ARTICLE
Auteur(s) : George KC
Wong1, Christopher WK Lam3, Mathew TV
Chan2, Tony Gin2, Wai S Poon1
1Division of Neurosurgery
2Department of Anesthesia and Intensive
Care
3Department of Chemical Pathology, The Chinese
University of Hong Kong, China
Spontaneous subarachnoid haemorrhage accounts for only 3-5% of
all strokes but the consequences can be devastating. Most are due
to ruptured intracranial aneurysms. Advances in understanding of
the disease, neuro-intensive care, endovascular treatment and
refinement of microsurgical treatment have all led to improvement
in management outcomes in the last decade. Nevertheless, its
associated complications, such as delayed ischemic neurological
deficit, remain a major cause of morbidity and mortality in this
group of patients. Magnesium is a cerebral vasodilator [1-3] and a
voltage-dependent calcium channel blocker [4, 5]. Furthermore, its
antagonistic action on NMDA receptors in the brain attenuates
glutamate stimulation and decreases calcium influx during ischemic
injury [4-8]. Though results in animal models on cerebral ischemia
have been conflicting [9], initial experimental results in humans
demonstrated its safety and effectiveness as compared to control
data [10-15].
In a study of brain availability of peripheral administered
magnesium sulfate by McKee et al. [16], the authors measured
the passage of intravenously administered Mg2+ into
cerebrospinal fluid in patients with acute brain injury requiring
ventricular drainage. During that experiment, total and ionized
cerebrospinal fluid Mg2+ was maximally increased by 15%
and 11% relative to baseline, respectively, during induced
hypermagnesemia. Lampl et al. [17] studied cerebrospinal fluid
magnesium levels as a prognostic factor in ischemic stroke and the
results demonstrated a decrease in the severity of neurological
deficits, as shown by the Matthew Neurological Score, with higher
cerebrospinal fluid (CSF) Mg2+ levels. However, little
is known about the bioavailability of hypermagnesemic treatment in
aneurysmal subarachnoid haemorrhage patients, especially over an
extended period of time, and its possible site of action in vivo.
One important question is whether elevated plasma magnesium can
result in elevated cerebrospinal fluid magnesium levels in
aneurysmal subarachnoid hemorrhage patients, to a larger magnitude
than in traumatic brain injury. If so, what is the magnitude of
increase? With these questions in mind, we carried out the current
study.
Patients and method
We concurrently recruited 22 IMASH-trial patients between March
2007 and October 2008 into the current study. Approval was obtained
from the local clinical research and ethics committee. Informed
consent was obtained from patients or next of kin as appropriate.
The intravenous magnesium sulfate after aneurysmal subarachnoid
hemorrhage (IMASH) trial was a multi-center double-blinded
randomized controlled clinical trial to study the effect of
magnesium sulfate (MgSO4) infusion in patients after
aneurysmal subarachnoid hemorrhage (SAH). The recruitment was
closed on 31st December 2008 and six month follow-up
results are awaited. The study protocol has been previously
described [13]. All IMASH-trial patients were randomized to either
the MgSO4 infusion group or the control group. For
patients assigned for MgSO4 infusion, MgSO4
20 mmol was administered over 30 minutes; this was followed by a
continuous infusion of magnesium sulfate 80 mmol/day for 10-14
days. Infusion was adjusted so that the plasma magnesium
concentration was raised to approximately twice the baseline value
and < 2.5 mmol/L. Patients in the control group received the
equivalent volume of normal saline.
Patients recruited into the current study had daily blood and
24-hour urine collection for magnesium level measurements. In the
13 patients with external ventricular drains inserted for
hydrocephalus, daily cerebrospinal fluid samples were collected
under aseptic techniques and sent for magnesium level measurements.
Blood and cerebrospinal fluid samples were sent at around 9am daily
and 9am was also the cut-off for daily 24-hour urine
measurement.
Plasma, cerebrospinal fluid and urinary magnesium concentrations
were measured by colorimetry using a dye-binding method on the
Roche D & P Modular Analyzer (Roche Diagnostics GmBH, Mannheim,
Germany). Patient characteristics, clinical and radiological
severity of subarachnoid hemorrhage, as well as biochemical data
were recorded.
