What evidence is available on use of IV magnesium sulfate for use in COPD exacerbation?

Introduction
Chronic obstructive pulmonary disease (COPD) is a condition caused by an impaired inflammatory response to noxious stimuli such as cigarette smoke and other air pollutants.1 The resultant impact of this altered response is airway fibrosis, pulmonary tissue destruction, and pulmonary vasculature changes causing progressive airflow limitation. Cardinal symptoms of COPD include dyspnea, cough, and sputum production. The progressive nature of COPD results in significant morbidity and mortality.1,2 Dyspnea causes significant impairment in activity and has a multifactorial impact on quality of life. In 2019, 3 million deaths were attributed to COPD making it the third leading cause of death.2

According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline, treatment decisions are guided by patient symptoms (dyspnea, exercise limitation), spirometric measures of airflow obstruction (forced expiratory volume in 1 second [FEV1]), functional capacity (timed walking test), and the frequency of exacerbations.1 Severe COPD exacerbations are an acute worsening of symptoms that lead to emergency room visits and/or hospitalization and can progress to acute respiratory failure. The management of a severe COPD exacerbation includes oxygen, short-acting bronchodilators, corticosteroids, and possibly, antibiotics (if indicated) and noninvasive ventilation. Despite these recommended treatments, the outcomes of treatment for COPD exacerbations are not optimal.3,4,5 The use of intravenous (IV) magnesium sulfate for patients with a COPD exacerbation has been evaluated in some recent studies and this review provides a summary of the currently available literature (see Table).

Intravenous Magnesium
Based on positive outcomes observed in patients experiencing severe asthma exacerbations, the postulated mechanisms of magnesium sulfate on the respiratory system are bronchial smooth muscle relaxation (calcium channel blockade/ inhibition of acetylcholine release from the neuromuscular junction) and anti-inflammatory properties (reduction in neutrophil and histamine release).3,4,6 Additionally, correlations between hypomagnesemia and COPD exacerbation have been reported by some authors.7,8,9

A recent meta-analysis has brought attention to the use of IV magnesium sulfate for use in acute exacerbation of COPD.10 The Cochrane review by Ni and colleagues evaluated 7 randomized controlled trials (RCTs) comparing the use of IV magnesium sulfate to placebo. With low or very-low certainty of evidence, the results demonstrated lower odds of hospital admission, a shorter length of hospital stay, and improved dyspnea with IV magnesium sulfate compared to placebo. No difference in the need for intubation was observed and the impact on airflow obstruction was inconclusive.

Two recent RCTs (from 2021) utilized different methods to assess airflow obstruction.3,4  The FEV1, used as a measure by Jahanian et al, did not demonstrate a significant difference with use of magnesium sulfate 2 g.3 In contrast, the change in peak expiratory flow rate (PEFR) was significantly improved with magnesium sulfate 2.5 g compared to placebo in the study by Vafadar and colleagues.4 Improvement in dyspnea scores with magnesium sulfate versus placebo was also conflicting between the 2 studies.3,4 Both studies did not demonstrate a significant impact on oxygen saturation with magnesium sulfate compared to placebo. In the Vafadar study, the rate of discharge from the emergency department (ED) was numerically higher for patients who received magnesium sulfate compared to placebo; however, this difference did not reach statistical significance.4

Airflow obstruction measured by FEV1 and forced vital capacity (FVC) was significantly improved with use of magnesium sulfate 2 g compared to placebo in a small study of 30 patients.11 In contrast, another small study (n=30), did not find significant differences in PEFR or FEV1-predicted with magnesium sulfate 2 g.12 Both studies found magnesium sulfate to have no significant reduction in length of hospital stay compared to placebo.11,12 A larger study of over 120 patients compared IV magnesium sulfate 1.5 g to nebulized ipratropium and found no difference in the clinical outcomes of mortality, hospital admission, need for ventilation, or length of stay.5 Dyspnea scores improved significantly from baseline in both groups. Ipratropium demonstrated greater improvement in PEFR compared to magnesium sulfate. Differences in measures of airflow obstruction limit the application of these results.

