The 3Mg Trial: Randomised controlled trial of intravenous or
nebulised magnesium sulphate or standard therapy for severe
acute asthma
Steve Goodacre PhD1, Judith Cohen PhD1, Mike Bradburn MSc1, Alasdair Gray MD2,
Jonathan Benger MD3, Timothy Coats MD4 on behalf of the 3Mg Research Team
1
School of Health and Related Research (ScHARR), University of Sheffield, 2Emergency
Department, Royal Infirmary of Edinburgh, 3Faculty of Health and Life Sciences, University
of the West of England, Bristol, 4Emergency Department, Leicester Royal Infirmary
Corresponding author
Steve Goodacre, Professor of Emergency Medicine
University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA
Email: s.goodacre@sheffield.ac.uk
Tel: +44 114 222 0842
This is the accepted version of an article that has been published in the Lancet Respiratory
Medicine: http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(13)70070-5/fulltext
Registration: http://www.controlled-trials.com/ISRCTN04417063
Lancet protocol 08PRT/503: http://www.thelancet.com/protocol-reviews/08PRT-503
1
Abstract
Background: Previous studies suggest that intravenous (IV) or nebulised magnesium
sulphate may improve respiratory function in acute asthma. We aimed to determine whether
IV or nebulised magnesium sulphate improve symptoms of breathlessness and reduce the
need for hospital admission in adults with severe acute asthma.
Methods: In a double-blind placebo-controlled trial undertaken in the emergency
departments of 34 hospitals we randomised 1109 adults with severe acute asthma to receive
either IV magnesium sulphate (2g over 20 minutes) or nebulised magnesium sulphate (3 x
500mg over one hour) alongside standard therapy including salbutamol, or standard therapy
alone. Consented participants were allocated to numbered treatment packs using a
telephone or internet randomisation system. A simple randomisation sequence was used in
20 hospitals participating at the outset, but switched to blocked randomisation, stratified by
hospital, for subsequent hospitals. Each treatment pack contained an IV infusion and three
nebuliser solutions, either of which could be active treatment or placebo. The primary
outcome measures were the proportion of patients admitted to hospital (either after
emergency department treatment or at any time over the subsequent seven days) and
breathlessness measured on a 100mm visual analogue scale (VAS) over two hours after
initiation of treatment. Participants were analysed in the groups to which they were allocated,
regardless of whether they actually received or completed the allocated treatment.
Recruitment continued towards a target of 1200 participants until funding expired and the
trial closed. ISRCTN04417063
Findings: Hospital admission was recorded for 1084 patients (394 IV magnesium sulphate,
332 nebulised magnesium sulphate, 358 placebo, mean age 36.1 years, 763/1084 (70%)
female) and VAS breathlessness for 976. IV magnesium sulphate was associated with an
odds ratio of 0.73 (95% confidence interval 0.51 to 1.04, p=0.083) for hospital admission, an
improvement in VAS breathlessness that was 2.6mm (-1.6 to 6.8mm, p=0.231) greater than
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placebo, and an improvement in percentage predicted peak expiratory flow rate (PEFR) that
was 0.4% (-2.3 to 3.0%, p=0.786) less than placebo. Nebulised magnesium sulphate was
associated with an odds ratio of 0.96 (0.65 to 1.40, p=0.819) for hospital admission, an
improvement in VAS breathlessness that was 2.6mm (-1.8mm to 7.0mm, p=0.253) less than
placebo, and an improvement in percentage predicted PEFR that was 0.6% (-2.1 to 3.4%,
p=0.652) less than placebo.
Interpretation: These findings suggest that there is no role for nebulised magnesium
sulphate in the management of severe acute asthma in adults and at best only a limited role
for IV magnesium sulphate.
Funding: National Institute for Health Research Health Technology Assessment Programme
(HTA06/01/02)
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Background
Acute asthma is responsible for around 60,000 hospital admissions per year in England1.
Current guidelines2,3 advise a stepwise approach to the management of exacerbations.
Initially all patients should receive oxygen, nebulised 2-agonists, nebulised anticholinergic
agent and corticosteroids. However, bronchodilators act within minutes whereas
corticosteroids require hours to take effect. This suggests a potential role for magnesium
sulphate as an additional treatment option in the therapeutic gap between nebulised
bronchodilators and corticosteroids.
Magnesium sulphate has been evaluated in both the intravenous (IV) and nebulised form.
The nebulised route offers the potential advantage of a quick onset of action and lower
incidence of side effects. Its disadvantages include a lower dose of drug delivered and the
patient requiring some respiratory effort to maximise its effectiveness. The IV route provides
direct access to the venous system, allowing the delivery of high drug concentrations. The
disadvantages include the requirement for intravenous access and the drug being
administered by infusion over 20 minutes.
