Elsevier

The Lancet

Volume 361, Issue 9375, 21 June 2003, Pages 2114-2117
The Lancet

Articles
Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in treatment of severe asthma in adults: randomised placebo-controlled trial

https://doi.org/10.1016/S0140-6736(03)13721-XGet rights and content

Summary

Background

Intravenous magnesium can cause bronchodilation in treatment of severe asthma, however its effect by the nebulised route is uncertain. We aimed to assess the effectiveness of isotonic magnesium sulphate as an adjuvant to nebulised salbutamol in severe attacks of asthma.

Methods

We enrolled 52 patients with severe exacerbations of asthma presenting to the emergency departments at two hospitals in New Zealand. A severe exacerbation was defined as a forced expiratory volume at 1 s (FEV1) of less than 50% predicted 30 min after initial administration of 2·5 mg salbutamol via nebulisation. In this randomised double-blind placebo-controlled trial patients received 2·5 mg nebulised salbutamol mixed with either 2·5 mL isotonic magnesium sulphate or isotonic saline on three occasions at 30 min intervals. The primary outcome measure was FEV1 at 90 min. Analysis was per protocol.

Findings

At 90 min the mean FEV1 in the magnesium group was 1·96 L (95% CI 1·68–2·24) and in the saline group 1·55 L (1·24–1·87). The difference in the mean FEV1 between the magnesium and saline groups was 0·37 L (0·13–0·61, p=0·003).

Interpretation

Use of isotonic magnesium as an adjuvant to nebulised salbutamol results in an enhanced bronchodilator response in treatment of severe asthma.

Introduction

Magnesium is an inorganic cation that is a cofactor in many intracellular phosphorylation processes. Hypomagnesaemia has been implicated in chronic asthma through mechanisms involving modulation of inflammatory processes.1, 2 Magnesium is also a powerful relaxant of smooth muscle in the airway,3, 4 and this is the mechanism through which intravenous magnesium is proposed to have a substantial bronchodilator effect in treatment of severe exacerbations of asthma in children and adults.5, 6, 7, 8, 9, 10, 11, 12 However, this mode of administration requires careful monitoring, since peripheral vasodilation and systolic hypotension can occur and patients sometimes have unpleasant flushing, nausea, and venous phlebitis from the infusion.

Previous attempts to administer magnesium by nebulisation have shown mixed results. Results of some13, 14 but not all15 studies have shown that magnesium administered in this way before challenge testing can cause a dose-dependent reduction in bronchial hyperresponsiveness. In stable asthma, results of a doseresponse study16 indicated that inhaled magnesium does not act as a bronchodilator. In acute exacerbations of asthma in adults, Mangat and colleagues17 have shown that nebulised magnesium results in a bronchodilator response similar in magnitude to salbutamol. A similar study in children18 reported that whereas inhalation of magnesium has a bronchodilator effect in acute asthma, the magnitude and duration of the effect was less than that due to salbutamol.

The effect of magnesium administered as an adjunct to nebulised salbutamol has been investigated in two studies.19, 20 Nannini and colleagues19 reported that administration of a single 2·5 mg dose of salbutamol with adjuvant magnesium sulphate caused a significantly greater improvement in peak expiratory flow than salbutamol administered in isotonic saline in patients with asthma and severe airflow obstruction. By contrast, Bessmertny and colleagues20 reported that use of adjunct magnesium provides no benefit to that of nebulised salbutamol therapy in adult patients in moderately severe exacerbations of asthma.

We have therefore undertaken a randomised placebocontrolled trial to investigate the effectiveness of nebulised isotonic magnesium sulphate as an adjuvant to salbutamol administered by nebuliser according to a standard emergency department protocol for treatment of severe asthma.

Section snippets

Participants

We invited all patients aged between 16 and 65 years who presented between July, 2000, and June, 2001, with severe attacks of asthma to the emergency departments of two university hospitals in New Zealand to participate in the study. Inclusion in the study required a known history of asthma, and presentation with a severe exacerbation with a recorded forced expiratory volume in 1 s (FEV1) of less than 50% predicted normal values. We excluded patients if they needed immediate intubation or had

Results

We initially enrolled 58 patients, six of whom were subsequently excluded after a review of their hospital notes revealed a history of chronic obstructive pulmonary disease (n=4) or there was radiographic evidence of pneumonia (n=2; figure 1). Of the 52 patients remaining, we randomly allocated 28 to the magnesium adjuvant group. Table 1 shows patients' baseline characteristics. Of note, prehospital use of inhaled β agonist was high in both groups.

At 90 min (30 min after the third

Discussion

Our results showed that use of isotonic magnesium sulphate as an adjuvant to salbutamol nebuliser solution results in an enhanced bronchodilator response in severe asthma. Administration of the salbutamol nebuliser solution with the magnesium adjuvant resulted in about twice the increase in FEV1 than the same dose of salbutamol administered with an isotonic saline nebuliser solution.

We considered several methodological issues in the design of the study that are relevant to its interpretation.

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