Intravenous Magnesium Sulfate as an

Adjunct in the Treatment of Acute Asthma

Helen Bloch, Robert Silverman, Noel Mancherje, Steven Grant,
Liudvikas Jagminas and Steven M. Scharf

Chest 1995;107;1576-1581
DOI 10.1378/chest.107.6.1576
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1995 by the American College of Chest Physicians
Intravenous Magnesium Sulfate as an
Adjunct in the Treatment of Acute
Asthma*
Helen Bloch, MD; Robert Silverman, MD; Noel Mancherje, MD;
Steven Grant, MD; Liudvikas Jagminas, MD; and
Steven M. Scharf, MD, PhD
Study objective: This study was conducted to determine
whether intravenous magnesium sulfate (MgSO4), when
used as part of a standardized treatment protocol, can
improve pulmonary function and decrease admission
rate in patients presenting to the emergency department
with exacerbations of asthma.
Design: In this randomized double-blind placebo-con-
trolled study, patients with acute asthma were treated
with inhaled fl-agonists at regular intervals and intra-
venous (IV) steroids. At 30 min after entry, patients re-
ceived either 2 g IV MgSO4 or IV placebo. Patients were
monitored for up to 4 h with regular measurements of
pulmonary function. Patients who were discharged
from the emergency department were contacted at 1 day
and 7 days for follow-up.
Setting: Emergency departments of a university-affili-
ated, voluntary hospital and municipal hospital.
Participants: Asthmatics aged 18 to 65 years during
acute exacerbation with FEVy less than 75% predicted
both before and after a single albuterol treatment.
Interventions: Patients were given 2 g of MgSO4 or
placebo as an adjunct to standardized emergency de-
partment procedure for acute asthma.
Measurements and results: One hundred thirty-five pa-
tients were studied. Hospital admission rates were
35.3% for placebo-treated group and 25.4% for the
magnesium-treated group (p=0.21). FEV, measured at
Athma affects approximately 5% of the population
and is a frequent cause of emergency depart-
ment (ED) visits and hospital admissions." 2 Between
19 and 36% of patients who present to the ED with
acute asthma require hospital admission despite
treatment with ,B-agonists, methylxanthines, and cor-
ticosteroids.3-5
It has been suggested that intravenous (IV) mag-
*From the Department of Emergency Medicine and Division of
Pulmonary and Critical Care, Long Island Jewish Medical Cen-
ter, Long Island Campus of the Albert Einstein College of Med-
icine, New Hyde Park, NY,
Supported in part by the Nina Weisman Pulmonary Research
Fund.
Manuscript received June 30, 1994; revision accepted November
16.
Reprint requests: Dr. Bloch, Long Island Jewish Medical Cen-
ter, 270-05 76th Avenue, New Hyde Park, NY 12042
1 576
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1995 by the American College of Chest Physicians
120 min was 56% predicted for the placebo-treated
group and 55% predicted for the magnesium-treated
group. (p=0.92) For subgroup analysis, patients were
divided into "severe" (baseline FEV1 <25% predicted
on presentation) or "moderate" (baseline FEV1, 25 to
75% predicted on presentation). For the severe group,
admission rates were 78.6% (11/14) for the placebo-
treated group and 33.3% (7/21) for the magnesium-
treated group (p=0.009). For the moderate patients, ad-
mission rates were 22.4% (11/49) for the placebo-treated
group and 22.2% (10/25) for the magnesium-treated
group (p=0.98). There was no significant improvement
in FEV, in the moderate group for magnesium-treated
patients. However, in the severe group, there was a sig-
nificant improvement in FEV1 at 120 min and 240 min
(p=0.014 and 0.026, respectively).
Conclusion: Intravenous MgSO4 decreased admission
rate and improved FEV, in patients with acute severe
asthma but did not cause significant improvement in
patients with moderate asthma.
