Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Magnesium sulphate

Bloch, 1995

Type of study: RCT

Setting and country: USA

Funding: Reported

Conflicts of interest: Not reported

Inclusion criteria:

-Aged 18-65 years

-Presenting with acute asthma at the ED

Exclusion criteria:

-History of congestive heart failure

-Suffering from diabetes mellitus, angina, chronic renal insufficiency, temperature >38°C, pneumonia or pregnant

-Patients requiring intubation

-Unable to perform spirometry

-Unable to give informed consent

-Patients with forced expired volume in 1 s (FEV1) was greater or equal to 75% predicted on ED presentation or after a single albuterol treatment

N total at baseline:

Intervention: 67 (severe asthma: n=21)

Control: 68 (severe asthma: n=14)

Important prognostic factors²:

Age ± SD:

Intervention: 36 ± 12.7 (severe: 34 ± 13.4)

Control: 38.6 ± 13.2 (severe: 42 ± 14)

Sex:

Intervention: 27% M (severe: 19% M)

Control: 29% M (severe: 43% M)

Groups comparable at baseline? Yes

Baseline medication:

Inhaled albuterol treatment (2.5 mg in 2.5 mL saline solution by high-flow nebulizer).

Patients with FEV1 < 40% predicted, or who received oral steroids within the past 6 months, received 125 mg of methylprednisolone IV within 30 minutes of presentation

Intervention:

2 g MgSO_{4 in} IV over 20 minutes

Baseline medication:

Inhaled albuterol treatment (2.5 mg in 2.5 mL saline solution by high-flow nebulizer).

Patients with FEV1 < 40% predicted, or who received oral steroids within the past 6 months, received 125 mg of methylprednisolone IV within 30 minutes of presentation

Control:

Placebo in 50 mL saline IV over 20 minutes

Length of follow-up:

1 week

Loss-to-follow-up:

No loss-to-follow-up in intervention or control group.

Incomplete outcome data:

149 patients were originally randomized (distribution unknown). 12 patients were enrolled more than once (first visit was used for analysis), 1 patient had irreversible airway disease, 1 patient had congestive heart failure, 4 patients were included as ITT because the study protocol was violated, in 6 patients baseline FEV1 was unavailable.

Hospital admission - severe asthma:

Intervention: 33.3% (7/21)

Control: 78.6% (11/14)

P=0.009

Hospital admission - moderate asthma:

Intervention: 22.2 (10/45)

Control: 22.4% (11/49)

P=0.98

Adverse effects:

Intervention: 58% of patients suffered from mild side effects: flushing, mild fatigue, burning at the IV stie and transient urticaria in the upper extremities

Control: no side effects reported

No comments

Boonyavorakul, 2000

Type of study: RCT

Setting and country: Thailand

Funding and conflicts of interest: Not reported

Inclusion criteria:

-Aged 15-65 years

-Diagnosed as acute severe asthma

Exclusion criteria:

-History of heart disease, hypertension, diabetes mellitus, chronic renal disease, infection, (suspected) pregnancy and FISCHL index of 4 or more

N total at baseline:

Intervention: 17

Control: 16

Important prognostic factors²:

Age ± SD:

Intervention: 42.88 ± 2.99

Control: 35 ± 3.03

Sex:

Intervention: 11.76% M

Control: 12.50% M

Groups comparable at baseline? Yes

Baseline medication:

5 mg IV dexamethasone, 2.5 mg nebulized salbutamol at 0, 20, 40, 60 min, and oxygen mask if necessary

Intervention:

2 g MgSO_{4 in} 50 mL of 0.9% saline

Baseline medication:

5 mg IV dexamethasone, 2.5 mg nebulized salbutamol at 0, 20, 40, 60 min, and oxygen mask if necessary

Control:

2 mL of sterile water in 50 mL of 0.9% saline

Length of follow-up:

240 min after receipt of treatment

Loss-to-follow-up:

No loss-to-follow-up in intervention or control group.

