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REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE Acta Pædiatrica ISSN 0803-5253 Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for
REGULAR ARTICLE
REGULAR ARTICLE

Acta Pædiatrica ISSN 0803-5253

Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for children with acute severe asthma

Sunit Singhi (sunit.singhi@gmail.com), Sudhanshu Grover, Arun Bansal, Kapil Chopra

Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Keywords

Acute asthma, Aminophylline, Children, Magnesium sulphate, Terbutaline

Correspondence

Prof. Sunit C. Singhi, MBBS, MD, FIAP, FAMS,

FISCCM, FICCM, FCCM, Head, Department of Pediatrics and Pediatric Emergency and Intensive care, Post graduate Institute of Medical Education And Research, Chandigarh 160012, India. Tel: +91 172 2755301 and 2755302 | Fax: +91 172 2747099 and 2744401 | Email: sunit.singhi@gmail.com

Received

27 January 2014; revised 16 July 2014;

accepted 18 August 2014.

DOI:10.1111/apa.12780

ABSTRACT

Aim: This study compared the efficacy of intravenous magnesium sulphate, terbutaline and aminophylline for children with acute, severe asthma poorly responsive to standard initial treatment. Methods: We enrolled 100 children, aged one to 12 years, who had failed to respond to initial standard treatment for acute, severe asthma, in this randomised controlled trial. They received either intravenous magnesium sulphate, terbutaline or aminophylline. Responses were monitored using a modified Clinical Asthma Severity (CAS) score. The primary outcome was treatment success, defined as a reduction in the CAS of four points or more 1 h after starting the intervention. Results: The magnesium sulphate group had higher treatment success (33/34, 97%) than the terbutaline and aminophylline groups (both 23/33, 70%) (p = 0.006) and faster resolution of retractions, wheeze and dyspnoea (p < 0.001). No adverse events occurred among patients receiving magnesium sulphate, but two patients receiving terbutaline had hypokalemia and nine patients receiving aminophylline had nausea and, or, vomiting. Conclusion: Adding a single dose of Intravenous magnesium sulphate to inhaled beta2- agonists and corticosteroids was more effective, and safer, than using terbutaline or aminophylline when treating a child with acute severe asthma poorly responsive to initial treatment.

INTRODUCTION

Asthma is one of the most common chronic diseases in children. Estimates suggest that the prevalence of childhood asthma varies from 10 to 30% in various geographical regions and that it is increasing globally by 50% every decade (1,2). Poorly controlled asthma is associated with significant morbidity and socio-economic consequences (3). Intermittent acute exacerbations are common and are characterised by episodes of coughing, respiratory distress, dyspnoea, wheezing, low arterial oxygen saturation and a widespread reduction in airflow (4). Acute severe exacer- bations are potentially life-threatening and often need hospitalisation. In our hospital, acute asthma is the third most common paediatric emergency (5). The emergency management of acute exacerbations includes rapidly assessing the severity, correcting hypoxa- emia, relieving breathing difficulties using therapies to reverse bronchospasms and inflammation of the airways, monitoring responses and stepping up therapy if the patient remains unresponsiveness (6,7). Initial treatment includes

Abbreviations

CAS, Clinical Asthma Severity; SpO2, Oxygen saturation.

oxygen, inhaled short acting beta2-agonists and ipratropi- um, and oral or parenteral corticosteroids (6,8). In acute severe exacerbations that show incomplete or poor response to initial treatment, additional interventions that are commonly considered are intravenous administration of magnesium sulphate, beta2-agonists in the form of terbutaline or salbutamol or aminophylline (68). There is no clear evidence to support which of these options is most effective. Therefore, the aim of this study was to compare the efficacy and safety of intravenous magnesium

Key notes

This study compared the efficacy of intravenous mag- nesium sulphate, terbutaline and aminophylline for children with acute, severe asthma who did not respond well to standard treatment. We enrolled 100 children, from one to 12 years of age and the primary outcome, treatment success, was measured using the Clinical Asthma Severity score. Adding a single dose of Intravenous magnesium sulphate to inhaled beta2-agonists and corticosteroids was more effective, and safer, than terbutaline or aminophylline.