(CHEST 1995; 107:1576-81)
ED=emergency department; FEVI=forced expiratory vol-
ume in 1 s; IV=intravenous; MgSO4=magnesium sulfate
Key words: asthma; emergency department; magnesium;
treatment
nesium sulfate (MgSO4) is a safe and effective adjunct
to the treatment of acute asthma.6 It has been shown
to have a relaxant effect on smooth muscle in vitro.7'8
There have been a number of case reports and
uncontrolled studies indicating its effectiveness in
relieving bronchospasm.9"10 However, recent con-
trolled clinical trials have not agreed on its effica-
cy.11-13
The goal of this placebo-controlled, double-blind,
randomized study was to determine if IV MgSO4 is
effective as an adjunct to a standardized treatment
protocol in patients who present to the ED with an
acute exacerbation of asthma. Primary end points
were admission rate and spirometry results. In addi-
tion, follow-up was obtained at 24 h and 7 days af-
ter discharge.
Clinical Investigations
 Table 1-Baseline Characteristics of All Repeated data were obtained 30 min following baseline mea-
Asthmatics (n=135)* surements. Patients were then randomized to receive either 2 g
of MgSO4 or placebo in 50 mL of normal saline solution IV over
Mg Placebo p Value 20 min. All physicians were blinded to the randomization that was
Sex
done by the pharmacy using computer-generated tables. Patients
M
were monitored for any side effects during the infusion and were
27% (18/67) 29% (20/68) NS
F 73% (49/67) 71% (48/68)
specifically asked about paresthesias, diaphoresis, weakness, or a
Age, yr 36±12.7 38.6±13.2 NS flushed sensation. All patients continued on the standard protocol,
History of intubation 16% (11/67) 9% (6/68) NS
which included obtaining repeated data at 30, 60, 120, and 240
URI past 2 weeks 55% (37/67) 59% (40/68) NS min following baseline, and receiving inhaled albuterol nebulizer
Smoking, past or present 42% (28/67) 50% (34/68) NS treatments at 0, 30, 60, 120, and 180 min. Although patients were
Theophylline use in past 55% (33/60) 48% (28/59) NS encouraged to stay for the full 240-min protocol, they were per-
24 h mitted to leave at 120 min if they demonstrated subjective
Oral steroid use in past 20% (13/65) 17.2% (11/64) NS
improvement and their FEV, was greater than 50% predicted. At
24 h
4 h, all patients were assessed for hospital admission. Guidelines
Inhaled steroids in past 24% (16/67) 21% (14/67) NS for hospital admission included shortness of breath at rest or
24 h
minimal exertion, respiratory rate greater than or equal to 28, or
ED visits past year 2.5 ±4.2 2.2 ± 4.3 NS FEV, less than 50% of predicted.
Hospital admissions past 0.6+ 1.7 0.24+.6 NS The treatment regimen of patients discharged from the hospi-
year
tal was standardized. Discharged patients were instructed to use
Attack duration, h 40.9 ± 36 42.9 ± 36.7 NS inhaled albuterol, two puffs every 4 h. Those given methylpred-
nisolone received prednisone 20 mg twice daily for 1 week. Any
*p<0.05 is considered significant. NS=not significant. Values are patient already taking theophylline or inhaled steroids at the time
expressed as mean ± SD. URI=upper respiratory tract infection. of the ED visit was told to continue his or her usual dose.
All patients discharged from the ED were called at 24 h and
then 1 week later to determine any subsequent ED visits or hos-
METHODS pital admission for asthma.
Patient Selection Data Analysis
Patients aged 18 to 65 years presenting with acute asthma to the We hypothesized that compared with placebo, adjunct therapy
ED of two teaching hospitals (Long Island Jewish Medical Cen- with magnesium would cause greater improvement in pulmonary
ter and Queens Hospital Center), between August 1990 and De- function (FEV1) and decreased hospital admission rate. Data were
cember 1991, were considered for the study. Asthma was defined analyzed using tests for unpaired variables, two-way analysis of
by the criteria set out by the American Thoracic Society.'4 variance, and logistic regression as appropriate. A p value of less
Patients were excluded if they had a history of congestive heart than or equal to 0.05 was taken as significant.
