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Arch Argent Pediatr 2012;110(4):291-296 / 291

Effectiveness of magnesium sulfate as initialtreatment of acute severe asthma in children,conducted in a tertiary-level universityhospital. A randomized, controlled trial

SUMMARYIntroduction. Magnesium sulfate is a calcium an-tagonist that inhibits bronchial smooth musclecontraction promoting bronchodilation. It is usedfor the management of acute severe asthma inchildren; however most of the studies have been

performed in adults.Objective. To evaluate the effectiveness of in-travenous magnesium sulfate for the treatmentof pediatric patients with acute severe asthmaexacerbations.Population and Methods. A clinical, random-ized, controlled trial was conducted betweenMarch 2006 and March 2011 at Hospital Uni-versitario Austral. Children with acute severeasthma admitted to the emergency departmentwere randomized into two groups. Group A(control group): standard protocol for the initialtreatment of acute asthma exacerbation. GroupB: treatment protocol with magnesium sulphatefor acute severe asthma exacerbation. The pri-

mary outcome was the requirement of invasiveor non invasive mechanical ventilation support.Results. One hundred and forty three patientsrandomized into 2 groups were analyzed. Thetreatment group included 76 patients receivingmagnesium sulfate within the first hour of theinitiation of rescue treatment at the hospital, andthe control group included 67 patients not treatedwith magnesium sulphate. Among the patientsin the control group, 33% (n= 22) required me-chanical ventilation support, compared to only5% (n= 4) of the patients in the treatment group(p= 0.001).Conclusions. Intravenous infusion of magnesiumsulfate during the first hour of hospitalization in

patients with acute severe asthma significantlyreduced the percentage of children who requiredmechanical ventilation support.Key words: magnesium sulphate, acute severe asth-ma in children, Woods score, mechanical ventilationsupport, emergency department.

http://dx.doi.org/10.5546/aap.2012.eng.291

INTRODUCTIONMagnesium sulphate is a physi-

ological calcium antagonist that acts

by inhibiting the contraction medi-ated by the bronchial smooth muscle.In addition, it interferes with the para-

a. Department ofMother and ChildHealth.Hospital Austral.Buenos Aires,Argentina.

E-mail address:Silvio Torres:[email protected]

Conflict of interest:None.

Received: 12-1-2011Accepted: 4-26-2012

sympathetic stimulation and preventsacetylcholine release to the axon ter-minal; therefore promoting a broncho-dilating effect.1

Magnesium sulphate also has a

role in the reduction of inflammationby inhibiting mast cell degranulationand reducing thromboxane, histamineand leukotrienes circulation.

The first publication on the useof magnesium sulphate for the treat-ment of asthma was the report ofa case2sixty years ago, but only in1989, Skobeloff et al. published thefirst randomized, double-blind, pla-cebo-controlled trial on the benefits ofmagnesium sulphate for acute asthma

exacerbations.3

Several subsequent publicationsshowed that magnesium sulphatewas effective for its use both in emer-gency departments and intensive careunits.4,5

In the last years, several studiesanalyzed the effectiveness of magne-sium sulphate in acute severe asthmaepisodes as an intravenous therapy orinhaled together with bronchodilators.However, most studies were devel-oped for adult populations, as shownin the 2000 Cochrane Collaborationsystematic review.6

In pediatric populations, the studyconducted by Ciarallo et al. should bepointed out, with a randomized, dou-ble-blind and controlled design basedon pulmonary function tests. Amongits weakness it is worth mentioningthat it only included patients olderthan 6 years and that pulmonary func-

tion tests measurements had been er-ratic, as shown in the studys editorialdiscussion.7

Silvio TorresaM.D., Nicols SticcoaM.D., Juan Jos BoschaM.D., Toms IolsteraM.D.,Alejandro SiabaaM.D., Manuel Rocca RivarolaaM.D. and Eduardo SchnitzleraM.D.

Original article


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292 / Arch Argent Pediatr 2012;110(4):291-296 / Original article

The lack of pediatric studies has been associ-ated with the difficulty of measuring pulmonaryfunction in younger children and the unwilling-ness of older children to be subjected to a test.

For this reason, studies developed in this agerange sought to measure the following: an im-provement in respiratory scores, hospitalizationlength-of-stay, and the use or not of mechanicalventilation (MV).6,8.

OBJECTIVETo evaluate the effectiveness of intravenous

magnesium sulphate for severe asthma exacerba-tions in pediatric patients.