All patients were treated according to a standard protocol in
the neurosurgical high dependency unit or intensive care unit if
mechanical ventilation was required. Normotension, defined as
systolic arterial pressure between 120 mmHg and 160 mmHg, was
maintained except during episodes of vasospasm when hemodynamic
therapy was induced. The intracranial aneurysm was either occluded
by endovascular coils or clipped microsurgically. Endovascular
coiling or microsurgical clipping was usually performed within 48
hours after admission. Patients also received nimodipine infusion
0.5 to 2 mg/hr and prophylactic anticonvulsant, sodium valproate
400 mg intravenously every 8 hours, switching to enteral
administration after aneurysm treatment, typically within 96 hours
after ictus.
Statistical analysis
Data were analyzed according to the day(s) of IMASH-study-drug
infusion, comparing the hypermagnesemic treatment group to the
control group using ANOVA. Statistical significances were taken as
p < 0.05 and trends were described for p between 0.10 and 0.05.
Statistical analysis was carried out with SPSS for Windows Version
15.0.
Results
Twenty-two patients were recruited into the current study with
plasma and urine magnesium levels measured. Thirteen (59%) patients
had, in addition, cerebrospinal fluid levels measured. A total
of 304 plasma magnesium samples, 194 cerebrospinal fluid magnesium
samples, and 258 24-hour urine magnesium samples were processed.
Age (mean ± SD) was 58.4 ± 10.2 years. Male to female
ratio was 3:2. WFNS grades on admission were: I in 5 (23%)
patients, II in 7 (32%) patients, III in 2 (9%) patients, and IV in
8 (36%) patients. Aneurysm distribution was: anterior cerebral
artery in 2 (9%) patients, anterior communicating artery in 9 (41%)
patients, internal carotid artery in 4 (18%) patients, middle
cerebral artery in 4 (18%) patients, and vertebrobasilar system in
3 (14%) patients. Embolization was done in 15 (68%) patients and
microsurgical clipping was done in 7 (32%) patients. Fifteen
patients received magnesium sulfate infusion (treatment group) and
7 patients received saline infusion (control group). Thirteen
patients had cerebrospinal fluid samples available, of which 9
patients received magnesium sulfate infusions and 4 patients
received saline infusions. Clinical outcome was not included in the
current report as they will be included in the IMASH report
subsequently.
Data on serum levels are described in table
1. The mean plasma levels of the hypermagnesemic treatment
group ranged from 1.59 mmol/L to 1.84 mmol/L and the mean plasma
levels of control group ranged from 0.85 mmol/L to 1.02 mmol/L.
Throughout the period of the drug infusion study, the
hypermagnesemic treatment group had significantly higher plasma
magnesium levels than the control group, as described in the
protocol.
Data on the cerebrospinal fluid magnesium levels are described
in table 2. Day 1, and day 10-13 were
not included for statistical analysis due to the small number (less
than 10) of patients. Otherwise, from day 2 to day 9, cerebrospinal
fluid levels of magnesium were higher for the hypermagnesemic
treatment group as compared to the control group, with
statistically significant differences reached on day 2, day 5 to
day 8, and trends were observed on day 3, day 4, and day 9. The
mean plasma levels of the hypermagnesemic treatment group ranged
from 1.22 mmol/L to 1.28 mmol/L, and the mean plasma levels of the
control group ranged from 1.09 mmol/L to 1.10 mmol/L, with a
percentage increase ranging from 10.5% to 21.3%.
Data on urinary magnesium levels are described in table 3. 24-hour urine levels of magnesium were
significantly higher for the hypermagnesemic treatment group as
compared to the control group. The mean 24-hour urine levels of the
hypermagnesemic treatment group ranged from 47.9 mmol to 77.3 mmol
and the mean 24-hour urine levels of the control group ranged from
2.7 mmol to 3.5 mmol, suggesting that most of the magnesium sulfate
infused was excreted on the same day.
Table 1 Plasma magnesium levels (mean ± SD, number
of patients with plasma samples).
