Magnesium Sulfate

and Asthma
in the Pediatric Population

Lauren Cantor
Advanced Medical Therapeutics
March 2, 2007
Quic k Ti me™ and a
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Outline:
• Background Information
– Asthma
• Definition, Epidemiology
– Magnesium Sulfate
• Mechanism of action in asthma, History
• Does It Work and What does the
literature say??
– Pros and Cons
• Current Clinical Practice at University of
Michigan and across North America
• Conclusions
Asthma:
• Definition: A chronic inflammatory and bronchospastic
disease with variable airway obstruction that is reversible
spontaneously or with drug treatment (alternative diagnoses
must be excluded)
• Symptoms: cough (day or night; after exercise), wheeze,
shortness of breath, chest tightness, tachypnea, noisy
breathing
– Patient may have history of respiratory tract infections
– Also associated with nasal polyps, rhinitis, atopic
dermatitis
• Triggers and Irritants: cold air, animal dander, dust,
cockroaches, pollens, molds, cigarette smoke, air pollution,
odors, strong emotional expressions, medicines (ASA, Beta
blockers), GERD, infections
Asthma: Increased inflammation and mucous production;
contraction of muscles; airways become hypersensitive

QuickTime™ and a
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are needed to see this picture.

http://www.nhlbi.nih.gov/health/dci/Diseases/Asthma/Asthma_WhatIs.html
 Why is the Pediatric Community
Concerned with ASTHMA?!
• Asthma is the MOST COMMON chronic pediatric disease
• Diagnosed in approximately 9 million children
• Each year, asthma accounts for:
– 10.4 million physician visits
– ***2 million ER visits***
– 200,000 pediatric hospitalizations
– 14 MILLION missed school days in 2002!
• Asthma is expensive… $14 BILLION in 2004
– Direct costs: hospitalizations, ER visits, drug expenses
– Indirect costs: lost time from school and work
2,000,000 visits to the Emergency Room each year…

A Typical ER Protocol:
History, Physical, FEV1 or PEF, O2
Saturation assessments; Start O2

FEV1 or PEF>50%: Impending or actual

Inhaled B2 agonist MDI or FEV1 or PEF<50%: High
respiratory arrest: dose inhaled B2 agonists
nebulizer q20 minutesx3,
INTUBATION and systemic
and systemic
corticosteroids corticosteroids

Admission to PICU
Blake, K. Review of Guidelines and the Literature in the Treatment of Acute Bronchospasm in Asthma.
Pharmacotherapy, 2006; 26:148S-155S.
Even with all of these medications, there are
still 5,000 deaths each year due to asthma,
billions of dollars spent on hospitalizations,
and millions of lost school days…

– Isn’t there anything else we can try??

*Magnesium Sulfate*
Magnesium Sulfate: Rationale
• “Calcium Asthma Hypothesis:” Increases in Ca2+ cause release of
histamine, prostaglandin, and acetylcholine causing smooth muscle
constriction
• Magnesium and Calcium share pumps; Ca2+ is pumped into the cell by
Ca2+ /Mg2+ -dependent ATPase and by voltage- and receptor-gated
channels
• Magnesium is a calcium antagonist; thus, magnesium theoretically has
the ability to counteract the effects of calcium on airways
• Furthermore, Mg2+ is a cation that modulates many other metabolic
processes by itself, including smooth muscle relaxation and
contraction (hypermagnesemia=relaxation;
hypomagnesemia=constriction)
• Magnesium is also hypothesized to inhibit cholinergic transmission,
stimulate nitric oxide and prostacyclin synthesis, and stabilize mast
cells and T-lymphocytes
History of Magnesium and Asthma:
• 1912: Trendelenburg discovered that magnesium
caused bronchodilation in cows
• 1936: Rosello and Pla found magnesium had the same
bronchodilatory property in asthmatic patients
• 1938: Haury published 2 papers: the first stated
that magnesium caused bronchodilation in guinea
pigs; the second showed that half of patients with
asthma exacerbations had low serum magnesium
levels
• 1989: McNamara et al published a case report about
a patient with asthma exacerbation who avoided
intubation and ventilation with MgSO4
What does the literature say?
• The 2007 Cochrane Database lists 2 review articles
summarizing clinical trials using IV magnesium sulfate
in asthma exacerbations
– Rowe et al reviewed a total of 665 patients from 7
randomized controlled trials where patients were
treated with IV MgSO4 vs placebo; 2 trials were
from the pediatric population.
– Blitz et al reviewed 296 patients from 6 randomized
controlled trials in which patients were treated with
MgSO4 alone or in combination with beta-agonists;
2 trials included were from the pediatric population.

