Skip to main content
Download PDF

Magnesium nebulization utilization in management of pediatric asthma (MagNUM PA) trial: study protocol for a randomized controlled trial

Trials volume 17, Article number: 261 (2016) Cite this article

Abstract

Background

Up to 30 % of children with acute asthma are refractory to initial therapy, and 84 % of this subpopulation needs hospitalization. Finding safe, noninvasive, and effective strategies to treat this high-risk group would substantially decrease hospitalizations, healthcare costs, and the psycho-social burden of the disease.

Whereas intravenous magnesium (Mg) is effective in severe refractory asthma, its use is sporadic due to safety concerns, with the main treatment goal being to prevent intensive care unit admission. In contrast, nebulized Mg is noninvasive, allows higher pulmonary drug concentrations, and has a much higher safety potential due to the lower rate of systemic delivery. Previous studies of inhaled Mg show disparate results due to the use of unknown/inefficient delivery methods and other methodological flaws.

Methods/Design

The study is a randomized double-blind controlled trial in seven Canadian pediatric Emergency Departments (two-center pilot 2011 to 2014, Canada-wide November 2014 to December 2017). The trial will include 816 otherwise healthy children who are 2 to 17 years old, having had at least one previous wheezing episode, have received systemic corticosteroids, and have a Pediatric Respiratory Assessment Measure (PRAM) ≥ 5 points after three salbutamol and ipratropium treatments for a current acute asthma exacerbation. Eligible consenting children will receive three experimental treatments of nebulized salbutamol with either 600 mg of Mg sulfate or placebo 20 min apart, using an Aeroneb Go nebulizer, which has been shown to maximize pulmonary delivery while maintaining safety. The primary outcome is hospitalization within 24 h of the start of the experimental therapy for persistent respiratory distress or supplemental oxygen. Secondary outcomes include all-cause hospitalization within 24 h, PRAM, vital signs, number of bronchodilator treatments by 240 min, and the association between the difference in the primary outcome between the groups, age, gender, baseline PRAM, atopy, and “viral induced wheeze” phenotype (Fig. 1).

Discussion

If effective, inhaled Mg may represent an effective strategy to minimize morbidity in pediatric refractory acute asthma. Unlike previous works, this trial targets nonresponders to optimized initial therapy who are the most likely to benefit from inhaled Mg. Future dissemination of results will include knowledge translation, incorporation into a Cochrane Review, presentation at scientific meetings, and a peer-reviewed publication.

Trial registration

NCTO1429415, registered 2 September 2011.

Peer Review reports

Background

Acute asthma is a leading cause of pediatric emergency department (ED) visits and of pediatric hospitalizations [1], with the annual asthma expenditures in the United States exceeding $37 billion [2]. In 2005, 754,000 pediatric ED asthma visits were reported in the US [3, 4], and 27 % of these resulted in hospitalization [4]. Practice guidelines recommend high dose ß2 agonists, inhaled anticholinergics, and oral corticosteroids to manage major acute exacerbations [5–9]. However, this initial optimal therapy [9–11] is not always effective [12] because up to 30 % of patients with asthma are resistant to initial bronchodilation [13] in part due to ß2 adrenoreceptor gene polymorphism [14–32], and gene polymorphisms also impact the frequently delayed response to corticosteroids [33–35]. Finding further effective strategies to decrease pediatric asthma hospitalizations in this high-risk population is necessary.

Magnesium sulfate (Mg) produces rapid bronchodilation by multiple mechanisms [36–39] and can be given either intravenously (IV) or by nebulization. Two key meta-analyses of adult and pediatric trials have confirmed that the addition of IV Mg to routine therapy significantly decreases hospitalizations and improves lung function [40, 41]. These authors, as well as various asthma guidelines, recommend that IV Mg be considered in children not responding to initial management [40, 42–44]. However, IV Mg is used infrequently and often as a last resort [45, 46]. In contrast, the nebulization route is noninvasive and offers a major advantage of targeted delivery to the lower airway and less potential for side effects [47]. However, the benefit of nebulized Mg has not been well established.

The investigation of the efficacy of nebulized Mg has been limited, with disparate results. The dose of Mg varied seven-fold among studies [48–60], and only one study [48] limited participants to nonresponders to bronchodilators. Two meta-analyses of mainly adult studies have found a trend toward reduction in hospitalizations in patients given nebulized Mg [40, 61], with the recent Cochrane review reaching similar conclusions [59]. The main limitations of past pediatric studies are failure to limit participants to nonresponders to bronchodilators, inadequate use of anticholinergics, use of inefficient delivery methods, and small sample size [49, 58, 60, 62]. In contrast, this study focuses on the poor responders to optimized baseline acute asthma therapy. This group is at the highest risk of hospitalization and the most likely to benefit from nebulized Mg intervention. Furthermore, previous studies have used nebulizers of suboptimal/unknown efficacy. In contrast, the device used in this study has been pre-tested and shown to deliver a considerably greater proportion of the drug into the lungs compared to the conventional nebulizers.

Research questions and study hypothesis

Primary question

The primary question is whether, in children 2–17 years of age with acute asthma who have persistent moderate to severe airway obstruction despite maximized initial bronchodilator and steroid therapy, a reduction can be achieved in the probability of hospitalization within 24 h of starting experimental therapy. Specifically, this trial compares those patients who receive three nebulized Mg and salbutamol treatments to those receiving only nebulized salbutamol.

Secondary questions

The trial seeks to determine the following for these treatment modalities:

  1. a)

    Is there a difference in the probability of all-cause hospitalization within 24 h of starting therapy?

  2. b)

    Is there a difference in the changes in the validated Pediatric Respiratory Assessment Measure (PRAM), respiratory rate, oxygen saturation, and blood pressure to 240 min?

  3. c)

    Does the treatment effect with respect to primary outcome vary among the subgroups defined by the following variables: age, sex, pre-randomization PRAM score, personal history of atopy and “viral-induced wheeze” phenotype?

Hypothesis

We hypothesize that the children with PRAM ≥5 points after optimized initial inhaled bronchodilator and systemic steroid therapy who are given nebulized Mg in addition to nebulized salbutamol will have a significantly lower probability of hospitalization compared to those given salbutamol only.

Methods/Design

Study design and population

This is a seven-center, randomized, double-blind controlled trial. Two study groups are compared: nebulized salbutamol with Mg sulfate and nebulized salbutamol with placebo. This study has received approval by the Research Ethics Board of the Hospital for Sick Children. Furthermore, local Research Ethics Boards have approved the study at all participating sites (see Additional file 1). A written informed consent and assent where appropriate is being obtained from all study participants.

