Abstract
Introduction
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild to moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This overview does not endorse or follow any particular protocol, but presents the evidence about a specific intervention, magnesium sulfate.
Methods and outcomes
We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of magnesium sulfate for acute asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).
Results
At this update, searching of electronic databases retrieved 50 studies. After deduplication and removal of conference abstracts, 24 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 10 studies and the further review of 14 full publications. Of the 14 full articles evaluated, one systematic review was updated and one systematic review was added at this update. We performed a GRADE evaluation for five PICO combinations.
Conclusions
In this systematic overview, we categorised the efficacy for two comparisons based on information about the effectiveness and safety of magnesium sulfate (iv) versus placebo and magnesium sulfate (nebulised) plus short-acting beta2 agonists (inhaled) versus short-acting beta2 agonists (inhaled) alone.
Key Points
About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. These people have an increased risk of death.
Most guidelines about the management of asthma follow stepwise protocols. This overview does not endorse or follow any particular protocol, but presents the evidence about a specific intervention, magnesium sulfate.
Inhaled short-acting beta2 agonists given in conjunction with systemic corticosteroids are considered the mainstay of treatment for acute asthma exacerbations.
The previous version of this overview on treatments for acute asthma in adults included a range of comparisons, such as controlled oxygen supplementation, corticosteroids, corticosteroids (inhaled), education about acute asthma, formoterol (inhaled), helium-oxygen mixture (heliox), ipratropium bromide (inhaled) plus short-acting beta2 agonists (inhaled), magnesium sulfate (nebulised), mechanical ventilation for people with severe acute asthma, oral corticosteroids alone, short-acting beta2 agonists, short-acting beta2 agonists delivered by metered-dose inhalers plus spacer devices/holding chambers, and specialist care.
This updated overview focuses on magnesium sulfate (iv) alone and magnesium sulfate (nebulised) plus short-acting beta2 agonists. Magnesium sulfate is an airway smooth muscle relaxant that has been used as a bronchodilator in patients with acute asthma. Its safety and efficacy have not previously been confirmed, and its use has been considered controversial.
As a result, the use of magnesium sulfate in acute asthma has been the focus of several studies published since the previous version of this overview. In contrast, there have been very few studies of other treatments of acute asthma in adults since the last overview.
We have searched for evidence from RCTs and systematic reviews of RCTs on the effectiveness and safety of magnesium sulfate (iv) alone and magnesium sulfate (nebulised) plus short-acting beta2 agonists in adults with acute asthma.
We don't know if adding nebulised magnesium to inhaled beta2 agonists improves lung function in people with acute asthma.
There is insufficient evidence to demonstrate a beneficial effect on lung function, symptoms, or hospital admissions when nebulised magnesium is added to standard therapy. Some studies suggest that patients presenting with severe disease may benefit, but the data are not conclusive.
The use of iv magnesium sulfate in adults with acute asthma appears to have a modest effect in reducing hospital admissions in patients who have failed to respond to standard therapy and may prevent seven admissions for every 100 patients.
We don't know whether iv magnesium sulfate is more effective for patients who present with a more severe attack.
We don't know the optimum dose or method of administration of iv magnesium sulfate in acute asthma exacerbations.
We don't know whether iv magnesium sulfate improves clinical outcomes if given to patients with acute asthma in the pre-hospital setting.
Intravenous magnesium sulfate appears to be well tolerated without significant adverse effects, other than minor flushing.
Clinical context
General background
Asthma is a common and heterogeneous chronic condition affecting 1 in 12 adults in the UK, characterised by variability in clinical symptoms and airflow obstruction. Sudden severe exacerbations or acute attacks of asthma may be unpredictable and life threatening; many occur in patients with severe asthma, but patients with mild disease are also at risk. Acute asthma often develops slowly over several hours, meaning that there is often sufficient time for therapeutic intervention to prevent hospital admissions. Despite this, there were 54,300 emergency hospital admissions for acute asthma in the UK in the 12 months to May 2014.
Focus of the review
There has been a lack of recent studies of the treatment of adults with acute severe asthma, with the exception of those evaluating the effects of magnesium sulfate. Magnesium sulfate is an airway smooth muscle relaxant that has been used as a bronchodilator in patients with acute asthma in conjunction with standard therapy. Its safety and efficacy have not previously been confirmed, and its use has been considered controversial.