The dose of magnesium sulfate used in the studies varied between 1.2 g in the 1995 study13 and 2 to 2.5 g in the 2021 studies.3.4 Common exclusion criteria in studies included the need for tracheal intubation or noninvasive ventilation, conditions that could mimic COPD like asthma, other serious illness, and hemodynamic instability. Additionally, standard treatment of COPD exacerbation differed slightly between studies with antibiotics and/or corticosteroids use reported in some but not all studies.

Table. Summary of studies on use of IV magnesium sulfate for COPD exacerbation.
Study
Sample size
Interventions
Outcomes
Meta-analysis
Ni 202210
Cochrane review
7 RCT
 
Mg IV
Placebo
 
Mg IV vs placebo:
Hospital admission (3 studies; n=170)
OR 0.45, 95% CI 0.23 to 0.88
 
Need for intubation (2 studies)
OR 0.74, 95% CI 0.31 to 1.75
 
Length of hospital stay (2 studies; n=54)
Mean difference: -2.7 days, 95% CI -4.73 to -0.66
 
Change in PEFR % predicted (1 study)
Mean difference: 10.64%; 95% CI 8.3 to 12.9
 
Dyspnea score (2 studies; n=101)
Mean difference -1.40, 95% CI -1.83 to -0.96
 
No difference in oxygen saturation, FEV1, or PEFR.
Randomized controlled trials
Jahanian 20213
DB, SC, RCT
60 patients with moderate COPD (FEV1/FVC < 70% and FEV1 between 30 and 50)
 
Setting: ED
 
 
Mg IV 2g in 100 mL saline over 30 mins (n=30)
 
Normal saline over 30 mins (n=30)
 
All patients received oxygen, inhaled salbutamol and ipratropium, IV hydrocortisone
Mg vs. saline 
FEV1(mL):
At 45 mins: 58.06 vs 55.96; p=NS
At 6 hours: 61.66 vs 59.83; p=NS
 
Borg score*:
At 45 mins: 6.33 vs 6.43; p=NS
At 6 hours: 4.73 vs 4.86; p=NS
 
SpO2:
At 45 mins: 94 vs 93.7; p=NS
At 6 hours: 95.23 vs 95.06; p=NS
 
From baseline to 6 hours, all outcomes demonstrated a significant improvement in both groups.
Vafadar  20214
RCT
 
 
77 patients with PEFR ≤ 50%
 
Setting: ED
Mg IV 2.5 g (5 mL of 50% solution) in 50 mL saline over 30 mins (n=39)
 
Normal saline over 30 mins (n=38)
 
All patients received oxygen, nebulized salbutamol and ipratropium, IV hydrocortisone, IV ceftriaxone, and oral azithromycin. Study treatment given within 60 minutes after standard therapy and when patients were clinically stable.
Primary (Mg vs. saline)
Measured 30 mins post administration
PEFR change:
15.67 vs 5.02
(mean difference 10.03; 95% CI 8.68 to 11.38; p<0.001)
 
DSS change:*
-3.69 vs -2.05
(mean difference 1.63; 95% CI 1.14 to 2.13; p<0.001)
 
RR change:
-7.74 vs -6.84
(mean difference 0.90; 95% CI 0.02 to 1.78; p=0.045)
 
Secondary:
SpO2 change:
8.74 vs 8.42
(mean difference 0.32; 95% CI -1.56 to 2.2; p=NS)
 
Need for intubation:
No significant difference between groups
 
ED discharge rate:
Mg group: 64.1% vs 42.1%
OR: 2.45, 95% CI 0.98 to 6.14; p=0.052
Mukerji 201511
SC, DB, PC, RCT
30 patients
 
Setting: ED
Mg IV 2 g in 20 mL normal saline over 15 mins (n=13)
 
Normal saline 20 mL over 15 min (n=17)
 
All patients received oxygen, nebulized salbutamol (given immediately, with treatment or placebo, at 60 min and 120 min), nebulized ipratropium, IV hydrocortisone or oral prednisone
Primary (Mg vs. saline)
Measured after initial bronchodilator therapy (TB), immediately after infusion (T0), at 60 mins (T60) and at 120 mins (120)
 
FEV1 (mL) T60 to T120
78.18 vs 18.7
(mean difference 59.52; 95% CI 11.47 to 107.56; p=0.02)
 