Several systematic reviews and meta-analyses have evaluated the role of IV or nebulised
magnesium sulphate in acute asthma4-10. The most recent10 showed that IV treatment
appeared to be effective in children but was unable to draw clear conclusions about
treatment in adults. Both IV treatment (10 trials, 955 adults) and nebulised treatment (7 trials,
430 adults) were associated with weak evidence of improved respiratory function compared
to control. No trials directly compared IV to nebulised magnesium sulphate. The
standardised mean difference (SMD) for IV treatment was 0.25 (95% CI -0.01 to 0.51,
p=0.06) and for nebulised treatment was 0.17 (95% CI -0.02 to 0.36, p=0.09). Meta-analysis
showed that IV treatment was associated with weak evidence of an effect on hospital
admission (relative risk (RR) 0.68, 95% CI 0.46 to 1.02, p=0.06) while nebulised treatment
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was associated with no significant effect (RR 0.87, 95% CI 0.70 to 1.08, p=0.22). One further
trial of IV magnesium sulphate in adults11 has since been published. Inclusion of this trial in
the meta-analysis12 resulted in the effect upon respiratory function being slightly larger and
statistically significant (SMD=0.35, 95% CI 0.06 to 0.64, p=0.02) but the effect on hospital
admission remained non-significant (RR=0.85, 95% CI 0.68 to 1.06, p=0.14). It is not clear
whether changes in measures of respiratory function are associated with important changes
in patient management or a clinically meaningful improvement in symptoms.
Uncertainty in the evidence is reflected in treatment recommendations. Current guidelines in
the United Kingdom2 and the United States3 suggest that IV magnesium sulphate should be
considered in adults with life-threatening features or severe acute asthma that has not
responded to inhaled bronchodilator therapy. No recommendations are made regarding
nebulised magnesium sulphate.
We measured the effectiveness of IV and nebulised magnesium sulphate in adults with
severe acute asthma. We specifically aimed to determine whether IV or nebulised
magnesium sulphate, used alongside standard treatment including salbutamol, reduces the
proportion of patients requiring hospital admission at initial presentation or during the
following seven days, and whether IV or nebulised magnesium sulphate improves patient
assessment of breathlessness over two hours after initiation of treatment.
Methods
Study design and patients
We undertook a multi-centre, double blind, placebo controlled, three-arm, randomised trial in
34 emergency departments in the United Kingdom. The trial protocol has been published13.
Adults (age>16) attending the emergency department with severe acute asthma were
eligible for recruitment (i.e. acute asthma with either PEFR < 50% of best or predicted,
respiratory rate > 25/min, heart rate > 110/min, or inability to complete sentences in one
5
breath). We excluded patients who had life threatening features (oxygen saturation < 92%,
silent chest, cyanosis, poor respiratory effort, bradycardia, arrhythmia, hypotension,
exhaustion, coma or confusion), those with a contraindication to either nebulised or
intravenous magnesium sulphate (pregnancy, hepatic or renal failure, heart block or known
hypermagnesaemia), those unable to provide written or verbal consent, and previous
participants in the 3Mg trial. We amended the protocol during the trial to also exclude those
who had received magnesium sulphate in the 24 hours prior to recruitment. Written or verbal
consent was sought from all participants. Those initially providing verbal consent were asked
for written consent as soon as their condition permitted.
Randomisation and masking
Consented participants were randomised through a telephone or internet randomisation
system managed by the Sheffield Clinical Trials Research Unit (CTRU). After being entered
into the trial participants were allocated to numbered treatment packs kept in the emergency
department. A simple randomisation sequence was used in the 20 hospitals participating at
the outset, but switched to blocked randomisation (block sizes of four or six), stratified by
hospital, for subsequent hospitals to safeguard against new centres recruiting too few in any
trial arm. Each treatment pack contained an IV infusion and three nebuliser solutions, either
of which could be active treatment or placebo. Participants, hospital staff and research staff
were blinded to the allocated treatment.
Interventions and concurrent treatments
The three treatment arms were as follows:
1. IV magnesium sulphate, 8 mmol (2g) in 100ml normal saline given over 20 minutes,
and three 7.5ml vials of 0.9% saline nebulised at 20 minutes intervals
2. IV normal saline, 100ml given over 20 minutes, and three 7.5ml vials of 2 mmol
(500mg) magnesium sulphate nebulised at 20 minutes intervals
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3. IV normal saline, 100ml given over 20 minutes, and three 7.5ml vials of 0.9% saline
nebulised at 20 minutes intervals
Standard therapy was provided in accordance with guidelines2 from the British Thoracic
Society (BTS) and Scottish Intercollegiate Guidelines Network (SIGN) and consisted of
oxygen, nebulised salbutamol (5mg), nebulised ipratropium (500mcg) and oral prednisolone
administered during recruitment, followed by up to 5mg salbutamol added to each trial
nebuliser. Other treatments were given at the discretion of the clinician. Patients were
managed in the emergency department and data collected until two hours after
randomisation. At this point, if not already undertaken, a final disposition decision was made
(hospital admission or discharge) and initial data collection completed.
Outcome measures
Two primary outcomes were specified:
1. The health service primary outcome was the proportion of patients admitted to
hospital, either after emergency department treatment or at any time over the
subsequent seven days.
2. The patient-centred primary outcome was the patient’s visual analogue scale (VAS)
for breathlessness over two hours after initiation of treatment. VAS breathlessness
has been used to measure breathlessness during exercise14 and has been shown to
correlate with respiratory function and symptomatic change in cohorts with acute
asthma15,16.
Secondary outcomes included mortality, adverse events, use of ventilation or respiratory
support, length of hospital stay, admission to a high dependency unit (HDU) or intensive
care unit (ICU), change in PEFR and physiological variables (oxygen saturation, heart rate,
respiratory rate, blood pressure) over two hours, quality of life at baseline and one month,
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number of unscheduled health care contacts over the subsequent month, and satisfaction
with care.