Comments on evidence
Interpretation of the studies of inhaled and intravenous magnesium sulfate in acute asthma in adults is hindered by wide variations in study methods. Particularly important are the differences in treatments given to control populations, which reflect variation in standard treatment guidelines between different healthcare settings. The use of systemic corticosteroids, nebulised beta2 agonists, and additional nebulised ipratropium is widely considered by clinicians to provide optimum treatment; and we have evaluated the evidence for magnesium as an additional treatment rather than an alternative bronchodilator. Some studies have suggested that magnesium treatment, particularly via the intravenous route, has a particular benefit in patients who present with severe features but, again, interpretation of the data here is difficult due to inconsistencies in the definition and categorisation of severity. Given the heterogeneous nature of asthma, this is an important caveat. Furthermore, many studies exclude patients with life-threatening asthma, making it difficult to generalise the findings to this patient population. This is problematic because, outside of clinical trials, it is often those patients presenting with life-threatening features who are considered for magnesium therapy when standard treatment regimens fail to control the disease. Additional limitations in the available evidence relate to differences in the dose, route, and precise method of administration of magnesium; and it remains possible that alternative dose regimens may have different effects. An important aim of treatment is to prevent hospital admissions, but consideration of this outcome variable between different trials is also problematic because hospital admission rates are likely to be dependent on several factors, including the organisation of healthcare, delays in presentation, psychosocial factors, and the availability and quality of community care. The findings of this overview are confined to acute asthma in adults; there appears to be a differential benefit from intravenous magnesium in children, and paediatric studies are not considered in this evaluation.
Search and appraisal summary
The update literature search for this overview was carried out from the date of the last search, April 2010, to November 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 50 studies. After deduplication and removal of conference abstracts, 24 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 10 studies and the further review of 14 full publications. Of the 14 full articles evaluated, one systematic review was updated and one systematic review was added at this update.
About this condition
Definition
Asthma is a common and heterogeneous chronic condition affecting 1 in 12 adults in the UK,[1] characterised by variability in clinical symptoms and airflow obstruction. Sudden severe exacerbations or acute attacks of asthma may be unpredictable and life threatening; many occur in patients with severe asthma, but patients with mild disease are also at risk. Acute asthma often develops slowly over several hours, meaning that there is often sufficient time for therapeutic intervention to prevent hospital admissions. Despite this, there were 54,300 emergency hospital admissions for acute asthma in the UK in the 12 months to May 2014.[2] Acute asthma is defined here as an exacerbation of underlying asthma requiring urgent treatment. Most guidelines about the management of asthma follow stepwise protocols. This overview does not endorse or follow any particular protocol, but it focuses on the effectiveness and safety of magnesium sulfate (iv) alone and magnesium sulfate (nebulised) plus short-acting beta2 agonists in adults with acute asthma.
Incidence/ Prevalence
The lack of a gold-standard definition of asthma, along with increasing recognition of the condition as a heterogeneous disease,[3] make the interpretation of epidemiological studies particularly challenging in asthma. The reported prevalence of asthma has been increasing worldwide, but may have currently reached a plateau.[4] [5] [6] About 10% of people have suffered an attack of asthma, but epidemiological studies have also found marked variations in prevalence between and within countries.[4] [7]
Aetiology/ Risk factors
Asthma is increasingly recognised as a heterogeneous condition with a range of clinically distinct phenotypes that are likely to have distinct aetiologies.[3] The risk of asthma is thought to be greatest in individuals with a genetic predisposition who are exposed to environmental stimuli that may have an allergic or irritant effect.[8] Approximately 50% of asthma occurs before the age of 10 years, and early life events (including low birth weight, early childhood infections, and environmental exposure to pollutants, tobacco smoke, and allergens) have all been causally implicated. Adult-onset asthma has been associated with rhinitis, smoking, weight gain, occupational exposures, and some drugs, including aspirin.[9] The risk factors for acute severe exacerbations of asthma are similarly diverse and may include respiratory viral or bacterial infections, exposure to dietary or inhaled allergens or irritants in the inhaled environment, and psychosocial factors such as emotional upset.[10]
Prognosis
About 10% to 20% of people presenting to the emergency department with asthma are admitted to hospital. Of these, less than 10% receive mechanical ventilation.[11] [12] Those who are ventilated are at 19-fold increased risk of ventilation for a subsequent episode.[13] It is unusual for people to die unless they have suffered respiratory arrest before they reach hospital.[14] One prospective study of 939 people discharged from emergency care found that 106/641 (17%, 95% CI 14% to 20%) relapsed by 2 weeks.[15] It is thought that as many as 75% of asthma admissions are preventable,[1] and a recent UK-wide national review of asthma deaths concluded that the majority of deaths were avoidable, with preventable factors identified in two-thirds of cases.[16]
Aims of intervention
To minimise or eliminate symptoms; to maximise lung function; to prevent hospital admissions; to prevent exacerbations; to minimise the need for medication; to improve quality of life; to minimise adverse effects of treatment; and to provide enough information and support to facilitate self-management of asthma.