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sulphate, terbutaline and aminophylline in reversing symp- toms of acute severe asthma in children who responded poorly to standard initial treatment.

MATERIAL AND METHODS

We enrolled 100 children aged from one to 12 years of age, with acute severe asthma poorly responsive to standard initial treatment, in a randomised open label controlled trial. The study was conducted in paediatric emergency unit of a teaching hospital in north India from 1 January 2008 to

  • 30 November, 2009. Other inclusion criteria were at least

three previous episodes of physician-diagnosed asthma treated with beta2-agonists and written informed consent from the parents. We excluded patients with an axillary temperature of more than 38°C, significant acute or chronic pulmonary diseases other than asthma, congenital or acquired heart disease, renal disease or hypotension. The study was approved by the ethics committee of the institute. The patients were assessed and monitored using a Clinical Asthma Severity (CAS) score, which is a modified version of a pulmonary index (9) and includes respiratory rate, wheeze, retractions, dyspnoea and oxygen saturation

(SpO 2 ) measured by pulse oximetry (Novametrix , Wallingford, Connecticut, USA). Each parameter was scored from zero to three with a maximum total score of

  • 15 (Table S1).

Enrolment and randomisation

All patients who presented to the paediatric emergency department with acute severe asthma were initially treated with oxygen inhalation (6 L/min), three nebuliser doses of salbutamol (0.15 mg/kg/dose), budesonide (800 lg/dose) and ipratropium bromide (250 lg/dose) every 20 min for 1 h and one dose of hydrocortisone (10 mg/kg) after the first nebulisation. The nebuliser doses were delivered using a Micromist nebulisation chamber (Hudson RCI , Research Triangle Park (Durham), NC, USA). Changes in the CAS score was recorded at the end of 1 h and the

patients who showed a poor response, defined as the CAS score improving by <4 points after the first hour of treatment, were consecutively enrolled. Patients were randomly allocated to three groups, A, B and C, by block randomisation. The blocks were permuted, randomly varied in size and were in multiples of three. A computer generated randomisation list was generated by a person not directly involved with the data collection, analysis or interpretation. The individual assignments were placed in opaque, serially numbered, sealed envelopes and were only opened after the parents had provided written consent. The intervention arms were not masked because of the nature of the study, but the statistician was blinded to the treatment assignment until the initial analysis.

Intervention and data recording

Group A received magnesium sulphate (50% solution of

  • 50 mg/kg in 30 ml 0.18% saline in D5W) as an intravenous

infusion over 20 min. Group B received intravenous

terbutaline (0.05% solution in 0.9% saline, 10 lg/kg as a bolus, followed by 0.1 lg/kg/min given as an intravenous infusion, which was stepped up by 0.1 lg/kg/min to a maximum dose of 1 lg/kg/min) until they responded. Group C received intravenous aminophylline (5 mg/kg bolus, followed by 0.9 mg/kg/h) until their symptoms resolved. All subjects continued to receive oxygen and continuous nebulised salbutamol (0.3 mg/kg/h) in line with our standard protocol (6). The individual elements of the CAS score were recorded by specially trained paediatric residents, at baseline, one, two, four, eight and 12 h after the infusion started, and this training continued after the study. The patients were also carefully assessed and monitored for skin flushing, warmth or burning at the intravenous site, hypotension, hypertension, respiratory failure, hypo-active tendon reflexes, tachycardia (a heart rate of 10% above the baseline) and electrocardio- graphic changes (prolonged PR, QRS and QT, heart block, arrhythmia). Blood sugar and serum electrolytes were mea- sured at baseline, and at six and 12 h after enrolment, to check for hyperglycaemia, and hypokalemia.

