From the Acute Stroke Unit, University Department of Medicine and
Therapeutics, Western Infirmary, Glasgow, Scotland.
Correspondence to Dr Keith W. Muir, Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, Scotland. E-mail k.r.lees@clinmed.gla.ac.uk or k.muir{at}clinmed.gk.ac.uk
Methods— Within 24 hours of the onset of clinically diagnosed
stroke, patients were randomized to receive placebo or one of three
intravenous MgSO4 infusions: a loading infusion
of 8, 12, or 16 mmol, followed by 65 mmol over 24 hours.
Cardiovascular parameters, serum magnesium
concentrations, and blood glucose concentrations were determined.
Outcome at 30 and 90 days was recorded.
Results—Twenty-five patients were recruited and treated at a mean
time of 20 hours after stroke. No tolerability problems were
identified. No effects of magnesium on heart rate, blood pressure, or
blood glucose were evident. Serum magnesium concentrations rose to
target levels most rapidly in the highest loading infusion group and
were maintained in all groups for at least 24 hours.
Conclusions—MgSO4 infusions that rapidly elevate the
serum magnesium concentration to potentially therapeutic levels are
well tolerated and have no major hemodynamic effects in
patients with acute stroke. The 16-mmol loading infusion achieved
target serum concentrations most rapidly and has been chosen for
further trials.
Previous small clinical trials of MgSO4 in
acute stroke have been undertaken21 22 without
evidence of undesirable neurological or cardiovascular
effects. A large, multicenter international trial of
MgSO4 is now underway. Previous studies have used
dosing schedules based on trials in acute MI or have aimed empirically
to elevate serum magnesium concentration to double that of the
physiological level. Serum concentrations of
1.49 mmol/L and above have been neuroprotective in preclinical
models of focal cerebral ischemia, and the doubling of serum
concentrations is known to be efficacious in the prophylaxis and
treatment of seizures in preeclamptic and eclamptic women and is
therefore a reasonable goal for optimization of dosing in the absence
of any useful clinical markers in small pilot trials. Because doubling
of the serum magnesium concentration was achieved only after 24 hours
of infusion in a previous pilot trial,21 this
study was undertaken to optimize the intravenous infusion
regime for further trials. This study therefore compared three
different loading infusions (given over 15 minutes) with identical
maintenance infusions against placebo. The primary end point
was the doubling of the serum magnesium concentration after the loading
infusion.
All patients presenting within 24 hours of a clinically diagnosed
acute stroke were eligible. Pregnancy, coma, or known renal failure
(serum creatinine concentration of >200 µmol/L)
were exclusions. All patients were examined neurologically at baseline,
and their stroke type was classified according to Oxfordshire Community
Stroke Project criteria.23 Functional outcome
was assessed by the Barthel activities of daily living
score24 and the modified Rankin
index25 26 of disability on days 30 and 90 after
stroke.
Blood pressure and heart rate were performed semiautomatically by
oscillometric recorders (Marquette). Blood was withdrawn from
indwelling venous cannulas for serum magnesium concentrations at
baseline; after the end of the bolus infusion (15 minutes); and at 12,
24, and 48 hours from the start of the maintenance infusion.
The primary end point of the study was serum magnesium concentration,
with the goal being elevation to double baseline levels by the end of
the loading infusion.
Cardiovascular data, serum magnesium concentrations,
and blood glucose were compared by repeated-measures ANOVA with
Scheffé multiple pairwise comparisons. Baseline data were
compared by 1-way ANOVA for parametric variables and
There were no differences in systolic (P=0.86),
diastolic (P=0.70), or mean arterial
pressure (P=0.92) between any groups (Figure 1
Serum magnesium concentration (Figure 3
Baseline blood glucose concentrations and those obtained 24 to 36 hours
later did not differ among groups (Figure 4
No significant differences in outcome were found, regardless of the
method of assessment (Table 3
Although in several animal studies the doses of magnesium have been
sufficiently large to produce profound blockade of neuromuscular
junctions causing apnea,27 30 in many studies the
concentrations known to be achievable in humans have resulted in
significant pharmacological effects. Anticonstrictor effects were seen
at plasma concentrations of 2.4 to 2.7
mmol/L,31 restoration of cerebral blood flow
after permanent MCAO to baseline levels with concentrations of
3.21 mmol/L,6 and reduction of
histological infarct volume in an intraluminal suture
MCAO plus reperfusion model was seen with plasma levels of 1.49
mmol/L.1 Brain and cerebrospinal fluid magnesium
concentrations are raised significantly after intravenous
administration,35 especially when the blood-brain
barrier is compromised by ischemia.36
MgSO4 has been used extensively in clinical
trials in MI and also in preeclampsia/eclampsia. The safety,
tolerability, and familiarity of magnesium in therapeutic settings
offer considerable advantages over many drugs presently in
development.