failure, diabetes mellitus, angina, chronic renal insufficiency, Patients were randomized according to a single table. The
temperature >380 C, pneumonia, or if pregnant. Patients re- group were analyzed as a whole and in subgroups. Those with an
quiring intubation, unable to perform spirometry, or unable to initial FEV, below 25% predicted were considered to have "se-
give informed consent were also excluded. Patients in whom the vere" asthma, and those with FEVI 25 to 75% predicted were
forced expired volume in 1 s (FEVI) was greater than or equal to considered to have "moderate" asthma. The division was made
75% predicted, either on ED presentation or after a single prior to unblinding the study. The cutoff of 25% was selected be-
albuterol treatment, were also excluded. All patients were treated cause this group is more frequently associated with hypercapnia
according to the same protocol. and severe obstruction.'7
The primary end points were FEV1 at 2 h after baseline and
Treatment Protocol hospital admission rates. Preinfusion FEV1 percent values were
This study was approved by the Human Subjects Review covaried to determine significant improvement in FEV1. Al-
Committee at both institutions. Baseline data were obtained on though the end points were analyzed separately, they are inter-
presentation, including a brief history and physical examination, dependent in that the hospital admission decision was in part
vital signs, spirometry, and modified Borg Scale ratings for dys- based on the FEVI.
pnea.'5 The latter is a cued, psychometric rating scale from 0 to
10, where 0 represents no dyspnea and 10 represents severe dys- RESULTS
pnea. A spirometer (Spiromate AS 600, Riko; Minato, Japan) was
used to measure FEVI. Following instructions, a minimum of two One hundred forty-nine patients originally were
spirograms was obtained at each datum point and the maximum randomized into the study; however, 135 were
FEV, was recorded. Age, sex, and height-adjusted predicted included in the final statistical analysis. Among the 14
normal values were from Knudsen et al.16 patients who were excluded, 12 were enrolled more
When patients presented in the ED, they received inhaled al- than once, 1 had irreversible airway disease, and 1
buterol treatment (2.5 mg in 2.5 mL normal saline solution by had congestive heart failure. Four patients were in-
high-flow nebulizer). Eligible patients were offered entry into the
study and informed consent was obtained. An IV line was started cluded as an intent to treat analysis because the study
and blood was drawn for complete blood cell count, electrolytes, protocol was violated. Violations include 1 patient
blood urea, nitrogen, creatinine, total magnesium, and theophyl- who received epinephrine, 1 patient who received
line level. Urine pregnancy testing was performed on all women theophylline, 1 patient with subsequent discovery of
of childbearing age. Patients whose initial FEVl was less than 40%
of the predicted value or those who had been receiving oral ste- fever, and 1 patient with subsequent discovery of
roids within the past 6 months were given 125 mg of methyl- pneumonia. In 6 patients, baseline FE1 was un-
prednisolone IV within 30 min of presentation. available because of the patients' inability to coop-
/
2011 107/6 JUNE,
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/ 1995 1577
1995 by the American College of Chest Physicians
 Table 2-Clinical Data (All)* Table 3-Hospital Admission Rates*
Mg Placebo p Value Magnesium Placebo p Value
Theo level, mg/dL 9.0±5.3 7.2 ±5.0 NS All 25.4% (17/67) 35.3% (24/68) NS
Mg level baseline, mg/dL 2.02 ± 0.37 2.09 ± 0.23 NS Severe 33.3% (7/21) 78.6% (11/14) 0.009
Respiratory rate/min Moderate 22.2% (10/45) 22.4% (11/49) NS
Baseline 25.7±6.4 25.8±5.4 NS
120 min 18.9±3.1 20±4.1 NS *p<0.05 is considered significant. NS=not significant.
Wheeze
Baseline 2.63±0.60 2.43±0.63 NS ALL
120 min 1.49±0.73 1.44±0.8 NS
Heart rate/min 80
Baseline 102.6±17.8 101.4±18.0 NS D 70
z -- Magnesium
a ,
> Placebo
120 min 102.5 ± 15.7 99.9 ± 16.3 NS
60
Systolic BP, mm Hg
Baseline 126.1 ± 22.4 133.5 ±22.4 NS
-mI.
a 50
ui
- V
2
A, --- -- -

120 min 122.7± 17.4 126.0± 15.6 NS

Borg Scale £ 40
Baseline 7.3±1.6 7.4±1.9 NS °.. 30
120 min 2.8±1.9 3.0±2.2 NS
> 20 _
*Theophylline (Theo) and magnesium (Mg) levels were drawn at LL
baseline. Clinical data shown at time 0 and 120 min. p<0.05 is 10
considered significant. NS=not significant. Values expressed repre- A
sent mean ± SD. Wheeze is expressed as average ± SD where O=no 0 30 60 120 150 180 210 240
wheezing, 1=end-expiratory wheezing, 2=expiratory wheezing, TIME (MINUTES)
3=inspiratory and expiratory wheezing, 4=poor air movement.