Acronyms:

SO4Mg: Magnesium sulphate.HUA:Hospital Universitario Austral.MV: Mechanical ventilation.PICU: Pediatric Intensive Care Unit.CPG: Clinical Practice Guidelines.

POPULATION AND METHODSBetween March 2006 and March 2011, a clini-

cal, open-label, randomized, controlled trial wasconducted at Hospital Universitario Austral. Theclinical treatment protocol was approved by theEthics Committee and the Clinical Research Unit

of Hospital Universitario Austral. The ClinicalPractice Guidelines on acute severe asthma usedin this study were prepared by HUAs ClinicalPractice Guidelines Sub-Committee and approvedby the Ethics Committee.

The study included patients aged 2 to 15 whoattended the hospital emergency department dueto acute severe asthma, classified according to aWoods score (Table 1) of 5 or more. This assess-ment was performed by the Pediatric IntensiveCare Unit (PICU) staff doctors, who indicated thepatients admission following such classification

(if Woods score was 5). Patients with hyper-thermia (temperature 38.3C [100.94F]), systol-ic blood pressure


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Effectiveness of magnesium sulfate as initial treatment of acute severe asthma in children, conducted in a tertiary-level university hospital. / 293

-vere asthma exacerbation. (Table 2b)

All patients were initially treated with 3 doses

of inhaled -2-adrenergic nebulization (salbuta-mol) at 0.15 mg/kg/dose (minimum 2.5 mg andmaximum 10 mg every 20 minutes during the firsthour), and methylprednisolone at 1 mg/kg/doseIV.4All patients in the treatment group receivedIV magnesium sulphate, at 25 mg/kg (maximum2 g) in a 20-minute infusion, within the first hourafter being admitted to the hospital.9

A nurse stayed next to the child during theentire infusion time, supervised by the physicianwho had prescribed the treatment.

The following parameters were monitored on

an ongoing basis: heart rate, respiratory rate, bloodoxygen saturation, and blood pressure. The phar-macy of Hospital Universitario Austral providedthe medication for the study in its usual commer-cially available presentation for children and adults.

Treatment discontinuation criteriaThe treatment protocol was discontinued and

the next stage in the CPGs was initiated if any of

the following occurred during the drug infusion:

2

0.35).

increase of >2 points in Woods score from ba-seline at study enrollment.

patients age). -

tion.

Statistical analysisFor the sample size required we observed

that, in accordance with the reviewed literature,the incidence for positive pressure support is 10-15%.10,11 Taking into consideration a reduction of

20% of the endpoint Use of MV (primary pre-determined endpoint) in the treatment group, andassuming a power of 80% and a 95% confidenceinterval (CI), the sample size estimated for the dif-ference in proportion between the 2 groups was65 patients per arm.

A database was established, where quantita-tive outcomes were analyzed using median andquartiles, when distribution was not parametric,

SBT 0.15 mg/kg x 3

MPD 2 mg/kg IV

O2

SBT 0.2 mg/kg x 3

CRIAInadequate

response

SBT 0.15-0.4 mg/kg/h

Mechanical ventilationInadequate

response

TABLE2A. Treatment group TABLE2B.Control group

SBT: Salbutamol. MPD: Methyprednisolone. SO4Mg: Magnesium sulphate. IARF: Impending Acute Respiratory Failure.

TABLE2.Treatment protocol with IV magnesium sulphate, included in the Clinical Practice Guidelines of HospitalUniversitario Austral

SBT 0.15 mg/kg x 3

MPD 2 mg/kg IV

O2

SO4Mg 25 mg/kg

SBT 0.2 mg/kg x 3

CRIAInadequate

response

SBT 0.15-0.4 mg/kg/h

Mechanical ventilation

Inadequate

response


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296 / Arch Argent Pediatr 2012;110(4):291-296 / Original article

CONCLUSIONSThe intravenous administration of magnesium

sulphate during the first hour of the patientsadmission to the hospital was associated with a

significant decrease in the number of children re-quiring mechanical ventilation support.17

AcknowledgmentsTo Mara Elina Serra M.D., for her collabora-

tion in this study.

BIBLIOGRAPHY1. Corbridge TC, Hall JB. The assessment and management

of adults with status asthmaticus.Am J RespirCrit Care Med1995;151(5):1296-316.

2. Hurry V Getal. Blood serum magnesium in bronchial asth-ma and its treatment by administration of magnesium sul-phate.J Lab ClinMed1940;26:340-6.

3. Skobeloff EM, Spivey WH, McNamara RM, GreensponL. Intravenous magnesium sulphate for the treatment ofacute asthma in the emergency department. JAMA 1989;262:1210-13.

