Effect of Inhaled MgSO 4 on FEV1 and PEF in Children with Asthma Induced by Acetylcholine: A Randomized Controlled Clinical Trail of 330 Cases

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1 JOURNAL OF TROPICAL PEDIATRICS, VOL. 60, NO. 2, 2014 Effect of Inhaled MgSO 4 on FEV1 and PEF in Children with Asthma Induced by Acetylcholine: A Randomized Controlled Clinical Trail of 330 Cases by Y. X. Sun, 1 C. H. Gong, 2 S. Liu, 2 X. P. Yuan, 3 L. J. Yin, 3 L. Yan, 3 T. T. Shi, 2 and J. H. Dai 3 1 Ministry of Education Key Laboratory of Child Development and Disorders 2 Laboratory of Pulmonary Function Test, Children s Hospital, Chongqing Medical University 3 Center of Respiratory Disorders, Children s Hospital, Chongqing Medical University, , Chongqing, China Correspondence: J. H. Dai, No. 136, 2nd Road of Zhongshan, Yuzhong District, Chongqing, China, <danieljh@163.com>. Summary Objectives: To determine the response of nebulized magnesium sulfate on the lung function of acetylcholine-induced asthma children. Methods: Three hundred and thirty children of asthma with positive bronchial provocation test were randomly divided into three groups: magnesium sulfate, albuterol, and a combination of magnesium sulfate and albuterol. Lung function was compared between the three groups. Results: Forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF) as percentage over predicted at 10 min and 20 min in albuterol and combination group were significantly improved when compared to magnesium group. The changes in FEV1 and PEF expressed as absolute and percentage over predicted was not statistically significant from baseline to 20 min in magnesium, albuterol, and combination of magnesium sulfate and albuterol. There was no significant adverse effect observed during the present study. Conclusion: Nebulized magnesium sulfate alone has a bronchodilatory effect in Ach-induced asthmatic children. The combination of MgSO 4 and albuterol did not has a synergistic effect. Key words: magnesium sulfate, nebulization, asthma, children, lung function. Introduction Magnesium sulfate (MgSO 4 ) seems to have potential as an adjunctive medication in asthma [1, 2]. Although its exact dose, route of administration and use based on severity of asthma is still controversial [3 5], its clinical use in asthma remains an interesting topic for further research. Several studies reported that nebulized MgSO 4 in adult patients with asthma exacerbation resulted in earlier improvement in clinical signs and symptoms, reduction of hospitalization and significant improvement in lung function [6 9]. Acknowledgements The author would like to thank Xia Li and Song Li for all their help and dedication to the study. Funding Chongqing Science & Technology Commission [grant number cstc2012jja0115]. As shown in the 2012 Cochrane Collaboration systematic review, most studies were developed for adult populations [10]. However, the role of MgSO 4 in acute exacerbation of childhood asthma is still unclear. Only a few studies of small samples reported the effect of nebulized MgSO 4 in the treatment of acute asthma in children, and the conclusions were controversial [3, 10, 11]. At present, there is no clinical trial to observe the effect of nebulized MgSO 4 or its combination with beta2-agonist in children with asthma after acetylcholine (Ach) provocation test. Thus, the aim of this study was to observe if nebulized MgSO 4 alone could improve lung function in children with induced asthma after acetylcholine provocation, and to determine whether the combination of nebulized MgSO 4 and albuterol has a synergistic effect. Methods Design This study was a prospective, randomized, controlled trial and was registered as a clinical trial ß The Author [2013]. Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com 141 doi: /tropej/fmt099 Advance Access published on 16 December 2013

