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tors, 2 reviewers (BR, JB) independently reviewed literature searches to identify potentially relevant trials for full
review. Searches of bibliographies and texts were conducted to identify additional studies. Second, from the
full text, using specific criteria, 2 reviewers (CB, GB)
independently selected trials for inclusion in this review.
Agreement was measured using statistics.30 Disagreement was resolved by consensus or third-party adjudication (BR).
Assessment of the methodologic quality of included
studies was conducted by 2 reviewers (JB, BR), working
independently; both used 2 different methods of assessment. First, using the assessment of allocation concealment,31 all trials were scored and entered using the following principles:
Grade A: Adequate concealment
Grade B: Uncertain
Grade C: Clearly inadequate concealment
In addition, each study was assessed using a 5-point
scale developed by Jadad et al32 that has been shown to be
valid and reliable. The scale examines issues of randomized, double-blind, withdrawals and dropouts, the methods of double-blinding, and randomization. Interrater
reliability was again measured using statistics.30
Data for the trials were extracted independently by 2
reviewers (BR, JB). Primary study authors were requested
to confirm data extraction and provide additional clarification and information for the review. Unfortunately,
most authors could not access their original data to perform supplemental analyses. In some cases, expansion of
graphic representations of data was used to estimate missing data.
All trials were combined using the Review Manager
(Update Software version 3.0; Update Software, Oxford,
UK). For dichotomous variables, individual statistics
were calculated as odds ratios (OR) with 95% confidence intervals (CIs). Pooling was completed using the
DerSimonian and Laird method33; a random effects model
was used. The DerSimonian and Laird method33 was also
used to estimate the absolute risk reduction and the number needed to treat (NNT).34
For continuous outcomes, individual statistics were
calculated as weighted mean differences (WMD) and 95%
CIs using a random effects model. The use of WMD is
common in many systematic reviews and is the difference
between the experimental and control group outcomes,
when similar units of measure are used.35 The weights
given to each study in the pooled analysis are based on the
inverse of the variance. Heterogeneity among pooled estimates was tested using the DerSimonian and Laird
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method.33 Sensitivity and subgroup analyses were performed to identify sources of heterogeneity when indicated.
Two specific subgroups were planned a priori. One was
to compare adults with children. The other was to compare patients with severe asthma with those with less
severe asthma. Sensitivity analyses were conducted on
fixed versus random effects and methodologic quality
(high versus low).
The debates about heterogeneity and the rationale for
the use of fixed versus random effect models are beyond
the scope of this article. Moreover, there is disagreement
on how to summarize the results of studies, and whether
they should be combined when substantial heterogeneity
is identified. We have adopted the following approach in
this review. First, we alert readers when there is substantial heterogeneity, and encourage cautious interpretation
of the aggregated results. When heterogeneity is visually
or statistically present, the pooled results should be interpreted cautiously. Second, we attempt to explore heterogeneity using subgroup and sensitivity analyses. Third,
we use a random effects model when heterogeneity is present; this provides a more conservative estimation of the
pooled estimate (and the CIs). Finally, we report the pooled
estimate, in an attempt to provide an average measure of
treatment effect.
R E S U LT S
Table 1.
Study and participant characteristics in 7 randomized trials of intravenous magnesium sulfate for acute asthma.
Initial Pulmonary Function
Study
Skobeloff et al38
Green & Rothrock39
Tiffany et al41
Bloch et al40
Silverman et al42
Devi et al36
Ciarallo et al37
Location, Year
US, 1988
US, 1992
US, 1993
US, 1995
US, 1996
India, 1997
US, 1996
Total Sample
38
120
48
135
249
47
31
Age Group
Adults
Adults
Adults
Adults
Adults
Children
Children
Sex
(%F/%M)
PEFR Absolute
(mean) L/min
PEFR % Predicted
(mean)
74:26
77:23
56:44
72:28
52:48
23:77
55:45
150
144
131
NR
NR
NR
155
NR
NR
NR
34*
23*
27
44
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continuous infusion was used. 41 The dosage of intravenous magnesium sulfate delivery varied among
studies; however, all studies used a placebo of similar
appearance. The dose in adults ranged from 1.2 g to 2
g IV and was generally administered over 20 minutes.
Table 2.
Study
Severe subgroup
Bloch et al40 (severe subgroup only)
Ciarallo et al37
Devi et al36
Skobeloff et al38
Silverman et al42
Mild-moderate severity
Bloch et al40 (moderate subgroup only)
Green & Rothrock39
Discordant severity*
Tiffany et al41
Placebo Group
Admission Rate (%)
79
100
94
88
100
24
18
Initial PEFR <200 L/min AND failure to double PEFR after 2 -agonist treatments
29
Discordant severity refers to discordance between authors description of asthma severity and the overall admission rate in the placebo group.