SEVERE
erate. These were included in the analysis as a whole 80
and excluded for subgroup analysis. Of the 12 70 ------ Magnesium
patients enrolled more than once, the first visit was 60 Placebo
used for the analysis.
0-
C) z
50
Patient baseline characteristic for the study popu- Lu
< E
lation as a whole are listed in Table 1. Clinical 40 . T
*
---- ---I
parlameters are listed in Table 2. There were no sig- IL
30
nificant differences between placebo-treated and 20
MgSO4-treated groups. The hospital admission rate 10 *p<0.05
was 35.3% (24/68) in the placebo group and 25.4% f
(17/67) for the MgSO4 group (p=0.21) (see Table 3). 0 30 60 120 150 180 210 240
The FEV1 was 56% predicted at 120 min for the TIME (MINUTES)
placebo group and 55% predicted for the MgSO4
group (p=0.92) (Fig 1).
MODERATE
Severe Group 80 z
LU
Thirty-five patients were classified as severe asth- 70
_ cm
9
matics based on their initial FEV1. There were no ~ 060 -
v-0R
significant differences in baseline characteristics (Ta- a 50
ble 4). Hospital admission rates for the severe asth- Ul
matics were 78.6% (11/4) for the placebo group and C 40
33.3% (7/21) for the MgSO4 group (p=0.009). When 30 _ ------ magnesium
Placebo
FEV1 at baseline and subsequent to study drug > 20 l
administration is covaried, the impact of magnesium IL
10
is statistically significant at 120 min (p=0.014) and --L-
11
240 min (p=0.026) (Fig 1). Of note, the impact re- 0 30 60 120 150 180 210 240
mains statistically significant even though 7 patients TIME (MINUTES)
who presumably were doing well (5 of 7 having re- FIGURE 1. FEV1, percent predicted as a function of time, where
ceived MgSO4) had elected to leave the ED at 120 time 0 is ED arrival and magnesium or placebo is given at 30 min.
min. Albuterol is given at 0, 30, 60, 120, and 180 min; steroids as noted
The impact of response to initial fl-agonist therapy in text. All=all patients; severe=patients with FEV1, less than 25%o
predicted at time 0; and moderate=patients with FEV1, 25 to 75%
as well as smoking history was also evaluated. There predicted at time 0. Results are expressed as mean ± SEM.

1578 Clinical Investigations

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1995 by the American College of Chest Physicians
 Table 4-Baseline Characteristics of Patients with As shown in Figure 1, FEV1 improved by an
Severe Asthma (n=35)* amount not significantly different between the treat-
Mg Placebo p Value ment group at measured points. Hospital admission
rates were also similar, with the placebo group hav-
Sex ing a rate of 22.4% (11/49) as compared with an ad-
M 19% (4/21) 43% (6/14) NS
F 81% (17/21) 57% (8/14) NS mission rate of 22.2% (10/45) for patients treated
Age, yr 34±13.4 42±14 NS with magnesium (p=0.98). There were no significant
History of intubation 10% (2/21) 0% (0/14) NS differences in respiratory rate, heart rate, blood
URI past 2 weeks 43% (9/21) 50% (7/14) NS pressure, severity of wheezing, or modified Borg
Smoking, past or 33% (7/21) 29% (4/14) NS
present
Scale rates between the two groups at 120 min.
Theophylline use in 65% (13/20) 46% (6/13) NS
Follow-up
past 24 h
Oral steroid use in 14% (3/21) 29% (4/14) NS Follow-up at 1 and 7 days following hospital dis-
past 24 h charge was done for 90 of 94 patients. One patient in
Inhaled steroids in 19% (4/21) 21% (3/14) NS
the moderate group was subsequently admitted to
past 24 h
ED visits past year 2.3±2.2 1.1±1.8 NS the hospital at day 2, and 1 patient in the severe group
Hospital admission 0.43±.75 0.07 ±0.27 NS was admitted at day 3. Both of these patients had
past year received magnesium.