2 (NCT ) with the US National Library of Medicine ( We conducted the trial at Children s Hospital of Chongqing Medical University from November 2011 to March Randomization was performed using a computer-generated random number sequence and Random Allocation Software Version 1.0 with the help of a statistician. Patients in follow-up visits were preliminarily enrolled for confirmed diagnosis of bronchial asthma, 4 16 years of age and positive Ach provocation results in previous tests. Patients were excluded if they had fever (axillary temperature ^38.5 C), history of having received corticosteroids (inhaled or systemic), beta2-agonist, ipratropium or theophylline in the last 3 days, history of chronic diseases like bronchopulmonary dysplasia or cystic fibrosis, history of renal insufficiency and known allergy to acetylcholine, albuterol or MgSO 4. We recorded demographic data which included age, gender, height and weight as well as the lung function test results. Forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF) were measured using a masterscope computer controlled lung function machine (MasterScreen TM PFT system, Jaeger), and repeated after the acetylcholine provocation test and at 10 min and 20 min after inhaled different drugs, respectively. After baseline FEV1 and PEF were recorded, all of the children were nebulized Ach in concentration of 0.5, 2, 8, 16 mg/dl for bronchial provocation test by using Pari turbo BOY nebulizer (Pari, Starnberg, Germany). Nebulization lasted for 1 min and was from low to high concentration gradually in each patient. Lung function tests were carried out after each inhalation. The provocation test was terminated once the patient s FEV1 and/or PEF decreased by more than 20% from the baseline. After completing the provocation test, 330 patients were finally included and randomly divided into 3 groups to receive different nebulizations immediately: magnesium sulfate group [M] (2 ml of isotonic MgSO 4, 286 mosm/l, 7.5% solution, 150 mg), albuterol group [A] (0.5 ml albuterol diluted in 1.5 ml normal saline, 2.5 mg) and combined therapy group [AþM] (0.5 ml (2.5 mg) albuterol mixed with 2 ml isotonic MgSO 4 (150 mg)). These were nebulized with a mouthpiece and 8 10 l/min of oxygen with a Pari LCD jet delivery apparatus (Pat No 022G876B, Pari, Starnberg, Germany)for 5min (Fig. 1). The doses and intervention methods of each bronchodilator agents were adopted based on study from Mahajan et al. [12] and were modified by the researchers. Patients could go home only when their PEF or FEV1 at 20 min rose over 10% compared to that of the post-acetylcholine test. If patients developed complications, side effects or adverse effects, they FIG. 1. Flow chart showing timing of lung function tests. All children underwent baseline lung function and acetylcholine provocation test, then were randomized to different groups (magnesium sulfate group [M], albuterol group [A] and a combination of magnesium sulfate and albuterol [MþA] group to undergo a bronchodilation test using different bronchodilator agents. Four different doses (0.5 mg/dl, 2 mg/dl, 8 mg/dl and 16 mg/dl) of acetylcholine were used, and patients were nebulized for 1 min from low to high levels of concentration. Lung function tests were repeated after every dose, and terminated if EFV1 or PEF decreased by more than 20%. Bronchodilator agents administered included a single dose of 150 mg (2 ml) isotonic magnesium sulfate (magnesium sulfate group) or 2.5 mg albuterol (0.5 ml) mixed with 1.5 ml of normal saline (albuterol group) or 2.5 mg (0.5 ml) albuterol mixed with 150 mg (2 ml) magnesium sulfate (combination of magnesium sulfate and albuterol group). These were nebulized with 8 10 l/min of oxygen and lasted 5 min. The study was terminated if children showed persistent hypoxia, rough cough or tendinous reflex drops. PEF or FEV1 at 20 min after bronchodilation test rose above 10% compared to after the acetylcholine provocation test, then children left, or nebulized necessary albuterol. If we found complications, side effects and adverse effects, the children would be given oxygen, albuterol or adrenaline. were treated with oxygen, albuterol, 10% calcium gluconate or adrenaline. In this study, vital signs, oxygen saturation (SpO 2 ) by pulse oximetry (Pulse Oximeter N560, Topchance, China), wheezing, use of accessory muscle and inability to speak in complete sentences were measured for each patient before and after each intervention. 142 Journal of Tropical Pediatrics Vol. 60, No. 2