Adverse events and side effects occurring during emergency department treatment were
routinely recorded on the Case Report Form by the treating clinician. Key events (cardiac
arrest, respiratory arrest, emergency intubation, non-invasive ventilation, pneumothorax and
arrhythmia) and common side effects (flushing, nausea, vomiting and hypotension (systolic
<100mmHg)) were specifically sought and recorded. Other events were recorded on a
general adverse event reporting form. Patient notes were reviewed by a research nurse who
recorded any side effects identified during treatment or adverse events occurring up to 30
days after treatment. Adverse events were identified and reported according to Good Clinical
Practice (GCP) guidance.
Sample size
We planned to recruit 1200 participants divided equally between the three trial arms to
provide the following statistical power:
1. Assuming that 80% of patients with severe acute asthma are admitted after
emergency department management and hospital admission is recorded for all
participants, the study would have 90% power to detect a 10% absolute reduction in
the proportion admitted (i.e. to 70%) for any pair of treatment groups compared (twosided alpha=0.05).
2. Assuming that 80% of participants have their VAS measured then the study would
have 90% power to detect a 8mm difference in a 100mm VAS at two hours after
treatment initiation (two-sided alpha=0.05). Previous data have established that the
standard deviation on a 100mm VAS is 30mm, and that 22mm represents a minimum
clinically significant difference15.
Statistical analysis
8
Participants were analysed in the groups to which they were allocated, regardless of whether
they actually received or completed the allocated treatment. Logistic regression was used for
analysis of admission rates. For length of stay, means (medians) were compared using
censored Normal (log-Normal) regression to account for interval censoring in discharged
patients (for whom no time of discharge was recorded) and also admissions which were
ongoing at 30 days. Number of days on ICU/HDU were compared using Mann-Whitney U
test. Analysis of covariance was used for all other outcomes. The primary analysis was
adjusted for hospital and is presented for observed data (complete case); further analyses
using different imputation strategies were used as confirmatory analyses. A secondary
explanatory analysis was undertaken limited to those who completed the treatment as per
protocol. We used Simes’s (1986) method17, which is a modification of the Bonferroni
method but has better power, to adjust for multiplicity arising from having two primary
outcomes. The two pre-planned comparisons between the three groups were (1) active
treatment (IV or nebulised) versus placebo and (2) IV versus nebulised magnesium
sulphate. We also present comparisons of IV magnesium sulphate versus placebo and
nebulised magnesium sulphate versus placebo for completeness. We undertook three preplanned subgroup analyses stratified by age (above or below 50 years), baseline PEFR
(above or below median) and whether the patient had received treatment with salbutamol
before the trial treatments.
An independent Data Monitoring Committee (DMC) reviewed trial data at regular intervals
and reported recommendations to the Trial Steering Committee in accordance with the DMC
charter. The Trial was approved by the Scotland A Research Ethics Committee. The trial
sponsor was Sheffield Teaching Hospitals NHS Foundation Trust.
Role of the funding source
The study funders had no role in study design; in the collection, analysis, and interpretation
of data; in the writing of the report; and in the decision to submit the paper for publication.
9
The corresponding author had full access to all the data in the study and had final
responsibility for the decision to submit for publication.
Results
Patients were recruited from 34 hospitals between 30/7/2008 and 30/6/2012. Recruitment
was slower than anticipated and ended when the trial funding expired. The flow of patients
through the trial is shown in figure 1. Of the 1109 patients recruited, 25 withdrew without
commencing trial medication, were recruited in error (protocol violations) or could not be
allocated to a treatment pack, so 1084 were included in the analysis. Table 1 shows the
baseline characteristics of the recruited patients. Age and sex characteristics were balanced
across the groups, but there were more white ethnicity patients in the IV magnesium group
and more patients who had never smoked in the nebulised magnesium group. Supplemental
tables 1 and 2 show the trial and concurrent medications received by the three patient
groups. There was a high degree of adherence to the trial protocol: the mean total dose of
nebulised solution was 21.3ml, with 85% receiving the full dose of 22.5ml, while the mean
total dose of IV infusion was 97.1ml with 89% receiving the full IV infusion.
The results of primary outcome analysis are shown in table 2 (admission to hospital) and
table 3 (VAS breathlessness). The odds ratios for admission to hospital were 0.84 (95% CI
0.61 to 1.15, p=0.276) for active treatment versus placebo, 0.76 (0.53 to 1.10, p=0.146) for
IV versus nebuliser, 0.73 (0.51 to 1.04, p=0.083) for IV versus placebo, and 0.96 (0.65
to1.40, p=0.819) for nebuliser versus placebo. The mean differences in improvement in VAS
were 0.0mm (95% CI -1.9 to 1.9mm, p=0.999) for active treatment versus placebo, 5.1mm
(0.8 to 9.4mm, p=0.019) for IV versus nebuliser, 2.6mm (-1.6 to 6.8mm, p=0.231) for IV
versus placebo, and -2.6mm (-7.0 to 1.8mm, p=0.253) for nebuliser versus placebo (a
positive value indicates a greater improvement than the comparator). Further analyses were
run with plausible imputations for the 108 (10%) patients with no 2-hour change in VAS
recorded; these had no material impact on the findings.
