J Pediatr (Rio J).

2017;93(s1):19---25

www.jped.com.br

REVIEW ARTICLE

Magnesium sulfate infusion for acute asthma in the

emergency department夽
Jose Enrique Irazuzta a,b,∗ , Nicolas Chiriboga a,b

a
Wolfson Children’s Hospital, Jacksonville, United States
b
University of Florida, Jacksonville, United States

Received 2 May 2017; accepted 26 May 2017

Available online 26 July 2017

KEYWORDS Abstract
Magnesium sulfate; Objectives: To describe the role of intravenous magnesium sulfate (MgSO4 ) as therapy for acute
High dose infusion; severe asthma in the pediatric emergency department (ED).
Severe asthma; Source: Publications were searched in the PubMed and Cochrane databases using the following
Pediatric; keywords: magnesium AND asthma AND children AND clinical trial. A total of 53 publications
Emergency were retrieved using this criteria. References of relevant articles were also screened. The
department; authors included the summary of relevant publications where intravenous magnesium sulfate
Cost-effective was studied in children (age <18 years) with acute asthma. The NAEPP and Global Initiative for
Asthma expert panel guidelines were also reviewed.
Summary of the data: There is a large variability in the ED practices on the intravenous admin-
istration of MgSO4 for severe asthma. The pharmacokinetics of MgSO4 is often not taken into
account with a consequent impact in its pharmacodynamics properties. The cumulative evi-
dence points to the effectiveness of intravenous MgSO4 in preventing hospitalization, if utilized
in a timely manner and at an appropriate dosage (50---75 mg/kg). For every five children treated
in the ED, one hospital admission could be prevented. Another administration modality is a
high-dose continuous magnesium sulfate infusion (HDMI) as 50 mg/kg/h/4 h (200 mg/kg/4 h).
The early utilization of HDMI for non-infectious mediated asthma may be superior to a MgSO4
bolus in avoiding admissions and expediting discharges from the ED. HDMI appears to be cost-
effective if applied early to a selected population. Intravenous MgSO4 has a similar safety profile
than other asthma therapies.
Conclusions: Treatment with intravenous MgSO4 reduces the odds of hospital admissions. The
use of intravenous MgSO4 in the emergency room was not associated with significant side

夽 Please cite this article as: Irazuzta JE, Chiriboga N. Magnesium sulfate infusion for acute asthma in the emergency department. J Pediatr

(Rio J). 2017;93:19---25.

∗ Corresponding author.

E-mail: [email protected]fl.edu (J.E. Irazuzta).

http://dx.doi.org/10.1016/j.jped.2017.06.002
0021-7557/© 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
20 Irazuzta JE, Chiriboga N

effects or harm. The authors emphasize the role of MgSO4 as an adjunctive therapy, while
corticosteroids and beta agonist remain the primary acute therapeutic agents.
© 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).

PALAVRAS-CHAVE Infusão de sulfato de magnésio para asma aguda no serviço de emergência