4. NHLBI Guidelines for the Diagnosis and Treatment ofasthma. Available at: http.//www.nhlbi.nih.gov/guide-lines/asthma.

5. Global strategy for asthma management and prevention2010 (update). Available at: http.//www.ginasthma.org.

6. Rowe BH, Bretzlaff JA, Bourdon C, Bota GW, Camargo CAJr. Magnesium sulphate for treating exacerbations of acuteasthma in the emergency department. Cochrane DatabaseSyst Rev 2000;(2):CDO01490.Review.

7. Ciarallo L, Sauer AH, Shannon MW. Intravenous magne-sium therapy for moderate to severe pediatric asthma: re-

sults of randomized, placebo-controlled trial. J Pediatrics1996;129:809-14.

8. Cheuk DK, Chau TC, Lee SL. A meta-analysis on intrave-nous magnesium sulphate for treating acute asthma.ArchDis Child 2005;90:74-77.

9. Oymar K, Halvorsen T. Emergency presentation and man-agement of acute severe asthma in children. Scandinavianjournal of trauma. Res Emerg Med 2009;17:40.

10. Paret G, Kornecki A, Szeinberg A, Vardi A, et al. Severeacute asthma in a community hospital pediatric intensivecare unit: a ten-year experience. Ann Allergy Asthma Im-munol1998;80:339-44.

11. Beers SI, Abramo TJ, Wiebe RA: Bilevel positive airwaypressure in the treatment of status asthmaticus in pediat-rics.Am J Emerg Med 2007;25:6-9.

12. Maffei FA, van der Jagt EW, Powers KS, et al. Duration ofmechanical ventilation in life-threatening pediatric asth-ma: description of an acute asphyxial subgroup. Pediatrics2004;114(3):762-7.

13. Cox RG, Barker GA, Bohn DJ. Efficacy, results, and com-plications of mechanical ventilation in children with sta-tus asthmaticus. PediatrPulmonol1991;11:120-6.

14. Malmstrom K, Kaila M, Korhonen K, et al. Mechanicalventilation in children with severe asthma. PediatrPulm-onol2001;31:405-11.

15. Bohn D, Kissoon N. Acute Asthma. Ped Crit Care Med 2001;2:151-63.

16. Alter HJ, Koepsell TD, Hilty WM. Intravenous magnesiumas an adyuvant in acute bronchoespasm: a meta-analysis.Ann Emerg Med 2000;36:191-7.

17. Rodrigo G, Rodrigo C, Burschtin O. Efficacy of magnesium

sulphate in acute adult asthma: a meta-analysis of random-ized controlled trials.Am J Emerg Med 2000;18:2-18.

of these children due to the high risk of compli-cations, such as barotrauma and alveolar air leaksyndrome, thus increasing their risk of death.15

Currently, the accepted ventilation strategies

are based on short inhaling times and prolongedexhaling times, with low tidal volumes, low re-spiratory rates, pressure-controlled ventilationmodes and permissive hypercapnia to avoid baro-trauma.9

It should be noted that our population com-prises a wide age range, from 2 to 15 years old.This is considered a weakness of our study dueto the small number of subjects included, whichprevents us from conducting a subset analysis,although the age distribution in both groups wasbalanced.

Another limitation is not having done pulmo-nary function tests, because it is difficult to imple-ment them in children younger than 6 years old,as pointed out by Ciarallo et al.7

The endpoint use of systemic corticosteroidson an outpatient basis was not recorded either,which could be important to classify bronchi-al inflammation status. In relation to the use ofWoods score 5 to be included in the study, al-though it was always done by the same healthcareprofessionals, it should be noted that subjectivityat assigning a score cannot be avoided.

In spite of an open-label design, those whotreated patients were different from those whocollected the data, and also different from thosewho processed and analyzed the data in order tomitigate such bias.

Among the study strengths, homogeneity be-tween both groups regarding their baseline char-acteristics and severity status to be eligible for thestudy are worth pointing out, together with themanagement of confounders by stratification andmultivariate regression analysis.

It should be noted that magnesium sulphate is

a drug approved by the National Administrationof Medicines, Food and Technology of Argentina(ANMAT) for its use in children, as stated in res-olution N 0798. It is safe and available for use, sowe believe it is feasible to disseminate its use inthe emergency department or PICU as shown byour study and the international literature.16

Our findings match the evidence obtainedfrom different reviews in this field, focused onobjectives similar to ours, regarding the shorterhospital length-of-stay and the smaller numberof children requiring mechanical ventilation sup-port.17

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