Support for the rationale of doubling serum magnesium concentration for
therapeutic effects in humans is derived from the use of
MgSO4 for seizure prevention in preeclampsia and
eclampsia.37 38 Previously empirical use of
magnesium salts as both prophylaxis and treatment of eclamptic seizures
has now been supported by two randomized, controlled trials that found
MgSO4 to be superior to both diazepam and
phenytoin for control of established eclamptic
seizures37 and more effective than phenytoin as
seizure prophylaxis in preeclampsia.38 In
preeclampsia, intravenously administered magnesium sulfate
increases cerebrospinal fluid magnesium concentration
significantly.39 Transcranial
Doppler studies show flow velocity changes consistent with
vasodilatation of the maternal and maternal/fetal
circulations40 41 in pregnancy-induced
hypertension and preeclampsia. The doses of MgSO4
typically given are from 5 to 6 g acutely (approximately 20 to
24 mmol). When reported, serum magnesium concentration after such
doses has been approximately 2 to 3 times the
physiological (eg, 2.28
mmol/L39).
LIMIT-242 43 used a regimen of 8 mmol
MgSO4 over 5 minutes followed by 65 mmol
over 24 hours. Mean serum magnesium concentration after
maintenance infusion in LIMIT-2 was 1.55 mmol/L; in a
previous trial in acute stroke using an identical regimen, the maximum
concentration was 1.38 mmol/L after 24 hours. Again, in the
current study, the 8-mmol bolus did not significantly raise serum
magnesium concentrations until 24 hours after the start of infusion.
Both of the other regimens successfully raised the serum concentration,
neither with any significant systemic hemodynamic
effects detectable within the limitations of the study design: the
16-mmol bolus doubled the serum concentration within 15 minutes (to a
mean of 1.67 mmol/L, rising to a mean of 1.91 mmol/L after 24
hours) and appears therefore to be optimal for further trials. All
patients in this group had serum levels above the minimum reported
neuroprotective concentration in the literature, and 5 of 6 had doubled
serum concentrations within 15 minutes. This dosage closely matches
that used in Swedish studies,22 in which 15
mmol infused over 20 minutes followed by 4 mmol/h for up to 5 days
produced serum concentrations of 1.5 to 2.5 mmol/L with no
significant hemodynamic effects.
Adverse events are uncommon with magnesium infusion regimens. The
largest single demonstration of safety and tolerability was
ISIS-4,44 in which 29 011 patients with acute MI
received MgSO4 intravenously as
8 mmol over 15 minutes followed by 72 mmol over 24 hours. The
incidence of both flushing and bradycardia was significantly greater
than among control patients, but in both instances was less than 1%; a
slight excess of significant hypotension, cardiac failure, and
cardiogenic shock was also reported (excess risk between 3 and 12 per
1000 patients, depending on side effect). The ISIS-4 trial was an open,
factorial design, and thus there is the possibility of reporting bias
for adverse events previously associated with magnesium in the
treatment arm; furthermore, a significant proportion of patients given
magnesium also received streptokinase, captopril, or oral nitrates, all
capable of of exaggerating the tendency to hypotension. Although in our
study few cardiovascular recordings were
undertaken, the time points included the those of peak magnesium
concentration (end of loading and maintenance doses), when
maximum hemodynamic effect may be anticipated. The long
time window (24 hours) in this study may disguise an effect on
cardiovascular parameters that occurs only
in the more acute phase of stroke; while this cannot be excluded, the
absence of major excess risk of hypotension in ISIS-4, LIMIT-2, or
trials in preeclampsia, in which patients are likely to be at greater
risk than acute stroke patients of cardiovascular
lability, is of some reassurance. Nevertheless,
cardiovascular effects of magnesium infusion in acute
stroke cannot be excluded by this study.