Sulfato de magnésio;
Resumo
Alta dose de infusão;
Objetivos: Descrever o papel do sulfato de magnésio intravenoso (MgSO4 ) como terapia para
Asma grave;
asma grave aguda no serviço de emergência pediátrica (SE).
Pediátrico;
Fonte: As publicações foram pesquisadas no banco de dados PubMed e Cochrane utilizando
Serviço de
as seguintes palavras-chave: magnésio E asma E crianças E ensaio clínico. Foi encontrado um
emergência;
total de 53 publicações utilizando esses critérios. As referências de artigos relevantes também
Custo-benefício
foram examinadas. Incluímos o resumo de publicações relevantes quando o sulfato de magnésio
intravenoso foi estudado em crianças (idade < 18 anos) com asma aguda. Revisamos também as
diretrizes do Programa Nacional para a Educação e Prevenção da Asma (NAEPP) e do painel de
especialistas da Iniciativa Global para Asma.
Resumo dos dados: Há uma grande variabilidade nas práticas do SE na administração intra-
venosa do MgSO4 para asma grave. A farmacocinética do MgSO4 normalmente não leva em
conta um impacto posterior em suas propriedades farmacodinâmicas. A comprovação cumu-
lativa aponta para a eficácia do MgSO4 intravenoso na prevenção da internação, se utilizado
quando necessário e em uma dosagem adequada (50-75 mg/kg). Uma internação hospitalar
pode ser evitada para cada cinco crianças tratadas no SE. Outra modalidade de administração
é a infusão prolongada de alta dose de sulfato de magnésio (HDMI) a 50 mg/kg/hora/4 horas
(200 mg/kg/4 horas). O uso precoce da HDMI, para asma não infecciosa mediada, pode ser supe-
rior a um MgSO4 em bolus para evitar internações e antecipar as altas do SE. A HDMI parece
ter bom custo-benefício se aplicada precocemente em uma população selecionada. O MgSO4
intravenoso possui um perfil de segurança semelhante a outras terapias de asma.
Conclusões: O tratamento com MgSO4 intravenoso reduz as chances de internações hospita-
lares. O uso de MgSO4 intravenoso no pronto socorro não é associado a efeitos colaterais ou
danos significativos. Enfatizamos o papel do MgSO4 como uma terapia adjuvante, ao passo que
os corticosteroides e as beta-agonistas continuam os agentes terapêuticos agudos primários.
© 2017 Sociedade Brasileira de Pediatria. Publicado por Elsevier Editora Ltda. Este é um artigo
Open Access sob uma licença CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.
0/).

Introduction reversible conditions in EDs.1,2 While asthma-related mor-

tality may be improving, one-third of the deaths occurred
Asthma is a reversible, diffuse lower airway obstruc- before medical attention was provided.3 ED management to
tion caused by airway inflammation and edema, bronchial revers the progression toward respiratory failure should be
smooth-muscle spasm, and mucous plugging. The composite structured and aggressive, as invasive mechanical ventila-
effect leads to expiratory airflow obstruction.1 Asthma could tion is fraught with many complications and an elevated
be life-threatening and must be promptly treated. Severe mortality.4 Due to the enormous health care burden of
asthma is often defined as failure to improve after 2 h of asthma, all medical treatments need to be scrutinized
conventional emergency department (ED) treatment, and regarding their cost-effectiveness.
commonly present with moderate hypoxemia. The presence
of hypoxemia should be assessed non-invasively with a pulse Pathophysiology
oximeter. Blood gas, serological or radiological studies are
not necessary to define or determine its severity.
Asthma involves a complex inflammatory cascade. There
is an antigen-mediated activation of epithelial cells and
Perspective on a health challenge infiltration of the airways by circulating cells releasing
soluble transmitters that intensify the inflammatory cas-
Asthma is the leading cause of chronic illness in children; cade. The immediate response is bronchospasm (smooth
19---24% of Brazilian children have been diagnosed with muscle contraction). The continued release of inflamma-
asthma at some time in their lives.2 It is the third leading tory mediators leads to airway edema, mucosal injury, and
cause of hospitalizations among children under the age of desquamation of the protective epithelium layer. Airway
15 years. Severe asthma is one of the most common severe, denudation decreases the production of normal mucus and
Magnesium sulfate infusion 21