Outcome measures

The primary outcome was treatment success, defined as an improvement of four or more points in the CAS 1 h after starting the interventional drug. Secondary outcomes were trends in the CAS score over 12 h, the number of hours

from enrolment to resolution of wheeze, retractions and dyspnoea and the frequency of adverse events.

Statistical analysis

Data entry and statistical analysis were performed using Microsoft Excel and SPSS software version 15, respec- tively. Normally distributed continuous variables were summarised as means and standard deviations and ordinal variables (CAS scores) as medians and interquartile ranges (IQR). The proportions were compared using the chi-square test. The change in CAS scores over time across three groups was compared with repeated measures analysis using mixed

linear models. The dependent variable was the CAS score. The fixed effects included the intercept, the group to which the patient belonged, and the interaction between each group and time. The random effect was intercept and time. An autoregressive covariance structure was used and the model converged. A two-way RM-ANOVA was performed to analyse the interaction between the groups and the overall change in respiratory rate and oxygen saturation over time, after testing for normality of distribution and equality of variances using Levene’s test. KaplanMeier analysis was used to estimate the time since enrolment to resolution of wheeze, retraction and dyspnoea. All tests were two-tailed, and a p value of <0.05 was considered significant.

OBSERVATIONS AND RESULTS

Of the 358 patients who were treated for acute severe

exacerbation of asthma during the study period, 104 responded poorly to initial treatment (Figure S1) and 100

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were enrolled. They were split into three groups, with 34 in the magnesium sulphate group and 33 each in terbutaline and aminophylline groups. The study groups were similar with respect to demographic and baseline clinical charac- teristics. All the patients had wheeze, retractions and dyspnoea, but the respiratory rates were somewhat lower in the magnesium sulphate group (Table 1). The proportion of patients with treatment success, defined as an improvement in the CAS score of four or more points after 1 h, was significantly higher in the magnesium sulphate group (33 of 34, 97%), than the terbutaline (23 of 33, 70%) and aminophylline groups (23 of 33, 70%) (p = 0.006). The magnesium sulphate group performed better than the terbutaline and aminophylline groups on all of the components of the CAS score at the end of the first hour (Table 2). Analysis of trends in the CAS scores over times showed that the overall CAS scores were significantly different in the three groups (Figure 1). They declined significantly over time and the rate of that decline differed in the three groups.(Table S2). The decline in CAS scores over time in the magnesium sulphate group was significantly greater than the other groups (Figure 1, Table S2). The improvement in respiratory rate and oxygen satura- tion over time was also significantly greater in the magne- sium sulphate group (Figure S2). Using the KaplanMeier analysis, we found that the resolution of wheeze, retractions and dyspnoea occurred significantly earlier in the magne- sium sulphate group than the other two groups (Table 2). There were no adverse events in the magnesium sulphate group, but two patients in the terbutaline group had

hypokalemia and nine patients in the aminophylline group had nausea and, or, vomiting. The blood pressure levels in the magnesium sulphate group were similar to the other two groups, but the heart rates were consistently higher in the terbutaline group (Figure S3).

DISCUSSION

We found that a single dose of intravenous magnesium sulphate resulted in a significant improvement in the CAS scores and other monitored parameters at the end of the first hour of treatment, when compared to treatment with terbutaline or aminophylline. We used a clinical scoring system that included a combination of symptoms, signs and an objective measure of oxygenation to evaluate the efficacy of the three drugs (9). We did not correlate the CAS scores with parameters such as forced expiratory volume in 1-sec

or peak expiratory flow rate. Nonetheless, such clinical scores have been used as objective and reproducible measures of the severity of acute asthma exacerbations in previous studies (10), are simple to apply and provide clinically relevant measures of the severity of the condition and the patient’s response to treatment. Our finding is consistent with findings of a meta-analysis of five randomised controlled trials in children from one to 18 years of age, which showed that intravenous magnesium sulphate decreased hospitalisations and improved pulmo- nary function and symptom scores (11). The doses of magnesium sulphate that we used reached levels that have bronchodilator and anti-inflammatory effects (12). These effects are mediated through inhibition of the release of