3 Deep tendon jerks were recorded and repeated at 10 min and 20 min after the interventions. Ethical approval The study protocol and informed consent form were approved and followed by the institutional ethics committee of Children s Hospital, Chongqing Medical University and written informed consent was obtained from all participants and their parents. Statistical analyses The SPSS software package v.17 (SPSS Inc., Chicago, IL, USA) was used to calculate statistical inferences. A statistician also advised on the use of statistical methods. Results Three groups did not differ significantly in age, sex, height, weight, baseline of lung function, dose of Ach and post-ach lung function (FEV1 absolute 1.26 l 0.44[M], 1.19 l 0.45[A], 1.23 l 0.49[AþM], p ¼ and % predicted % 15.18%[M], % 13.84%[A], % 15.12%[AþM], p ¼ PEF absolute 3.01 l/s 0.96 [M], 2.88 l/s 1.08[A], 2.98 l/s 1.18[AþM], p ¼ and % predicted 99.04% 17.44%[M], 99.14% 18.02%[A], 98.31% 17.67% [AþM], p ¼ ) (Table 1). FEV1 and PEF as percentage over predicted at 10 min and 20 min in [A] and [AþM] group were significantly improved when compared to [M] group (FEV1, % predicted, 10 min, 97.79% 16.13% vs % 14.62%, 95.72% 15.37% vs % 14.62%, respectively, p ¼ FEV1, % predicted, 20 min, % 16.70% vs % 15.07%, % 14.79% vs % 15.07%, respectively, p ¼ PEF, % predicted, 10 min, 94.82% 19.13% vs % 15.62%, 94.83% 15.25% vs % 15.62%, respectively, p ¼ PEF, % predicted, 20 min, 99.39% 19.31% vs % 16.40%, % 17.47% vs % 16.40%, respectively, p ¼ 0.011). But there was no statistical difference of FEV1 and PEF as absolute value between three groups (Tables 2 and 3). After Ach provocation, FEV1 and PEF as absolute value and percentage over predicted in [M], [A] and [AþM] group were decreased compared to their baselines. Then at 10 min and 20 min after inhalation of magnesium sulfate, albuterol and combination of magnesium sulfate and albuterol, FEV1 and PEF both expressed as absolute value and percentage over predicted improved compared to post-ach. Only in [M] group, there was a statistical difference in FEV1 and PEF at 10 min post-ach expressed as absolute value and percentage over predicted when compared to its baseline lung function (FEV1, TABLE 1 Baseline characteristics of the patients in all three groups Variable M group (n ¼ 110) A group (n ¼ 110) A þ M group (n ¼ 110) p-value Gender (n/%) p ¼ Male 56 (50.9%) 66 (60.0%) 60 (54.5%) Female 54 (49.1%) 44 (40.0%) 50 (45.5%) Age (years) p ¼ Height (cm) p ¼ Weight (kg) p ¼ Ach (mg/dl) p ¼ FEV1, baseline (l) p ¼ FEV1, % predicted p ¼ PEF, baseline (l/s) p ¼ PEF (% predicted) p ¼ FEV1, post-ach (l) p ¼ FEV1, post-ach (% predicted) p ¼ PEF, post-ach (l/s) p ¼ PEF, post-ach (% predicted) p ¼ M group: magnesium sulfate, A group: albuterol, AþM group: albuterolþmagnesium sulfate The numerical data were reported as proportions, which analysed with chi-square test ( 2 ) to examine the differences in all groups between each other, and the statistical significance was set at p-values < 0.05, two-tailed. The quantitative data were presented as means SD. Analysis of variance (ANOVA) or rank test was (if the variance is not homogeneous) used to identify the differences in mean values on quantitative data with repeated measures between the groups and a value of p < 0.05 was taken as significant, two-tailed. (FEV1 and PEF represent values after acetylcholine provocation test. FEV1, % predicted and PEF, % predicted represent the percentage of predicted in FEV1 and PEF, respectively, at different time points.) Journal of Tropical Pediatrics Vol. 60, No