Blitz M, Blitz S, Beasely R, Diner B, Hughes R, Knopp J, Rowe B. [Review] Inhaled magnesium sulfate in the treatment of acute
asthma. Chochrane Database Systematic Review, 2007.
Rowe B, Bretzlaff J, Bourdon C, Bota G, Camargo C. [Review] Magnesium sulfate for treating exacerbations of acute asthma in the
emergency department. Cochrane Database of Systematic Reviews, 2007; Issue 1.
Rowe et al’s Analysis:
• Results when ALL studies were analyzed:
– Non-significant improvements in PEFR of patients
who used IV MgSO4 over controls
– Hospital admissions not reduced
• Results of studies including only patients
with SEVERE asthma:
– PEFR improved by 52.3 L/min (95% CI; 27-77.5)
– FEV1 improved by 9.8% predicted (95% CI; 3.8-
15.8)
– Hospital admissions reduced

Rowe B, Bretzlaff J, Bourdon C, Bota G, Camargo C. [Review] Magnesium sulfate for treating exacerbations of acute asthma
in the emergency department. Cochrane Database of Systematic Reviews, 2007; Issue 1.
Blitz et al’s Analysis:
• Results when all studies were
analyzed:
– Significant difference in pulmonary
function between study group (IV
MgSO4 + beta 2 agonist) and control
group (beta 2 agonist alone)
– Hospitalizations similar between study
and control groups

Blitz M, Blitz S, Beasely R, Diner B, Hughes R, Knopp J, Rowe B. [Review] Inhaled magnesium sulfate in the treatment of acute
asthma. Chochrane Database Systematic Review, 2007.
Conclusions from Cochrane:
• Rowe et al’s conclusion: “Current evidence does not
support the routine use… in all patients. Magnesium
sulfate appears to be safe and beneficial in patients
who present with severe acute asthma.”
• Blitz et al’s conclusion: “Nebulized inhaled magnesium
sulfate in addition to beta 2-agonist in the treatment
of an acute asthma exacerbation appears to have
benefits with respect to improved pulmonary function
and there is a trend towards benefit in hospital
admission. The benefit is significantly greater in more
severe asthma exacerbations.”

Blitz M, Blitz S, Beasely R, Diner B, Hughes R, Knopp J, Rowe B. [Review] Inhaled magnesium sulfate in the treatment of acute
asthma. Chochrane Database Systematic Review, 2007.
Rowe B, Bretzlaff J, Bourdon C, Bota G, Camargo C. [Review] Magnesium sulfate for treating exacerbations of acute asthma in the
emergency department. Cochrane Database of Systematic Reviews, 2007; Issue 1.
 Let’s take a closer look at the
pediatric trials…
• In 2004, Manajan et al conducted a prospective, double-blind, randomized
controlled trial
• 62 patients aged 5-17 years old; FEV1 45-75% predicted; no steroids in last
3 days
– Study Group: albuterol 2.5 mg-MgSO4 16 mg neb q30 minutes x3 doses
– Control Group: albuterol 2.5 mg q30 minutes x3 doses
– All patients: prednisolone 2 mg/kg after first dose of study drug
• Main outcome measured: FEV1
• Conclusions: FEV1 significantly improved in albuterol-magnesium group after
10 minutes as compared to albuterol control group (Alb-MgSO4 FEV1=
1.41+0.53 L; Alb FEV1=1.13+0.34 L; p=0.03). No significant difference found
at 20 minutes)