Incomplete outcome data:

Not applicable

Hospital admission:

Intervention: 17.65% (3/17)

Control: 25% (4/16)

RR: 0.71 95% CI [0.19-2.67]

No comments

Bradshaw, 2007

Type of study: RCT

Setting and country: UK

Funding and conflicts of interest: Not reported

Inclusion criteria:

-Aged >16 years

-Past diagnosis of asthma

-PEF<75% predicted indicating a moderate to severe attack

Exclusion criteria:

-COPD or other chronic lung disease, pneumonia, congestive cardiac failure, coronary artery disease, renal insufficiency, hypertension treated with medication, pregnancy

-Inability to perform peak flow measurements

N total at baseline:

Intervention: Overall (62), life-threatening (12), severe (30), moderate (20)

Control: Overall (67), life-threatening (17), severe (31), moderate (19)

Important prognostic factors²:

Age ± SD:

Intervention: Overall (36, 18-73), life-threatening (38.1 ± 16.8), severe (34.8 ± 11.2), moderate (35.2 ± 14.3)

Control: : Overall (38.8, 17-73), life-threatening (34.5 ± 14.1), severe (42.8 ± 17.1), moderate (36.2 ± 13.1)

Sex:

Intervention: Overall (39% M), life-threatening (33% M), severe (43% M), moderate (35% M)

Control: Overall (45% M), life-threatening (29% M), severe (61% M), moderate (32% M)

Groups comparable at baseline? Yes

Baseline medication:

35% of oxygen, 5 mg nebulised salbutamol, 500 mcg nebulised ipratropium and 200 mg IV hydrocortisone

Intervention:

1.2 g MgSO₄ in 50 mL saline IV over 15 minutes

Baseline medication:

35% of oxygen, 5 mg nebulised salbutamol, 500 mcg nebulised ipratropium and 200 mg IV hydrocortisone

Control:

50 mL saline IV over 15 minutes

Length of follow-up:

60 min after receipt of treatment

Loss-to-follow-up:

No loss-to-follow-up in intervention or control group.

Incomplete outcome data:

150 patients were recruited into the study and 129 were included in the final analysis. Patients were excluded due to subsequent recognition of PEF >75% predicted or missing record data.

Hospital admission - overall:

Intervention: 79% (49/62)

Control: 78% (52/67)

P=0.98

Hospital admission – life-threatening:

Intervention: 100% (12/12)

Control: 88% (15/17)

P=0.50

Hospital admission - severe:

Intervention: 70% (21/30)

Control: 84% (26/31)

P=0.32

Hospital admission - moderate:

Intervention: 80% (16/20)

Control: 58% (11/19)

P=0.18

Adverse events – overall:

Intervention: 5/62 patients suffered from minor side effects (headache, flushing and dizziness)

Control: one patient suffered from flushing

No comments

Goodacre, 2014

Type of study: RCT

Setting and country: UK

Funding and conflicts of interest: Both reported

Inclusion criteria:

-Aged >16 years

-Presenting at the ED with acute severe asthma (PEFR<50% best or predicted, >25 breaths per minute, heart rate > 110 bpm or inability to complete sentences in one breath

Exclusion criteria:

-Patients with life-threatening features

-Patients with a contraindication to either nebulised or IV magnesium sulphate (pregnancy, hepatic or renal failure, heart block or known hypermagnesemia)

-Unable to provide written or oral consent

-Previous participants in the 3Mg trial

-Patients who had received IV or nebulised MgSO₄ in the 24 hours prior to attendance at the ED

N total at baseline:

Intervention: 394

Control: 358

Important prognostic factors²:

Age ± SD:

Intervention: 35.6 ± 13.1

Control: 36.4 ± 14.1

Sex:

Intervention: 29% M

Control: 30% M

Groups comparable at baseline? Yes

Baseline medication:

Oxygen, nebulised salbutamol, nebulised ipratropium bromide and oral prednisolone administered during recruitment, followed by up to 5 mg salbutamol added to each trial nebuliser. Three 7.5-mL vials of 0.9% saline nebulised at 20-minutes intervals

Intervention:

IV MgSO₄ 2 gram (8 mmol) in 100 mL saline given over 20 minutes

Baseline medication:

Oxygen, nebulised salbutamol, nebulised ipratropium bromide and oral prednisolone  administered during recruitment, followed by up to 5 mg salbutamol added to each trial nebuliser. Three 7.5-mL vials of 0.9% saline nebulised at 20-minutes intervals

Control:

IV 100 mL saline given over 20 minutes

Length of follow-up:

30 days

Loss-to-follow-up:

No loss-to-follow-up in intervention or control group.

Incomplete outcome data:

1109 patients were recruited, of which 25 either withdrew or were recruited in error (protocol violations).