The therapeutic index of magnesium in pregnancy appears to be large
(probably much more so than for other neuroprotective drugs). Serum
concentrations of 4 to 6 mmol/L are necessary before
symptomatic inhibition of neuromuscular transmission
(clinically manifested as loss of deep tendon reflexes) is encountered,
although caution is necessary in patients with renal impairment whose
magnesium excretion may be diminished.
Some investigators have found neuroprotective effects in rodent
models of cerebral ischemia to be counteracted by a
hyperglycemic effect of magnesium.45 46 This
appears to result from impaired endogenous insulin release
from pancreatic islet cells, and it has been seen especially in rat
models involving intraperitoneal administration of
magnesium chloride. When normoglycemia has been maintained by insulin
infusion, magnesium demonstrates significant neuroprotective effects in
standard paradigms of cerebral ischemia.4
It has been proposed that the hyperglycemic effects may not be seen
with all magnesium salts,1 because different
vascular effects are seen with chloride and sulfate
salts.47 No evidence of hyperglycemia has been
found in human studies to date. Blood glucose levels were unchanged
after magnesium infusions in a previous study21
and were similarly unaffected in this trial. No reports of
hyperglycemia resulting from magnesium have come from ISIS-4 or other
large trials in other indications.
This study was not powered to detect differences in clinical outcome,
and efficacy cannot be inferred from the results. Despite the small
numbers, however, there was a trend toward favorable outcome in
magnesium-treated patients. This is consistent with previous
observations.21
This study confirms that rapid elevation of serum magnesium
concentration to double the physiological level is
well tolerated by patients with acute stroke and that undesirable
cardiovascular or biochemical effects are unlikely with
such a regimen.
Received October 17, 1997;
revision received January 5, 1998;
accepted February 2, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Dose Optimization of Intravenous Magnesium Sulfate After Acute Stroke
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and
Purpose—Parenterally administered
MgSO4 is neuroprotective in standard animal models of focal
cerebral ischemia and in many other paradigms of brain injury.
Previous small clinical trials in stroke patients have explored the
safety and tolerability of different infusion regimens. This study was
undertaken to optimize the regimen for a multicenter trial.
Key Words: clinical trials • randomized controlled trials • neuroprotection • magnesium
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Magnesium is
neuroprotective in many preclinical models of ischemic and
excitotoxic brain injury.1 2 3 4 5 Unlike the great
majority of other neuroprotective agents, there is extensive clinical
experience with magnesium, largely in preeclampsia/eclampsia and MI,
which confirm its safety and tolerability. There are a number of
possible mechanisms by which magnesium may act, including increased
regional cerebral blood flow to ischemic brain
areas,6 nonspecific antagonism of all subtypes of
voltage-sensitive calcium channel,7
noncompetitive blockade of the NMDA subclass of glutamate
receptor,8 9 10 11 12 13 14 glutamate release
inhibition,15 16 17 enhanced recovery of cellular
energy metabolism after
ischemia,18 19 and enhanced mitochondrial
calcium buffering.20
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The study was approved by the local hospital ethics committee.
Written informed consent was obtained from all patients or from their
next of kin. The study was a randomized, double-blind,
placebo-controlled, parallel group study. All infusions were prepared
by the study pharmacist in the hospital sterile pharmacy unit. Patients
were randomized to three regimens of MgSO4 or
identical volumes of placebo (normal saline). The three regimens were
loading infusions of 8, 12, or 16 mmol MgSO4
in 100 mL normal saline given over 15 minutes, with all bolus infusions
followed by 65 mmol MgSO4 in 100 mL normal
saline over 24 hours. Randomization of 6 subjects per group was
planned. 
2 tests for proportions. Outcome assessment
was compared by the Kruskal-Wallis test and by
2 tests (Statistica software, Statsoft
Inc).
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
A total of 25 subjects were recruited. All completed the study
protocol. Numbers and demographic characteristics are detailed in Table 1
. The overall median time-to-treatment
was 19.25 hours. The cause of stroke demonstrated on CT scan was
cerebral infarction in 21 subjects and primary
intracerebral hemorrhage in 2; in 1 case
(clinically posterior circulation stroke) the CT scan was normal.
View this table:
[in a new window]
Table 1. Demography and Stroke Characteristics of Treatment
Groups ). A trend for lower blood pressure in
the highest dosage group at the end of the bolus infusion was not
significant. Heart rate similarly did not differ between groups (Figure 2; P=0.68). Hypotension that
was sufficiently pronounced to be recorded by the investigators as
a medical event (although asymptomatic) was reported in 1
subject who received placebo (Table 2).