exposes the terminal nerves to excessive cholinergic stimu- Methylxanthines and subcutaneous or intravenous ␤-
lation, exacerbating smooth muscle contraction.5 agonists are not routinely utilized as a first line therapy
The progression of this physiopathology results in in the United States. However, a study from Porto Ale-
widespread lung heterogeneity with severe bronchocon- gre that assessed the effects of intravenous salbutamol
striction. Lung areas with mucus plugging and atelectasis in ED, observed a decrease in the ␤2 adrenergic nebu-
alternate with areas of hyperinflation due to air trapping. lization requirements subsequent to the patients’ hospital
The combined effects of the aforementioned processes lead admission.8 That study only addressed changes in respira-
to ventilation perfusion mismatch (V/Q mismatch), with tory rate and did not control for alterations in other clinical
the clinical expression of hypoxemia. Air trapping puts findings. It also did not state whether vital signs monitor-
the diaphragm in a disadvantageous position, losing its ing was performed in a blinded fashion. Heliox may improve
area of apposition and producing an ineffective effort. The the aerosol delivery of ␤2 adrenergic to the lower air-
respiratory work load increases dramatically, and inspira- way; nonetheless, it is expensive and does not appear to
tory substernal retractions are observed, progressing to a offer a consistent and significant clinical benefit.9,10 and
paradoxical thoraco-abdominal breathing pattern. In severe cost-effective studies are required. BIPAP support in the
cases, the cardiac output is compromised, with a combina- ED appears to stabilize patients with status asthmaticus
tion of dehydration, increased pulmonary venous pressure before the hospital admission; however, the cumulative data
creating a dynamic decreased venous return to the right (two publications) is scarce to recommend it as standard
atrium, and a shift of the intraventricular septum, impinging therapy.11,12
the left ventricle preload. In turn, the use of intravenous MgSO4 has emerged as a
proven strategy to reduce hospital admissions. This study
aimed to review the different regimens for MgSO4 admin-
Clinical presentation
istration and its contribution in the management of severe
asthma.
The majority of severe asthma exacerbations occur after an
exposure to allergic triggers or in the setting of a viral upper
respiratory infection. Most children present with cough,
wheezing, prolonged expiratory phase, and increased work
of breathing while under mild hypoxemic conditions and MgSO4 mechanism of action and kinetics
dehydration. The degree of wheezing does not correlate
well with severity of the disease. Clinical asthma scoring The primary mechanism of action of intravenous MgSO4
systems, such as the Woods score, lack granularity, but are is thought to be secondary to its spasmolytic proper-
helpful in patient follow-up.6 This and other clinical scores ties. Supra-physiologic unbound serum magnesium (Mg),
express categorical variables (mild/moderate/severe) as directly related to ionized Mg, produces a transient block
a number,1---3 which facilitates the trending of acuity on of the N-methyl-d-aspartate receptor-gated calcium chan-
a single patient; nonetheless, any statistical analysis of nels with subsequent muscle relaxation. Blocking the Ca
these results should be performed as categorical variable. entry into the airway smooth muscle interferes with smooth
Peak expiratory flow rate (PEFR), in cooperative previously- muscle contraction, inducing bronchodilation.13---15 While
trained patients, provides a more granular assessment. other mechanisms modulating the inflammatory reaction,
However, it is an effort-dependent technique and difficult such the attenuation of the neutrophil respiratory burst,
to perform while in respiratory distress, unless the investi- have putative beneficial effects, their degree of contri-
gators are previously trained to perform spirometry testing.7 bution in the therapeutic management of acute asthma
The presence of pulsus paradoxus denotes severity, but it is is less clear.16 The Mg2+ ion, due to its effects on Ca,
difficult to be repeatedly assessed in a busy ED. also inhibits the release of acetylcholine from motor nerve
terminals, inhibiting histamine release from mast cells
Initial ED management and decreasing the production of mucus in the secretory
glands.17
An organized and resolute ED initial management is needed, Intravenous MgSO4 has a rapid onset of action and,
due to the compounded facts that severe asthma is: (a) similarly, a rapid renal elimination. This presents a ther-
a condition with a high incidence, (b) has a potential for apeutic challenge and an opportunity. Achieving sustained
reversibility, (c) has the risk to progress toward respiratory spasmolytic effects is difficult, as renal tubular reabsorp-
failure, and (d) the ED needs to judiciously manage hospi- tion of Mg is at maximal capacity with normal serum
tal admission. The primary goal is to stabilize patients and levels and renal clearance rises linearly with higher
rapidly identify those in whom the process is not rapidly concentrations.18 Therefore, the maximum serum level
reversible or who are at a high risk of deterioration. during therapy depends more on the rate of infusion
The initial treatments include oxygen, intravenous fluids, rather than on the total dose or duration of the infu-
intravenous or oral corticosteroid, repeated or continuous sion. In children, a retrospective study described that the
nebulization of a ␤2 adrenergic (i.e., salbutamol), nebulized MgSO4 distribution volume was 0.3 L/kg, with a half-life
muscarinic anticholinergic (i.e., ipratropium), and intra- of 2---2.7 h.19 Often, the bolus dose of intravenous MgSO4
venous MgSO4 . has been limited to 2000 mg, regardless of patient size
Failure to improve after the aforementioned regimen, and renal function. This practice is contradictory with a
assessed as persistence of respiratory distress upon clinical pharmacokinetic rationale and affects its pharmacodynamic
exam, is defined as severe asthma (or status asthmaticus). properties.
22 Irazuzta JE, Chiriboga N

