Asthma is one of the most common chronic disorders worldwide and symptom control is often elusive. Exacerbations are common in response to various triggers such as upper respiratory tract infections, air pollution,1 occupational irritants,2 and failure to adhere to appropriate management regimens. Mild exacerbations might be manageable by primary-care doctors; however, moderate-to-severe acute asthma attacks often need assessment in an emergency department. The accepted approach to acute asthma is to relieve acute bronchospasm, start treatments addressing airway oedema, identify the cause, and observe the patient for response or complications. Although most patients can be discharged home after assessment and treatment, some individuals require extended observation or hospital admission.
Numerous national and international guidelines exist to guide management of acute asthma.3—5 Most recommend short-acting β-agonists such as salbutamol with metered-dose inhalers or nebulisers,6 short-acting anticholinergics such as ipratropium, and systemic corticosteroids (either by oral or intravenous routes)7 for the treatment of acute asthma. In severe asthma, additional treatment such as intravenous magnesium sulphate (MgSO4),8 inhaled corticosteroids, and epinephrine (intramuscular or nebulised) can be considered. In the most severe cases, clinicians require interventions that reduce the risk of airway complications (ie, intubation), hospital admissions, and other serious sequelae.
The role of MgSO4 for treatment of asthma is evolving rapidly. Magnesium is an important intracellular and extracellular cation and is a cofactor of important intracellular enzymatic reactions.9 Magnesium may act in acute asthma through various mechanisms; for example, it can directly relax smooth muscles, and might be involved with inhibition of smooth-muscle contraction. It is also involved in acetylcholine release from cholinergic nerve terminals and histamine release from mast cells. Moreover, the effect of magnesium might be related to its ability to block the calcium ion influx to respiratory smooth muscles.10 Finally, an anti-inflammatory action has been shown.11 Overall, magnesium is an element with many complex functions in asthma; however, the precise mechanisms and their relative importance are unclear.
MgSO4 asthma treatment can be delivered via nebulised or intravenous routes. Two new trials12, 13 in The Lancet Respiratory Medicine expand our understanding of the efficacy of these modes of delivery. Although randomised controlled trials provide strong evidence, risk of bias means that not all trials are equally valid.14 In these two trials, however, the methodological rigour deserves special mention. Both trials were funded by unbiased sources, registered, and undertaken with the highest methodological quality (eg, appropriate sequence generation, randomisation, masking, outcome assessment, attention to loss to follow-up, and comprehensive reporting). In addition to their high-quality methods, the large sample sizes assessed suggests the evidence presented is at a low risk of bias. Although one trial should not generally result in practice change, incorporation of trial findings into systematic reviews and the totality of evidence clearly should lead to practice changes.
One of these trials, MAGNETIC,12 was a randomised trial of nebulised MgSO4 in children aged 2—16 years presenting with severe acute asthma to 30 hospital emergency departments in the UK.12 All patients received nebulised salbutamol and ipratropium bronchodilator treatments and either three nebulised treatments of isotonic MgSO4 or a saline placebo every 20 min. Overall, 227 patients received nebulised MgSO4, which resulted in significantly lower asthma severity scores in the adjusted primary analysis after 60 min than were noted in 243 children in the placebo group. This effect was largest in children with the severest asthma exacerbations. However, the investigators noted no differences in hospital admission, intravenous bronchodilator use, or length of inpatient stay for children treated with MgSO4 or placebo.
This new evidence for inhaled treatment needs to be interpreted in view of the systematic review of nebulised MgSO4 available in the present version of the Cochrane library.15 Overall, 16 studies (seven of adults, four of children, three mixed, and two unclear) of 896 patients examined the use of nebulised MgSO4 in acute asthma. Overall, seven studies examined the same comparison as the MAGNETIC trial, and the evidence failed to identify important differences (in pulmonary functions, admission, or symptom scores) in adults or children associated with inhaled MgSO4. Although reassurance was provided that the treatment was safe, the cumulative evidence fails to support the use of nebulised MgSO4, apart from perhaps in severe acute paediatric asthma.
The second trial, 3Mg, was a double-blind, randomised controlled trial enrolling adults with severe acute asthma undertaken in 34 hospital emergency departments in the UK.13 1084 patients received nebulised short-acting β-agonists, short-acting anticholinergics, and systemic corticosteroids at baseline and were then randomly allocated to receive 2 g of intravenous MgSO4, a cumulative dose of 1500 mg of nebulised MgSO4, or standard care. At 2 h, the investigators noted no difference for admission among the groups; however, there was a small difference between intravenous and nebulised magnesium groups with respect to breathlessness scores. The authors concluded there was no role for nebulised MgSO4 in the management of severe acute asthma in adults and at best only a limited role for intravenous MgSO4. However, the outcome assessment could be considered premature compared with many other emergency department studies and the trial included patients with less severe asthma than have been assessed in other MgSO4 trials. Moreover, the data do suggest a potential trend in favour of intravenous MgSO4, which when added to the systematic review evidence, supports its use in some situations.
The original systematic review8 of intravenous MgSO4 was published in the Cochrane Library in 2000 and uptake of use of intravenous MgSO4 was relatively rapid.16 That review, and other trials published since then, provided variable support for the role of intravenous MgSO4 in acute asthma. The original systematic review included 13 studies (eight in adults and five in children) of 965 patients and examined the addition of intravenous MgSO4 to short-acting β-agonists and systemic corticosteroids. A subsequent systematic review17 confirmed some of these earlier results but called for additional research to clarify others. Although the evidence in all severity groups was heterogeneous, intravenous MgSO4 reduced rates of hospital admission by about 40% and improved pulmonary function in severe acute asthma (ie, admission rates >30%). Nevertheless, the 3Mg trial reconfirms the absence of efficacy of intravenous MgSO4 in the treatment of moderate acute asthma. Notably, intravenous treatment was relatively safe in 3Mg and is inexpensive but until additional research is published, intravenous MgSO4 use should be restricted to adults with severe acute asthma.
Overall, the two trials need to be considered in view of all of the available evidence from systematic reviews. Both nebulised and inhaled MgSO4 seem efficacious in children with severe acute asthma. Conversely, the cumulative evidence of efficacy of inhaled MgSO4 in adults is limited. Although intravenous MgSO4 should be restricted to those patients who are unresponsive to bronchodilators or who have very severe asthma, these individuals are precisely the patients in whom aggressive management could prevent serious adverse events.
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