Jenna Chiu August 2014

 Background  Study hypothesis  Methods  Results  Analysis  Future practice

 Common presentation to ED  National Asthma Council Australia ◦ Australian Asthma Handbook 2014  British Thoracic Society / Scottish Intercollegiate Guidelines Network ◦ British Guidelines on the Management of Asthma 2012

Australian guidelines  Can walk and speak whole sentences in one breath British guidelines  Increasing symptoms  PEF > 50-75% best or predicted  No features of acute severe asthma

Australian guidelines  Unable to speak in sentences  Visibly breathless  Increased work of breathing  Oxygen saturation % British guidelines  Inability to complete sentences in one breath  PEF 33-50% best or predicted  RR ≥ 25/min  HR ≥ 110/min

Australian guidelines  Drowsy  Collapsed  Exhausted  Cyanotic  Poor respiratory effort  Oxygen saturation < 90% British guidelines  Altered conscious level  Exhaustion  Arrhythmia  Hypotension  Cyanosis  Silent chest  Poor respiratory effort  PEF < 33% best or predicted  SpO 2 < 92%  PaO2 < 8kPa  “normal” PaCO 2 ( kPa)

AGENTRECOMMENDED USE IN ACUTE ASTHMA Administration and dosage Notes IV magnesium sulphate Second-line bronchodilator in severe or life- threatening acute asthma, or when poor response to repeated maximal doses of other bronchodilators IV infusion over 20 minutes Adults: 2g (20 mmol) Children ≥ 2 years: mmol/kg Avoid magnesium sulphate in children younger than 2 years

 Stepwise approach to the management of acute asthma including oxygen, nebulisers and steroids  Bronchodilators act within minutes whereas corticosteroids require hours to take effect

 Potential role for magnesium sulphate (MgSO 4 ) as an additional treatment option in the therapeutic gap between nebulised bronchodilators and corticosteroids

Advantages  Quick onset of action  Reduced incidence of side-effects Disadvantages  Reduced dose of drug delivered compared with the intravenous form  Respiratory effort on the part of the patient to increase its effectiveness

Advantages  Provides direct access to the venous system allowing delivery of high drug concentrations Disadvantages  Need for intravenous access  Drug administration by infusion lasting 20 mins

 Differing conclusions regarding the effectiveness of treatment  Previous primary outcome- PEFR  No trials have directly compared intravenous MgSO 4 with nebulised MgSO 4  No recommendations are made regarding nebulised MgSO 4

 Multicentre double-blind randomised placebo-controlled trial across 34 emergency departments in the UK  July 2008 – June 2012

 Adults (aged ≥ 16 years) attending an ED with severe acute asthma ◦ Acute asthma with either a PEFR < 50% of best or predicted, RR ≥ 25/min, HR ≥ 110/min, or inability to complete sentences in one breath  Written or verbal consent obtained

 Exclusion criteria ◦ Life-threatening features (oxygen saturation < 92%, silent chest, cyanosis, poor respiratory effort, bradycardia, arrhythmia, hypotension, exhaustion, coma, or confusion) ◦ Contraindication to either nebulised or intravenous MgSO 4 (pregnancy, hepatic or renal failure, heart block, or known hypermagnesaemia) ◦ Individuals who were unable to provide written or verbal consent ◦ Individuals who had received MgSO 4 in the 24 h prior to recruitment

 Randomly allocated with either a telephone or internet randomisation sequence  Given numbered treatment packs  Each treatment pack contained an intravenous infusion and three nebuliser solutions, either which could be active treatment or placebo  Participants, hospital staff, and research staff were masked to allocated treatment

Intravenous MgSO 4 group IV MgSO 4 (8 mmol [2 g] in 100 mL normal saline provided over 20 min) + three 7.5 mL vials of 0.9% saline nebulised at 20 min intervals Nebulised MgSO 4 group IV normal saline (100 mL given over 20 min) + three 7.5 mL vials of 2 mmol (500mg) MgSO 4 nebulised at 20 min intervals Placebo group IV normal saline (100 mL given over 20 min) + three 7.5 mL vials of 0.9% saline nebulised at 20 min intervals

 Standard therapy ◦ Oxygen ◦ Nebulised salbutamol (5 mg) ◦ Nebulised ipratropium (500  g) ◦ Oral prednisolone ◦ Additional – nebulised salbutamol (5 mg) added to each trial nebuliser

Primary outcome measures 1) Proportion of patients admitted to hospital within 7 days 2) Patient’s visual analogue scale (VAS) for breathlessness in the 2 h after initiation of treatment

 Power calculation ◦ For 90% power to detect a 10% change in admission rate would require 1200 patients, i.e. 400 patients in each group ◦ Assuming 80% of participants had a VAS measurement, this would provide a 90% power to detect an 8 mm difference in a 100 mm VAS at 2 h after treatment initiation

 Secondary outcomes ◦ Mortality ◦ Adverse events ◦ Use of ventilation or respiratory support ◦ Length of hospital stay ◦ Admission to a HDU or ICU ◦ Change in peak expiratory flow rate ◦ Physiological variables (oxygen saturation, heart rate, respiratory rate, blood pressure) over 2 h ◦ Change in quality of life between baseline and 1 month ◦ Number of unscheduled health-care contacts over the subsequent month ◦ Satisfaction with care

 Our findings suggest nebulised MgSO 4 has no role in the management of severe acute asthma in adults and at best suggest only a limited role of intravenous MgSO 4 in this setting

 Relevance  Value ◦ Largest trial of MgSO 4 undertaken in acute asthma ◦ Directly compares intravenous treatment with nebulised treatment  Study Design ◦ Multicentre, double-blind, placebo-controlled, randomised trial ◦ Involved 34 emergency departments across UK

 Comparison with previous studies ◦ Differing results  Limitations ◦ Underpowered ◦ Primary outcomes and their relevance ◦ Exclusion of life-threatening asthma ◦ Unable to power study to detect differences in serious adverse outcomes (including death) ◦ Co-morbidities not evaluated

 Unlikely to change our current practice using intravenous MgSO 4  Unlikely to commence using nebulised MgSO 4 in adults  Further studies in the future with different treatment endpoints

 National Asthma Council Australia. (accessed Aug 3, 2014)  British Thoracic Society/Scottish Guidelines Intercollegiate Network. thoracic.org.uk/document-library/clinical- information/asthma/btssign-guideline-on-the- management-of-asthma/ (accessed Aug 3, 2014) thoracic.org.uk/document-library/clinical- information/asthma/btssign-guideline-on-the- management-of-asthma/  Mohammed S, Goodacre S. Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis. Emerg Med J 2007; 24:823-30