ARTICLE
Auteur(s) : K Pasternak1, W Dąbrowski2,
T Wyciszczok1, A Korycińska3, J
Dobija1, J Biernacka2, Z
Rzecki2
1Department of General Chemistry
2Department of Anaesthesiology and Intensive Care
3Department of Clinical Immunology
4Feliks Skubiszewski Medical University of Lublin,
Poland
It is well known that magnesium (Mg) is the fourth most common
mineral salt in humans and that it plays a vital role in the
physiology, particularly during stress situations. Hypomagnesemia
is frequent perioperatively and causes considerable morbidity. The
physiological level of Mg in blood serum ranges from 0.8 to
1.2 mmol/lL- 24% combined with proteins, 10% in complexes and
65% in the ionized form; deficiency of Mg in blood may cause many
disorders which often require intensive treatment. Therefore, many
researchers underline the role of normomagnesemia in blood,
especially in patients with myocardial pathology [1, 2]. Myocardium
dysfunctions are mostly associated with abnormal irritability and
conductivity of the stimulus-transmitting system, which on ECG
initially manifests itself as longer P-R and Q-T waves, while at
higher levels of deficiency – as tachycardia, atrial fibrillation,
pre-term ventricular beats and in extreme cases – ventricular
fibrillation. Lower serum Mg concentrations have been found to be
associated with an increased incidence of atrial fibrillation after
cardiac surgery [3]. England et al. [4] underline a beneficial role
of Mg supplementation in reducing ventricular dysrhythmias.
Therefore, this problem is particularly important in patients
subjected to cardiosurgical procedures with extracorporeal
circulation (ECC) [5]. The complex nature of such procedures,
especially intraoperative normovolemic hemodilution (NH) may alter
blood Mg levels, which is likely to result in some degree of stress
adrenergic reaction and dysfunctions of many organs, particularly
postoperatively stunned myocardium. The aim of the study was to
analyze the changes in blood magnesium levels compared to blood
epinephrine and norepinephrine concentrations in patients
undergoing coronary artery bypass procedures with ECC and
normovolemic hemodilution.
Patients and methods
The study was approved by the Bioethical Committee of the Medical
University of Lublin (no KE-0254/244/2000) and included
patients who underwent operations due to I° and II° coronary
disease (according to CCS - Canadian Cardiovascular Society).
In the evening preceding the operation the patients were
administered premedication – oral lorazepam (Lorafen, Polfa, PL) –
2 mg and i.m. Promethiazine (Dophergan, Polfa, Pl) –
50 mg. One hour before anaesthesia all the patients received
oral lorazepam – 3 mg and i.m. morphine (Morphicum
hydrochloricum, Polfa, Pl) – 0.1 mg/kg body weight. The
patients underwent general anaesthesia with fentanyl (Fentanyl,
Polfa, Pl) at the dose of 0.01-0.02 mg/kg body weight.,
midazolam (Dormicum, Roche,)- 0.05-0.1 mg/kg body weight. and
etomidat (Hypnomidat, Janssen, G)-0.1-0.5mg/kg. Muscle relaxation
was obtained by injecting a single dose (0.08-0.1 mg/kg body
weight) of pancuronium (Pavulon, Organon-Teknica, F). The
anaesthesia was maintained throughout the procedure using
midazolam-fentanyl infusion and inhalatory fractionated doses of
foran (Izofluran, Abbot, USA). During the implantation of
aorto-coronary grafts circulation and ventilation were maintained
by a heart-lung machine S III (Stockert). The following substances
were used for priming: Ringer`s solution (Ringer, Fresenius-Kabi,
G) – 1000 mL, 6% solution of hydroxyethylated starch (HAES,
Fresenius-Kabi, G) – 500 mL, 20% mannitol (Mannitol,
Fresenius-Kabi, G) – 250 mL, sodium hydroxycarbonate (Natrium
bicarbonatum, Polfarma Pl) – 20 mL and heparin – 75 mg.
The same composition of priming solution was used for all patients.
Cardioplegia was prepared using 0.9% salt solution supplemented
with 3 g of potassium chloride (Kalium chloratum, Polfa, Pl)
and 20 mL of sodium hydroxycarbonate. The degree of NH induced
by constant volume of priming (1800 mL) was determined on the
basis of hematocrit measurements and body weight. The patients
received supplementation of potassium chloride during surgery.
