. ECC was performed in mild
hypothermia (34.45°C ± 0.9). The mean BMI was 26.16
kg/m2 ± 3.83 (table 1). The
mean artery pressure was between 45 and 100 mmHg during ECC. Ninety
two of patients had had myocardial infarction during the past 3
years and 103 were treated due to concomitant arterial hypertension
(I° or II° according to WHO classification) (table 1). None of the patients was treated for
endocrinological, neurological and other systemic disease nor was
resuscitated because of circulatory arrest. Before surgery, 109 of
patients took β-blockers, 11 – Ca+2 blockers and 59
diuretic drugs (table 1). Forty one
patients took Asmag (24 mg Mg), 17 took Aspimag (21 mg Mg) and 2 –
Magne B6 (48 mg Mg) (Aspimag, Asmag and MgB6
were produced by Farmapol, Poznan, Poland) (table 1).
In all cases, the disconnection of the heart-lung machine was
uneventful and intra-aortal counterpulsation was not necessary.
None of the patients required intensive fluid therapy and possible
insufficiency of intravascular fluids in the early postoperative
period was supplemented with gelatine preparations or crystalloids
– with haemodynamic and haematologic parameters monitored.
In all, the mean serum Mgt concentrations were within
normal limits at consecutive time points: -0.93 mmol/L ± 0.2; -0.83
mmol/L ± 0.21; -0.88 mmol/L ± 0.2; -0.96 mmol/L ± 0.17; and -0.96
mmol/L ± 0.14, respectively). Importantly, ECC resulted in a
significant decrease in Mgt and the lowest values were
noted at point 2 and 3 (figure 1). In group A, ECC
resulted in a decrease in Mgt from point 2 to 5 and the
lowest value was noted immediately after ECC. In group B,
Mgt decreased at point 2, 3 and 4 whereas in groups C
and D at point 2 and 3. Interestingly, Mgt increased
from point 2 to 5 in group E, and from point 2 to 5 in group F
(table 2).
The baseline values of Mgt were similar in groups A,
C and E. There were no differences in Mgt in groups B, D
and F at individual time points. However, serum Mgt
concentrations were significantly higher in preoperative
supplementation groups (table 3).
According to catecholamine infusion, the mean serum
Mgt concentrations were similar in groups O, DOP and DOB
at point 1 (0.91 mmol/L ± 0.13; 0.98 mmol/L ± 0.16; 0.86 mmol/L ±
0.19; respectively). In all groups, Mgt decreased at
points 2 and 3; the lowest values were noted in the DOP group (figure 2). Moreover,
there were significant differences in Mgt in groups DOB
and DOP at point 3 (table 4).
Atrial fibrillation was noted in 33 patients (27.5%). In groups
A and B, AF occurred in 9 patients (45%). In groups C, D, E
and F AF was noted in 5 (25%), 4 (20%), 4 (20%) and 2 (10%)
patients, respectively (figure 3). Atrial
fibrillation was observed in 15 patients, who received preoperative
Mg supplementation (45.5%), and in 18 patients, who did not take
preoperative Mg (54.5%). There were no significant differences
between these groups (χ2 = 0.38, p = 0.5397,
χ2 with Yates correction = 0.17 for p = 0.6826).
Moreover, AF was noted in 12 patients in group DOP (36.36%), in 13
patients (39.39%) in group DOB and in 8 patients (24.24%) in group
O.
Patients with AF had a significantly lower serum Mgt
concentration just after ECC and surgery (figure 4, table 5). There were no differences between groups
O, DOP and DOB. In patients with AF, who received preoperative Mg
supplementation, serum Mgt concentration was
significantly higher at time points 1, 4 and 5 (table 5).
Table 1 Demographic data and preoperative treatment of
studied patients.