Mahajan P, Haritos D, Rosenberg N, et al. Comparison of nebulized magnesium plus albuterol to nebulized albuterol plus
saline in children with mild to moderate asthma. Journal of Emergency Medicine, 2004; 27: 21-25.
 Another pediatric randomized
controlled trial:
• In 1996, Meral et al investigated the use of magnesium sulfate and
salbutamol sulfate in acute asthma exacerbations
• 20 patients in each arm of the trial
– Study group: 135 mg IV MgSO4 x1, cointervention of albuterol
2.5 mg
– Control group: albuterol 2.5 mg
• Main outcomes measured: respiratory score, peak expiratory flow
rate
• Conclusions: “Treatment of acute asthma using salbutamol sulfate
inhalation was found to be more successful and its effect continued
for six hours”

Meral A, Coker M, Tanac R. Inhalation therapy with magnesium sulfate and salbutamol in bronchial asthma. Turkish Journal
of Pediatrics, 1996; 38: 169-175.
 Should all children receive IV MgSO4…
some say “NO!”
• Rodrigo, in a “Letter to the Editor”, commented on
Blitz’s Cochrane review article pointing out many of its
shortcomings, including:
– Failure to demonstrate reduction in hospitalizations
– Omission of other articles that would have changed
the overall outcomes
– An editing error in one of the tables
• “So, the use of nebulized MgSO4 should not be
considered in the treatment of acute asthma.”

Rodrigo G. There is No Evidence To Support the Use of Aerosolized Magnesium for Acute Asthma. Chest, 2006; 130:
304-306.
MgSO4’s efficacy is still under debate, but
what about its safety profile?

• Kowal et al, in a basic science review of magnesium

sulfate and its physiologic effects, summarize:
– “A single dose of intravenous magnesium sulfate
given to patients with acute asthma exacerbations
has been shown to be safe, but its efficiency is still
being discussed…The safety of magnesium
treatment should be emphasized, as there were no
life-threatening side effects noted in any of the
trials.”

Kowal A, Panaszek B, Barg W, Obojski A. The use of magnesium in bronchial asthma: a new approach to an old problem. Archives of
Immunologic Therapeutics Exp, 2007; 55: 35-39.
 Side Effects of IV Magnesium
Sulfate:
• Burning at the site of infusion, decreased systolic blood pressure,
increased serum magnesium levels 1 hour after infusion, skin flushing,
feeling warm
• If Mg>3 mg/dl:
– CNS depression
• If Mg>5 mg/dl:
– Decreased deep tendon reflexes
– Facial flushing
– Somnolence
• If Mg>12 mg/dl:
– Muscle weakness
– Respiratory depression
– Cardiac conduction abnormalities (complete heart block)
– Hypotension, diarrhea, abdominal cramping
What is done here at
THE MECCA?
QuickTi me™ and a
TIFF ( Uncompressed) decompressor
are needed to see thi s pi ctur e.

• In the University of Michigan’s “Asthma Guidelines for

Clinical Care,” magnesium sulfate is not even mentioned!
• It is used mostly in the ER; but remains a controversial
topic among ER, pulmonology, and critical care
physicians alike
• Dr. Cyril Grum, Professor of Pulmonary and Critical
Care Medicine at The University of Michigan, states:
– “I remain unconvinced that it [MgSO4] substantially
improves our care of the asthmatic patient. We
need to pay more attention to prevention, to
accurately assessing patients with acute asthma and
to aggressively use correct standard therapy in
acute situations.”
What is done in Emergency Departments
across the US and Canada?
• Rowe and Camargo reviewed the use of MgSO4 in EDs across
the US and Canada
• Conclusions:
– 240/9745 ED patients received MgSO4
– Factors influencing use of MgSO4 included: increasing age, previous
intubation, higher initial respiratory rate, lower initial PEF, higher
number of beta-agonists used in the ED, and the use of systemic
corticosteroids.
– 96% of Emergency Departments reported “severity and failure to
respond to initial beta-agonists (87%) as factors prompting their
use of MgSO4”
– Although only 2.5% of cases received MgSO4, it appeared that the
ED physicians were “appropriately restrict[ing] its use to patients
with severe acute asthma.”