Mortality:

Intervention: 0.3% (1/394)

Control: 0.3% (1/358)

Hospital admission:

Intervention: 71% (279/394)

Control: 78% (278/358)

ICU admission:

Intervention: 3% (11/394)

Control: 1% (5/358)

Days on ICU:

Intervention: 3.1 ± 5.0

Control: 2.9 ± 3.9

Mechanical ventilation:

Intervention: 2% (6/394)

Control: 1% (4/358)

Adverse events:

Intervention: 13.4% (53/394)

Control: 10.1% (36/358)

Serious adverse events:

Intervention: 11.4% (45/394)

Control: 7.8% (28/358)

No comments

Green, 1992

Type of study: RCT

Setting and country: USA

Funding and conflicts of interest: Not reported

Inclusion criteria:

-Aged 18-65 years

-Presenting at the ED with acute asthma

Exclusion criteria:

-Patients with atherosclerotic heart disease, angina, chest pain, uncontrolled hypertension, congestive heart failure, heart block, metastatic cancer, renal disease, temperature above 38.3°C, systolic blood pressure below 120 mm Hg or pregnancy

-Patients with radiographic evidence of confounding pulmonary disease

-Patients requiring mechanical ventilation at any point during their ED visit or subsequent hospitalization

N total at baseline:

Intervention: 58

Control: 62

Important prognostic factors²:

Age ± SD:

Intervention: 40

Control: 39.8

Sex:

Intervention: 21% M

Control: 16% M

Groups comparable at baseline? Yes

Baseline medication:

Treatment with oxygen and inhaled albuterol. Albuterol was administered either as a nebulized aerosol (0.5 mL in 2.5 mL saline) or through supervised inhalations of a metred-dose inhaler with spacer titrated to a therapeutic effective dose. If no improvement was observed, patient received 125 mg IV methylprednisolone

Intervention:

2 g MgSO₄ diluted in 50 mL D₅W IV over 20 minutes

Baseline medication:

Treatment with oxygen and inhaled albuterol. Albuterol was administered either as a nebulized aerosol (0.5 mL in 2.5 mL saline) or through supervised inhalations of a metred-dose inhaler with spacer titrated to a therapeutic effective dose. If no improvement was observed, patient received 125 mg IV methylprednisolone

Control:

No MgSO₄

Length of follow-up:

Not reported

Loss-to-follow-up:

No loss-to-follow-up in intervention or control group.

Incomplete outcome data:

Not applicable

Hospital admission:

Intervention: 22% (13/58)

Control: 18% (11/62)

No comments

Porter, 2001

Type of study: RCT

Setting and country: USA

Funding and conflicts of interest: Not reported

Inclusion criteria:

-Aged 18-55 years

-History of asthma

-PEF≤100 l/min or ≤25% predicted (moderate to severe asthma)

-Ability to provide informed consent

Exclusion criteria:

-Possible non-asthmatic causes of wheezing

-Patients who on arrival appeared to require endotracheal intubation

-Pregnant patients

N total at baseline:

Intervention: 18

Control: 24

Important prognostic factors²:

Age ± SD:

Intervention: 32 ± 13

Control: 38 ± 15

Sex:

Intervention: 50% M

Control: 25% M

Groups comparable at baseline? Yes

Baseline medication:

2.5 mg albuterol sulphate via nebulizer, 125 mg methylprednisolone IV

Intervention:

2 g MgSO₄ in 50 mL saline IV over 20 minutes

Baseline medication:

2.5 mg albuterol sulphate via nebulizer, 125 mg methylprednisolone IV

Control:

50 mL saline IV over 20 minutes

Length of follow-up:

60 minutes

Loss-to-follow-up:

No loss-to-follow-up in intervention or control group.

Incomplete outcome data:

There were 55 asthma episodes meeting inclusion criteria. These episodes represented visits by 42 different patients, with all consenting to participate on all episodes. Patients completed the study protocol in each of the 55 episodes. The following results refer to the first asthma episodes in the 42 study patients

Mortality:

Intervention: 0% (0/18)

Control: 0% (0/24)

Hospital admission:

Intervention: 28% (5/18)

Control: 21% (5/24)

Adverse events:

Intervention: 22% (4/18)

Control: 13% (3/23)

No comments

Silverman, 2002

Type of study: RCT

Setting and country: USA

Funding and conflicts of interest: Not reported

Inclusion criteria:

-Aged 18-60 years

-Presenting with acute severe asthma at the ED

-Diagnosed with asthma in the past by a clinician and using asthma medication in the previous 6 months

-FEV1≤30% predicted

-Willing to remain in the ED for 4 hours

-Ability to provide informed consent

Exclusion criteria:

-History of COPD or other chronic lung disease, congestive heart failure, coronary artery disease, diabetes mellitus, renal insufficiency or hypertension treated with medication

-Temperature above 38.9°C

-Suspected of having pneumonia

-Pregnant patients

-Patients requiring intubation or unable to perform spirometry

N total at baseline:

Intervention: 122

Control: 126

Important prognostic factors²:

Age ± SD:

Intervention: 36.4 ± 11.1

Control: 36.5 ± 11.4

Sex:

Intervention: 45% M

Control: 51% M

Groups comparable at baseline? Yes

Baseline medication:

0.5 mL of 0.5% albuterol (2.5 mg) administered via wet nebulizer with 100% oxygen, 125 mg of IV methylprednisolone. Albuterol was readministered 30, 60, 120 and 180 min after ED arrival

Intervention:

2 g MgSO₄ in 50 mL saline IV over 10-15 minutes

Baseline medication:

0.5 mL of 0.5% albuterol (2.5 mg) administered via wet nebulizer with 100% oxygen, 125 mg of IV methylprednisolone. Albuterol was readministered 30, 60, 120 and 180 min after ED arrival

Control:

Placebo in 50 mL saline IV over 10-15 minutes

Length of follow-up:

7 days

Loss-to-follow-up:

No loss-to-follow-up in intervention or control group.

Incomplete outcome data:

254 patients were randomized, but 6 patients were inadvertently enrolled twice. 248 patients formed the ITT population

Hospital admission:

Intervention: 32% (39/122)

Control: 32% (41/126)

No comments

Singh, 2008

Type of study: RCT

Setting and country: India

Funding and conflicts of interest: Not reported

Inclusion criteria:

-Aged 18-60 years

-Presenting with acute severe asthma at the ED

-Diagnosed with asthma in the past by a clinician with spirometry records showing a reversibility of 12%, and using asthma medication in the previous 6 months

-FEV1<30% predicted

-Willing to remain in the ED for 3 hours

Exclusion criteria:

-History of COPD or other chronic lung disease, and other known cardiac, renal and hepatic dysfunctions

-Pregnant or lactating patients

-Patients requiring intubation or unable to perform spirometry

N total at baseline:

Intervention: 30

Control: 30

Important prognostic factors²:

Age ± SD:

Intervention: 34.79 ± 8.05

Control: 35.9 ± 8.76

Sex:

Intervention: 46.7% M

Control: 50% M

Groups comparable at baseline? Yes

Baseline medication:

Nebulising solution consisting of 1 mL of 2.5% salbutamol (2.5 mg), 250 mg of 1.5 mL of ipratropium bromide administered in 2.5 mL of saline aerosolized via a wet nebuliser with 100% oxygen at 0, 20, 40 minutes

Intervention:

2 g MgSO₄ in 250 mL saline IV over 20 minutes

Baseline medication:

Nebulising solution consisting of 1 mL of 2.5% salbutamol (2.5 mg), 250 mg of 1.5 mL of ipratropium bromide administered in 2.5 mL of saline aerosolized via a wet nebuliser with 100% oxygen at 0, 20, 40 minutes

Control:

Placebo in 250 mL saline IV over 20 minutes

Length of follow-up:

Not reported

Loss-to-follow-up:

No loss-to-follow-up in intervention or control group.

Incomplete outcome data:

75 patients were screened, 5 patients were excluded before randomization, 10 patients randomized had protocol violations (in both groups: n=5)

Hospital admission:

Intervention: 6.7% (2/30)

Control: 30% (9/30)

No comments

Skobeloff, 1989

Type of study: RCT

Setting and country: USA

Funding and conflicts of interest: Not reported

Inclusion criteria:

-Aged 18-70 years

-Presenting with acute moderate to severe asthma at the ED

-Patients met the diagnostic criteria for asthma as set forth by the American Thoracic Society

Exclusion criteria:

-Rectal temperature >38°C

-Systolic blood pressure below 120 mm Hg

-History of kidney disease, purulent sputum, infiltrate on a chest roentgenogram, pregnancy

N total at baseline:

Intervention: 19

Control: 19

Important prognostic factors²:

Age ± SD:

Intervention: 39.9 ± 12.4

Control: 36.2 ± 11.5

Sex:

Not reported

Groups comparable at baseline? Yes

Baseline medication:

Nebulized treatment of 0.3 mL metaproterenol sulfate in 3.0 mL saline, or 0.5 mL albuterol sulfate in 2.5 mL saline, 125 mg methylprednisolone sodium succinate IV. If necessary, theophylline was given IV.

