The 3Mg Trial

Goodacre S, Cohen J, Bradburn M, Gray A, Benger J, Coats T; 3Mg Research Team. Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma (3Mg trial): a double-blind, randomised controlled trial. Lancet Respir Med. 2013 Jun;1(4):293-300. doi: 10.1016/S2213-2600(13)70070-5. Epub 2013 May 17. PubMed PMID: 24429154.

• Does intravenous or nebulised MgSO4 improve symptoms of breathlessness and reduce the need for hospital admissions in adults with severe acute asthma?

TYPE OF STUDY

• Multi-centre double-blind placebo-controlled three-arm randomised controlled trial

POPULATION

• n=1,109 patients (2,783 assessed for eligibility) from 34 UK emergency departments

Inclusion criteria

• Adults (age ≥ 16) attending an emergency department with severe asthma:
  • Peak flow < 50% predicted
  • RR > 25/min
  • HR > 110/min
  • Unable to complete a sentence in one breath

Exclusion criteria

• Life-threatening features:
  • SaO2 <92%
  • Silent chest
  • Cyanosis
  • Poor respiratory effort
  • Bradycardia
  • Arrhythmia
  • Hypotension
  • Exhaustion
  • Coma or confusion
  • Contraindication to MgSO4 (nebulised or intravenous)
  • Inability to consent
  • Previously on 3Mg trial

INTERVENTIONS/ COMPARISONS

• IV MgSO4 + nebulised saline, n= 339
• IV saline + nebulised MgSO4, n= 406
• IV saline + nebulised saline (placebo), n= 364

OUTCOMES

Primary outcomes

• Health service outcome: proportion of patients admitted to hospital after ED treatment, or proportion of patients admitted to hospital within 7 days
  • Rates of admission did not differ between active treatment and placebo groups (OR 0.84 95% CI 0.61-1.15; p=0.276), IV MgSO4 and nebulised MgSO4 (OR 0.76 95% CI 0.53-1.10; p=0.146), IV MgSO4 and placebo (OR 0.73 95% CI 0.51-1.04; p=0.083), or nebulised MgSO4 and placebo (0.96 95% CI 0.6=5-1.40; p0.819).
• Patient-centred outcome: visual analogue scale (VAS) for breathlessness in the 2 h after start of treatment
  • Mean improvement in VAS did not differ between active treatment and placebo groups but changes were greater in the IV MgSO4 group than the nebulised group (5.1mm, 95% CI 0.8-9.4; p= 0.019).

Secondary outcomes

• There were no statistically significant differences in these secondary outcomes:
  • Mortality
  • Adverse events
  • Use of ventilation or respiratory support
  • Length of hospital stay
  • Admission to HDU or ICU
  • Change in peak flow and physiological variables (oxygen sats, HR, RR, BP) over 2 hours
  • Change of quality of life between baseline and 1 month
  • Number of unscheduled health-care contacts over the subsequent month
  • Satisfaction with care

Strengths

• Double blind RCT
• large multi-centre study
• reasonable baseline balance
• pragmatic trial with most patients receiving adequate medical treatment
• good follow up in ED
• although there were two primary outcomes, the study was powered for both a priori

Criticisms

• Ran out of funding – only recruited 92% target number – and slightly underpowered as a result
  • had 84% power to detect a 10% difference in admission rate for nebulised treatment versus placebo and 87% power for intravenous MgSO4 versus placebo
  • had 90% power to detect an 8 mm difference in a 100 mm VAS at 2 h after treatment initiation (two-sided α=0·05
• High percentage of exclusions
• low follow up at 30 days
• Only applicable to emergency department patients
• as a pragmatic trial, some patients may ave been misdiagnosed
• Exclusion of life-threatening asthma, which is a particularly relevant group to ICU practitioners – these patients are highly unlikely to be included in future RCTs
• The types of patients that typically receive IV MgSO4 in our setting are almost certainly going to be admitted to hospital regardless

Commentary

• a possible interpretation is that magnesium may have little additional benefit if maximal bronchodilator therapy is used – IV MgSO4 may still have some role as a salbutamol sparing agent
• previously, the MAGNETIC trial found a benefit for nebulised MgSO4 in children, it is possible that both nebulised and IV magnesium is more effective in children
• there was one death in each of the IV and nebulised MgSO4 groups
• there were few side-effects from nebulsied and IV MgSO4 compared to placebo (e.g. hypotension: 9% Nebulised MgSO4, 8% IV MgSO4 and 6% placebo)

• The 3Mg suggests there is no role for nebulised MgSO4 in adult patients with severe asthma. Although no benefit was found for IV MgSO4, there is still scope for its use in life-threatening asthma given that these patients were excluded and MgSO4 is inexpensive and has an acceptable side effect profile.