All otherwise healthy children 2–17 years of age with a past history of asthma/recurrent wheeze arriving in the ED when the study nurses are on duty with a presenting PRAM ≥5 are considered potentially eligible. Following assessment by the ED physician, the patients receive oral/IV corticosteroid plus three salbutamol and ipratropium inhalations according to the local management guidelines [63–68]. If the PRAM is still ≥5 after the initial therapy, the study nurse confirms eligibility, measures the pre-randomization PRAM score, and obtains informed consent.

PRAM score

PRAM is a validated 12-point clinical asthma severity score [69], exhibits the most comprehensive measurement properties of all asthma scores [70], and has been successfully used as an outcome in major trials [71]. It is the only score with demonstrated criterion validity, using respiratory resistance as the gold standard [72]. PRAM has been validated in both preschool and school-aged children who have been assessed in the ED for asthma and has a strong association with admission [73]. The score has inter-rater reliability consistently above 70 % [73] and is currently implemented in virtually all pediatric EDs across Canada. Children with PRAM ≥5 following initial bronchodilator therapy have at least a 30 % probability of hospitalization and represent 84 % of all acute asthma admissions in children. All participating EDs now measure the PRAM score as part of routine clinical assessment in their EDs in children with acute asthma. Because Calgary is situated 1000 m above sea level, oxygen saturations there can be expected to be approximately 2 % lower than in Toronto (International Civil Aviation Organization, Manual of the ICAO Standard Atmosphere, Doc 7488-CD, Third Edition, 1993, ISBN 92-9194-004-6). Therefore, the oxygen saturation component of the PRAM is adjusted in Calgary.

Inclusion criteria

Inclusion criteria are (1) 2 to 17 years of age, (2) diagnosis of asthma/reactive airways/viral-induced wheeze plus at least one prior acute episode of wheezing treated with inhaled ß2 agonists or oral corticosteroids, (3) persistent moderate to severe airway obstruction after oral steroid and three doses of salbutamol and ipratropium, defined as a PRAM ≥5 [73].

Exclusion criteria

Exclusion criteria are (1) no past history of wheezing or bronchodilator therapy; (2) prior IV Mg therapy during the index visit; (3) critically ill children requiring immediate intubation; (4) coexistent renal, chronic pulmonary, neurologic, cardiac, or systemic disease; (5) children who in the opinion of the treating physician require a chest radiograph due to atypical clinical presentation and are diagnosed to have lobar consolidation with pneumonia, felt to be the primary cause of respiratory distress; (6) known hypersensitivity to Mg sulfate; (7) patients previously enrolled; (8) insufficient command of the English or French language; and (9) lack of a phone.

Delivery device

To ensure adequate delivery of the experimental treatment into the lungs, we have pre-tested the Aeroneb™ Go Micropump Nebulizer along with the Idehaler™ Pocket system without valves that connects with a facemask in vitro and in vivo. We found that this device deposited 20 % of the charge dose compared to 4 % by conventional nebulizers, while also maintaining acceptable osmolarity and safety [74]. This device has been distributed to all participating sites, related training provided, and Health Canada approval obtained. All experimental treatments are delivered with this device. This device is fully licensed both in the United States and in Europe and is currently awaiting license approval in Canada. We do not anticipate any difficulties with its official adoption by the time this trial is concluded.

Sample selection

Children presenting to the collaborating EDs at The Hospital for Sick Children, Children’s Hospital of Eastern Ontario, Ste Justine’s Hospital, Alberta Children’s Hospital, Stollery Hospital, Children’s Hospital of Winnipeg and the B.C. Children’s Hospital who meet eligibility criteria are approached for enrollment when the research nurses are on duty. The research nurses keep a log of all children presenting to the ED with acute asthma during the study period whether randomized or not in order to assess the generalizability of the study. All aforementioned hospitals are tertiary care centers, which see the entire clinical and demographic spectrum of the asthma population.

Pre-study screening and baseline evaluation

All previously healthy children 2 and 17 years of age with acute asthma have a PRAM score measured in triage. Those meeting local ED criteria for enhanced therapy receive either oral dexamethasone, oral prednisolone/prednisone, or IV hydrocortisone plus three salbutamol and ipratropium inhalations via a Metered Dose Inhaler/Valved Holding Chamber (MDI/VHC)/nebulizer according to the local asthma pathway and 20 min apart.

Study procedures

At the conclusion of the three baseline inhalations, the research nurse assesses eligibility and measures the pre-randomization PRAM score. Eligible children with PRAM ≥5 are approached, and informed consent is obtained. Subjects are randomly allocated to receive three consecutive nebulizations of salbutamol with either diluted Mg sulfate or diluted 5.5 % saline placebo 20 min apart [48] using the Aeroneb™ Go Micropump Nebulizer along with the Idehaler™ Pocket system. Specifically, each treatment utilizes 600 mg (1.2 mL) of Mg sulfate or 1.2 mL 5.5 % saline, 5 mg (1 mL) of salbutamol, and 3.8 mL of sterile water (Fig. 1).

Fig. 1
figure1

Flow diagram of participant study flow. The intervention consists of two treatment arms with solutions of identical osmolarity consisting of inhaled salbutamol with Mg sulfate (experimental arm) and with equivalent saline placebo (control arm). The primary outcome is hospitalization to inpatient unit for asthma-related symptoms within 24 h of randomization. *PRAM Pediatric Respiratory Assessment, **Mg magnesium

Full size image

Randomization and masking

The Research Coordinating Pharmacist at SickKids produced Master Randomization tables, stratified by site and age (≥6 years versus less), using a permuted block randomization of six and eight in a 1:1 ratio of active Mg sulfate to placebo, using random number generating software. The Master Randomization tables are held at the site Research Pharmacies. Consecutively numbered kits are prepared by each pharmacy according to the step-by-step procedure manual provided by Research Coordinating Pharmacist at SickKids. Upon receiving the informed consent, the study nurse obtains the next appropriate numbered study kit from the locked research fridge in the ED (Mg has to be refrigerated) and enters the number in the confidential logbook. Since Mg sulfate solution is hypertonic, 5.5 % saline was chosen as a placebo. Using sterile water as a top-up diluent in both arms produces solutions of identical isotonicity 380 mOsm/L in both study groups. Because the deposition of inhaled drugs is weight-independent [64], a uniform Mg dose is used in all children.