Depending on NH, the patients were divided into 2 groups: A)
those weighing < 75 kg and B) those weighing > 75 kg.
All the patients consumed their last meal 12 hours before
surgery; immediately after the procedure they were transported to
the Postoperative Intensive Care Unit (PICU) where they received a
short-term infusion of 5% glucose solution with insulin and 3 or
6 g of potassium chloride. None of the patients received Mg
infusion or any β blocker drug during surgery and the postoperative
period.
The blood specimens were obtained in 5 stages: 1) just before
anesthesia after the radial artery cannulation, 2) during NH and
ECC, 3) immediately after surgery, 4) in the morning of the
1st postoperative day, 5) in the morning of the
2nd postoperative day.
The blood samples were collected from the radial artery and
immediately centrifuged (25000 rpm., temp. 0°C); the obtained
serum was frozen at -20°C. The blood Mg concentrations were
determined by spectrophotometric methods. The blood epinephrine and
norepinephrine concentrations were measured by radioimmunoassay
methods.
The results were statistically analyzed using the Wilcoxon,
Mann-Whitney U and Spearman rank correlation tests in interstage
and intergroup comparisons.
Results
The assessments were carried out in 16 men aged 53-70 (61 ± 6.9).
13 patients had myocardial infarction during the past 3 years and
14 were treated due to concomitant arterial hypertension (I° or II°
according to WHO classification). None of the patients was treated
for endocrinological, neurological and other systemic diseases or
was resuscitated because of circulatory arrest. The mean duration
of the procedure was 205 min ± 35 and of anaesthesia
235 min ± 30. In all the patients the aorta was typically
clamped and the mean closure time was 45.1 min ± 15.5. The
aorto - coronary by pass grafts were implanted in mild hypothermia
34.5°C ± 0.4. In all the cases weaning from the heart-lung machine
was uneventful and there was no need of intra-aortic
contrapulsation. Two patients from group A (7 patients) required
dopamine infusions, 3- dobutamine infusions and 2 did not need
catecholamine infusions. In group B (9 patients) two patients
required dopamine infusion, 5 required dobutamine infusion and 2
required no inotropic drugs. In all the cases the postoperative
course was without complications and the patients were extubated in
the morning of the first postoperative day. During the examination
period there were no important dysrythmias or significant ST
changes observed.
The hemodilution at initiation of cardiopulmonary bypass caused
a decrease in hematocrit in both groups, however lower values were
observed in group A. There were significant differences between
group A and B in the 2nd (p < 0.001) and
3th (p < 0.05) stages (table 1( Table 1 )).
The observation of blood epinephrine concentrations showed an
increase in the 2nd stage (in comparison with the
1st stage) only in patients with a body weight lower
than 75 kg (p < 0.05). At the same stage there were significant
differences between groups A and B (p < 0.05), and threefold
blood epinephrine concentrations were noted in patients with a body
weight lower than 75 kg (table 1, ( figure 1 )).
The blood norepinephrine concentrations analysis showed the
highest increase in the morning of first postoperative day in group
A (p < 0.05). These values were significantly higher than those
in group B (table 1, ( figure 2 )).
The blood Mg concentrations decreased in the 2nd
stage (p < 0.01) in group A (table 1, figures 3,4) and
increased in the 4th stage in group B (p < 0.05).
The statistical analysis showed a significant relationship
between blood Mg concentrations in the 1st stage and
norepinephrine in the 2nd stage, Mg in the
2nd stage and norepinephrine in the 3rd stage
(p < 0.05; R = -0.7907 and p < 0.01; R = -0.85714,
respectively) in group A. A significant correlation was detected in
the 1st stage between blood Mg and epinephrine
concentrations (p < 0.05; R = 0.8), and between Mg and
epinephrine in the 2nd and 4th stages (p <
0.01; R = -0.89286).
There were correlations between the blood levels of hematocrit
and epinephrine in the 2nd stage (p < 0.01, R =
0.8829) in group A.