10
Table 4 shows the analysis of PEFR as a percentage of predicted PEFR. The mean
differences in improvement in % predicted PEFR were -0.5% (95% CI -2.9 to 1.9%, p=0.676)
for active treatment versus placebo, 0.3% (-2.4 to 3.0%, p=0.841) for IV versus nebuliser, 0.4% (-3.0 to 2.3%, p=0.786) for IV versus placebo, and -0.6% (-3.4 to 2.1%), p=0.652) for
nebuliser versus placebo (a positive value indicates a greater improvement than the
comparator). There were no significant differences in any comparisons of physiological
measures. Full details of physiological measures and oxygen flow rates are provided in
supplemental tables 3 to 8.
Table 5 shows analysis of length of stay, admission to the ICU or HDU, and use of
respiratory support. There was no significant difference between the three groups in these
outcomes. Figure 2 shows the proportion of patients in hospital by treatment group as a
function of time from hospital admission. Any small difference between the groups had
disappeared by 24 hours.
Table 6 shows adverse events and side effects. The odds ratios for suffering any side effect
were 1.68 (95% CI 1.11 to 2.52, p=0.014) for active treatment versus placebo, 1.00 (0.66 to
1.52, p=0.988) for IV versus nebuliser, 1.68 (1.07 to 2.63, p=0.025) for IV versus placebo,
and 1.67 (1.05 to 2.66, p=0.031) for nebuliser versus placebo. Table 7 shows the
medications prescribed to patients discharged after emergency department treatment. Most
patients received prednisolone and a few received additional inhalers.
There were no significant findings on pre-planned subgroup analysis. In particular, the odds
ratio for hospital admission with IV treatment versus placebo was 0.76 (95% CI 0.45 to 1.30)
in patients presenting with more severe asthma (defined as PEFR<=50% of predicted) and
0.67 (95% CI 0.42 to 1.06) in those presenting with less severe asthma.
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Discussion
The 3Mg trial is the largest trial of magnesium sulphate ever undertaken in acute asthma,
the first powered on the basis of detecting a meaningful difference in admission to hospital
and the only trial to directly compare IV to nebulised treatment. We were unable to
demonstrate a clinically worthwhile benefit from either IV or nebulised magnesium sulphate
compared to placebo. There was some evidence of IV magnesium sulphate having an effect
upon hospital admission and the confidence interval for this estimate includes the possibility
of both a worthwhile effect and no effect, but any effect on breathlessness was smaller than
the minimum clinically significant difference14. There was no suggestion of an effect from
nebulised magnesium sulphate in either primary outcome.
Meta-analysis of previous trials suggested evidence of benefit from both IV and nebulised
magnesium sulphate10. This contrasts with our findings of no benefit from nebulised
treatment and weak evidence of benefit from IV treatment. There are a number of potential
reasons for this inconsistency. Meta-analysis of previous trials may be subject to publication
bias if positive trials are preferentially submitted and accepted for publication. Some previous
trials may have been limited by inadequate allocation concealment or blinding that inflated
estimates of treatment effects. All three arms of the 3Mg trial received treatment with
nebulised β-agonists which may have limited the potential for magnesium sulphate to
provide additional bronchodilatation, whereas it was not always clear that all patients
received optimal standard treatment in previous trials. In this respect it is worth noting that
patients in the control arm showed marked improvements in peak expiratory flow rate and
VAS breathlessness, and few required respiratory support, indicating a good response to
standard treatment alone.
One potential explanation that can probably be discounted is that the trial treatment was
inadequate, in terms of the planned dosage and actual amount of drug given. The protocol
specified dosages of IV and nebulised magnesium sulphate that were at the top end of
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dosages used in previous trials. Data presented in the supplemental tables show high
adherence to the trial protocols with most patients receiving the full dose of the relevant
drugs. Pragmatic trials carry a risk that trial treatment will be delivered in a suboptimal
manner, but we found no evidence of this in the 3Mg trial.
Our findings for nebulised magnesium sulphate contrast with those of the MAGNETIC trial
which showed an improvement in asthma severity score at 60 minutes post-treatment with
nebulised magnesium sulphate compared to placebo in acute severe pediatric asthma18.
Previous meta-analysis10 suggested that IV magnesium sulphate is more effective in children
than adults. The findings of 3Mg and MAGNETIC suggest that the same is true of nebulised
magnesium sulphate.
The 3Mg trial had strengths and limitations that need to be considered when interpreting the
findings. The trial terminated when funding expired and recruited 1084 patients against a
target of 1200. Despite this shortfall, it still had 84% power to detect a 10% difference in
admission rate for nebulised treatment versus placebo and 87% power for IV treatment
versus placebo based on the original sample size projections. Furthermore, VAS
breathlessness was recorded for 90% of the study population, as opposed to the anticipated
80% in the power calculation, so there was no loss of power to detect a difference in this
outcome. 3Mg is therefore the largest trial of IV or nebulised magnesium sulphate in acute
asthma and the only trial powered to detect clinically important differences in admission rate.
3Mg designed as a pragmatic trial to determine the effectiveness of using magnesium
sulphate alongside other treatments as part of routine emergency department practice. The
study population was pragmatically defined using information routinely available to
emergency department staff. This means that the findings are generalisable to typical
patients attending hospital with acute asthma, but also means that the study population
could have included some patients with other diagnoses. We evaluated magnesium sulphate
13
alongside standard treatment rather than comparing it to elements of standard treatment.