Outcomes
Symptom severity (daytime and nocturnal, excluding lung function); lung function, in terms of peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1), need for rescue medication (such as inhaled beta2 agonists), variability of flow rates, and activities of daily living; hospital admissions (includes re-admission and discharge); quality of life; and adverse effects.
Methods
Search strategy BMJ Clinical Evidence search and appraisal date November 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to November 2014, Embase 1980 to November 2014, The Cochrane Database of Systematic Reviews 2014, issue 11 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews of RCTs and RCTs published in English, containing more than 20 individuals, of whom more than 80% were followed up. There was no minimum length of follow-up. No restriction was placed on level of blinding of studies. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the overview. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following previously reported interventions from this overview: Controlled oxygen supplementation; Corticosteroids; Corticosteroids (inhaled); Education about acute asthma; Formoterol (inhaled); Helium–oxygen mixture (heliox); Ipratropium bromide (inhaled) plus short-acting beta2 agonists (inhaled); Mechanical ventilation for people with severe acute asthma; Oral corticosteroids alone; Short-acting beta2 agonists; Short-acting beta2 agonists delivered by metered-dose inhalers plus spacer devices/holding chambers; Specialist care. Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Asthma in adults (acute): magnesium sulfate treatment.
| Important outcomes | Hospital admissions, Lung function, Quality of life, Symptom severity | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of magnesium sulfate for acute asthma? | |||||||||
| 4 (485) | Symptom severity | IV magnesium sulfate versus placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for use of active co-interventions |
| 12 (1983) | Lung function | IV magnesium sulfate versus placebo | 4 | 0 | –1 | –1 | 0 | Low | Consistency point deducted for statistical heterogeneity in larger analysis; directness point deducted for use of active co-interventions |
| 11 (1769) | Hospital admissions | IV magnesium sulfate versus placebo | 4 | 0 | –1 | –1 | 0 | Low | Consistency point deducted for statistical heterogeneity in one subgroup analysis, and for difference in statistical significance of effect across subgroup analysis; directness point deducted for use of active co-interventions |
| At least 2 (at least 135) | Lung function | Magnesium sulfate (nebulised) plus short-acting beta2 agonists (inhaled) versus short-acting beta2 agonists (inhaled) alone | 4 | 0 | –1 | –1 | 0 | Low | Consistency point deducted for heterogeneity among RCTs; directness point deducted for inclusion of active co-interventions and inclusion of children in one RCT |
| 2 (87) | Hospital admissions | Magnesium sulfate (nebulised) plus short-acting beta2 agonists (inhaled) versus short-acting beta2 agonists (inhaled) alone | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for sparse data; directness points deducted for inclusion of active co-interventions and for limitation to people with severe asthma |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Borg Dyspnoea Scale
A 10-point scale used to quantify the level of dyspnoea, where 0 is no difficulty in breathing and 10 is maximal dyspnoea.
- Forced expiratory volume in 1 second (FEV1)
The volume breathed out in the first second of forceful blowing into a spirometer, measured in litres.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Peak expiratory flow rate (PEFR)
The maximum rate that gas is expired from the lungs when blowing into a peak flow meter or a spirometer. It is measured at an instant, but the units are expressed as litres per minute.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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