|
Parameters
|
Values
|
Groups of patients
|
|
All patients
|
A
|
B
|
C
|
D
|
E
|
F
|
|
Age (years)
|
Mean
|
66
|
67
|
63
|
67
|
65
|
66
|
66
|
|
SD
|
7.24
|
6.94
|
7.07
|
7.13
|
9.03
|
6.19
|
5.63
|
|
Duration of:
|
Anaesthesia (min)
|
Mean
|
260
|
262.5
|
262
|
239
|
284
|
258
|
250.5
|
|
SD
|
35.23
|
26.24
|
30.91
|
17.29
|
45.86
|
39.69
|
25.39
|
|
Surgery (min)
|
Mean
|
203
|
202
|
194
|
196
|
221
|
201
|
204
|
|
SD
|
28.70
|
19.71
|
16.87
|
24.78
|
40.36
|
32.54
|
22
|
|
ECC (min)
|
Mean
|
118
|
128
|
91
|
129
|
133
|
114
|
112
|
|
SD
|
30.45
|
22.27
|
18.59
|
23
|
37.84
|
29.31
|
24.67
|
|
Aorta clamping (min)
|
Mean
|
63
|
68
|
54
|
64
|
76
|
60
|
58
|
|
SD
|
21.31
|
20.56
|
16.80
|
17.94
|
30.76
|
14.71
|
14.19
|
|
BMI (kg/m2)
|
Mean
|
26.16
|
24.92
|
28.57
|
23.93
|
26.56
|
26.38
|
26.63
|
|
SD
|
3.80
|
3.23
|
3.62
|
3.15
|
3.58
|
2.88
|
4.31
|
|
Temperature (°C)
|
Mean
|
34.45
|
34.83
|
34.64
|
34.66
|
34.02
|
34.3
|
34.24
|
|
SD
|
0.85
|
0.40
|
0.83
|
0.68
|
1.17
|
0.64
|
0.84
|
|
Previous MI
|
92
|
16
|
16
|
15
|
14
|
16
|
15
|
|
Hypertension history
|
103
|
18
|
17
|
17
|
18
|
16
|
17
|
|
EF (%)
|
Mean
|
51.2
|
48.6
|
52.3
|
50.1
|
55.3
|
45.1
|
50.2
|
|
SD
|
7.35
|
8.6
|
6.5
|
7.9
|
8.1
|
5.7
|
7.3
|
|
Patients, who were treated before surgery
|
β-blockers
|
109
|
17
|
18
|
17
|
18
|
20
|
19
|
|
Ca+2 antagonists
|
11
|
3
|
2
|
3
|
2
|
-
|
1
|
|
Diuretics
|
59
|
11
|
9
|
12
|
10
|
9
|
10
|
|
Asmag
|
41
|
15
|
-
|
14
|
-
|
12
|
-
|
|
Aspimag
|
17
|
5
|
-
|
5
|
-
|
7
|
-
|
|
MgB6
|
2
|
0
|
-
|
1
|
-
|
1
|
-
|
Table 2 The median and quartiles of total serum Mg
concentrations according to different forms of Mg supplementation
in studied groups of patients.
|
Changes in serum Mgt concentrations (mmol/L)
|
|
Values
|
Time points
|
|
1
|
2
|
3
|
4
|
5
|
|
Group A
|
Minimum
|
0.73
|
0.42
|
0.45
|
0.52
|
0.67
|
|
Quartile 1
|
0.83
|
0.53
|
0.58
|
0.72
|
0.84
|
|
Median
|
0.89
|
0.67
|
0.73
|
0.82*
|
0.9
|
|
Quartile 3
|
0.94
|
0.73
|
0.79
|
0.89
|
0.96
|
|
Maximum
|
1.01
|
0.85
|
0.85
|
0.97
|
1.32
|
|
Group B
|
Minimum
|
0.83
|
0.36
|
0.47
|
0.62
|
0.86
|
|
Quartile 1
|
0.93
|
0.64
|
0.65
|
0.82
|
0.91
|
|
Median
|
1
|
0.73
|
0.73
|
0.91*
|
0.97
|
|
Quartile 3
|
1.05
|
0.93
|
0.89
|
0.99
|
1
|
|
Maximum
|
1.231
|
1
|
1
|
1.32
|
1.23
|
|
Group C
|
Minimum
|
0.73
|
0.54
|
0.55
|
0.72
|
0.71
|
|
Quartile 1
|
0.84
|
0.64
|
0.64
|
0.82
|
0.89
|
|
Median
|
0.89
|
0.73
|
0.76*
|
0.9
|
0.95
|
|
Quartile 3
|
0.95
|
0.79