This may have reduced the potential for magnesium sulphate to make a difference, but
withholding standard treatment would have been unethical. We selected primary outcomes
that measured the effect of treatment upon symptoms (VAS breathlessness) and
management (hospital admission). We also measured physiological parameters and PEFR
as secondary outcomes. It is possible that other measures, such as forced expiratory volume
in one second (FEV1) might have been more sensitive to changes in respiratory function, but
these are not routinely measured in the emergency department, and would not provide
evidence of clinical effectiveness. Demonstrating clinical effectiveness involves showing a
meaningful improvement in patient symptoms or management, not just a change in
respiratory parameters. Finally, we deliberately excluded patients with life-threatening
asthma and were unable to power the study to detect differences in serious adverse
outcomes (including death), so we are unable to determine whether magnesium sulphate
may have an effect upon serious adverse outcomes in life-threatening asthma.
The findings of this trial suggest that there is no role for nebulised magnesium sulphate in
the management of severe acute asthma in adults and at best a limited role for IV
magnesium sulphate. Patients receiving standard treatment showed marked improvements
in breathlessness and PEFR, and few required respiratory support. Although most were
admitted to hospital, we found no evidence that nebulised magnesium sulphate reduced the
admission rate and only weak evidence of an effect from IV magnesium sulphate. The low
rate of side effects and adverse events (other than those related to the underlying illness)
suggests a low risk of harm from IV administration but the corresponding evidence of benefit
is modest and uncertain.
Further clinical trials of magnesium sulphate in adults with acute asthma are unlikely to be
worthwhile. If IV treatment has an effect upon admission rate or adverse events that was not
detected by 3Mg then it would need a much larger trial to detect such an effect. The logistic
14
barriers to undertaking clinical trials in patients with a medical emergency would seem to
prevent a larger trial being feasible at an acceptable cost.
Research in context
Systematic review
A 2007 systematic review, updated in 2009, identified eleven trials of IV magnesium
sulphate in 1018 adults and seven trials of nebulised magnesium sulphate in 430 adults with
acute asthma. Meta-analysis suggested that both IV and nebulised treatment had potentially
worthwhile effects on respiratory function (standardised mean difference for IV
treatment=0.35, 95% CI 0.06 to 0.064, p=0.02; standardised mean difference for nebulised
treatment=0.17 (95% CI -0.02 to 0.36, p=0.09) and showed non-significant trends towards
reduced admission to hospital (relative risk for IV treatment=0.85, 95% CI 0.68 to 1.06,
p=0.14; relative risk for nebulised treatment=0.87, 95% CI 0.70 to 1.08, p=0.22).
Interpretation
Our large pragmatic study failed to provide convincing evidence that IV or nebulised
magnesium sulphate produce clinically worthwhile benefits in adults with severe acute
asthma. Although magnesium sulphate is a safe treatment with few significant side effects,
current data do not support a role in the standard treatment of adults with severe acute
asthma.
Conflicts of interest
None to declare
Sources of funding
The 3Mg Trial was funded by the National Institute for Health Research Health Technology
Assessment Programme (reference 06/02/01). The views and opinions expressed are those
of the authors and do not necessarily reflect those of the Department of Health.
15
Contributors
Membership of the 3Mg Research Team is outlined in the linked online appendix. The coapplicants designed the trial. The Project Management Group and Local Investigators
undertook the trial with independent oversight from the Trial Steering Committee and Data
Monitoring Committee. Steve Goodacre wrote the first draft of this paper. Mike Bradburn
undertook the statistical analysis. Steve Goodacre, Mike Bradburn, Judith Cohen, Alasdair
Gray, Tim Coats and Jonathan Benger contributed to redrafting of the paper and approved
the final draft.
The 3Mg Research Team
Writing Group: Steve Goodacre, Judith Cohen, Mike Bradburn, John Stevens (University of
Sheffield), Alasdair Gray (Royal Infirmary of Edinburgh), Jonathan Benger (University of the
West of England), Tim Coats (University of Leicester); Project Management Group: Steve
Goodacre (Chief Investigator), Judith Cohen (Trial Manager), Mike Bradburn, Chin Maguire,
Yvonne Meades (University of Sheffield), Alasdair Gray, Moyra Masson (Royal Infirmary of
Edinburgh), Jonathan Benger (University of the West of England), Tim Coats (University of
Leicester); Trial Steering Committee: Andrew Greening (Independent Chair, Western
General Hospital, Edinburgh), Magdy Sakr (Independent, University Hospitals of Coventry
and Warwickshire), Roseanne McNamee (Independent, University of Manchester), Jenny
Negus (Independent, Patient Representative), Steve Goodacre, Alasdair Gray, Judith
Cohen; Data Monitoring and Ethics Committee: Sandra Eldridge (Chair, Queen Mary
University of London), Mark Elliott (St James University Hospital, Leeds), Steve Crane (York
Hospital); Co-applicants: Steve Goodacre, Jon Nicholl, Mike Campbell, Julie Ratcliffe
(University of Sheffield), Alasdair Gray (Royal Infirmary of Edinburgh), Jonathan Benger
(University of the West of England), Tim Coats (University of Leicester), Stephen Holgate
(University of Southampton), Peter Jackson (Sheffield Teaching Hospitals NHS Foundation
Trust); Local Investigators: Abdul Jalil (Doncaster Royal Infirmary), Alasdair Corfield (Royal
16
Alexandra Hospital, Paisley), Alasdair Gray (Royal Infirmary of Edinburgh), Alastair
Stevenson (Ayr Hospital), Angus Cooper (Aberdeen Royal Infirmary), Ann Marie Morris
(University Hospital of North Staffordshire), Colin Dewar (Fife, Queen Margaret Hospital and
Victoria Hospital), Crawford McGuffie (Crosshouse Hospital), David Robinson (Bradford
Royal Infirmary), Barbara Madigan (Royal United Hospital Bath ), Frank Coffey (Queen’s
Medical Centre , Nottingham), Gary Kitching (York Hospital), Gavin Lloyd (Royal Devon &
Exeter Hospital), Iain Lennon (Derbyshire Royal Infirmary), Jason Smith (Derriford Hospital,
Plymouth), John Keaney (Hairmyres Hospital), Jonathan Benger (Bristol Royal Infirmary),
Julian Humphrey (Barnsley Hospital), Khurram Iftikhar (Southend University Hospital), Matt
Shepherd (Pinderfields Hospital), Matthew Pereira (Addenbrooke's Hospital,- Cambridge),
Mehmood Chaudhry (University Hospital Coventry), Nathan Spencer (Kettering General
Hospital), Patrick Dissmann (James Cook University Hospital, Middlesbrough), Samuel
McBride (Lancaster Royal Infirmary), Simon Chapman (Bristol Frenchay Hospital), Steve
Goodacre (Northern General Hospital, Sheffield), Suzanne Brady (Rotherham General
Hospital), Taj Hassan (Leeds Teaching Hospitals), Tim Coats (Leicester Royal Infirmary),
Tim Harris (The Royal London Hospital), Tristan Dyer (Northampton General Hospital),
William Townend (Hull Royal Infirmary).