Intervention:

1.2 g MgSO₄ in 50 mL saline IV over 20 minutes

Baseline medication:

Nebulising solution consisting of 1 mL of 2.5% salbutamol (2.5 mg), 250 mg of 1.5 mL of ipratropium bromide administered in 2.5 mL of saline aerosolized via a wet nebuliser with 100% oxygen at 0, 20, 40 minutes

Control:

50 mL saline IV over 20 minutes

Length of follow-up:

Not reported

Loss-to-follow-up:

No loss-to-follow-up in intervention or control group.

Incomplete outcome data:

40 patients entered the study, 2 patients were excluded due to protocol violation or entering the study twice (only the first entry was used).

Hospital admission:

Intervention: 36.8% (7/19)

Control: 78.9% (15/19)

P<0.01

Only patients who did not to the baseline treatment (β-agonist non-responders) were included in the study and randomized to either intervention or control

Leukotriene antagonists

Camargo, 2010

Type of study: RCT

Setting and country: USA and 15 other countries

Funding and conflicts of interest: Reported

Inclusion criteria:

-Aged ≥15 years

-≥1 year history of physician-diagnosed asthma

-Presenting with acute asthma at the ED

-Patients >54 years were included if they also had FEV1 reversibility ≥15% predicted after β-agonist treatment during the current episode or within the past 5 years or if their lifetime tobacco exposure was ≤10 pack-years

Exclusion criteria:

-Clinically significant, active comorbid disease

-Body mass index >35 kg/m²

-Smoking history of >15 pack-years

N total at baseline:

Intervention: 292

Control: 291

Important prognostic factors²:

Age ± SD:

Intervention: 41.1 ± 15.0

Control: 41.0 ± 15.3

Sex:

Intervention: 47% M

Control: 40% M

Groups comparable at baseline? Yes

Baseline medication:

Oxygen, inhaled short-acting β-agonist (2.5-5mg in 3 mL saline every 20 min) as needed, and inhaled ipratropium or nebulized ipratropium as needed

Intervention:

IV administration (manual bolus over 2-5 min) of 7 mg montulekast (within 60 min after initiation of standard treatment).

Systemic corticosteroids (60 mg prednisone or 50 mg prednisolone orally)

Continued baseline medication

Baseline medication:

Oxygen, inhaled short-acting β-agonist (2.5-5mg in 3 mL saline every 20 min) as needed, and inhaled ipratropium or nebulized ipratropium as needed

Control:

IV administration (manual bolus over 2-5 min) of placebo.

Systemic corticosteroids (60 mg prednisone or 50 mg prednisolone orally)

Continued baseline medication

Length of follow-up:

14 days

Loss-to-follow-up:

No loss-to-follow-up in intervention or control group.

Incomplete outcome data:

Intervention: n=291 enrolled, 4 patients discontinued or had no baseline FEV1 measurement

Placebo: n=292 enrolled, 8 patients discontinued or had no baseline FEV1 measurement.

1 or more AEs

Intervention: 19.6%

Control: 20.2%

Drug-related AEs

Intervention: 0%

Control: 0%

Serious AEs

Intervention: 9.6%

Control: 8.9%

AEs leading to discontinuation from the study

Intervention: 0%

Control: 0.3%

No comments

Çýllý, 2003

Type of study: RCT

Setting and country: Turkey

Funding and conflicts of interest: Not reported

Inclusion criteria:

-History of at least 1 year of chronic asthma

-FEV1 40-80% predicted and with a ≥15% improvement in FEV1 after inhaled β-agonist

-non-smokers

-Had not taken oral, intravenous or intramuscular corticosteroids during the month prior to the start of the study

Exclusion criteria:

-Patients taking long acting antihistamines within 2 weeks, short acting antihistamines during the 48h before the visit or theophylline, oral or long-acting inhaled β-agonists, cromolyn sodium or nedocromil, or inhaled anticholinergics within 1 week

N total at baseline:

Intervention: 23

Control: 22

Important prognostic factors²:

Age ± SD:

Intervention: 64.0 ± 7.7

Control: 64.6 ± 7.6

Sex:

Intervention: 30.4% M

Control: 31.8% M

Groups comparable at baseline? Yes

Baseline medication:

1 mg/kg prednisolone IV, 3 aerosol treatments of 0.5 mg terbutaline sulphate as dry powder inhaler separated by 20 min intervals

Interventions:

10 mg tablet oral montulekast

Baseline medication:

1 mg/kg prednisolone IV, 3 aerosol treatments of 0.5 mg terbutaline sulphate as dry powder inhaler separated by 20 min intervals

Control:

No additional treatment/placebo

Length of follow-up:

24 hours

Loss-to-follow-up:

No loss-to-follow-up in intervention or control group.

Incomplete outcome data:

Not applicable.

Adverse events –

No severe adverse events

Most frequent adverse events included malaise (8%) and headache (6%) in the intervention group

No comments

Silverman, 2004

Type of study: RCT

Setting and country: USA

Funding and conflicts of interest: Not reported

Inclusion criteria:

-Aged 12-65 years

-Presenting with acute asthma at the ED

-History of asthma

-FEV1<70% predicted both at ED entry and 25 min after receiving a single aerosol treatment with 2.5 mg albuterol

Exclusion criteria:

-History of smoking of >10 pack-years

-Positive pregnancy test result

-Recent history of oral corticosteroid use (≥5 days) or treatment with a leukotriene-modifying drug within 2 weeks of ED entry

-Need for intubation before randomization

-Pneumonia or elevated temperature (>38.9°C)

-Chronic lung disease other than asthma, diabetes mellitus or any other clinically significant medical condition that could affect the required conditions

-Willingness to stay in the ED for at least 4 hours and participation in a 28-day outpatient treatment program

N total at baseline:

Intervention 1: 162

Intervention 2: 158

Control: 321

Important prognostic factors²:

Age ± SD:

Intervention 1: 32.3 ± 12.6

Intervention 2: 32.5 ± 11.4

Control: 32.6 ± 11.7

Sex:

Intervention 1: 54.3% M

Intervention 2: 36.7% M

Control: 40.2% M

Groups comparable at baseline? Yes

Baseline medication:

At ED entry: nebulized albuterol (2.5 mg). 25 min after ED entry: patients with FEV1<70% predicted were randomized.

60 mg po dose of prednisone, nebulized albuterol, additional albuterol at 60, 120 and 180 min after ED entry.

Interventions:

1: 160 mg zafirlukast

2: 20 mg zafirlukast

Baseline medication:

At ED entry: nebulized albuterol (2.5 mg). 25 min after ED entry: patients with FEV1<70% predicted were randomized.

60 mg po dose of prednisone, nebulized albuterol, additional albuterol at 60, 120 and 180 min after ED entry.

Control:

Placebo

Length of follow-up:

42 days

Loss-to-follow-up:

No loss-to-follow-up in intervention or control group.

Incomplete outcome data:

Not applicable.

Hospital admission:

Intervention 1: 9.9% (16/162)

Intervention 2: 16.5% (26/158)

Control: 15% (48/321)

Adverse events – headache ED period:

Intervention 1: 1% (2/162)

Intervention 2: 1% (2/158)

Control: 2% (5/321)

No comments

Salbutamol IV

Cheong, 1998

Type of study: RCT

Setting and country: District general hospital (secondary care centre).

Funding and conflicts of interest:

Not reported.

Inclusion criteria:

-16 and 70 years

-Admitted to hospital with severe acute asthma

Exclusion criteria:

-History of cardiovascular disease

-Corticosteroid or intravenous bronchodilator treatment before admission

N total at baseline:

Intervention: 37

Control: 34

Important prognostic factors²:

Age (range):

Intervention: 37 (16-69)

Control: 35 (16-66)

Sex:

Intervention: 70% M

Control: 68% M

Groups comparable at baseline? Yes

Baseline medication:

At admission, 5 mg nebulised salbutamol with a Hudson nebuliser driven by oxygen at 6 l/min and an intravenous bolus of 200 mg hydrocortisone. Patients with a peak flow rate below half of the predicted value 30 minutes after nebulised treatment were randomised. No other bronchodilator was used. All were given continuous 35% inspired oxygen.