|
0.86
|
0.99
|
0.99
|
|
Maximum
|
1.64
|
1.2
|
1.27
|
1.23
|
1.1
|
|
Group D
|
Minimum
|
0.7
|
0.63
|
0.6
|
0.79
|
0.77
|
|
Quartile 1
|
0.89
|
0.74
|
0.80
|
0.88
|
0.89
|
|
Median
|
0.95
|
0.78
|
0.82*
|
0.97
|
0.99
|
|
Quartile 3
|
1.05
|
0.89
|
0.96
|
1.05
|
1.06
|
|
Maximum
|
1.31
|
1.02
|
1.25
|
1.21
|
1.26
|
|
Group E
|
Minimum
|
0.61
|
0.65
|
0.69
|
0.69
|
0.7
|
|
Quartile 1
|
0.65
|
0.75
|
0.72
|
0.73
|
0.73
|
|
Median
|
0.75
|
0.77
|
0.78
|
0.77
|
0.8**
|
|
Quartile 3
|
0.83
|
0.81
|
0.82
|
0.89
|
0.93
|
|
Maximum
|
0.98
|
1.16
|
1.14
|
1
|
1
|
|
Group F
|
Minimum
|
0.89
|
0.7
|
0.67
|
0.82
|
0.76
|
|
Quartile 1
|
0.97
|
0.91
|
0.86
|
0.98
|
1.08
|
|
Median
|
1.03
|
1*
|
1.01*
|
1.07
|
1.17
|
|
Quartile 3
|
1.1
|
1.11
|
1.12
|
1.15
|
1.26
|
|
Maximum
|
1.66
|
1.27
|
1.32
|
1.31
|
1.35
|
Table 3 The intergroup differences in total serum Mg
concentrations according to different forms of Mg supplementation
(p value of Mann-Whitney U test).
|
Intergroup differences in total serum Mg concentrations
|
|
Groups
|
Time points
|
Groups
|
|
A
|
B
|
C
|
D
|
E
|
F
|
|
p = 0.0000
|
p = 0.7994
|
p = 0.0001
|
p = 0.0524
|
p = 0.0000
|
1
|
A
|
|
p = 0.0965
|
p = 0.1207
|
p = 0.0004
|
p = 0.0003
|
p = 0.0000
|
2
|
|
p = 0.3407
|
p = 0.1917
|
p = 0.0000
|
p = 0.0375
|
p = 0.0000
|
3
|
|
p = 0.0121
|
p = 0.0079
|
p = 0.0001
|
p = 0.9680
|
p = 0.0000
|
4
|
|
p = 0.0210
|
p = 0.2422
|
p = 0.0375
|
p = 0.0965
|
p = 0.0000
|
5
|
|
p = 0.0038
|
p = 0.1492
|
p = 0.0000
|
p = 0.3140
|
1
|
B
|
|
p = 0.6204
|
p = 0.3407
|
p = 0.3688
|
p = 0.0001
|
2
|
|
p = 0.9466
|
p = 0.0121
|
p = 0.3272
|
p = 0.0006
|
3
|
|
p = 1.0106
|
p = 0.1738
|
p = 0.0195
|
p = 0.0029
|
4
|
|
p = 0.4290
|
p = 0.6395
|
p = 0.0004
|
p = 0.0001
|
5
|
|
p = 0.1417
|
p = 0.0000
|
p = 0.0001
|
1
|
C
|
|
p = 0.0634
|
p = 0.0762
|
p = 0.0000
|
2
|
|
p = 0.0263
|
p = 0.3983
|
p = 0.0006
|
3
|
|
p = 0.1653
|
p = 0.0094
|
p = 0.0008
|
4
|
|
p = 0.1826
|
p = 0.0131
|
p = 0.0000
|
5
|
|
p = 0.0000
|
p = 0.0142
|
1
|
D
|
|
p = 0.8830
|
p = 0.0001
|
2
|
|
p = 0.0195
|
p = 0.0244
|
3
|
|
p = 0.0002
|
p = 0.0210
|
4
|
|
p = 0.0029
|
p = 0.0011
|
5
|
|
p = 0.0000
|
1
|
E
|
|
p = 0.0002
|
2
|
|
p = 0.0015
|
3
|
|
p = 0.0000
|
4
|
|
p = 0.0000
|
5
|
|
1
|
F
|
|
2
|
|
3
|
|
4
|
|
5
|
Table 4 The p values of differences in total serum Mg
concentrations between patients, who did not received catecholamine
infusion, who received dopamine infusion and who received
dobutamine infusion.
