Magnesium Sulfate and Asthma in the Pediatric Population Lauren Cantor Advanced Medical Therapeutics...

Magnesium Sulfate and Asthma

in the Pediatric Population

Lauren CantorAdvanced Medical Therapeutics

March 2, 2007QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.

QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.

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

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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:

FEV1 or PEF>50%:

Inhaled B2 agonist MDI or nebulizer q20 minutesx3,

and systemic corticosteroids

History, Physical, FEV1 or PEF, O2 Saturation assessments; Start O2

Impending or actual respiratory arrest: INTUBATION

Admission to PICU

FEV1 or PEF<50%: High dose inhaled B2 agonists

and systemic corticosteroids

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


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


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?

• 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.”

QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.

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 CitedAgarwal 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.


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.


Villeneuve E, Zed P. Nebulized Magnesium Sulfate in the Management of Acute Exacerbations of Asthma. The Annals of Pharmacotherapy, 2006; 40: 1118-

1124.

Magnesium Sulfate and Asthma in the Pediatric Population Lauren Cantor Advanced Medical Therapeutics...

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