FEV1 (mL) TB to T120
166.36 vs 80
(mean difference 86.36; 95% CI 1.48 to 171.25; p=0.04)
Mean % FEV1 change TB to T120
27.07 vs 11.38
(mean difference 15.68; 95% CI 3.7 to 27.7; p=0.01)
 
FVC (mL) TB to T0
140.9 vs 16.7
(mean difference 124.2; 95% CI 27.42 to 221.07; p=0.01)
 
FVC (mL) TB to T120
333.6 vs 149.3 
(mean difference 184.3; 95% CI 33.33 to 335.27; p=0.02)
 
Secondary
No difference between groups in hospital admission, need for ventilation, or length of stay
Nouria 20145
SC, DB, RCT
124 patients with dyspnea within 2 weeks, PaCO2 > 45 mm Hg and 2 of the following: RR> 24 /min,
Arterial pH < 7.35, and PaO2 < 50 mm Hg
 
Setting: ED
Mg 150 mg in 4 mL normal saline nebulized + Mg IV 1.5 g in 10 mL normal saline (n=62)
 
Ipratropium 0.5 mg in 3 mL normal saline nebulized + IV normal saline (n=62)
 
All patients received oxygen, IV methylprednisolone, IV fluids, antibiotics, and nebulized terbutaline
Primary (Mg vs ipratropium):
Hospital admission:
43.5% vs 32.2 %, p=NS
Need for intubation:
17.7% vs 11.3%, p=NS
Mortality:
1.6% vs 3.2%, p=NS
 
Secondary (measured at 3 hours post-treatment) (Mg vs ipratropium):
PEFR:
26 L/min vs 58 L/min; p<0.05
Length of stay (days):
7.7 vs 6.6, p=NS
Dyspnea score:
significantly improved from baseline in both groups; no significant difference between groups was observed
Solooki 201412
SC, DB, RCT
30 patients admitted to internal medicine ward after standard treatment for COPD exacerbation
 
Setting: ED and hospital
Mg IV 2 g in 100 mL saline over 20 mins (n=15)
 
Normal saline 100 mL (n=15)
 
All patients received oxygen, nebulized salbutamol and ipratropium, IV methylprednisolone, oral azithromycin
Mg vs. saline:
PEFR:
At 45 min: 130 L/min vs 145 L/min; p=NS
At 3 days: 139 L/min vs 149 L/min; p=NS
 
FEV1 % predicted:
At 45 min: 27% vs 36%; p=NS
At 3 days: 32% vs 41%; p=NS
 
SpO2:
At 3 days: 90% in both groups p=NS
 
Hospital stay:
No difference between groups (specific results not reported)
Skorodin 199513
DB, PC, RCT
72 patients
 
Setting: ED
Mg IV 1.2 g in 150 mL normal saline over 20 mins (n=36)
 
Normal saline 2.4 mL in 150 mL normal saline over 20 min (n=36)
 
All patients received oxygen, nebulized albuterol prior to study treatment.
PEF increase (baseline to 45 mins):
Mg: 136.7 L/min to 161.3 L/min
Placebo: 137 L/min to 143 L/min
 
PEF difference/% change (Mg vs placebo):
25.1 L/min/22.4% vs 7.4 L/min/6.1%; p=0.03/p=0.01
 
Dyspnea score: no significant difference between groups
 
Hospitalization rate (Mg vs. placebo):
28.1% vs 41.9%; p=NS
 
ED visit within 2 weeks:
no significant difference
 
Oxygen saturation/vital signs:
no significant changes observed
*Borg score/DSS score: a scale from 0 to 10; zero indicates the absence of dyspnea and 10 is severe dyspnea;
Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; DB, double-blind; DSS, dyspnea severity score; ED, emergency department; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; IV, intravenous; Mg, magnesium sulfate; NS, not significant; OR, odds ratio; PaCO2, partial pressure of arterial carbon dioxide; PaO2, partial pressure of arterial oxygen; PC, placebo-controlled; PEF(R), peak expiratory flow (rate); RCT, randomized controlled trial; RR, respiratory rate; SC, single-center; SpO2, peripheral capillary oxygen saturation.