|
Intergroup differences in total serum Mg concentrations (p
value)
|
|
Time points
|
O: DOP
|
O: DOB
|
DOP: DOB
|
|
1
|
p = 0.0645
|
p = 0.8515
|
p = 0.0852
|
|
2
|
p = 0.4978
|
p = 0.7202
|
p = 0.2355
|
|
3
|
p = 0.2109
|
p = 0.2177
|
p = 0.0118
|
|
4
|
p = 0.1988
|
p = 0.8134
|
p = 0.0766
|
|
5
|
p = 0.0936
|
p = 0.3787
|
p = 0.2497
|
Table 5 The p value of differences in total serum Mg
concentrations between groups: O, DOP and DOB (Mann – Whitney
U-test). Patients with atrial fibrillation (p value for
Mann-Whitney U test).
|
The differences in serum Mgt concentration according
to cathecholamine infusion. Patients with AF (p value)
|
|
Groups
|
Number of patients
|
Time points
|
|
1
|
2
|
3
|
4
|
5
|
|
DOB: DOP
|
13: 12
|
0.1860
|
0.8100
|
0.1095
|
0.0768
|
0.0678
|
|
O: DOP
|
8: 12
|
0.2082
|
0.9101
|
0.4726
|
0.4726
|
0.2082
|
|
O: DOB
|
8: 13
|
0.8596
|
0.5002
|
0.2381
|
0.4136
|
0.5466
|
|
OPS: without OPS
|
18: 15
|
0.0223
|
0.0793
|
0.4006
|
0.0477
|
0.0674
|
Discussion
The efficiency of Mg supplementation has been studied for the last
three decades. However, the dose of Mg infused has been not fully
defined in these studies. Our study is the first one to define
precisely the beneficial dose of Mg infused in patients undergoing
CABG with ECC. Additionally, the beneficial effect of preoperative
Mg supplementation was evaluated. We showed that the serum
Mgt concentrations were significantly higher in all
patients who took preoperative Mg compared to patients without
preoperative Mg supplementation. Moreover, Mg infusion at a dose of
3.33 mg/min had little effect for the prevention of postoperative
AF and the infusion of 10 mg/min of MgSO4 maintained the
level of Mgt during CABG and most effectively reduced
AF. Interestingly, dopamine infusion significantly reduced serum Mg
concentrations in comparison to dobutamine infusion.
Changes in serum Mg concentrations in patients undergoing ECC
have also been previously discussed [3-6, 20]. Three mechanisms of
hypomagnesaemia were implicated: 1st – NH during ECC,
2nd – renal loss and 3rd – Mg influx into
intracellular space [23-26]. According to Polderman and Girbes [5],
this pathology resulted from disorders in renal tubule filtration
during ECC with normovolemic haemodilution (NH). Additionally, NH
per se decreased serum Mg concentrations. This finding was
confirmed by Wronska et al. [4], who examined changes in Mg during
cardiac procedures and NH. They showed significantly lower total
serum Mg concentrations in patients with higher blood dilution.
Moreover, changes in serum Mg concentrations depended on the age of
patients and the degree of hypothermia [27, 28]. Therefore, it can
be assumed that Mg disturbances are multifactorial in patients
undergoing ECC.
NH is the most significant cause of hypomagnesaemia.
Interestingly, the priming solution containing an extra dose of Mg
prevents hypomagnesaemia in children during ECC; however, this
method reduces Mg abnormalities only during ECC, because urinary Mg
excretion is significantly higher in such cases during the first 24
postoperative hours [26]. Thus, the continuous infusion of Mg
should be more effective than a single dose. Many authors have
described the intravenous Mg infusion as a good method to correct
hypomagnesaemia [4, 10, 21, 29, 30]. Additionally, some of them
documented the beneficial effects of preoperative Mg
supplementation [18, 21]. According to them, this method
effectively reduced changes in serum Mg concentration. Furthermore,
the frequency of intra- and postoperative cardiac arrhythmias were
significantly lower in such cases [18]. Likewise, in the present
study, the changes in serum Mgt concentrations were
significantly lower in patients with preoperative oral
supplementation. Nevertheless, continuous, intravenous infusions of
Mg are still the best method of supplementation. Various studies
have reported different doses of Mg infusion in patients undergoing
ECC, yet the precise dose which stabilizes serum concentration has
not been defined [4, 6, 8, 17, 18, 24, 31]. The form and dose of Mg
supplementation depend on local standards and clinicians’
experience. In the present study, effects of different doses of Mg
on its serum concentrations were precisely documented. The 10
mg/min of MgSO4 infusion stabilized serum concentration
during ECC and the early postoperative period. Moreover, the
disturbances in serum Mg content were similar in patients receiving
such intravenous doses, irrespective of preoperative
supplementation; however, the preoperative treatment resulted in
significantly higher serum Mgt concentrations. Another
important finding is that the infusion of 3.33 mg/min or 6.66
mg/min of MgSO4 (groups A, B, C and D) resulted in
decreased Mg serum concentrations during ECC. Interestingly, the
lowest serum Mgt concentration was noted during dopamine
infusion. Moreover, changes in Mgt were similar in
patients who did not receive catecholamines and those who received
the dobutamine infusion.