Attack duration, h 46.0±38.2 37.0±38.6 NS
*p<0.05 is considered significant. NS=not significant. Values are
Side Effects
expressed as mean ± SD. URIlupper respiratory tract infection. There were no life-threatening side effects noted in
patients who received magnesium. Minor side effects
was no significant effect of these variables on hospi- were noted in 58% of patients who received magne-
tal admission rate and FEV1 in the severe group. sium. These included the sensation of flushing, mild
There were no significant differences in respiratory fatigue, and burning at IV site. One patient receiv-
rate, heart rate, blood pressure, severity of wheezing, ing magnesium experienced transient urticaria in the
or modified Borg Scale rates between the two groups upper extremities.
at 120 min (Table 5).
DISCUSSION
Moderately III Patients
Ninety-four patients were classified as "moderate- This study failed to demonstrate significant bene-
ly ill" based on their initial ED presentation. Of these, fit from the use of 2 g of IV MgSO4 as an adjunct to
49 had received placebo, and 45 had received mag- a standardized treatment protocol for asthma in a
nesium. No significant differences were found be- diverse group of asthmatics. However, it does dem-
tween any baseline variables. onstrate significant improvement in the subgroup of
patients presenting to the ED with severe airway
Table 5-Clinical Data (Severe)* obstruction. Improvement was demonstrated by a
Placebo p Value
decrease in hospital admission rate and an increase in
Mg
FEV1. We did not demonstrate benefit from MgSO4
Theo level, mg/dL 8.9 ±4.5 7.0±7.23 NS in patients with more moderate airway obstruction.
Mg level baseline, ,gg/dL 1.9±0.50 2.2±0.19 NS Previous controlled studies using adjunct therapy
Respiratory rate
Baseline 27±6.8 27±5.4 NS with MgSO4 have yielded conflicting conclusions.
120 min 19.2 ± 2.7 21 ±3.9 NS Skobeloff et a16 found that giving 1.2 g of IV MgSO4
Wheeze to patients in the ED significantly improved peak
Baseline 2.9 ±0.5 2.7 ±0.6 NS flow and decreased admission rates compared to
120 min 1.8 ± 0.9 1.8 ±0.9 NS patients receiving placebo. Green and Rothrock,12
Heart rate BP, mm Hg
Baseline 103 ±18.2 113 ±17.7 NS using 2 g of MgSO4, failed to find any difference. Our
120 min 105 ±17.3 108 ±17.7 NS findings may help to explain this apparent conflict.
Systolic BP, mm Hg The group studied by Skobeloff et a16 represented a
Baseline 131 ± 23 133 ± 27 NS population with more severe asthma as demonstrated
120 min 127±14.1 122±12.5 NS by failure to respond to two A-agonist inhalational
Borg Scale
Baseline 7.6 ±1.7 7.8 ±1.6 NS treatments and an admission rate of 79%, which is
120 min 3.0t±1.7 3.25 ±2.3 NS similar to that of our placebo-treated "severe" group.
*Theophylline (Theo) and magnesium (Mg) levels were drawn at
However, patients studied by Green and Rothrock'2
baseline. Clinical data shown at time 0 and 120 min. p.0.05 is likely represented a group with less severe disease, as
considered significant. NS-not significant. Values expressed as shown by an admission rate of 17% for the placebo
mean ± SD. group, which is similar to our "moderate" placebo-
107/6 / JUNE, 1995 1579
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2011
1995 by the American College of Chest Physicians
treated group. This suggests that in the dosages used
in these studies, MgSO4 may be beneficial only in
patients with severe asthma.
It is not clear why MgSO4 appears to work better
in the group with severe asthma. One possible
explanation is that patients with acute severe asthma
are relatively refractory to d-agonist therapy. There-
fore, if IV MgSO4 improves airway obstruction by a
different mechanism than A-agonists, this effect is less
likely to be evident in the moderate group in whom
the larger response to f-agonists might mask any
additional improvement by IV MgSO4. It is also pos-
sible that the amount of magnesium used in patients
with moderate asthma was not sufficient to offer ad-
ditional benefit. A dose response curve generated in
patients with stable asthma with moderate obstruc-
tion demonstrated maximal bronchodilatation after a
total of 3.45 g of magnesium was given.11
It is not known whether magnesium works via
pharmacologic effects or repletion of body stores.