4 TABLE 2 FEV1 (absolute) and PEF (absolute) after different interventions in three groups Variable M group (n ¼ 110) A group (n ¼ 110) A þ M group (n ¼ 110) p-value FEV1 (l) 10 min p ¼ min p ¼ PEF (l/s) 10 min p ¼ min p ¼ TABLE 3 FEV1 and PEF as percent predicted after different interventions in three groups Variable M group (n ¼ 110) A group (n ¼ 110) AþM group (n ¼ 110) p-value FEV1 (% predicted) 10 min a a p ¼ min a a p ¼ PEF (% predicted) 10 min a a p ¼ min a a p ¼ a represents significant difference compared to M group. absolute, 10 min, 1.10 l 0.38 vs l 0.44, p ¼ FEV1, % predicted, 10 min, 90.37% 14.62%, vs % 15.18%. PEF, absolute, 10 min, 2.68 l/s 0.87 vs l/s PEF, % predicted, 10 min, 87.34% 15.62% vs % 17.44%) (Tables 4 and 5). The changes in FEV1 and PEF expressed as absolute and percentage over predicted was not statistically significant from baseline to 20 min in [M], [A] and [AþM] group (Tables 4 and 5). Only in [M] group, three children had persistent cough and four children s PEF or FEV1 increased <10% at 20 min, but after inhaling albuterol the lung function recovered to baseline with no obvious cough or dyspnea. Apart from this none of the patients in each group showed any other adverse reactions or side effects. Discussion The effect of magnesium sulfate administrated intravenously in the treatment of acute asthma exacerbation has been demonstrated by a number clinical trials and systematic reviews [10, 13, 14]. The Global Initiative for Asthma has mentioned nebulized salbutamol administered in isotonic magnesium sulfate provides greater benefit than if it is delivered in normal saline (Evidence A) [15]. However, this conclusion was mainly derived from the studies in adults and the effect in nebulization form is controversial [3, 4]. To our knowledge, there are only a few clinical trails of inhaled MgSO 4 in children with acute asthma attacks [12, 13]. One trail showed that the addition of magnesium to albuterol seems to provide short-term benefits in children with acute exacerbations of mild to moderate asthma [12]. Another trail conducted by Meral et al. [16] comparing albuterol and magnesium as monotherapy showed that magnesium sulfate neither improved the lung function nor decreased the admission rate. Though the importance of MgSO 4 in acute asthma attacks has been demonstrated, there are no trails looking at the MgSO 4 alone and a combination with beta2-agonist on lung function of children with asthma induced by Ach. The present study is the first to investigate the effect of inhaled MgSO 4 on FEV1 and PEF of children with asthma induced by Ach. Our results showed that nebulized MgSO 4 has a definite bronchodilatory effect in asthmatic children with acetylcholine-induced bronchoconstriction, but the improvement in FEV1 and PEF was not better than nebulized albuterol alone either at 10 min or at 20 min. The peak effect of MgSO 4 seemed to be at 20 min or over and the effectiveness of 144 Journal of Tropical Pediatrics Vol. 60, No. 2

5 TABLE 4 FEV1 (absolute) and PEF (absolute) at different time points in three groups Variable Baseline Inhaled Ach 10 min 20 min p-value FEV1 (l) M group a a,b a P ¼ A group a a a P ¼ A þ M group a a a P ¼ PEF (l/s) M group a a,b a P ¼ A group a a a P ¼ A þ M group a a a P ¼ ( a represents significant difference compared to post-acetylcholine in all groups, b represents significant difference between baseline and 10 min in M group.) TABLE 5 FEV1 and PEF as percent of predicted at different time points after interventions in three groups Variable Baseline Inhaled Ach 10 min 20 min FEV1, (% predicted) M group a,b b A group a a A þ M group a a,b PEF (% predicted) M group a a,b a,c A group a a a A þ M group a a a,c ( FEV1, % predicted and PEF, % predicted represent percent of predicted in FEV1 and PEF, respectively. a represents significant difference compared with M group. b represents significant difference between baseline and 10 min in M group. c represents significant difference from 10 min to 20 min.) bronchodilatation gradually increased along with the extension of time, but this conclusion could not be confirmed in the present study because we just investigated the changes of lung function until 20 min after interventions. In addition, there was no evidence to support the combination of nebulized MgSO 4 and albuterol had a synergistic effect. But in [AþM] group the percentage over predicted of FEV1 and PEF at 20 min had a significant improvement when compared to 10 min, which was not differ in [A] group. We hypothesize it may be associated with the increasing effectiveness of magnesium with time. This requires more studies with a longer duration of follow-up. In the present study, we found that FEV1 and PEF as percentage over predicted but not as