The effect of dopamine or dobutamine has not been documented in
patients undergoing CABG. Kaseno et al [32] demonstrated that the
15-20 μg kg-1 min-1 dopamine infusion
significantly decreased plasma Mg levels in dogs, while dobutamine
did not change its concentration. They speculated that this
pathology resulted from the stimulation of β2 receptors. The
stimulation of β-adrenergic receptors promoted a loss of Mg from
circulation [33, 34]. Such effects were observed during
hypercatecholaminaemia induced by stress [35]. Previously, the
correlation between serum Mgt and catecholamine
concentrations has been shown, however, the effects of dopamine or
dobutamine infusions were not analysed [21, 36]. On the other hand,
it has been documented that serum Mg concentrations did not
correlate with dopamine or dobutamine infusion demand [37].
Therefore, it seems that intra-operative hypomagnesaemia might have
resulted from endogenous hypercatecholaminaemia and dopamine, but
not dobutamine infusion.
It is well known that hypomagnesaemia results in different forms
of cardiac arrhythmias. Atrial fibrillation is one of the most
spectacular events in patients after cardiopulmonary bypass.
Several authors have shown an increased frequency of atrial
fibrillation in patients with hypomagnesaemia [10, 17, 18, 31].
Moreover, most of them documented a strong correlation between such
pathology and serum Mg concentrations. Nevertheless, the cause of
AF after ECC is not clear. The main risk factors include age,
history of AF, severe left ventricular dysfunction, mitral valve
diseases and low serum Mg concentrations. Moreover, massive blood
transfusions, haemodilution, use of diuretics and catecholamine
infusions predispose to AF in the early postoperative period.
Therefore, several studies underlined the beneficial effects of
different forms and doses of Mg supplementation on the incidence of
postoperative AF [7, 10, 11, 13, 16-19, 38-41]. However, most of
them demonstrated only the effect of intra- and postoperative Mg
supplementation on prevention of different postoperative cardiac
arrhythmias. Only four of them (Kaplan et al. [10], Toraman et al.
[17], Dagdelen et al. [38], Forlani et al. [39]) suggested that
preoperative Mg infusions had beneficial effects in AF prevention.
The intravenous infusion of 6 mmol of Mg sulphate for 4 hours one
day before surgery significantly reduced the frequency of AF [17,
39]. This fact implies that preoperative Mg treatment may decrease
the incidence of postoperative cardiac arrhythmias. This is
confirmed by our study. Magnesium stabilized cellular metabolism,
mitochondrial ion transport, calcium channel activity and
bioenergics status, thus preventing abnormal pacemaker activity [2,
42]. Moreover, intracardiac Mg blocks the β-adrenergic stimulation.
On the other hand, the application of drugs which stimulate
β-adrenoreceptors decreases, slowly yet significantly, the myocyte
Mg content [42]. Importantly, high serum Mg concentration
significantly reduces such disorders, which is confirmed by the
present study. The serum Mg concentration was significantly lower
in patients who had episodes of AF in the early postoperative
period. Interestingly, the differences were particularly visible
10 min after ECC and immediately after surgery. Moreover, the
lowest serum Mgt concentration was observed in patients
with AF receiving the dopamine infusion; however, the differences
between groups O, DOP, and DOB were not significant. The infusion
of 10 mg/min of MgSO4 maintained its total serum
concentration at the same level during CABG. Furthermore, the
lowest incidence of AF was noted in patients who received such a
dose of MgSO4. Therefore, it can be assumed that
intraoperative Mg deficiency is one of the main causes of
postoperative AF in patients undergoing CABG.