Acknowledgements
We thank Katie Biggs, Timothy Chater, Joseph Clark, Christopher Ellis, Amanda Loban,
Kathryn MacKellar, Diana Papaioannou and Martina Santarelli for their help with trial
administration, monitoring and co-ordination, and data management.
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unpublished. http://www.shef.ac.uk/polopoly_fs/1.44176!/file/Mg-meta-analysisupdated-Feb-2009.pdf - accessed 4/12/2012.
18
13. Protocol 08PRT/503: The 3Mg trial: randomised controlled trial of intravenous or
nebulised magnesium sulphate or standard therapy for acute severe asthma
(ISRCTN04417063). Lancet 2008, http://www.thelancet.com/protocolreviews/08PRT-503
14. Wilson RC, Jones PW. Comparison of the visual analogue scale and Borg scale for
measurement of dyspnoea during exercise. Clin Sci 1989;76:277-282.
15. Karras DJ, Sammon ME, Terregino CA, Lopez BL, Griswold SK & Arnold GK.
Clinically meaningful changes in quantitative measures of asthma severity. Acad
Emerg Med 2000;7:327-334.
16. Gupta D, Aggarwal AN, Sublamaxi MV, Jindal SK. Assessing severity of asthma:
spirometric correlates with visual analogue scale (VAS). Indian J Chest Dis Allied Sci
2000;42:95-100.
17. Simes RJ. An improved Bonferroni procedure for multiple tests of significance.
Biometrika 1986;73, 751-4.
18. Powell C, Kolamunnage-Dona R, Lowe J, Boland A, Petrou S, Doull I, Hood K,
Williamson P on behalf of the MAGNETIC study group.MAGNESIUM TRIAL IN
CHILDREN MAGNETIC: A Randomised, Placebo Controlled Trial of Nebulised
Magnesium Sulphate in Acute Severe Asthma in Children. Lancet Respiratory
Medicine 2013
19
Figure 1: CONSORT flow chart
Assessed for eligibility (n=2783)
Enrolment
Excluded (n= 1674)
 Ineligible (n=847)
- Life threatening asthma (n=466)
- Contraindicated (n=73)
- Received magnesium in previous
24 hours (n=19)
- Previous participant (n=319)
 Declined to participate (n=200)
 Administrative reasons (ED too
busy, staff not trained no treatment
pack available; n=306)
 Unable to give consent (n=31)
 Other reasons (n=201)
 Not recorded (n=89)
Randomised (n=1109)
Allocation
Allocated to nebulised magnesium
sulphate (n=339)
 Received intervention (n=333)
 Did not receive intervention (n=6)
Withdrew consent prior to treatment (n=2)
Treatment pack not available (n=4)
Allocated to IV magnesium sulphate
(n=406)
 Received allocated intervention (n= 396)
 Did not receive intervention (n=10)
Withdrew consent prior to treatment (n=7)
Treatment pack not available (n=2)
Self-discharged prior to treatment (n=1)
Allocated to placebo (n=364)
 Received allocated intervention (n=358)
 Did not receive intervention (n=6)
Withdrew consent prior to treatment (n=2)
Treatment pack not available (n=3)
Self-discharged prior to treatment (n=1)
Follow-Up
Completed follow-up in ED (n=332)
30-day questionnaire completed (n=152)
Completed follow-up in ED (n=393)
30-day questionnaire completed (n=186)
Completed follow-up in ED (n=357)
30-day questionnaire completed (n=162)
Analysis
Analysed (n=332)
 Excluded from analysis (n=7)
Treatment not started (n=6)
Ineligible patient, prisoner (n=1)
Analysed (n=394)
 Excluded from analysis (n=12)
Treatment not started (n=10)
Ineligible patient, previous participant
(n=2)
20
Previous participant (n=2)
Analysed (n=358)
 Excluded from analysis (n=6)
Treatment not started (n=6)
Figure 2: Length of stay following initial attendance