|
Day of study drug infusion
|
Magnesium group
|
Control group
|
p-value
|
|
1
|
1.59 ± 0.47 mmol/L, 15
|
0.85 ± 0.09 mmol/L, 7
|
< 0.001
|
|
2
|
1.76 ± 0.30 mmol/L, 15
|
0.89 ± 0.09 mmol/L, 7
|
< 0.001
|
|
3
|
1.76 ± 0.29 mmol/L, 15
|
0.89 ± 0.06 mmol/L, 7
|
< 0.001
|
|
4
|
1.70 ± 0.30 mmol/L, 15
|
0.89 ± 0.08 mmol/L, 7
|
< 0.001
|
|
5
|
1.76 ± 0.28 mmol/L, 15
|
0.90 ± 0.07 mmol/L, 7
|
< 0.001
|
|
6
|
1.70 ± 0.16 mmol/L, 15
|
0.90 ± 0.09 mmol/L, 7
|
< 0.001
|
|
7
|
1.72 ± 0.17 mmol/L, 15
|
0.88 ± 0.10 mmol/L, 7
|
< 0.001
|
|
8
|
1.73 ± 0.19 mmol/L, 15
|
0.87 ± 0.10 mmol/L, 7
|
< 0.001
|
|
9
|
1.80 ± 0.29 mmol/L, 15
|
0.88 ± 0.10 mmol/L, 7
|
< 0.001
|
|
10
|
1.79 ± 0.30 mmol/L, 15
|
0.88 ± 0.10 mmol/L, 7
|
< 0.001
|
|
11
|
1.80 ± 0.23 mmol/L, 15
|
0.91 ± 0.06 mmol/L, 7
|
< 0.001
|
|
12
|
1.84 ± 0.20 mmol/L, 15
|
0.91 ± 0.07 mmol/L, 5
|
< 0.001
|
|
13
|
1.80 ± 0.27 mmol/L, 15
|
0.89 ± 0.06 mmol/L, 3
|
< 0.001
|
Table 2 Cerebrospinal fluid magnesium levels (mean
± SD, number of patients with cerebrospinal fluid samples).
|
Day of study drug infusion
|
Magnesium group
|
Control group
|
p-value
|
|
2
|
1.22 ± 0.06 mmol/L, 7
|
1.10 ± 0.05 mmol/L, 4
|
0.013
|
|
3
|
1.27 ± 0.15 mmol/L, 9
|
1.10 ± 0.04 mmol/L, 4
|
0.058
|
|
4
|
1.28 ± 0.18 mmol/L, 9
|
1.09 ± 0.07 mmol/L, 4
|
0.064
|
|
5
|
1.28 ± 0.14 mmol/L, 8
|
1.10 ± 0.03 mmol/L, 4
|
0.029
|
|
6
|
1.27 ± 0.13 mmol/L, 7
|
1.10 ± 0.05 mmol/L, 4
|
0.035
|
|
7
|
1.26 ± 0.10 mmol/L, 7
|
1.05 ± 0.06 mmol/L, 4
|
0.015
|
|
8
|
1.26 ± 0.11 mmol/L, 7
|
1.04 ± 0.07 mmol/L, 4
|
0.007
|
|
9
|
1.25 ± 0.13 mmol/L, 7
|
1.09 ± 0.10 mmol/L, 4
|
0.065
|
Table 3 24-urine magnesium levels (mean ± SD,
number of patients with 24-hour urine samples).
|
Day of study drug infusion
|
Magnesium group
|
Control group
|
p-value
|
|
1
|
48.0 ± 10.5 mmol, 9
|
3.0 ± 3.6 mmol, 7
|
< 0.001
|
|
2
|
58.6 ± 12.6 mmol, 13
|
2.7 ± 1.4 mmol, 7
|
< 0.001
|
|
3
|
61.3 ± 9.6 mmol, 14
|
2.8 ± 1.0 mmol, 7
|
< 0.001
|
|
4
|
60.8 ± 15.5 mmol, 15
|
2.8 ± 0.7 mmol, 6
|
< 0.001
|
|
5
|
66.0 ± 24.5 mmol, 15
|
3.4 ± 1.4 mmol, 7
|
< 0.001
|
|
6
|
67.6 ± 21.7 mmol, 15
|
2.9 ± 1.0 mmol, 7
|
< 0.001
|
|
7
|
68.2 ± 17.3 mmol, 15
|
2.8 ± 1.2 mmol, 7
|
< 0.001
|
|
8
|
69.7 ± 20.3 mmol, 15
|
3.0 ± 1.2 mmol, 7
|
< 0.001
|
|
9
|
69.5 ± 21.0 mmol, 15
|
3.2 ± 1.6 mmol, 7
|
< 0.001
|
|
10
|
77.3 ± 24.6 mmol, 15
|
3.2 ± 1.4 mmol, 6
|
< 0.001
|
|
11
|
74.7 ± 25.0 mmol, 14
|
3.5 ± 1.7 mmol, 3
|
< 0.001
|
|
12
|
75.0 ± 29.0 mmol, 13
|
3.4 ± 1.9 mmol, 3
|
0.001
|
|
13
|
69.2 ± 25.1 mmol, 10
|
2.8 ± 0.4 mmol, 2
|
0.005
|
Discussion
One of the proposed mechanisms for magnesium sulfate infusion to
improve outcome after aneurysmal subarachnoid hemorrhage is through
neuroprotection. In order for this mechanism to be plausible,
magnesium sulfate infusion must permeate through the blood-brain
barrier and be sustained throughout the at risk period.