Table 1 Changes of hematocrite, epinephrine,
norepinephrine and magnesium blood concentrations.
|
CHANGES OF PARAMETERS IN CONSECUTIVE STAGES (comparison with first
stage)
|
|
Parameters
|
Stages
|
|
1
|
2
|
3
|
4
|
5
|
|
GROUP A
|
Hematocrit (%)
|
median
|
40.3
|
21**
|
28.9**
|
33.1**
|
37.8
|
|
quartile 1
|
37.3
|
20.15
|
28.55
|
32.85
|
35.75
|
|
quartile 3
|
41.9
|
21.5
|
29.85
|
33.65
|
39.15
|
|
Epinephrine (ng/mL)
|
median
|
0.063
|
0.167*
|
0.098
|
0.117
|
0.085
|
|
quartile 1
|
0.0605
|
0.15
|
0.0545
|
0.082
|
0.0545
|
|
quartile 3
|
0.066
|
0.332
|
0.103
|
0.2035
|
0.117
|
|
Norepinephrine (ng/mL)
|
median
|
0.205
|
0.208
|
0.143
|
0.563*
|
0.44
|
|
quartile 1
|
0.111
|
0.1285
|
0.099
|
0.4835
|
0.2035
|
|
quartile 3
|
0.2195
|
0.449
|
0.252
|
0.8365
|
1.02
|
|
Magnesium (mmol/L)
|
median
|
0.7998
|
0.687*
|
0.978
|
0.8675
|
0.9778
|
|
quartile 1
|
0.786
|
0.6733
|
0.81775
|
0.7815
|
0.8225
|
|
quartile 3
|
1.09935
|
0.9365
|
0.993
|
0.9878
|
0.982
|
|
GROUP B
|
Hematocrit (%)
|
median
|
39.7
|
27.9*
|
30*
|
36.8*
|
39.9
|
|
quartile 1
|
38.1
|
27.5
|
29.4
|
36.4
|
38.6
|
|
quartile 3
|
41.2
|
28.2
|
31.2
|
39.4
|
40.1
|
|
Epinephrine (ng/mL)
|
median
|
0.039
|
0.066
|
0.062
|
0.077*
|
0.071
|
|
quartile 1
|
0.035
|
0.043
|
0.038
|
0.076
|
0.058
|
|
quartile 3
|
0.06
|
0.101
|
0.097
|
0.089
|
0.075
|
|
Norepinephrine (ng/mL)
|
median
|
0.083
|
0.081
|
0.221
|
0.399
|
0.247
|
|
quartile 1
|
0.042
|
0.071
|
0.074
|
0.18
|
0.155
|
|
quartile 3
|
0.128
|
0.091
|
0.268
|
0.644
|
0.515
|
|
Magnesium (mmol/L)
|
median
|
0.7845
|
0.7786
|
0.824
|
0.909*
|
0.967
|
|
quartile 1
|
0.6998
|
0.756
|
0.7643
|
0.798
|
0.8562
|
|
quartile 3
|
0.798
|
0.7998
|
0.8698
|
1
|
1
|
|
INTERGROUP RELATIONSHIPS IN EACH STAGEE
|
|
Hematocrit
|
A:B
|
–
|
p < 0.001
|
p < 0.05
|
–
|
–
|
|
Epinephrine
|
A:B
|
–
|
p < 0.05
|
–
|
–
|
–
|
|
Norepinephrine
|
A:B
|
–
|
p < 0.001
|
–
|
–
|
–
|
|
Magnesium
|
A:B
|
–
|
–
|
–
|
–
|
–
|
Discussion
It is well known that stress situations result in the
catecholamines release. The stress of intubation is associated with
higher blood epinephrine concentration, tachycardia and increased
blood pressure. The catecholamine release from the adrenal medulla
and adrenergic nerve endings is reduced by Mg. Patients treated
with Mg showed a lower increase in heart rate and systolic blood
pressure after intubation [6], and plasma epinephrine and
norepinephrine concentrations are markedly lower in such patients
[7]. It seems that this problem is very important in critically ill
and hemodynamically unstable patients, as increased blood
catecholamine concentrations are undesirable in such cases. Their
increased levels are likely to lead to myocardial ischaemia
manifesting itself in the changes in ST waves on ECG and to
hemodynamic insufficiency [8]. However, it may be thought that
blood concentrations of epinephrine and norepinephrine are also
affected by the depth and kind of anaestheisa used. It is worth
stressing that the high doses of analgesics applied in our study
seem to minimize the effects of operative stress on the adrenergic
reaction [9]. Thus it may be assumed that the increased epinephrine
and norepinephrine levels observed in our study resulted mainly
from the extracorporeal circulation procedure itself. However, it
should be emphasized that high blood concentrations of
catecholamines unfavorably affect the myocardium [10], which is
undoubtedly an undesirable condition in patients operated on for
myocardial organic injury [11]. The above-mentioned disorders may
also be influenced by decreased blood concentrations of Mg, which
are likely to intensify them to a great extent [1, 3, 4, 6]. The
increase in catecholamine concentration and decrease in blood Mg
concentration observed in our study may be thought to have adverse
effects on the myocardium, however an explicit explanation of such
disorders requires further studies.