Experience in the use of intravenous MgSO4 in The need to return to the ED after discharge has
asthmatic children not been well documented. One study with 47 children
reports a reduced length of stay of 5.3 h on patients who
MgSO4 is inexpensive, has minimal adverse effects at the were admitted.28 This is an elusive variable as, once the
doses indicated, and is widely available. The onset of action patient is admitted, discharge may not be solely depen-
of intravenous MgSO4 is rapid (within minutes), a neces- dent on the patient’s condition but rather on the availability
sity in emergency settings. Since its original description in of medical personnel, time of the day, and day of the
1936, the optimal dose of IV MgSO4 as a bolus has not been week.
established, leading to the utilization of a wide dose range,
from 25 to >100 mg/kg.18---22 Multicenter studies have failed
to demonstrate a consistent decrease in hospital admissions High-dose MgSO4 continuous infusion (HDMI)
or early discharge.23---25
These inconsistent results could be in part due to: (a) Much of the magnesium in serum is attached to albu-
failure to take into consideration the MgSO4 pharmacokine- min, while ionized Mg (IoMg; the free form) is the
tics, (b) failure to conceptualize MgSO4 as a time-sensitive pharmacologically active form in asthma. IoMg makes
therapy, (c) the inherent challenges of the aforementioned up 55% of extracellular Mg; however, the relation of
‘‘outcome variables’’ in asthma, or (d) enrollment of indi- Mg/IoMg is adversely altered in asthma and critically ill
viduals with current infectious process, with ongoing stimuli patients.24,25,27 Animal studies indicate that IoMg concen-
for bronchoconstriction and damage to the airway. trations ≥1 mmol/L are required to produce smooth muscle
Some clinical studies indicate the need for higher-dose relaxation.15
regimens.22,26 Ciarallo et al. reported positive results in two These and other factors lead the authors to study
clinical trials, separated by a period of four years, where high-dose MgSO4 continuous infusion (HDMI) in children
the dose was increased from 25 mg/kg to 40 mg/kg, adminis- in the setting of severe asthma and status asthmaticus.
tered over 20 min.22 A retrospective pharmacokinetic study HDMI has been used in patients with pulmonary hyper-
involving 54 children suggested the need for 50---75 mg/kg tension, brain injury, and subarachnoid hemorrhage, as
bolus to attain a Mg level near 4 mg/dL (1.64 mmol/L).19 In well as extensively in preeclampsia.30---33 In these scenar-
a study conducted in India with 47 children, Devi et al. used ios, the strategy is to maintain a consistent therapeutic
100 mg/kg over 35 min with a co-administration of intra- level to compensate for MgSO4 ’s rapid elimination. This
venous aminophylline. The results show an improvement approach has been rarely adopted in asthma cases.28,34
in clinical and PEFR scores; the graphic display implied The obstetrics and gynecology literature targets Mg infu-
beneficial effects in oxygenation starting in the first few sion to clinical signs of weakening, but not losing, patellar
hours and continuing for 10---12 h.27 Nevertheless, the co- reflexes as reflection of adequate spasmolysis. This usu-