The patients, research nurses and ED physicians are blinded to the treatment assignment. Only the pharmacies are unblinded. Each site is given detailed requirements for drug accountability and handling to ensure compliance with Health Canada regulations. The active Mg and placebo hypertonic saline mixture with salbutamol and sterile water are very similar in volume, color, taste, and smell when nebulized (tested in the research pharmacy at SickKids). To assess blinding, the research nurse and parents are asked at the conclusion of the experimental therapy which intervention they think the child had received.

In case of increasing respiratory distress, IV Mg may be given after the experimental therapy, provided the patient is not hypotensive. In the unlikely event that the patient develops hypotension requiring therapy or apnea and the ED physician feels that the experimental therapy cannot be safely continued, further doses of the experimental treatment are stopped. If these Mg side effects are also accompanied by severe distress and additional IV Mg is warranted, the code may be broken for that patient. Unblinding will only occur if the clinical treatment of the patient will change because the physician knows which arm of the study the patient was previously enrolled. The study PI/local PI and the study nurses will remain blinded. No patients participating in our inhaled Mg study received experimental therapy unblinded.

The study nurses also keep continuous study logs with the characteristics and outcome of the participating and nonparticipating eligible acute asthmatics ≥2 years of age; these logs will also be used to track missed patients, those excluded for criteria, and patients who refused participation, which will help document any selection bias.

After the intervention

Following the study medication, the patients continue to receive further salbutamol as frequently as clinically warranted as per the treating ED physician. Disposition is also determined by blinded ED physicians. Discharged patients receive a prescription for inhaled salbutamol every 4 h as necessary for the next week and daily oral corticosteroid according to local practice. All participating families receive instructions to visit their primary care provider/ED if salbutamol has to be given more often than every 4 h for increased work of breathing/severe cough and if the respiratory status interferes with usual play/normal speech or activity.

Outcome measures

Primary outcome measure

The primary outcome measure is hospitalization (based on the ED physician’s decision to admit) to an inpatient unit within 24 h of the start of the experimental therapy for persistent respiratory distress or for supplemental oxygen. Children deemed to be admitted but who due to lack of bed availability are never transferred to the ward will be analyzed as hospitalized. Extended ED stays without a decision to admit are not considered admitted.

Secondary outcome measures

The two groups will also be compared with respect to the following:

  1. a.

    All cause hospitalization rate by 24 h to examine Mg impact on side effects, such as hypotension necessitating admission.

  2. b.

    Changes in the PRAM, respiratory rate, and oxygen saturation from the start of the first experimental nebulization to 60, 120, 180, and 240 min and the changes in the blood pressure from the first experimental nebulization to 20, 40, 60, 120, 180, and 240 min.

  3. c.

    Number of salbutamol treatments within 240 min of starting study medication.

  4. d.

    An association between hospitalization and age, sex, symptom duration <24 h [60], pre-randomization PRAM score, personal history of atopy, and “acute viral induced wheeze” phenotype [75–81].

Other outcomes

Major side effects such as hypotension (systolic blood pressure below the 5th percentile for age) or apnea is tracked as is admission to ICU for airway stabilization.

The clinical outcomes are measured by trained study nurses in the ED. The research nurses also ascertain subsequent return visits/hospitalizations from the telephone follow-ups according to standardized interviewing techniques, as well as from a review of the patient health records at 72 h.

Sample size

The sample size calculation is based on the targeted minimal significant between-group difference in proportions of hospitalizations of 10 %, which has previously been shown to impact treatment decisions. The estimated probability of hospitalization is based on our fully blinded pilot data (pilot patients form an integral part of this trial), where the overall hospitalization rate is close to 50 %. This is a superiority study in which the adoption of the Mg therapy can only be recommended for future practice if the probability of the primary outcome in the Mg group is significantly lower than in the placebo group. With 408 patients per arm (816 in total), a two-sided test with a type I error of 0.05 will have 80 % power to achieve statistical significance if Mg therapy reduces the probability of hospitalization from 50 to 40 % (that is, absolute reduction of 10 %) [82].

Analyses

Primary analysis

The proportion of patients hospitalized will be compared between treatment groups using a two-sided Fisher’s exact test at the 5 % level. An intention-to-treat analysis will be used with all randomized participants included in the analysis as part of the groups to which they were randomized regardless of whether they completed the study medication or not.

Secondary analysis

Secondary analysis will include the following:

  1. a)

    A Fisher’s exact test to compare the rates of all cause admissions in the two arms.

  2. b)

    A repeated measures ANOVA to compare treatment arms with respect to the PRAM score, respiratory rate, heart rate, oxygen saturation, and blood pressure over time. Baseline values will be added to the model as a covariate.

  3. c)

    A Poisson model will be used to compare the number of salbutamol treatments used in the ED in the regression analysis of the two study arms, including interaction terms with the treatment group, which will be used to examine the subgroup effects with respect to the primary outcome. The following variables will be used to define subgroups: age, sex, pre-randomization PRAM score, and personal history of atopy. The statistical tests of hypotheses for the secondary outcomes a) through d) will be two-sided at the 0.00625 level to account for the issue of multiple testing and to maintain an overall type 1 error of 0.05.

Interim analysis

To assure safety, one planned interim analysis will be conducted on the first 200 patients randomized (a quarter through the study) conducted by a statistician not involved in the trial and evaluated by the independent data safety monitoring board. The interim analysis will be a one-sided test of the null hypothesis of no difference versus the alternative hypothesis that the probability of hospitalization is higher on Mg therapy at the 0.01 level. That is, we are looking for evidence that Mg therapy is less effective, and the trial will be stopped at an interim analysis only if the null hypothesis is rejected in favor of the control arm. Therefore, the interim analysis is only for safety and not for efficacy, and it will not increase the probability of erroneously rejecting the null hypothesis in favor of Mg therapy at the final analysis. The reason we are doing one-sided (for harm) interim analysis is because if there is early strong evidence that Mg increases the probability of hospital admission, we want to stop the trial. On the other hand, we do not want to stop the trial early for benefit because a smaller sample size will not be convincing.

Safety

Magnesium blocks the neuromuscular transmission and acts as a CNS depressant. Therefore, the theoretical adverse effects with IV Mg may include a transient drop in blood pressure or apnea [83]. The potential for these problems after nebulized Mg is lower than with IV Mg because this treatment route will result in a lower systemic delivery of Mg (1/4 of the IV dose) and a lower systemic effect. Since hypotension is the only major side effect of IV Mg occurring with appreciable frequency, all patients are monitored using continuous automated blood pressure devices, and if the systolic blood pressure drops below 5th percentile for age, the study will be stopped, treatment given as necessary, and the DSMC will be notified. Of note, a recent Cochrane review of 896 patients given inhaled Mg confirmed the safety of this agent [59]. No child in this study had experienced hypotension or apnea.