The increased blood levels of epinephrine and norepinephrine
found in our study seem to confirm the literature findings
concerning extracorporeal circulation procedures [9, 12].
Significant differences in epinephrine concentrations in patients
of both groups in the 3rd stage are worth pointing out.
These changes may result from the dopamine or dobutamine infusions
used [13], yet the relations between the blood epinephrine
concentration and treatment used were not dealt with in this study.
Furthermore, intraoperative NH applied in the study is likely to
cause fluctuations of the above mentioned hormones. According to
Estafanois et al. [17], who studied the effects of normovolemic
hemodilution on blood norepinephrine concentrations in dogs, the
higher the blood dilution, the higher the norepinephrine
concentration. Therefore it may be supposed that higher
norepinephrine concentrations during the deepest hypothermia and
hemodilution in patients with lower body weight may result from
higher hemodilution. It is not easy, however, to explain an
increase in this parameter during the first postoperative day. This
increase is likely to result from the late reaction to higher
hemodilution, which is inconsistent with the findings of others
[14, 15]. Dopamine infusions administered to some patients in the
3rd stage may also be of some importance [13], which
also seems to explain the discrepancies in concentrations of this
parameter in both groups examined. Nevertheless, further
comprehensive studies are needed to explain precisely the causes of
norepinephrine increases in the first postoperative day.
NH also alters the serum Mg levels [16-18]. According to Inoue
et al. [16], intraoperative hemodilution is a major factor
contributing to decreased Mg blood levels. Ichikawa [17] reported
that decreased blood levels of this element was not only the result
of hemodilution but might also be observed in the direct
postoperative period. Polderman and Girbes [5] suggest that the
mechanism responsible for this may be a combination of increased
urinary excretion and intracellular shift, induced by a multi-stage
character of ECC procedures, not only by NH. A decrease in body
temperature during surgery and high urinary magnesium excretion
play the main role in this pathology. Probably tubular dysfunction
of the kidney results in urinary Mg excretion [5] but the effects
of ECC on the kidney function are difficult to assess. Furthermore,
hypomagnesemia during CABG is attributed to NH [19]. Examining the
changes in blood Mg concentrations in cardiosurgical patients,
Satur et al. [19] observed that initiation of NH caused a 17.3%
decrease in serum Mg levels, which persisted until the first
postoperative day. They concluded that the main reasons of Mg
depletion are: the most important – NH and the second one –
intraoperative and postoperative cellular depletions. Likewise,
similar changes of blood Mg concentrations were observed in our
examinations, particularly in patients with body weight lower than
75 kg. The use of mild hypothermia (34.5°C) suggests that the
degree of NH may be a significant factor indicating the level of
hypomagnesiemia. Thus it may be stated that the degree of NH
significantly alters Mg blood levels; however further observations
are needed to determine the above relations in detail.
Analysing the changes in blood Mg levels, the correlations
between Mg decreases and epinephrine and norepinephrine changes are
worth stressing. Studying the effects of Mg infusion on blood
norepinephrine concentration Shimosawa et al. [20] demonstrated,
that Mg ions block N-type Ca+2 channels at nerve endings
inhibiting norepinephrine release and its blood concentration.
Furthermore, the effects on intramyocardial norepinephrine
concentrations are worth stressing. Ohtsuka et al. [21] analyzed
the effects of Mg substitution on levels of the hormone in question
and observed its significantly lower levels in patients with Mg
infusions, which in their opinion, indicates inhibitory effects of
Mg on intracardiac norepinephrine release. In our study, high blood
Mg concentrations correlated with low norepinephrine levels and
decreased blood Mg levels during NH significantly correlated with
increased concentrations of both catecholamines. Therefore our
findings are consistent with the data from the literature [20,
21].
Conclusions
1. Procedures with extracorporeal circulation result in increased
epinephrine and norepinephrine concentrations and decreased Mg
concentrations.
2. Higher hemodilution intensifies adrenergic reactions.
3. Procedures with extracorporeal circulation do not affect
relationships between changes of blood Mg, epinephrine, and
norepinephrine levels.
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