Table 1 Demographic and baseline clinical characteristics of the three study groups at the time of randomisation

 

Magnesium sulphate (n = 34)

Terbutaline (n = 33)

Aminophylline (n = 33)

p-Value

Age, years*

5.0 (3.08.5)

4.0 (2.58.0)

4.0 (3.08.0)

0.115

Sex, boys:girls

18:16

23:10

24:9

0.186

Number (percentage) of patients

16 (47%)

14 (42%)

14 (42%)

ns

hospitalised in the past Number of patients on inhaled beta2-agonists and, or, inhaled steroids

27 (79%)

24 (73%)

22 (67%)

ns

CAS Scores

10 (911)

10 (9.512)

11 (9.512)

0.061

Respiratory rate/min

52 (6)

57 (8)

59 (8)

0.001

SpO2, %

94.2 (1.3)

94.8 (1.8)

95 (1.8)

0.107

Heart rate per min

132 (10)

136 (11)

136 (11)

0.814

Systolic BP, mm Hg*

102 (100110)

102 (98110)

104 (97106)

0.927

Diastolic BP, mm Hg*

68 (6470)

66 (6270)

66 (6270)

0.573

PulsusParadoxus, mm Hg*

24 (2226)

22 (2224)

22 (2224)

0.200

Blood gas pH*

7.37 (7.347.39)

7.34 (7.327.38)

7.35 (7.347.38)

ns

pCO 2 *

35 (30.339.0)

37 (30.438.8)

35 (29.038.6)

ns

Number of patients

30

16

31

CAS = Clinical Asthma Severity; SpO2 = Oxygen saturation by pulse oximetry. *Median (95% CI). Mean (SD). Includes those on regular inhaled salbutamol and or budesonide by metered dose inhalers.

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Table 2 Secondary outcomes in three treatment groups

 

Magnesium Sulphate (n = 34)

Terbutaline (n = 33)

Aminophylline (n = 33)

p-Value

At the end of 1 h Improvement in CAS scores, median (IQR)

7 (58)

5 (37)

5 (37)

0.002

Fall in respiratory rate (breaths/min)

16 (4)*

10 (7)

11 (10)

0.003

Increase in SpO 2 percentage Number of patients at the end of 1h having

3.4 (1.6)*

1.8 (1.6)

1.5 (2.1)

0.001

Wheeze

19 (57%)

31 (91.2%)

30 (88.2%)

0.001

Retraction

15 (45.5%)

25 (73.5%)

24 (70.6%)

0.038

Dyspnoea

11 (33%)

23 (67.6%)

24 (70.6%)

0.002

Length of time in hours from enrolment to resolution of Wheeze

2 (1.22.7)

8.0 (1.614.4)

8.0 (3.912.2)

0.001

Retraction

1.1 (0.41.1)

4.0 (2.55.5)

8.0 (4.911.1)

0.001

Dyspnoea

1.0 (0.351.65)

4.0 (2.65.3)

4.0 (2.75.3)

0.001

To reach CAS Score <4

1.65 (1.052.4)

4.0 (1.96.1)

4.0 (2.45.6)

0.001

*Mean (SD). Median (95% CI).

Drugs for acute severe asthma Singhi et al. Table 2 Secondary outcomes in three treatment groups

Figure 1 Trend of Clinical Asthma Severity (CAS) Scores over 12 h in the three study groups (Terbutaline group, Aminophylline group and Magnesium sulphate group).