Table 3.
Interventions and outcomes in 7 randomized trials of intravenous magnesium sulfate for acute asthma.
Study
Start of
Magnesium
Sulfate*
Skobeloff et al38
90 min
Magnesium
Sulfate Regimen
1.2-g loading dose over
20 min
2-g loading dose over
20 min
2-g loading dose 2-g/h
infusion
Corticosteroid
Regimen
Reported
Outcomes
Authors
Overall
Conclusion
Jadad
Quality
Score
50 mL saline
solution
No placebo
125 mg IV MP
Admissions, PFTs
Effective
125 mg IV MP
Admissions, PFTs
No effect
Saline solution
loading dose and
infusion
50 mL saline solution
125 mg IV MP
Admissions, PFTs
No effect
Overall: no
effect;
Severe group:
effective
Effective
Effective
Effective
Control Regimen
Tiffany et al41
90 min
Bloch et al40
30 min
Silverman et al42
30 min
50 mL saline solution
Devi et al36
60 min
Ciarallo et al37
After 3 ED
-antagonist
treatments
25-mg/kg loading
dose over 20 min;
no maximum
equi-volume saline
solution
30 mL saline solution
125 mg IV MP if
Admissions, Borg
initial FEV1
Index
40% or oral CS
in the last 6 mo
125 mg IV MP
Admissions, Borg
Index, PFTs
IV or PO corticoAdmissions,
steroids (no dose Pulmonary Index
provided)
score, PFTs
2 mg/kg IV MP
Admissions, PFTs
(75% of patients
in study)
MP, Methylprednisolone; PFTs, pulmonary function test results reported; CS, corticosteroids.
*
In minutes from time of arrival to ED.
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Figure.
This systematic review examined the best available evidence for the use of intravenous magnesium sulfate in
the ED management of acute asthma. Several important
points arise from this meta-analysis. The pooled results
failed to demonstrate statistically significant evidence
of a beneficial effect of magnesium sulfate in terms of
admission rates or pulmonary functions. Although the
drug was well tolerated, the lack of effect argues against
its indiscriminate use in the ED treatment of acute
asthma.
Nevertheless, there is sufficient evidence to support
its use in a subgroup of patients experiencing severe
asthma attacks who appear to respond differently to the
administration of magnesium. Patients who presented
with severe asthma appeared to benefit from the use of
Severe
Skobeloff et al
38
40
Bloch et al
37
Ciarallo et al
36
Devi et al
Pooled effect
Moderate
Bloch et al
40
39
Discordant
Tiffany et al
41
Pooled effect
0.001
0.01
0.1
Favors magnesium
10
Favors placebo
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intravenous magnesium sulfate, both in terms of pulmonary functions and admission rates. The NNT for this
treatment in severe asthma is small (5 patients), further
illustrating its effectiveness.
The clinical significance of the magnitude of the pulmonary function improvement is difficult to determine,
since the minimally clinically important difference for
lung function tests in severe acute asthma have not been
determined. In chronic asthma, an improvement of 12%
predicted has been quoted,12 and for acute studies, some
have suggested an increase in PEFR of as little as 30 L/min
is clinically important.41 The improvement of approximately 10% predicted FEV1 or 50 L/min PEFR demonstrated in this review represents what we believe may be
important improvement in lung function, especially considering the severity at the start of therapy. Moreover,
these lung function improvements correspond with
important reductions in admissions.
In support of these subgroup findings, others have
demonstrated magnesium sulfate to be of benefit in severe
acute asthma. For example, Schiermeyer and Finkelstein43
reported success with rapid magnesium sulfate infusion
in children experiencing severe asthma and impending
respiratory failure. Pabon et al44 reported on the success
of intravenous magnesium sulfate in children who had
not responded to conventional treatment. Finally, high
doses of intravenous magnesium sulfate have been used
to treat ventilated patients to decrease peak airway pressure.45 In summary, the use of magnesium sulfate in
Table 4.
% predicted FEV1
All Studies
WMD (95% CI)
Severe Subgroup*
WMD (95% CI)
+29 L/min
95% CI 3 to 62
n=5 studies
Heterogeneity
P=.05
+4% predicted
95% CI 2 to 11
n=3 studies
Heterogeneity
P=.02
+52 L/min
95% CI 27 to 78
n=3 studies
No heterogeneity
P=.62
+10% predicted
95% CI 4 to 16
n=3 studies
No heterogeneity
P=.11
All heterogeneity testing performed with DerSimonian and Laird method.33 All results are
reported using random effects modeling.
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