Rowe B, Camargo C. The use of magnesium sulfate in acute asthma: Rapid uptake of evidence in North American
emergency departments. The Hournal of Allergy and Clinical Immunology, 2006; 1: 53-58.
Conclusions
• IV MgSO4 and its use in asthma continues
to be a controversial issue
• In severe acute asthma exacerbations in
children, IV magnesium sulfate may be
helpful in addition to or after first-line
agents (beta-2 agonists, corticosteroids)
are initiated
• IV magnesium sulfate is safe as long as
appropriate doses are used and the child is
monitored for side effects
The need for more research:
• Is it truly effective?
• Are there better outcome measurements?
• Is there a dose/response relationship?
• Are there negative trials in the literature
(none were reviewed in the Cochrane
review articles)?
• Is it cost effective if the drug does NOT
reduce hospital admissions?
• Are there any long-term sequela to using
this drug?
Works Cited
Agarwal R, Gupta D. No role for inhaled magnesium sulfate in the treatment of acute
asthma (Letter to the Editor). Pulmonary Pharmacology and Therapeutics, 2005.
Blake K. Review of Guidelines and the Literature in the Treatment of Acute Bronchospasm
in Asthma. Pharmacotherapy, 2006; 26: 148-155.
Blitz M, Blitz S, Beasely R, Diner B, Hughes R, Knopp J, Rowe B. Aerosolized Magnesium
Sulfate for Acute Asthma: A Systematic Review. Chest, 2005; 128: 337-344.
Blitz M, Blitz S, Beasely R, Diner B, Hughes R, Knopp J, Rowe B. [Review] Inhaled
magnesium sulfate in the treatment of acute asthma. Chochrane Database Systematic
Review, 2007.
Ciarallo L, Brousseau D, Reinert S. Higher-Dose Intravenous Magnesium Therapy for
Children With Moderate to Severe Acute Asthma. Archives of Pediatric and
Adolescent Medicine, 2000; 154: 979-983.
Green L, Baldwin J, Brinley J, Freer J, Grum C, Hurwitz M, Johnson C, Song B. Asthma
Guidelines for Clinical Care. University of Michigan Medical Center, 2006.
Kelley P, Arney T. Use of Magnesium Sulfate for Pediatric Patients With Acute Asthma
Exacerbations. Journal of Infusion Nursing, 2005; 28: 329-336.
Kowal A, Panaszek B, Barg W, Obojski A. The use of magnesium in bronchial asthma: a new
approach to an old problem. Archives of Immunologic Therapeutics Exp, 2007; 55: 35-
39.
Works Cited (continued)
Mahajan P, Haritos D, Rosenberg N, et al. Comparison of nebulized magnesium plus
albuterol to nebulized albuterol plus saline in children with mild to moderate asthma.
Journal of Emergency Medicine, 2004; 27: 21-25.
Meral A, Coker M, Tanac R. Inhalation therapy with magnesium sulfate and salbutamol in
bronchial asthma. Turkish Journal of Pediatrics, 1996; 38: 169-175.
Rodrigo G. There is No Evidence To Support the Use of Aerosolized Magnesium for Acute
Asthma. Chest, 2006; 130: 304-306.
Rolla G, Bucca C, Bugiani M, Arossa W, Spinaci S. Reduction of histamine-induced
bronchoconstriction by magnesium in asthmatic subjects. Allergy, 1987; 42: 186-188.
Rosello HJ, Pla JC. Sulfato de magnesio en la crisis de asma. Prensa Med Argent, 1936; 23:
1677–1680.
Rowe B, Camargo C. The use of magnesium sulfate in acute asthma: Rapid uptake of
evidence in North American emergency departments. The Hournal of Allergy and
Clinical Immunology, 2006; 1: 53-58.
Rowe B, Bretzlaff J, Bourdon C, Bota G, Camargo C. [Review] Magnesium sulfate for
treating exacerbations of acute asthma in the emergency department. Cochrane
Database of Systematic Reviews, 2007; Issue 1.
Villeneuve E, Zed P. Nebulized Magnesium Sulfate in the Management of Acute
Exacerbations of Asthma. The Annals of Pharmacotherapy, 2006; 40: 1118-1124.