Mg2+ is actively transported into the cerebrospinal
fluid by an adenosine triphosphate-dependent mechanism in the
choroid plexus. We have shown that hypermagnesemic treatment will
certainly bring an increase in cerebrospinal fluid but the
magnitude was modest. The more important observation was that it
could be sustained for at least nine days. In fact, the 11-21%
increase in cerebrospinal fluid magnesium was at the same magnitude
as in the previous studies of other clinical conditions. Thuraut
et al. [18] reported on 21 patients in whom spinal anesthesia
was used for delivery. Ten patients with preeclampsia with
therapeutic serum magnesium levels made up the study group and 11
term normotensive gravid women served as controls. At the time of
spinal anaesthesia, a 1 mL aliquot of cerebrospinal fluid was
obtained from each patient. Induced hypermagnesemia was
administered by intravenous magnesium sulfate in the following
manner: a 24 mmol loading dose was given over 15 to 20 minutes,
followed by an 8 mmol/hour maintenance dose. Induced
hypermagnesemia in parturients generated cerebrospinal fluid
magnesium levels 15% higher than in untreated patients. Fuchs-Buder
et al. [19] recruited 20 patients undergoing general
anesthesia for neurosurgery and needing cerebrospinal fluid
drainage. In this study, a single intraoperative intravenous bolus
of 60 mg/kg magnesium sulfate increased cerebrospinal fluid
magnesium levels by 19% and led to a significant increase at least
for 90 minutes. McKee et al. [16] investigated 30 patients
with acute brain injury secondary to subarachnoid hemorrhage,
traumatic brain injury, primary intracerebral hemorrhage, subdural
haematoma, brain tumour, central nervous system infection or
ischemic stroke. First, a bolus of 20 mmol magnesium sulfate was
given over 30 minutes. This was immediately followed by adjustment
of the infusion rate to 8 mmol/hour. Induced hypermagnesemia
increased the total cerebrospinal fluid magnesium level by 15%
maximally. Although they also included aneurysmal subarachnoid
hemorrhage patients, the authors acknowledged the hetereogeneity of
their study population to assess the differential effect on
different clinical entities. Moreover, these studies focused on
cerebrospinal fluid magnesium levels within the first 24 hours.
In terms of dosage, it should be noted that our study used a
higher level of hypermagnesemia that most other studies [11, 20].
Given the modest increase in cerebrospinal fluid magnesium in our
study, it is possible that the regimen used in other studies may
not obtain sufficient hypermagnesemia to bring an increase in
cerebrospinal fluid magnesium. Although there was a suggestion that
higher cerebrospinal fluid magnesium levels were associated with
better clinical outcome in ischemic strokes [17], the exact level
required in the human central nervous system remains unknown.
The mean 24-hour urine levels of the hypermagnesemic treatment
group ranged from 47.9 mmol to 77.3 mmol, suggesting most of the
infused magnesium sulfate was excreted on the same day. It
concurred with a previous study in preeclamtic women that 75% of
the infused magnesium was excreted during infusion and 90% within
24 hours [21].
The limitations of the current study included the small sample
size and no clinical outcome data (as a participating centre for a
phase III clinical trial). Nevertheless, this is an important
contribution to elucidate that peripheral magnesium infusion
significantly increases cerebrospinal fluid magnesium for an
extended period of time and that the site of action of peripheral
magnesium infusion may indeed be the central nervous system rather
than on cerebral vasculature.
Conclusion
In patients with aneurysmal subarachnoid hemorrhages, magnesium
sulfate infusion to double the baseline plasma magnesium level
brought an 11% to 21% increase in cerebrospinal fluid magnesium in
a sustained fashion for at least nine days. Whether this mild
elevation in cerebrospinal fluid magnesium levels was adequate for
neuroprotection awaits the results of ongoing clinical trials.
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