Length of stay following initial attendance
1.00
0.75
0.50
0.25
0.00
0 4 8 12
24
Placebo
48
Time to discharge (hours)
Nebulised Mg
21
72
96
IV Mg
Table 1: Baseline demographics and characteristics
Nebulised
magnesium
sulphate
(N=332)
IV
magnesium
sulphate
(N=394)
Placebo
(N=358)
Total
(N=1084)
36.5 (14.8)
35.0 (23, 47)
16, 85
35.6 (13.1)
34.0 (25, 44)
16, 84
36.4 (14.1)
34.5 (24, 47)
16, 88
36.1 (14.0)
34.0 (24, 46)
16, 88
Gender
Male
Female
100 (30%)
232 (70%)
115 (29%)
279 (71%)
106 (30%)
252 (70%)
321 (30%)
763 (70%)
Ethnicity
White
Mixed
Asian or Asian British
Black or Black British
Other
Not stated
Missing
286 (86%)
2 (1%)
14 (4%)
2 (1%)
2 (1%)
22 (7%)
4 (1%)
369 (94%)
1 (<1%)
8 (2%)
5 (1%)
0
8 (2%)
3 (1%)
319 (89%)
5 (1%)
16 (4%)
4 (1%)
0
11 (3%)
3 (1%)
974 (90%)
8 (1%)
38 (4%)
11 (1%)
2 (<1%)
41 (4%)
10 (1%)
Smoking status
Never
Current
Previous
Missing
151 (45%)
98 (30%)
72 (22%)
11 (3%)
156 (40%)
138 (35%)
95 (24%)
5 (1%)
143 (40%)
127 (35%)
81 (23%)
7 (2%)
450 (42%)
363 (33%)
248 (23%)
23 (2%)
324
430.0 (118.8)
425.0
(350, 500)
100, 700
29 (9%)
389
431.8 (116.9)
435.0
(350, 500)
140, 800
42 (11%)
346
435.0 (110.8)
425.0
(350, 500)
150, 790
27 (8%)
1059
432.3 (115.4)
425.0
(350, 500)
100, 800
98 (9%)
69 (21%)
66 (17%)
68 (19%)
203 (19%)
Age
Mean (s.d.)
Median (i.q.r.)
Min-max
Predicted PEFR
n
Mean (s.d.)
Median (i.q.r.)
Min-max
Other previous serious
lung disease
Other serious illness
22
Table 2: Admission to hospital at presentation or within seven days
Status at four hours
Admitted
Discharged
Dead
Unknown
Subsequent hospital admission
within seven days
Subsequent hospital admission
following discharge at initial
attendance
Admitted to hospital at any
time within seven days
Nebulised
magnesium
sulphate
(N=332)
IV magnesium
sulphate
(N=394)
Placebo
(N=358)
Total
(N=1084)
254 (77%)
77 (23%)
0
1 (<1%)
279 (71%)
114 (29%)
0
1 (<1%)
278 (78%)
80 (22%)
0
0
811 (75%)
271 (25%)
0
2 (<1%)
15 (5%)
10 (3%)
7 (2%)
32 (3%)
6 (2%)
5 (1%)
3 (1%)
14 (1%)
261 (79%)
285 (72%)
281 (78%)
827 (76%)
Comparisons
Active v placebo
IV v nebuliser
IV v placebo
Nebuliser v placebo
Odds ratio (95% CI)
0.84 (0.61,1.15)
0.76 (0.53,1.10)
0.73 (0.51,1.04)
0.96 (0.65,1.40)
23
p-value
0.276
0.146
0.083
0.819
Table 3: Change in VAS breathlessness from baseline to two hours
Nebulised
magnesium IV magnesium
Placebo
(N=332)
(N=394)
(N=358)
VAS at baseline
No. of obs.
326
386
349
Mean (s.d.)
61.6 (23.3)
61.9 (22.8)
63.1 (23.5)
Change in VAS at 1 hour
No. of obs.
Mean (s.d.)
314
-18.4 (22.8)
372
-24.2 (24.4)
Overall
(N=1084)
1061
62.2 (23.2)
344
-21.5 (24.7)
1030
-21.5 (24.1)
Change in VAS at 2 hours
No. of obs.
296
357
323
Mean (s.d.)
-28.2 (27.4)
-34.3 (27.7)
-31.3 (29.4)
Comparisons
Mean difference (95% CI)
Active v placebo
0.0 (-1.9,1.9)
IV v nebuliser
-5.1 (-9.4,-0.8)
IV v placebo
-2.6 (-6.8,1.6)
Nebuliser v placebo
2.6 (-1.8,7.0)
976
-31.5 (28.2)
p-value
0.999
0.019
0.231
0.253
24
Table 4: Change in PEFR (% of predicted) from baseline to two hours
Nebulised
magnesium
(N=332)
%PEFR at baseline
No. of obs.
Mean (s.d.)
IV magnesium
(N=394)
308
50.0 (19.6)
Placebo
(N=358)
Overall
(N=1084)
375
54.3 (20.2)
327
50.5 (19.1)
1010
51.7 (19.7)
282
349
304
935
9.9 (15.0)
11.4 (15.7)
10.2 (14.7)
10.6 (15.2)
Change in %PEFR at 2 hours
No. of obs.
270
Mean (s.d.)
13.4 (18.0)
337
14.4 (17.4)
291
14.4 (16.3)
898
14.1 (17.2)
Change in %PEFR at 1 hour
No. of obs.