Although favourable effects of Mg supplementation during ECC
have been discussed, the optimal therapeutic dose for reducing the
frequency of postoperative AF episodes has not been specified.
Fanning et al. [43] reported that the infusion of magnesium
sulphate at the dose of 84 mmol/96 h reduced AF from 28% to
14.3%; however, the decline was not statistically significant.
Similarly, Jensen et al. [44] demonstrated a non-statistical
reduction in AF in patients treated with an infusion of 110 mmol Mg
per 80 h. On the other hand, Speziale et al [40] noted a
complete elimination of AF in patients who received 1g of Mg in
pump priming solution and the infusion of 10 mmol of
MgSO4 for the first 24 postoperative hours. According to
them, this kind of administration kept the serum Mg concentration
at an unchanged level during ECC and in the early postoperative
period. Nurözler et al. [45] demonstrated a significant reduction
in AF (from 20% to 4%) during the infusion of Mg for 5 days (100
mmol/5 days). Some authors showed that the pre-operative Mg
supplementation drastically decreased the incidence of
postoperative AF [17, 18, 38, 39]. According to them, this method
was better than intra- and postoperative treatment. They used
intravenous supplementation, which was not comfortable for patients
and required hospitalization. The present study is the first to
demonstrate the beneficial effects of oral Mg supplementation. Many
patients are treated with acetylsalicylic acid drugs and some of
them are combined with Mg. The preoperative oral Mg supplementation
is easy, inexpensive and does not require hospitalization.
Furthermore, most of patients accept this kind of treatment very
quickly. Previously, significantly higher serum Mgt
concentrations were shown in patients with preoperative oral Mg
administration [21]. The present study demonstrated the lower
occurrence of postoperative AF in patients who received
preoperative oral Mg supplementation. Nonetheless, this effect was
observed only in groups D and F. The infusion of 3.33 mg/min of
MgSO4 did not change the occurrence of AF in the
postoperative period, and the infusion of 10 mg/min of
MgSO4 was just the most effective dose of
intra-operative Mg supplementation.
There are many other methods for prevention of AF. Several
authors have described favourable effects of β-blockers or
amiodarone [15, 39, 41, 46-48]. The efficiency of amiodarone and
β-blockers seems to be similar [47]. There is strong evidence that
prophylactic β-blockers significantly reduce the incidence of AF,
irrespective of the type of cardiac surgery performed [47-49]. The
majority of studies have emphasized the necessity of Mg
supplementation for more effective prevention of AF [11, 15, 19,
39, 47, 49]. In the present study, the preventive effect of
β-blockers was not analyzed. Interestingly, the administration of
such drugs is likely to reduce the intravenous dose of magnesium;
however, this hypothesis requires further research.
Limitation
The strict exclusion criteria were the main limitation of the
present study. None of patients had endocrine diseases, chronic
diarrhoea and other digestive disorders and none of them took
hormonal drugs. The social status and nutritional customs were not
analyzed. The difficulties of patient selection resulted in small
numbers of patients in individual groups. Moreover, it was
difficult to select patients receiving preoperative Mg
supplementation who were not treated for endocrinal, neurological,
respiratory or severe gastrointestinal diseases. Additionally, only
total serum Mg concentrations were examined. Therefore the analyses
of ionized and intracellular Mg require further examination.
Notwithstanding such limitations, we believe that the present study
may be very relevant to cardiac anaesthesiologists and cardiac
surgeons as well as other clinicians.
Finally, in the present study the depressive effect of cardiac
surgery with NH under general anaesthesia was documented.
Additionally, dopamine infusion caused the most severe disturbances
in serum Mgt concentration. The incidence of AF was
related to the degree of hypomagnesaemia. The occurrence of
hypomagnesaemia and AF were significantly lower in patients who
received preoperative, oral Mg supplementation. Nevertheless, this
kind of supplementation was insufficient to prevent postoperative
AF. Therefore, intra- and postoperative Mg infusions were
indispensable for AF prevention. The intravenous infusion of
MgSO4 at the dose of 10 mg/min stabilized the serum
total magnesium concentration, was the best method to reduce the
incidence of AF in the early postoperative period, and should be
used for patients undergoing extracorporeal circulation.
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