Regarding pharmacologic effects, several mecha-
nisms have been proposed to explain the potential
beneficial effect of magnesium in asthma. In vitro,
magnesium causes relaxation of bronchial smooth
muscle.8 This may occur by the modulation of
calcium ion movement both within the cell and
through transmembrane calcium channels.18 In ad-
dition, magnesium decreases the amount of neuro-
transmitter released at motor nerve terminals, di-
minishes the depolarizing action of acetylcholine at
the neuromuscular end plate, and depresses excit-
ability of smooth muscle membranes.19 There is some
evidence that prostaglandin and isoproterenol-medi-
ated vascular smooth muscle relaxation may be
magnesium dependent.20 It has been suggested that
MgSO4 may potentiate the effect of d-agonists on
adenyl-cyclase.21 It is also possible that magnesium
can alter the inflammatory process. In vitro, exposing
activated polymorphonuclear cells from adult asth-
matics to magnesium caused a decrease in super-
oxide production.22
It is not known whether magnesium acutely ben-
efits patients by replacing deficient stores of magne-
sium. Although studies have demonstrated normal
serum magnesium levels in patients with acute asth-
ma,23 serum levels may not reflect body stores.24 It is
possible that some of our patients may have had de-
pleted body stores of magnesium since only serum
levels were obtained. In animal studies, chronic
magnesium deficiency leads to an increased synthe-
sis of prostanoids and increased release of hista-
mine.25'26 The effects of hypomagnesemia on the
airway of patients with asthma have not been well
studied. It is known that f-agonist treatment of pa-
tients with acute asthma can decrease serum mag-
nesium levels by 15%.27 However, it is not known
1580
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1995 by the American College of Chest Physicians
whether normalization of serum levels is in part re-
sponsible for the beneficial effect of magnesium.
Magnesium appears to be safe and well tolerated
in the doses used in previous studies to treat acute
asthma (1.2 to 3.0 g).6'9"12"13 In general, only mild
transient reactions were noted. We did note one ur-
ticarial reaction that responded promptly to diphen-
hydramine. In reviewing the literature, we found
only two cases of urticarial reactions, both of which
resolved after the magnesium infusion was discon-
tinued.28
Of the patients reached for telephone follow-up
within 7 days of their ED discharge, 2 required sub-
sequent ED reevaluation. Both of these patients had
received MgSO4 during their ED visit. It is possible
that once the beneficial effect of magnesium wears
off, the patient's condition can worsen despite re-
ceiving oral steroids. This may require further study.
A possible limitation of this study was the method
of dividing patients into severe and moderate groups.
Although the decision to analyze the patients as two
separate groups was made prior to the unblinding,
the study was initially designed to evaluate patients
as a single group, and therefore patients were ran-
domized by a single table. This accounts for the un-
even distribution of patients in the severe group. The
improvement in outcome in the severe group is con-
sistent with other reports but needs to be confirmed
with further study.
CONCLUSION
In summary, our data indicate that when 2 g of
MgSO4 is given as an adjunct to standardized asthma
therapy, there is no improvement in pulmonary
function or admission rates in patients presenting to
the ED. However, when patients with severe asthma
are analyzed separately, there is a significant im-
provement in FEV, and hospital admission rate when
magnesium is received. Thus, confirming these re-
sults in the most severe patients would support the
routine use of MgSO4 in patients with severe acute
asthma. Further studies should address the optimal
dose and infusion rates of IV MgSO4.
ACKNOWLEDGMENTS: We would like to express special con-
sideration to Pamela Arsove, MD, FACEP, for her contribution
in the design and implementation of the study. We would also like
to express our appreciation to Rich Thailer, PA, for computer
work; Bernadette Belcastro and Denise Foti, for secretarial work;
Neal Richmond, MD, and Dawn Williamson, MD, f or patient
recruitment; and Michael Borenstein, PhD, and Ruth Bernstein
Hyman, PhD, for statistical analysis.
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CHEST / 107/6 / JUNE, 1995 1581
 Intravenous Magnesium Sulfate as an Adjunct in the Treatment of
Acute Asthma
Helen Bloch, Robert Silverman, Noel Mancherje, Steven Grant, Liudvikas
Jagminas and Steven M. Scharf
Chest 1995;107; 1576-1581
DOI 10.1378/chest.107.6.1576
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