administration of aminophylline in this study leads to doubts ally represents serum Mg of 4.8---8.4 mg/dL with IoMg
about whether MgSO4 alone caused this effect. 0.9---1.6 mmol/L.15,35,36
The prompt initiation of therapy may be correlated A retrospective study by Glover et al. on continuous intra-
with its efficacy. A study performed in Argentina indi- venous MgSO4 use in children attempted to assess safety, but
cated that early administration in the ED was associated had many confounding variables. Those authors described a
with fewer patients, later on, requiring mechanical ven- heterogeneous group with a large variation in dosage and
tilation in a pediatric intensive care unit (PICU).25 Of regimen duration, bolus of 35.3 ± 12.7 mg/kg, infusion of
note, the control group comprised younger subjects and 21.6 ± 6 mg/kg/h for 93.8 h ± 89.2 h, without significant side
may have included infants with bronchiolitis. A large ran- effects.26
domized clinical trial with 100 patients in India, using a In this practice, the present authors retrospectively ana-
modified asthma clinical severity score, demonstrated the lyzed the use of HDMI in the setting of status asthmaticus
superiority of an early intravenous MgSO4 bolus over terbu- within the confines of the pediatric intensive care unit
taline or aminophylline infusions20 ; of note, many of these (PICU).37 The HDMI regimens consisted of an initial bolus
patients were very young and infection-mediated asthma that was weight-dependent: 50 mg/kg (>30 kg) or 75 mg/kg
was not identified. Another randomized trial in a Brazil- (≤30 kg) over a period of 30---45 min; followed by a continu-
ian ED demonstrated the superiority of intravenous MgSO4 ous infusion of 50 mg/kg/h, for 4 h. Serum magnesium levels
over placebo, with almost identical effects to intravenous were 4.4 ± 0.8 mg/dL, and IoMg 0.95 ± 0.2 mmol/L at the
Salbutamol while using surrogate variables of efficacy in end of the infusion, within the target range. In 12 patients,
patients that were later hospitalized.8 An earlier meta- troponin levels and electrocardiograms were all normal.37
analysis conducted by Cheuk et al. including five trials that In a following prospective study, the authors determined
assessed MgSO4 versus placebo demonstrated MgSO4 effec- the HDMI pharmacokinetics VD of 0.4 ± 0.13 L/kg, clearance
tiveness in preventing hospitalization.28 A more recent and of 1.58 ± 0.24 mL/kg/min, and safety, documented levels
stricter meta-analysis involving three trials (115 children) of IoMg associated with smooth muscle relaxation and the
concluded that the true estimated reduction in admission absence of significant side effects.38 This regimen was phar-
was between 86% and 26%, due to the wide confidence inter- macologically precise, but complex, and lead to errors in
val (odd ratio: 0.32, 95% CI: 0.14---0.74). Nevertheless, an administration. After trying several regimens, a simplified
number needed to treat (NNT) of 5 could be ascribed to the regimen of 50 mg/kg/h for 4 h was adopted. In a subsequent
use of intravenous MgSO4 in the ED to prevent one hospital study, the authors compared the initial and the simplified
admission.29 regimen, demonstrating similar serum levels.39
Magnesium sulfate infusion 23