View larger version (20K):
[in a new window]
Figure 1. Mean arterial pressure ±SEM with
magnesium infusions.
View larger version (19K):
[in a new window]
Figure 2. Heart rate by group after magnesium infusions.
Error bars represent SEM.
View this table:
[in a new window]
Table 2. Medical Events During Magnesium Study ) was not significantly different
between groups at baseline, but it was significantly elevated by both
bolus and maintenance infusions (P<0.0001).
Multiple between-groups comparisons showed no significant elevation of
magnesium concentration by the lowest dosage group (8+65 mmol)
until 24 hours after initiation of infusion. Both the 12+65-mmol and
16+65-mmol groups caused significant increase in serum magnesium
concentration from 15 minutes to 24 hours after the start of infusion.
Serum concentrations in all groups were not significantly different
from placebo by 48 hours. Serum magnesium >190% of baseline was
achieved by 15 minutes in none of the patients in the placebo and
8-mmol groups, 3 in the 12-mmol group, and 5 of 6 in the 16-mmol group.
Serum concentrations of at least the minimum reported in the literature
to be neuroprotective in preclinical studies (1.49 mmol/L) were
achieved during the course of the infusion in no placebo patients, 5 of
6 patients in the 8-mmol group, 4 of 6 in the 12-mmol group, and all
patients in the 16-mmol group.
View larger version (19K):
[in a new window]
Figure 3. Serum magnesium concentrations by group after
differing loading infusions. Error bars represent SEM. ). No dose related effect was found
(P=0.90, ANOVA). The higher blood glucose in the highest
dosage group was attributable to 1 diabetic individual with elevated
baseline glucose (15 mmol/L) that rose further during treatment.
When data for this individual were excluded, no differences between
groups could be found.
View larger version (11K):
[in a new window]
Figure 4. Blood glucose concentrations by group before (Pre
Infusion) and after (Post Infusion) treatment period
(P=0.90 by ANOVA). ; Figures 5 and 6).
View this table:
[in a new window]
Table 3. Favourable Outcome by Different Criteria
View larger version (34K):
[in a new window]
Figure 5. Graph showing Barthel Index scores at day 30 in
the placebo group and the 8-mmol, 12-mmol, and 16-mmol dosage
groups.
View larger version (27K):
[in a new window]
Figure 6. Graph showing Barthel Index scores at day 90 in
the placebo group and the 8-mmol, 12-mmol, and 16-mmol dosage
groups.
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Significant neuroprotective effects of parenteral magnesium salts
have been shown in several animal models of cerebral ischemia,
including permanent MCAO in the rat,1 4 global
ischemia by four-vessel occlusion in the
rat,27 direct intrastriatal NMDA
injection,3 and focal fluid percussion
injury.5 There are several potential mechanisms
of neuroprotection, which include noncompetitive NMDA receptor
blockade,10 enhanced regional cerebral blood flow
to areas of focal ischemia,6 antagonism
of voltage-gated calcium ion channels,7 and more
favorable recovery of cellular energy metabolism after
restoration of perfusion. In addition, magnesium infusions have
improved neurological recovery after MCAO28; have
been neuroprotective in spinal cord
ischemia29 30 and isolated white matter
anoxia2; and have shown potent anticonstrictor
effects against relevant mediators, including endothelin-1,
angiotensin II,31
prostaglandin F2
,
serotonin,32 and excitatory amino
acids.33 Systemic infusion of magnesium reversed
basilar artery vasoconstriction in a rat model of subarachnoid
hemorrhage.34
Selected Abbreviations and Acronyms
ISIS-4
=
Fourth International Study of Infarct Survival
LIMIT-2
=
Second Leicester Intravenous Magnesium Intervention Trial
MCAO
=
middle cerebral artery occlusion
MI
=
myocardial infarction
NMDA
=
N-methyl-D-aspartate
Acknowledgments
The authors wish to thank Elizabeth Colquhoun for assistance
with the conduction of the study; Dr Richard Spooner of Gartnavel
General Hospital (Glasgow, Scotland) for biochemical analyses;
and Prof J.L. Reid, Dr G.T. McInnes, and Dr P.F. Semple for allowing
the inclusion of their patients in the study.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
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