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Three Part Question

[In adult patients presenting with acute exacerbation of chronic obstructive pulmonary disease to the Emergency Department] does [intravenous magnesium sulphate] improve [airflow obstruction] ?

Clinical Scenario

A 67-year-old male presents to A&E with shortness of breath. He is found to be hypoxic, tachycardiac and tachypnoeic. Chest auscultation reveals bilateral wheeze and reduced air entry throughout. A clinical diagnosis of acute exacerbation of COPD is made. Patient is given Salbutamol and Ipratropium nebulisers followed by intravenous hydrocortisone. He is also given titrated supplemental oxygen. Since patient is already on theophylline and its serum levels is not available, intravenous aminophylline is not given. NIV is considered. You wonder if giving intravenous Magnesium Sulphate is of any benefit.

Search Strategy

A comprehensive literature search was conducted across Healthcare databases using NHS Athens. In addition, the Cochrane Databases of Systematic Reviews was also searched.
[{(exp chronic disease OR exp hospitals, chronic disease OR chronic.mp) AND (exp lung disease, obstructive OR obstructive.mp)} OR COPD OR acute exacerbation of chronic obstructive pulmonary disease] AND [Magnesium OR Magnesium sulphate OR Magnesium Sulfate] AND [IV OR Intravenous]

Search Outcome

A total of 8 papers were selected, but 4 were excluded due to one not being in English Language, one being performed in Internal Medicine ward, one being a duplicate and one used Magnesium Sulphate in nebulized form.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Nouira S, Bouida W, Grissa MH, Beltaief K, Trimech MN, Boubaker H, Marghli S, Letaief M, Boukef R 2014	Patient presenting with exacerbation of COPD to the Emergency Department. Total of 124 patients were included in this study.	Patients were randomized to either receive nebulized ipratropium bromide or combined nebulized and intravenous bolus of magnesium sulphate.	Primary outcomes were hospital admission, endotracheal intubation and hospital death rates. Secondary outcomes included improvement in peak expiratory flow, dyspnea score and arterial blood gas changes within the first 3 hours.	There were no significant differences in primary outcome between magnesium sulphate and ipratropium bromide.	Small sample size with possibility of type II error.
Shivanthan MC and Rajapakse S 2014 Srilanka	The 2 trials which compared intravenous magnesium sulphate alone with placebo had 24 and 72 patients.	The trial comparing nebulized magnesium sulphate with placebo had 109 patients and the trial comparing combined effect of nebulized plus intravenous magnesium sulphate with intravenous salbutamol and nebulized ipratropium had 124 patients.	The outcome measure in the two trials which compared intravenous magnesium sulphate alone with placebo were improvement in forced expiratory volume in 1s (FEV1) at 15, 30 or 45 minutes and increase in peak expiratory flow rate (PEFR) at 30 and 45 minutes. In the trial which compared nebulized magnesium sulphate with placebo, the outcome measure was forced expiratory volume in 1 s (FEV1) at 90 minutes. The trial comparing combined effect of nebulized plus intravenous magnesium sulphate with intravenous salbutamol and nebulized ipratropium set the outcome measures as likelihood of hospital admission, intubation, hospital mortality and length of hospital stay.	The two trials comparing intravenous magnesium sulphate alone with placebo had contrary results. Administration of intravenous magnesium sulphate alone did not have any effect of FEV1 at 15, 30 and 45 minutes compared with placebo but when salbutamol inhaler was added, the increase in FEV1 was higher in group receiving magnesium sulphate intravenously. When intravenous magnesium sulphate was used after administration of beta-2 agonist, the increase in PEFR was greater at 30 and 45 minutes compared to placebo. In the trial comparing nebulized magnesium sulphate with placebo, there was no difference in FEV1 measured at 90 minutes between nebulized magnesium sulphate and placebo groups. In the trial where combined effect of nebulized plus intravenous magnesium sulphate with intravenous salbutamol and nebulized ipratropium was compared, there were no statistically significant difference in the primary outcomes however, ipratropium bromide group showed increase in PEFR from baseline compared with magnesium sulphate group.	Non-randomized trials, case-control studies, and retrospective studies were excluded. Relatively small number of patients and not adequately powered. Moderate methodological quality. Lack of comparable outcome prevented meta-analysis. Primary outcomes were soft rather than hard outcomes such as need for invasive ventilation, duration of hospital stay or readmission.
Skorodin MS, Tenholder MF, Yetter B, Owen KA, Waller RF, Khandelwahl S, Maki K, Rohail T, D’Alfonso 1995 USA	Patient presenting with exacerbation of COPD to the Veterans Affairs Emergency Department. Total of 72 patients were included in this study.	Patients received either 1.2 g magnesium sulfate or placebo over 20 minutes after they first received albuterol nebulizer.	Primary outcome was increase in peak expiratory flow (PEF) rate compared to with the PEF at start of infusion, at 30 minutes and at 45 minutes. Secondary outcome was need for hospitalization.	There was significant difference in peak expiratory flow (PEF) rates at start, at 30 minutes and at 45 minutes between the two groups with the group receiving magnesium sulfate doing much better. The difference between magnesium sulfate and placebo groups was 22.4% +/- 28.5% vs 6.1% +/- 24.4%; P=.01. There was also statistically non-significant trend towards reduced need for hospitalization in magnesium sulfate group compared with placebo group.	Small sample size, non-pragmatic exclusion criteria and protocol violation.
Mukerji S, Shahpuri B, Clayton-Smith B, Smith N, Armstrong P, Hardy M, Marchant G, Marsh E 2015 New Zealand	Patient presenting with exacerbation of COPD to the Emergency Department. Total of 30 patients were included in this study.	Randomised, single centre, double blinded, parallel group, placebo controlled trial. Patients were randomly allocated in a double blind fashion to either receive 2 gm intravenous magnesium sulphate made up to 20 mls in 0.9% sodium chloride solution or 20 mls of intravenous saline as placebo.	Primary outcomes were percentage change in FEV1 and FVC at 0, 60 and 120 minutes. Secondary outcomes included admission rates, length of stay and requirement for NIV or mechanical ventilation.	Greater improvements were seen in FEV1 at 0, 60 and 120 minutes compared to standard bronchodilator therapy in magnesium group (at 120 minutes, mean percentage change in FEV1 was 27.07% with magnesium versus 11.39% in placebo group, 95% CI 3.7 to 27.7, p=0.01). Similar significantly greater improvements were noted with FVC in the magnesium group, compared to standard bronchodilator therapy group.	Pilot study, small sample size, less patients recruited (study was powered for 160 patients, but only 30 patients included), physiological outcomes as primary outcomes, skewed data (no data collected regarding severity of COPD), missed patients (15 patients missed due to lack of investigators or departmental overload).