All adverse events are being reported to the Hospital for Sick Children Research Ethics Board according to the Hospital for Sick Children’s adverse event reporting requirements. Adverse events will be classified as mild, moderate or severe and as expected or unexpected. Expected adverse events will include cough, respiratory distress, asthma-related hospitalization, IV insertion, sinus tachycardia and bitter/salty taste of the experimental solution. Adverse reactions are managed according to the standard clinical management practices. Furthermore, we plan to document episodes of severe cough necessitating interruption of the experimental therapy for more than approximately 3 min to examine the safety profile of magnesium.

All serious, unexpected adverse drug reactions to the study medication will be reported to Health Canada within 15 calendar days, and those resulting in death or life-threatening events, within 7 calendar days. Serious adverse events include ICU admission, hypotension <5th percentile for age, apnea, and any other medical event which may jeopardize the patients.

Due to the osmolarity of the study solutions being well under 500 mOsm/L throughout nebulization and co-administration of salbutamol, we do not anticipate side effects due to the aforementioned composition of the study solutions. However, should the highly unlikely event of respiratory deterioration occur, the experimental therapy will be discontinued, appropriate additional treatment started, and the event will be reported to the DSMC within 48 h. Salbutamol may cause tachycardia, and this has been the case in many children enrolled to date. However, this has been uniformly well tolerated, and no patient has had to stop/interrupt experimental therapy due to this issue.

The Data Safety and Monitoring Committee (DSMC) consists of a non-study biostatistician, a researcher, and a child health scientist, specifically Dr. Annie Dupuis, Dr. Neil Sweezey, Dr. Patricia Parkin. The members of this committee are not collaborators of this trial. They are notified of all serious adverse events by the study coordinator within 48 h. The DSMC meets once per asthma season or ad hoc if necessary.

Trial management

The Hospital for Sick Children Research Institute will act as a central repository for all study data and will be responsible for study data management technology and clinical data management services. Dr. Willan will supervise all data analyses. Dr. Schuh takes overall responsibility for the study. The study has a Steering Committee which includes senior research team members: Dr. Nathan Kuppermann (past chair of Pediatric Emergency Children’s Research Network), Dr. Joseph Zorc (senior ED clinician investigator), Dr. Amy C. Plint (past chair of PERC) and Dr. Allan L. Coates (expert in inhaled drug delivery).

Discussion

If effective, inhaled Mg will represent an effective strategy to minimize morbidity in pediatric refractory acute asthma. Furthermore, the potential for side effects in this study can reasonably be expected to be low, since the inhaled delivery route will result in a lower systemic delivery of magnesium, a lower systemic effect, and a substantially enhanced margin of safety compared to the intravenous administration. To ensure study safety, all severe adverse events will be reported to the Research Ethics Board and the Data Safety and Monitoring Committee as well as to the Steering Committee. A safety interim analysis is planned after the first 200 patients have been randomized and appropriate unblinding procedures have been defined.

Future dissemination of results will include knowledge translation, incorporation into a Cochrane Review, presentation at scientific meetings, and a peer-reviewed publication.

We plan to disseminate the results of this study widely and rapidly to all relevant stakeholders. This will be accomplished via the Pediatric Emergency Research Canada (PERC) network, which has a unique partnership with the Translating Research Emergency Knowledge for Kids (TREKK) group, encompassing 36 general EDs across Canada and 12 PERC sites. In addition, the PERC network is part of the worldwide Pediatric Emergency Research Network (PERN), consisting of 122 hospitals on five continents.

Trial status

As of 15 September 2015, 207 children had been enrolled.

Abbreviations

ANOVA:

analysis of Variance

ED:

Emergency Department

IV:

intravenous

Mg:

magnesium

PRAM:

Pediatric Respiratory Assessment Measure

References

  1. 1.

    Mannino DM, Homa DM, Pertowski CA, Ashizawa A, Nixon LL, Johnson CA, et al. Surveillance for asthma–United States, 1960–1995. MMWR CDC Surveill Summ. 1998;47:1–27.

    CAS  PubMed  Google Scholar 

  2. 2.

    Kamble S, Bharmal M. Incremental direct expenditure of treating asthma in the United States. J Asthma. 2009;46:73–80.

    Article  PubMed  Google Scholar 

  3. 3.

    Akinbami L. Asthma prevalence, health care use and mortality: United States, 2003–2005. November: Centers for Disease Control and Prevention; 2006. http://www.cdc.gov/nchs/data/hestat/asthma03-05/asthma03-05.htm. Accessed 19 Jan 2016.

  4. 4.

    Moorman JE, Rudd RA, Johnson CA, King M, Minor P, Bailey C, et al. National surveillance for asthma–United States, 1980–2004. MMWR Surveill Summ. 2007;56:1–54.

    PubMed  Google Scholar 

  5. 5.

    National Heart, Lung and Blood Institute. Global Initiative for asthma. Global strategy for asthma management and prevention. NHLBI/WHO workshop report. Bethesda, Md: NIH; 2002. Report No.: 02-3659.

    Google Scholar 

  6. 6.

    National Institutes of Health and National Heart, Lung, and Blood Institute. Guidelines for the diagnosis and management of asthma–update on selected topics 2002. Washington, DC: US Dept of Health and Human Services; 2002. Report No.: 97-4051.

    Google Scholar 

  7. 7.

    National Asthma Council. Asthma management handbook 2002. Melbourne: National Asthma Council Australia, Ltd; 2002.

    Google Scholar 

  8. 8.

    British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax. 2003;58 Suppl 1:i1–94.

    Google Scholar 

  9. 9.

    Becker A, Lemiere C, Berube D, Boulet LP, Ducharme FM, Fitzgerald M, et al. Summary of recommendations from the Canadian Asthma Consensus guidelines, 2003. Can Med Assoc J. 2005;173(6 Suppl):S3–11.

    Google Scholar 

  10. 10.

    Scarfone RJ, Fuchs SM, Nager AL, Shane SA. Controlled trial of oral prednisone in the emergency department treatment of children with acute asthma. Pediatrics. 1993;92:513–8.

    CAS  PubMed  Google Scholar 

  11. 11.

    National Asthma Education and Prevention Program. Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute; 2007.

    Google Scholar 

  12. 12.