absolute value at 10 min and 20 min in [A] and [AþM] group were significantly improved when compared to [M] group. As we know, lung function indices differ not only between the sexes but also with age and height. FEV1 and PEF expressed as percentage over predicted seem to be more useful than absolute values in comparison of their changes. There are several factors which influence the effect of aerosol MgSO4 or its combination therapy with beta2-agonist such as function of 2 receptor, concentration, osomolarity, nebulizer and so on. Firstly, we evaluated the bronchodilatory effect of nebulized magnesium through measuring the changes of lung function by inhaling acetylcholine and then induced bronchoconstriction in asthmatic children. The Journal of Tropical Pediatrics Vol. 60, No

6 airway responsiveness, the number and the function of 2 receptor in those patients were different from those with acute exacerbation [17]. Therefore, it cannot completely demonstrate bronchodilatory effect of nebulized MgSO4 in children with acute asthma attack. Secondly, pharmacokinetic studies have shown that the onset time of MgSO4 was not identical due to different delivery routes. Meral et al. [16] and Mangat et al. [18] demonstrated that the effect of nebulized MgSO4 could continue for 1h. But we only observed changes of lung function at 10 min and 20 min, which could not accurately describe the relationship between the bronchodilatory effect of MgSO4 and its duration of action. Thirdly, hyperosmolar solutions delivered by a jet nebulizer might induce bronchoconstriction, so we chose a 7.5% solution of isotomic MgSO4. However, the osomolarity in [AþM] group has changed as the concentration of MgSO4 reduced from 7.5% to 6% in present study, which might affect the synergistic effect of nebulized albuterol and MgSO4. Otherwise, the concentration and the dose of MgSO4 used in our study differed from studies of Nannini et al. (7.5%, 3 ml) [19], Mahajan et al. (6.3%, 2.5 ml) [12] and Meral et al. [16] (280 mmol/ l, 2 ml) which might lead to inconsistent conclusions. Whether there is a dose response relationship between the concentration, dose and effect needs to be addressed by future studies. We aimed our study to determine whether a single dose of nebulized MgSO4 alone has bronchodilatory effect and the combination of MgSO4 and albuterol has a synergistic effect. In the present study, we could not answer repeated doses of these agents would be sustainable in improvement of FEV1 and PEF. Finally, Coates et al. [20] demonstrated superior performance of Aeroneb Go/Idehaler system with respect to pulmonary aerosol delivery and optimal particle size while maintaining acceptable osmolarity. Unlike above studies, we used 8 10 l/min of oxygen to deliver each medication, which might have impact on airway deposition. In present study, there were seven patients with poor response to inhalation of MgSO 4. None of the patients in our study showed any adverse reactions or side effects, which means the use of nebulized magnesium in children was safe. Conclusion The present study showed that nebulized MgSO 4 alone has bronchodilatory effect in asthmatic children with Ach-induced bronchoconstriction, but the improvement in FEV1 and PEF was not better than nebulized albuterol alone. In addition, the synergistic effect of combination of magnesium sulfate and albuterol has not been demonstrated, and the dose response time relationship needs to be explored in future studies. References 1. 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7 17. Bhatnagar P, Guleria R, Kukreti R. Pharmacogenomics of beta2-agonist: key focus on signaling pathways. Pharmacogenomics 2006;7: Mangat HS, D Souza GA, Jacob MS. Nebulized magnesium sulphate versus nebulized salbutamol in acute bronchial asthma: a clinical trial. Eur Respir J 1998;12: Nannini LJ Jr, Pendino JC, Corna RA, et al. Magnesium sulfate as a vehicle for nebulized salbutamol in acute asthma. Am J Med 2000;108: Coates AL, Leung K, Vecellio L, et al. Testing of nebulizers for delivering magnesium sulfate to pediatric asthma patients in the emergency department. Resp Care 2011;56: Journal of Tropical Pediatrics Vol. 60, No