calcium from vesicles in the sarcoplasmic reticulum, which relaxes the bronchial smooth muscle (13), reduction in the neutrophilic respiratory burst associated with inflammation (14) and inhibition of the release of histamine from mast cells (15). The use of intravenous beta2-agonists, such as terbuta- line, for treating severe asthma has been controversial. Studies have shown that terbutaline significantly shortened the length of stay in an intensive care unit and reduced hospital charges (16) and a single dose of intravenous salbutamol over 10 min resulted in faster relief of symptoms and early discharge than a placebo (17). However, other studies and a systematic review have concluded that the

evidence to support the use of intravenous beta2-agonists in acute severe asthma is inadequate (18,19). Very limited evidence supports the theory that adding intravenous beta2- agonists to inhaled beta2-agonists shortens the recovery time and improves pulmonary index scores (20). Higher doses of terbutaline may lead to better efficacy, but this has been associated with higher incidence of adverse cardiac events (20). We found that intravenous aminophylline and beta2- agonists had similar efficacy with respect to recovering CAS scores and oxygen saturation. This is in line with the conclusion of a recent systematic review, which stated that there was no consistent evidence favouring either intrave- nous beta2-agonists or aminophylline for acute asthma (21). The use of aminophylline may be appropriate in children with severe acute exacerbations that have not responded to maximal inhaled bronchodilators and sys- temic steroids (22). A survey among emergency physicians in the USA and Canada revealed that even though they were aware of evidence supporting the use of intravenous magnesium sulphate in severe acute asthma in children, they were reluctant to use it because they were concerned about the risk of hypotension (23). Our finding that a single dose of magnesium sulphate was safe and did not cause hypoten- sion, or any other significant adverse event, together with the results of previous studies (12,24), should help allay these concerns. On the other hand, terbutaline can cause hypokalemia and tachycardia, and aminophylline can cause nausea and vomiting in a significant number of patients

(21,22).

There are some limitations to our study. Firstly, no formal attempt was made to determine the inter-rater or intrarater agreement for the CAS scores recorded by the paediatric residents. We regarded the CAS scores as an objective and reproducible measure and regularly trained, and retrained, the paediatric residents involved in the data collection on

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how to apply the CAS score. Secondly, the study was not double blind. However, it was not feasible to use two placebo infusions, or prepare similar looking dosage forms, because the composition and rates of infusion of the study drugs were too heterogeneous. Thirdly, we did not formally look for infections caused by respiratory syncytial virus. However, we excluded patients under 1 year of age, febrile patients with wheeze and patients having their first or second episode of wheezing. The major strength of the study was the use of clinical assessments for therapeutic decisions in a paediatric emergency setting, as this enhances the general applicability of our results to similar settings elsewhere. The sample size seemed to be adequate, as a post hoc calculation for 80% power and a 5% alpha error showed that the required sample size for the observed effect size was 26 patients per group. In conclusion, the addition of a single dose of intravenous magnesium sulphate to inhaled beta2-agonists and corti- costeroids led to faster resolution of acute severe asthma in patients who responded poorly to standard initial treat- ment, compared to intravenous boluses and infusions of terbutaline and aminophylline. The efficacy of aminophyl- line and terbutaline was similar. There is a need to compare these three drugs using multicentre studies in different geographical regions, to draw clear guidelines on the best therapy for children who respond poorly to standard initial treatment for acute severe asthma.

ACKNOWLEDGEMENTS

We are grateful to Mr Rakesh Mohindra, Statistician, and

Dr Saurabh Dutta, Additional Professor of Pediatrics, for the data analysis and to Dr Joseph Mathew, Associate Professor, and Professor Pratibha Singhi for critical review of the manuscript.

FUNDING

No specific funding was received.

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SUPPORTING INFORMATION

Additional Supporting Information may be found in the

online version of this article:

Table S1 Clinical Asthma Severity (CAS) scoring system. Table S2 Results of mixed linear model analysis of changes in the CAS scores over time in the three study groups.

Figure S1 Flowchart showing enrolment and allocation of patients to the three study groups. Figure S2 Trends of oxygen saturations and respiratory rates in the three study groups over 12 h. Figure S3 Trends of heart rates and blood pressures over 12 h in the three study groups.

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