    Kercsmar CM, McDowell KM. Love it or lev it: levalbuterol for severe acute asthma–for now, leave it.[comment]. J Pediatr. 2009;155:162–4.

    Article  PubMed  Google Scholar 

  13. 13.

    Fischl MA, Pitchenik A, Gardner LB. An index predicting relapse and need for hospitalization in patients with acute bronchial asthma. New Engl J Med. 1981;305:783–9.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Hall IP. Pharmacogenetics of asthma. Eur Respir J. 2000;15:449–51.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Drazen JM, Silverman EK, Lee TH. Heterogeneity of therapeutic responses in asthma. Br Med Bull. 2000;56:1054–70.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Palmer LJ, Silverman ES, Weiss ST, Drazen JM. Pharmacogenetics of asthma. Am J Respir Crit Care Med. 2002;165:861–6.

    Article  PubMed  Google Scholar 

  17. 17.

    Koga T, Kamimura T, Oshita Y, Narita Y, Mukaino T, Nishimura M, et al. Determinants of bronchodilator responsiveness in patients with controlled asthma. J Asthma. 2006;43:71–4.

    Article  PubMed  Google Scholar 

  18. 18.

    Tsai HJ, Shaikh N, Kho JY, Battle N, Naqvi M, Navarro D, et al. Beta 2-adrenergic receptor polymorphisms: pharmacogenetic response to bronchodilator among African American asthmatics. Hum Genet. 2006;119:547–57.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Johnson M. The beta-adrenoceptor. Am J Respir Crit Care Med. 1998;158:S146–53.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Taylor DR, Epton MJ, Kennedy MA, Smith AD, Iles S, Miller AL, et al. Bronchodilator response in relation to beta2-adrenoceptor haplotype in patients with asthma. Am J Respir Crit Care Med. 2005;172:700–3.

    Article  PubMed  Google Scholar 

  21. 21.

    Lipworth BJ, Hall IP, Tan S, Aziz I, Coutie W. Effects of genetic polymorphism on ex vivo and in vivo function of beta2-adrenoceptors in asthmatic patients. Chest. 1999;115:324–8.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM, Chinchilli VM, et al. The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med. 2000;162:75–80.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term beta agonist use: influence of beta(2) adrenoceptor polymorphism. Thorax. 2000;55:762–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial.[see comment]. Lancet. 2004;364:505–12.

    Article  Google Scholar 

  25. 25.

    Palmer CN, Lipworth BJ, Lee S, Ismail T, Macgregor DF, Mukhopadhyay S. Arginine-16 beta2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol.[see comment]. Thorax. 2006;61:940–4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JP. Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes. J Allergy Clin Immun. 2005;115:963–72.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest. 1997;100:3184–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Carroll CL, Schramm CM, Zucker AR. Slow-responders to IV beta2-adrenergic agonist therapy: defining a novel phenotype in pediatric asthma. Pediatr Pulm. 2008;43:627–33.

    Article  Google Scholar 

  29. 29.

    Liggett SB. Polymorphisms of the beta2-adrenergic receptor and asthma. Am J Respir Crit Care Med. 1997;156:S156–62.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Thakkinstian A, McEvoy M, Minelli C, Gibson P, Hancox B, Duffy D, et al. Systematic review and meta-analysis of the association between {beta}2-adrenoceptor polymorphisms and asthma: a HuGE review. Am J Epidemiol. 2005;162:201–11.

    Article  PubMed  Google Scholar 

  31. 31.

    Choudhry S, Ung N, Avila PC, Ziv E, Nazario S, Casal J, et al. Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma.[see comment]. Am J Respir Crit Care Med. 2005;171:563–70.

    Article  PubMed  Google Scholar 

  32. 32.

    Martin AC, Zhang G, Rueter K, Khoo SK, Bizzintino J, Hayden CM, et al. Beta2-adrenoceptor polymorphisms predict response to beta2-agonists in children with acute asthma. J Asthma. 2008;45:383–8.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Tantisira KG, Hwang ES, Raby BA, Silverman ES, Lake SL, Richter BG, et al. TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids. Proc Natl Acad Sci U S A. 2004;101:18099–104.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Tantisira KG, Lake S, Silverman ES, Palmer LJ, Lazarus R, Silverman EK, et al. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum Mol Genet. 2004;13:1353–9.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Tantisira KG, Silverman ES, Mariani TJ, Xu J, Richter BG, Klanderman BJ, et al. FCER2: a pharmacogenetic basis for severe exacerbations in children with asthma. J Allergy Clin Immun. 2007;120:1285–91.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Middleton Jr E. Antiasthmatic drug therapy and calcium ions: review of pathogenesis and role of calcium. J Pharmaceut Sci. 1980;69:243–51.

    CAS  Article  Google Scholar 

  37. 37.

    Hill J, Britton J. Dose-response relationship and time-course of the effect of inhaled magnesium sulphate on airflow in normal and asthmatic subjects. Br J Clin Pharmacol. 1995;40:539–44.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Iseri LT, French JH. Magnesium: nature’s physiologic calcium blocker. Am Heart J. 1984;108:188–93.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Classen HG, Jacob R, Schimatschek H. Interactions of magnesium with direct and indirect-acting sympathomimetic amines. 1987. p. 80–7.

    Google Scholar 

  40. 40.

    Mohammed S, Goodacre S. Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis. Emerg Med J. 2007;24:823–30.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Cheuk DK, Chau TC, Lee SL. A meta-analysis on intravenous magnesium sulphate for treating acute asthma. Arch Dis Child. 2005;90:74–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Bandura A. Social learning theory. New York: General Learning Press; 1977.

    Google Scholar 

  43. 43.

    Canadian Asthma Consensus Group. Management of patients with asthma in the emergency department and in hospital. Can Med Assoc J. 1999;161(11 Suppl):S53–9.

    Google Scholar 

  44. 44.

    British Thoracic Society and Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. 2009. https://www.brit-thoracic.org.uk/document-library/clinical-information/asthma/btssign-guideline-on-themanagement-of-asthma/. Accessed 19 January 2016.

    Google Scholar 

  45. 45.

    Schuh S, Macias C, Freedman S, Plint A, Zorc J, Bajaj L, et al. North American practice patterns of IV magnesium therapy in severe acute asthma in children. Acad Emerg Med. 2010;17:1189–96.

    Article  PubMed  Google Scholar 

  46. 46.

    Schuh S, Zemek R, Plint A, Black KJ, Freedman S, Porter R, et al. Magnesium use in asthma pharmacotherapy: a Pediatric Emergency Research Canada study. Pediatrics. 2012;129:852–9. doi:10.1542/peds.2011-2202.