50% 47% of hypotension requiring intervention, and 23% had con-

cerns about its side effects. An online survey, a methodology
40% that suffers from self-selection bias and subjective recall
bias, emphasized the general predisposition of physicians to
30%
develop opinions when there is lack of data.34
20%
In four HDMI studies, no significant side effects were
11% 11% observed, except for one patient reporting nausea, two
10% pain at the injection site, and two generalized flushing. No
0% patient experienced significant muscle weakness or the need
0% for respiratory support. Low diastolic blood pressure should
Bolus HDMI be expected during HDMI if measured by automated sphyg-
momanometer. The authors observed normal troponin levels
12 hrs. 24 hrs. of 0.05 ± 0.01 ng/mL and no EKG changes during HDMI.38
Of note, in a non-invasive method, the changes in tonality
Figure 1 Percentage of patients discharged home from the ED between the 4th to the 5th Korotkoff determine the diastolic
by group. Bolus, 50 mg/kg/1 h; HDMI, 200 mg/kg/4 h. Columns blood pressure.43 Automated sphygmomanometers have dif-
represent patients discharged, by group. HDMI, high-dose mag- ficult elucidating this change when patients are receiving
nesium infusion. a high dose ␤2 adrenergic or HDMI. A study with invasive
intra-arterial line may be able to refine this point.
A contemporary problem is that an increased propor-
MgSO4 HDMI vs. Bolus
tion of patients with asthma are obese,44,45 which requires
adjustments in the intravenous dose. In this practice, the
In a prospective, randomized ED study for severe asthma,
authors adjust the dosage to ideal body weight when BMI is
with patients without underlying co-morbidity or infectious
≥ 25. Further studies in this area are also needed.
etiology, the authors determined that HDMI was superior to
MgSO4 bolus (Fig. 1) in shortening the ED length of stay while
reducing costs.40
Patients were randomized to receive intravenous MgSO4 Inhaled MgSO4 in asthma
50 mg/kg bolus (over 1 h) or HDMI (50/mg/kg/h for 4 h),
diluted in 0.9% saline solution at a concentration of The large efficacy of the nebulized ␤-agonists in the treat-
10 mg/mL. The HDMI group presented a lower length of ment of asthma makes their role undisputed. However,
stay (HDMI, 34 ± 19 h; bolus, 48 ± 19 h; p = 0.031; 95% CI: inhaled medications are difficult to deliver to the affected
1.3---26.5). Moreover, at 24 h, nine out of 19 patients (47%) bronchi, even under ideal conditions. Studies have shown
in the HDMI group were discharged, versus two out of 21 that only about 10% of bronchodilators reach the lung and
(10%) in the bolus group (p = 0.012), with an absolute risk are largely affected by respiratory rate, tidal volumes, dead
reduction (ARR) 37% (95% CI: 11---63). HDMI was superior to a space ventilation (Vd/Vt), bronchoconstriction, method of
bolus as an early adjunctive treatment, with a NNT of 3 (95% delivery, mouth breathing, and particle size and deposi-
CI: 1.6---9.5) to facilitate a discharge at 24 h from the ED.39 tion.
Interim analysis at 12 and 36 h presented the same trends The use of inhaled magnesium sulfate has presented
favoring the HDMI group; two-thirds of the patients in this inconsistent results. A systematic review showed that clin-
group were discharged at 36 h (p = 0.009; ARR: 42%; 95% CI: ical trials that assessed the use of inhaled MgSO4 failed
14---70%; NNT: 3; 95% CI: 1.4---7.3). The use of HDMI in the to find a beneficial effect, and its use is not widely
ED management of asthma was cost-effective in the present recommended.46
institution.39

Side effects and potential challenges Conclusions

MgSO4 -induced muscle weakness, with the consequent risk Improvements in the ED management of severe asthma,
of respiratory failure, and potential vasodilatation, with a leading diagnosis for admission to hospitals, could have
subsequent hypotension, are of concerns when utilized in a significant economic impact, in particular in areas with
the context of asthma.41,42 Although many earlier studies lower socioeconomic resources. A preplanned, organized,
showed minimal or no adverse effects, the fear of these side and decisive ED initial management is paramount to reverse
effects is pervasive. Minor side effects were described in 16% a condition that can evolve toward respiratory failure.
of patients: epigastric warmth, tingling, numbness, and pain The authors emphasize the role of MgSO4 as an adjunc-
at the site of infusion, all of them appearing within 5 min tive therapy in the initial management of asthma, while
of the initiation and disappearing shortly afterwards.27 Of ␤2 adrenergic and corticosteroids remain the primary ther-
note, that study appears to have used a bolus of 100 mg/kg apy. It is possible that the inconsistent results from previous
over 35 min.27 Schuh et al. found contradictory behavior in MgSO4 studies were due to a failure to achieve sustained
an online survey of ED physicians. While more than 80% of serum magnesium and spasmolytic effects for ␤2 adrenergic
responders agreed that there were data to support use of to reach the site of action. Incorporating HDMI at 50 mg/kg/h
MgSO4 , it was utilized in less than 20% of the time; 24% of for 4 h in the ED facilitates early discharge, reduces hospi-
surveyed physicians recalled observing at least one episode talization rates, and is cost-effective.
24 Irazuzta JE, Chiriboga N

Conflicts of interest 19. Rower JE, Liu X, Yu T, Mundorff M, Sherwin CM, Johnson M. Clin-
ical pharmacokinetics of magnesium sulfate in the treatment
of children with severe acute asthma. Eur J Clin Pharmacol.
The authors declare no conflicts of interest.
2017;73:325---31.
20. Singhi S, Grover S, Bansal A, Chopra K. Randomised comparison
of intravenous magnesium sulphate, terbutaline and amino-
phylline for children with acute severe asthma. Acta Paediatr.
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