Conclusion
Due to inconsistencies in magnesium sulfate doses and outcomes measured, specifically for airflow obstruction, the impact of magnesium on acute exacerbation of COPD is unclear. Despite smaller studies demonstrating no impact on clinical outcomes, a recent meta-analysis has demonstrated, with low certainty, a potential benefit of magnesium on hospital admission, length of hospital stay, and symptoms of dyspnea as an add-on treatment.10 Larger studies using consistent outcomes and standard treatments as recommended by the GOLD guidelines will help further establish whether IV magnesium sulfate has a role in management of COPD exacerbation. Although well tolerated in the studies, magnesium sulfate should be used cautiously in patients with electrocardiogram abnormalities, electrolyte disturbances, and kidney dysfunction.3-5, 11-14 If used, patients should be monitored for potential adverse events including hypotension, cardiovascular arrest, dysrhythmia, and respiratory depression (at high doses).4,14

References

  1. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2022 report. Accessed October 24, 2022. https://goldcopd.org/2022-gold-reports-2/
  2. World Health Organization. Chronic obstructive pulmonary disease (COPD). Accessed October 24, 2022. https://www.who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd)
  3. Jahanian F, Khatir IG, Ahidashti HA, Amirifard S. The effect of intravenous magnesium sulphate as an adjuvant in the treatment of acute exacerbations of COPD in the emergency department: A Double-Blind Randomized Clinical Trial. Ethiop J Health Sci. 2021;31(2):267-274. doi: 10.4314/ejhs.v31i2.9.
  4. Vafadar Moradi E, Pishbin E, Habibzadeh SR, Talebi Doluee M, Soltanifar A. The adjunctive effect of intravenous magnesium sulfate in acute exacerbation of chronic obstructive pulmonary disease: a randomized controlled clinical trial. Acad Emerg Med. 2021;28(3):359-362. doi: 10.1111/acem.14050.
  5. Nouira S, Bouida W, Grissa MH, et al. Magnesium sulfate versus ipratropium bromide in chronic obstructive pulmonary disease exacerbation: a randomized trial. Am J Ther. 2014;21(3):152-8. doi: 10.1097/MJT.0b013e3182459a8e.
  6. Kwofie K, Wolfson AB. Intravenous magnesium sulfate for acute asthma exacerbation in children and adults. Am Fam Physician. 2021;103(4):245-246.
  7. Makwana S, Patel A, Sonagara M. Correlation between serum magnesium level and acute exacerbation in patients with chronic obstructive pulmonary disease (COPD). Cureus. 2022;14(6):e26229. doi: 10.7759/cureus.26229.
  8. Kshirsagar K, Patil VC. Chronic obstructive pulmonary disease: Is serum magnesium level a risk factor for its acute exacerbation?. Caspian J Intern Med. 2021;12(2):223-227. doi: 10.22088/cjim.12.2.223.
  9. Gumus A, Haziroglu M, Gunes Y. Association of serum magnesium levels with frequency of acute exacerbations in chronic obstructive pulmonary disease: a prospective study. Pulm Med. 2014;2014:329476. doi: 10.1155/2014/329476.
  10. Ni H, Aye SZ, Naing C. Magnesium sulfate for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2022 ;5(5):CD013506. doi: 10.1002/14651858.CD013506.pub2.
  11. Mukerji S, Shahpuri B, Clayton-Smith B, et al. Intravenous magnesium sulphate as an adjuvant therapy in acute exacerbations of chronic obstructive pulmonary disease: a single centre, randomised, double-blinded, parallel group, placebo-controlled trial: a pilot study. N Z Med J. 2015;128(1425):34-42.
  12. Solooki M, Miri M, Mokhtari M, Valai M, Sistanizad M, Kouchek M. Magnesium sulfate in exacerbations of COPD in patients admitted to internal medicine ward. Iran J Pharm Res. 2014;13(4):1235-9.
  13. Skorodin MS, Tenholder MF, Yetter B, et al. Magnesium sulfate in exacerbations of chronic obstructive pulmonary disease.
    Arch Intern Med. 1995;155(5):496-500.
  14. Magnesium sulfate: drug information. Hudson, OH: Lexicomp, 2022. http://online.lexi.com. Accessed October 25, 2022.

Prepared by:
Rita Soni, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

November 2022

The information presented is current as of October 25, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.