    Article  PubMed  Google Scholar 

  47. 47.

    Okayama H, Aikawa T, Okayama M, Sasaki H, Mue S, Takishima T. Bronchodilating effect of intravenous magnesium sulfate in bronchial asthma. JAMA. 1987;257:1076–8.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Hughes R, Goldkorn A, Masoli M, Weatherall M, Burgess C, Beasley R. Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in treatment of severe asthma in adults: randomised placebo-controlled trial.[see comment]. Lancet. 2003;361:2114–7.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Mahajan P, Haritos D, Rosenberg N, Thomas R. Comparison of nebulized magnesium sulfate plus albuterol to nebulized albuterol plus saline in children with acute exacerbations of mild to moderate asthma. J Emerg Med. 2004;27:21–5.

    Article  PubMed  Google Scholar 

  50. 50.

    Aggarwal P, Sharad S, Handa R, Dwiwedi SN, Irshad M. Comparison of nebulised magnesium sulphate and salbutamol combined with salbutamol alone in the treatment of acute bronchial asthma: a randomised study. Emerg Med J. 2006;23:358–62.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Drobina BJ, Kostic MA, Roos JA. Nebulized magnesium has no benefit in the treatment of acute asthma in the emergency department. Acad Emerg Med. 2006;13:S26.

    Article  Google Scholar 

  52. 52.

    Kokturk N, Turktas H, Kara P, Mullaoglu S, Yilmaz F, Karamercan A. A randomized clinical trial of magnesium sulphate as a vehicle for nebulized salbutamol in the treatment of moderate to severe asthma attacks.[see comment]. Pulm Pharmacol Therap. 2005;18:416–21.

    CAS  Article  Google Scholar 

  53. 53.

    Bessmertny O, Digregorio RV, Cohen H, Becker E, Looney D, Golden J, et al. A randomized clinical trial of nebulized magnesium sulfate in addition to albuterol in the treatment of acute mild-to-moderate asthma exacerbations in adults. Ann Emerg Med. 2002;39:585–91.

    Article  PubMed  Google Scholar 

  54. 54.

    Nannini LJ, Pendino JC, Corna RA, Mannarino S, Quispe R. Magnesium sulfate as a vehicle for nebulized salbutamol in acute asthma. Am J Med. 2000;108:193–7.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Abreu-Gonzalez J, Rodriguez-Diaz C. Magnesium and bronchodilator effect of beta-adrenergic. Am J Respir Crit Care Med. 2002;162:165–A85.

    Google Scholar 

  56. 56.

    Gallegos-Solorzano MC, Perez-Padilla R, Hernandez-Zenteno RJ. Usefulness of inhaled magnesium sulfate in the coadjuvant management of severe asthma crisis in an emergency department. Pulm Pharmacol Ther. 2010;23:432–7. doi:10.1016/j.pupt.2010.04.006.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Gaur SN, Singh A, Kumar R. Evaluating role of inhaled magnesium sulphate as an adjunct to salbutamol and ipratropium in severe acute asthma. Chest J. 2008;134:91003. doi: 10.1378/chest.134.4_MeetingAbstracts.p91003. Accessed 19 January 2016.

  58. 58.

    Khashabi J, Asadolahi S, Karamiyar M, Salari LS. Comparison of magnesium sulfate to normal saline as a vehicle for nebulized salbutamol in children with acute asthma: a clinical trial. European Respiratory Society Annual Congress; Berlin. 2008.

    Google Scholar 

  59. 59.

    Powell C, Dwan K, Milan SJ, Beasley R, Hughes R, Knopp-Sihota JA, et al. Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database Syst Rev. 2012;12, CD003898. doi:10.1002/14651858.CD003898.pub5.

    PubMed  Google Scholar 

  60. 60.

    Powell C. A randomised, double blind, placebo controlled study of nebulised magnesium sulphate in asute asthma in children–the MAGNETIC study. Arch Dis Child. 2012;97 Suppl 1:A2–3. doi:10.1136/archdischild-2012-301885.6.

    Article  Google Scholar 

  61. 61.

    Blitz M, Blitz S, Beasely R, Diner BM, Hughes R, Knopp JA, et al. Inhaled magnesium sulfate in the treatment of acute asthma. [update in Cochrane Database Syst Rev. 2005; (4):CD003898; PMID: 16235345] [update of Cochrane Database Syst Rev. 2005; (2):CD003898; PMID: 15846687]. Cochrane Database Syst Rev. 2005;3:CD003898.

    PubMed  Google Scholar 

  62. 62.

    Ashtekar C, Powell C, Hood KID. Magnesium nebuliser trial (magnet): a randomised double-blind placebo controlled pilot study in severe acute asthma. Arch Dis Child. 2008;93:A100–6.

    Article  Google Scholar 

  63. 63.

    Chua HL, Collis GG, Newbury AM, Chan K, Bower GD, Sly PD, et al. The influence of age on aerosol deposition in children with cystic fibrosis. Eur Respir J. 1994;7:2185–91.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Tal A, Golan H, Grauer N, Aviram M, Albin D, Quastel MR. Deposition pattern of radiolabeled salbutamol inhaled from a metered-dose inhaler by means of a spacer with mask in young children with airway obstruction. J Pediatr. 1996;128:479–84.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Wildhaber JH, Dore ND, Wilson JM, Devadason SG, Lesouef PN. Inhalation therapy in asthma: nebulizer or pressurized metered-dose inhaler with holding chamber? In vivo comparison of lung deposition in children.[see comment]. J Pediatr. 1999;135:28–33.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Wildhaber JH, Devadason SG, Hayden MJ, Eber E, Summers QA, Lesouef PN. Aerosol delivery to wheezy infants: a comparison between a nebulizer and two small volume spacers. Pediatr Pulm. 1997;23:212–6.

    CAS  Article  Google Scholar 

  67. 67.

    Qureshi F, Pestian J, Davis P, Zaritsky A. Effect of nebulized ipratropium on the hospitalization rates of children with asthma. New Engl J Med. 1998;339:1030–5.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Qureshi F, Zaritsky A, Poirier MP. Comparative efficacy of oral dexamethasone versus oral prednisone in acute pediatric asthma. J Pediatr. 2001;139:20–6. doi:10.1067/mpd.2001.115021.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Chalut DS, Ducharme FM, Davis GM. The Preschool Respiratory Assessment Measure (PRAM): a responsive index of acute asthma severity.[see comment]. J Pediatr. 2000;137:762–8.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Birken CS, Parkin PC, Macarthur C. Asthma severity scores for preschoolers displayed weaknesses in reliability, validity, and responsiveness. J Clin Epidemiol. 2004;57:1177–81.