Comment(s)

The available evidence suggests that intravenous magnesium sulphate when given after beta-2 agonist therapy enhances the broncho-dilatory effect. Myocardial stabilizing benefit of intravenous magnesium sulphate in AECOPD patients need to be investigated as this could lead to reduction in mortality in this sub-group of patients. Use of intravenous magnesium sulphate could be of benefit in patients presenting with AECOPD.

Clinical Bottom Line

Intravenous Magnesium Sulphate could be of benefit in acute exacerbation of chronic obstructive pulmonary disease.

References

1. Nouira S, Bouida W, Grissa MH, Beltaief K, Trimech MN, Boubaker H, Marghli S, Letaief M, Boukef R Magnesium Sulfate versus ipratropium bromide in chronic obstructive pulmonary disease exacerbation: a randomized trial.
2. Shivanthan MC and Rajapakse S Magnesium for acute exacerbation of chronic obstructive pulmonary disease: A systematic review of randomised trials.
3. Skorodin MS, Tenholder MF, Yetter B, Owen KA, Waller RF, Khandelwahl S, Maki K, Rohail T, D’Alfonso N Magnesium sulfate in exacerbations of chronic obstructive pulmonary disease.
4. Mukerji S, Shahpuri B, Clayton-Smith B, Smith N, Armstrong P, Hardy M, Marchant G, Marsh E Intravenous magnesium sulphate as an adjuvant therapy in acute exacerbation of chronic obstructive pulmonary disease: a single centre, randomised, double-blinded, parallel group, placebo-controlled.