Mean (s.d.)
Comparisons
Active v placebo
IV v nebuliser
IV v placebo
Nebuliser v placebo
Mean difference
-0.5 (-2.9,1.9)
0.3 (-2.4,3.0)
-0.4 (-3.0,2.3)
-0.6 (-3.4,2.1)
25
p-value
0.676
0.841
0.786
0.652
Table 5: Analysis of length of stay and use of ICU, HDU and ventilation
Length of stay (hours)
n
Mean (s.d.)
Median (i.q.r.)
Min-max
Days on ICU
No (%) with any stay
Mean (s.d.)
Median (i.q.r.)
Days on HDU
No (%) with any stay
Mean (s.d.)
Median (i.q.r.)
Required ventilation
Non-invasive
Emergency intubation
Nebulised
magnesium
sulphate
IV
magnesium
sulphate
Placebo
Total
(N=332)
(N=394)
(N=358)
(N=1084)
329
63.2 (79.7)
35.1 (5, 88)
3, 623
388
57.0 (75.1)
31.5 (4, 78)
4, 723
353
63.3 (84.3)
36.4 (5, 87)
1, 694
1070
61.0 (79.6)
34.1 (4, 84)
1, 723
9 (3%)
3.3 (4.8)
2.0 (1, 4)
11 (3%)
3.1 (5.0)
2.0 (0, 4)
5 (1%)
2.9 (3.9)
2.0 (0, 4)
22 (7%)
3.3 (4.8)
2.0 (1, 4)
23 (6%)
3.1 (5.0)
2.0 (0, 4)
3 (1%)
2 (1%)
2 (1%)
6 (2%)
2 (1%)
4 (1%)
26
P-values
Active v
placebo
IV v
nebuliser
0.659
0.432
0.379
0.230
25 (2%)
3.1 (4.6)
2.0 (0, 4)
0.161
0.947
0.159
0.941
20 (6%)
2.9 (3.9)
2.0 (0, 4)
65 (6%)
3.1 (4.6)
2.0 (0, 4)
0.690
0.661
0.715
0.630
4 (1%)
3 (1%)
1 (<1%)
13 (1%)
7 (1%)
7 (1%)
0.936
0.458
Table 6: Adverse events and side effects
Adverse events
Any adverse event
Arrhythmia
Cardiac arrest
Death
Intubation
Non-invasive ventilation
Other asthma related
Other non-asthma
related
Side effects
Any side effect
Flushing
Hypotension
Nausea
Vomiting
Other
Comparisons*
Active v placebo
IV v nebuliser
IV v placebo
Nebuliser v placebo
Nebulised
magnesium
sulphate
(N=332)
IV magnesium
sulphate
(N=394)
Placebo
(N=358)
Overall
(N=1084)
41 (12.3%)
0
0
1 (0.3%)
2 (0.6%)
2 (0.6%)
26 (7.8%)
53 (13.5%)
1 (0.3%)
1 (0.3%)
1 (0.3%)
4 (1.0%)
2 (0.5%)
26 (6.6%)
36 (10.1%)
1 (0.3%)
0
0
1 (0.3%)
3 (0.8%)
22 (6.1%)
130 (12.0%)
2 (0.2%)
1 (0.1%)
2 (0.2%)
7 (0.6%)
7 (0.6%)
74 (6.8%)
14 (4.2%)
20 (5.1%)
12 (3.4%)
46 (4.2%)
(N=332)
(N=394)
(N=358)
(N=1084)
52 (15.7%)
3 (0.9%)
31 (9.3%)
5 (1.5%)
6 (1.8%)
12 (3.6%)
61 (15.5%)
7 (1.8%)
31 (7.8%)
14 (3.5%)
6 (1.5%)
15 (3.8%)
36 (10.1%)
2 (0.6%)
22 (6.1%)
7 (2.0%)
3 (0.8%)
5 (1.4%)
149 (13.7%)
12 (1.1%)
84 (7.7%)
26 (2.4%)
15 (1.4%)
32 (2.9%)
Odds ratio (95% CI)
1.68 (1.11,2.52)
1.00 (0.66,1.52)
1.68 (1.07,2.63)
1.67 (1.05, 2.66)
p-value
0.014
0.988
0.025
0.031
n.b. Numbers refer to patients experiencing an event of each type.
Total number of events will not equal the sum of individual events if a patient experiences
multiple side effects.
* comparison is any side effect (yes/no)
27
Table 7: Medications given at discharge
Discharged at 4 hours
Any medication
Prednisolone
Salbutamol
Seretide
Beclometasone
Pulmicort
Ipratropium
Salmetarol
Combivent
Other
Nebulised
magnesium
sulphate
(N=332)
77
IV magnesium
sulphate
(N=394)
114
Placebo
(N=358)
80
Overall
(N=1084)
271
64 (83%)
62 (81%)
21 (27%)
3 (4%)
1 (1%)
3 (4%)
1 (1%)
0
1 (1%)
0
98 (86%)
93 (82%)
44 (39%)
4 (4%)
4 (4%)
3 (3%)
1 (1%)
1 (1%)
0
2 (2%)
64 (80%)
63 (79%)
27 (34%)
2 (3%)
3 (4%)
0
0
0
0
0
226 (83%)
218 (80%)
92 (34%)
9 (3%)
8 (3%)
6 (2%)
2 (1%)
1 (<1%)
1 (<1%)
2 (1%)
28