    Article  PubMed  Google Scholar 

  71. 71.

    Panickar J, Lakhanpaul M, Lambert PC, Kenia P, Stephenson T, Smyth A, et al. Oral prednisolone for preschool children with acute virus-induced wheezing. New Engl J Med. 2009;360:329–38.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Ducharme FM, Davis GM. Respiratory resistance in the emergency department: a reproducible and responsive measure of asthma severity.[see comment]. Chest. 1998;113:1566–72.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Ducharme FM, Chalut D, Plotnick L, Savdie C, Kudirka D, Zhang X, et al. The Pediatric Respiratory Assessment Measure: a valid clinical score for assessing acute asthma severity from toddlers to teenagers. J Pediatr. 2008;152:476–80.

    Article  PubMed  Google Scholar 

  74. 74.

    Coates AL, Leung K, Chan J, Ribeiro N, Charron M, Schuh S. Respiratory system deposition with a novel aerosol delivery system in spontaneously breathing healthy adults. Respir Care. 2013;58:2087–92. doi:10.4187/respcare.02455.

    Article  PubMed  Google Scholar 

  75. 75.

    Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J. 2008;32:1096–110. doi:10.1183/09031936.00002108.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Ducharme FM, Lemire C, Noya FJ, Davis GM, Alos N, Leblond H, et al. Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. New Engl J Med. 2009;360:339–53. doi:10.1056/NEJMoa0808907.

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Oommen A, Lambert PC, Grigg J. Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial. Lancet. 2003;362:1433–8. doi:10.1016/S0140-6736(03)14685-5.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Vuillermin PJ, Robertson CF, South M. Parent-initiated oral corticosteroid therapy for intermittent wheezing illnesses in children: systematic review. J Paediatr Child Health. 2007;43:438–42. doi:10.1111/j.1440-1754.2007.01107.x.

    Article  PubMed  Google Scholar 

  79. 79.

    Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, et al. Community study of role of viral infections in exacerbations of asthma in 9–11 year old children. Br Med J. 1995;310:1225–9.

    CAS  Article  Google Scholar 

  80. 80.

    Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. New Engl J Med. 1995;332:133–8. doi:10.1056/NEJM199501193320301.

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000;162:1403–6. doi:10.1164/ajrccm.162.4.9912111.

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Fleiss JL. Statistical methods for rates and proportions. 2nd ed. Wiley series in probability and mathematical statistics. New York, NY: Wiley; 1981.

    Google Scholar 

  83. 83.

    Reynolds JEF, Parfitt K, Parsons AV, Sweetman SC. Magnesium Sulphate: Adverse Effects. Council of the Royal Pharmaceutical Society of Great Britain, Department of Pharmaceutical Sciences, editors. The extra pharmacopoeia. 29th ed. London: Pharmaceutical Press; 1989. p. 1033.

Download references

Acknowledgments

This study was approved for funding by the Thrasher Research Fund, the Canadian Institutes for Health Research and Physician Services Incorporated Foundation. These funding bodies played no role in the study design, data collection, data interpretation, or analysis or in the preparation of relevant manuscript.

Author information

Affiliations

  1. Division of Paediatric Emergency Medicine, The Hospital for Sick Children, Child Health Evaluative Sciences, SickKids Research Institute, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Suzanne Schuh

  2. Sections of Pediatric Emergency Medicine and Gastroenterology, Alberta Children’s Hospital, Alberta Children’s Hospital Research Institute, University of Calgary, 2888 Shaganappi Trail NW, Calgary, AB, T3B 6AB, Canada

    Stephen B. Freedman

  3. Departments of Paediatrics, Pharmacology and Physiology, Alberta Children’s Hospital Research Institute, Faculty of Medicine, University of Calgary, C4,643, 2888 Shaganappi Trail NW, Calgary, AB, T3B 6AB, Canada

    David W. Johnson

  4. Division of Pediatric Emergency Medicine, Alberta Children’s Hospital, University of Calgary, 2888 Shaganappi Trail NW, Calgary, AB, T3B 6AB, Canada

    Graham Thompson

  5. Division of Paediatric Emergency Medicine, Department of Pediatrics, Centre Hospitalier Universitaire Ste-Justine, Université de Montréal, 3175 Cote Sainte-Catherine, Montreal, QC, H3T 1C5, Canada

    Jocelyn Gravel

  6. Department of Pediatrics, Centre Hospitalier Universitaire Ste-Justine, Université de Montréal, 175 Cote Sainte-Catherine, Montreal, QC, H3T 1C5, Canada

    Francine M. Ducharme

  7. Division of Pediatric Emergency Medicine, Children’s Hospital of Eastern Ontario (CHEO), 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada

    Roger Zemek

  8. Division of Emergency Medicine, Children’s Hospital of Eastern Ontario (CHEO), 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada

    Amy C. Plint

  9. Divsion of Pediatric Emergency Medicine, The Children’s Hospital of Winnipeg, University of Manitoba, 820 Sherbrook Street, Winnipeg, MB, R3J 1R9, Canada

    Darcy Beer

  10. Children’s Hospital Research Institute of Manitoba (formerly Manitoba Institute of Child Health), Academic Faculty of Medicine, 715 McDermot Ave, Winnipeg, MB, R3E 3P4, Canada

    Terry Klassen

  11. Department of Pediatrics and Child Health, University of Manitoba, 715 McDermot Ave, Winnipeg, MB, R3E 3P4, Canada

    Terry Klassen

  12. Child Health Program, Winnipeg Health Region MICH, 715 McDermot Ave, Winnipeg, MB, R3E 3P4, Canada

    Terry Klassen

  13. Division of Paediatric Emergency Medicine, Stollery Children’s Hospital, University of Alberta, 8440 112 Street Northwest, Edmonton, AB, T6G 2B7, Canada

    Sarah Curtis

  14. Division of Pediatric Emergency Medicine, University of British Columbia, BC Children’s Hospital, 4480 Oak St, Vancouver, BC, V6H 3N1, Canada

    Karen Black

  15. SickKids Research Institute, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Allan L. Coates

  16. Child Health Evaluative Sciences, SickKids Research Institute, Dalla Lana School of Public Health, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Andrew R. Willan

  17. SickKids Research Institute, The Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada

    Judy Sweeney & Darcy Nicksy

Authors
  1. Suzanne Schuh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Judy Sweeney
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen B. Freedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Allan L. Coates
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David W. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Graham Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jocelyn Gravel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francine M. Ducharme
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roger Zemek
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Amy C. Plint
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Darcy Beer
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Terry Klassen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sarah Curtis
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Karen Black
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Darcy Nicksy
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Andrew R. Willan
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of Pediatric Emergency Research Canada Group

Corresponding author

Correspondence to Suzanne Schuh.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

SS conceived the study idea, designed the study, wrote the protocol, supervised study execution and drafted the manuscript. JS was involved in the multi-site phase of the study development process and has made a critical contribution to the overall study management and to the preparation of this manuscript. SBF helped design the study and assisted with supervision of the overall study execution, manuscript preparation and preparation of the manuscript. ALC participated in study design and protocol preparation, chaired site education in the use and management of the study device and of the technical aspects of the inhaled study drugs and helped with preparation of the manuscript. DWJ conceived the study idea and helped with the preparation of the protocol and manuscript. GT assisted with study protocol, manuscript preparation and preparation of the manuscript. JG participated in study design and protocol preparation and preparation of the manuscript. FMD participated in study design and protocol preparation and preparation of the manuscript. RZ participated in study design and protocol preparation, overall study execution, and preparation of the manuscript. ACP participated in study design and protocol preparation, overall study execution, and preparation of the manuscript. DB assisted with study protocol, manuscript preparation and preparation of the manuscript. TK helped design the study protocol and prepare the manuscript. SC critically reviewed the study protocol and assisted with manuscript preparation and preparation of the manuscript. KB participated in study design and protocol preparation and preparation of the manuscript. DN critically reviewed the protocol, provided input on technical aspects of the inhaled study drugs and critically reviewed the manuscript. ARW participated in study design and protocol preparation, supervised the interpretation of the data and study analysis and critically reviewed the manuscript. All participating authors also coordinated study execution at their respective sites. All authors read and approved the final manuscript. PERC is a Canada-wide research network of 15 pediatric emergency departments. All authors read and approved the final manuscript.

Authors’ information

Primary and corresponding author

Dr. Suzanne Schuh (SS): Division of Paediatric Emergency Medicine, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto ON, M5G 1X8, Canada. Email: Suzanne.schuh@sickkids.ca

Co-Investigators

Dr. Stephen B. Freedman (SBF): Sections of Pediatric Emergency Medicine and Gastroenterology, Alberta Children’s Hospital, Alberta Children’s Hospital Research Institute, University of Calgary, 2888 Shaganappi Trail NW, Calgary AB, T3B 6AB, Canada.

Email: Stephen.freedman@albertahealthservices.ca

Dr. David. W. Johnson (DWJ): Departments of Paediatrics, Pharmacology and Physiology, Alberta Children’s Hospital Research Institute, Faculty of Medicine, University of Calgary, C4,643, 2888 Shaganappi Trail NW, Calgary AB, T3B 6AB, Canada.

Email: david.johnson@albertahealthservices.ca

Dr. Graham Thompson (GT): Department of Paediatrics, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary AB, T3B 6AB, Canada.

Email: graham.thompson@albertahealthservices.ca

Dr. Jocelyn Gravel (JG): CHU Sainte-Justine, 3175 Cote Sainte-Catherine, Montreal QC, H3T 1C5, Canada.

Email: graveljocelyn@hotmail.com

Dr. Francine M. Ducharme (FD): General Pediatrics, Department of Pediatrics, Faculty of Medicine, CHU Sainte-Justine, 3175 Cote Sainte-Catherine, Montreal QC, H3T 1C5, Canada.

Email: francine.m.ducharme@umontreal.ca

Dr. Roger Zemek (RZ): Division of Pediatric Emergency Medicine, Children’s Hospital of Eastern Ontario (CHEO), 401 Smyth Road, Ottawa ON, K1H 8L1, Canada.

Email: rzemek@cheo.on.ca

Dr. Amy C. Plint (ACP): Division of Emergency Medicine, Children’s Hospital of Eastern Ontario (CHEO), 401 Smyth Road, Ottawa, ON K1H 8L1, Canada.

Email: plint@cheo.on.ca

Dr. Darcy Beer (DB): The Children’s Hospital of Winnipeg, 820 Sherbrook Street, Winnipeg MB, R3J 1R9, Canada.

Email: darcybeer@gmail.com

Terry Klassen (TK): CEO and Scientific Director, Children’s Hospital Research Institute of Manitoba (formerly Manitoba Institute of Child Health), Associate Dean, Academic Faculty of Medicine; Director of Research, Department of Pediatrics and Child Health, University of Manitoba; and Pediatric Emergency Physician, Child Health Program, Winnipeg Health Region. MICH, 715 McDermot Ave, Winnipeg MB, R3E 3P4.

Email: TKlassen@mich.ca

Dr. Sarah Curtis (SC): Stollery Children’s Hospital, 8440 112 Street Northwest, Edmonton AB T6G 2B7, Canada

Email: scurtis@ualberta.ca

Dr. Karen Black (KB): Division of Pediatric Emergency Medicine, University of British Columbia, BC Children’s Hospital, 4480 Oak St, Vancouver BC, V6H 3N1, Canada. Email: kjlblack@gmail.com

Dr. Allan L. Coates (ALC): The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto ON, M5G 1X8, Canada.

Email: allan.coates@sickkids.ca

Dr. Andrew Willan (AW): Child Health Evaluative Sciences, SickKids Research Institute, Dalla Lana School of Public Health, University of Toronto, 555 University Avenue, Toronto ON, M5G 1X8, Canada.

Email: andy@andywillan.com

Collaborator

Judy Sweeney (JS): SickKids Research Institute, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto ON, M5G 1X8, Canada.

Email: judy.sweeney@sickkids.ca

Darcy Nicksy (DN): The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto ON, M5G 1X8, Canada.

Email: darcy.nicksy@sickkids.ca.

Paediatric Emergency Research Canada (PERC): Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa ON, K1H 8L1, Canada

Email: lbialy@cheo.on.ca

Additional file

Additional file 1:

REB names. List of REB approving study. (PDF 78 kb)

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schuh, S., Sweeney, J., Freedman, S.B. et al. Magnesium nebulization utilization in management of pediatric asthma (MagNUM PA) trial: study protocol for a randomized controlled trial. Trials 17, 261 (2016). https://doi.org/10.1186/s13063-015-1151-x

Download citation

Keywords

  • Randomized controlled trial
  • children
  • acute asthma
  • magnesium

Trials

ISSN: 1745-6215