Intervention:

Intravenous salbutamol as a continuous infusion in a dose of 12.5 µg/min starting 30 minutes after admission and lasting for a further four hours. 2g potassium was added to the infusion (because of the occurrence of hypokalemia).

Baseline medication:

At admission, 5 mg nebulised salbutamol with a Hudson nebuliser driven by oxygen at 6 l/min and an intravenous bolus of 200 mg hydrocortisone. Patients with a peak flow rate below half of the predicted value 30 minutes after nebulised treatment were randomised. No other bronchodilator was used. All were given continuous 35% inspired oxygen.

Control:

5 mg nebulized salbutamol 30 minutes after the first treatment on admission and again two hours later.

Length of follow-up:

Not reported.

Loss-to-follow-up:

Not reported.

Incomplete outcome data:

Five patients were withdrawn because of either adverse effects or non-response to treatment.

Adverse events:

5% (n=2) of patients in IG withdrawn because of tachycardia.

Tachycardia was prominent in IG.

No comments.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Magnesium sulphate

Bloch, 1995

Definitely yes;

Reason: Randomization using computer-generated tables

Definitely yes;

Reason: Physicians were blinded, randomization by the pharmacy

Probably yes;

Reason: Patients, health care providers and outcome assessors blinded (blinding of data collectors and analysts not reported)

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group. No description of the use of adequate imputation methods

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: The authors did not include all enrolled patients in the statistical analysis. 135/149 enrolled patients (<10% of patients were excluded) were included in the statistical analysis. 12 patients were enrolled more than once (first visit was used for analysis), 1 patient had irreversible airway disease, 1 patient had congestive heart failure, 4 patients were included as ITT because the study protocol was violated, in 6 patients baseline FEV1 was unavailable.

LOW

Boonyavorakul, 2000

Definitely yes;

Reason: Randomization using computer-generated random lists

Probably yes;

Reason: Study investigators were blinded, method unknown

Probably yes;

Reason: Patients, health care providers and outcome assessors blinded (blinding of data collectors and analysts not reported)

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group. No description of the use of adequate imputation methods

Definitely yes;

Reason: All relevant outcomes were reported

Definitely yes;

Reason: No other problems noted

LOW

Bradshaw, 2008

Probably yes;

Reason: Generation of allocation sequence not described

Probably yes;

Reason: Study investigators were blinded, method unknown

Probably yes;

Reason: Patients, health care providers and outcome assessors blinded (blinding of data collectors and analysts not reported)

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group. No description of the use of adequate imputation methods

Definitely yes;

Reason: All relevant outcomes were reported

Probably no;

Reason: The authors did not include all enrolled patients in the statistical analysis. 129/150 recruited patients (>10% of patients were excluded were included in the final analysis. Patients were excluded due to subsequent recognition of PEF >75% predicted or missing record data.

SOME CONCERNS

Hospital admission

Goodacre, 2014

Definitely yes;

Reason: The recruiting clinician accessed a web-based randomisation system or automated telephone hotline and participants were allocated to a numbered treatment pack kept in the ED.

Definitely yes;

Reason: The randomisation system only revealed the allocated pack number. Each treatment pack contained either magnesium or placebo solution. A 24-hour unblinding service was available via the randomisation system. Tamper stickers were checked regularly to ensure that envelopes had not been opened and were returned, still sealed, to the central study team. If an envelope was opened, it was reported and recorded as a participant unblinding

Probably yes;

Reason: Patients, health care providers and outcome assessors blinded (blinding of data collectors and analysts not reported)

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group. Adequate imputation methods (multiple imputation) were used.

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: The authors did not include all enrolled patients in the statistical analysis. 1109 patients were recruited, of which 25 either withdrew or were recruited in error (protocol violations)(<10% of patients were excluded).

LOW

Green, 1992

Definitely no;

Reason: Patients on odd days were given 2 mg of magnesium sulphate

Definitely no;

Reason: Due to the allocation method, investigators were not blinded.

Probably no;

Reason: Patients and respiratory therapists were unaware that a study was being performed. Physicians were not blinded.

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group. No description of the use of adequate imputation methods

Definitely yes;

Reason: All relevant outcomes were reported

Definitely yes;

Reason: No other problems noted

HIGH

Porter, 2001

Definitely yes;

Reason: Allocation according to a random number generator

Definitely yes;

Reason: Enrolment packets containing data recording sheets and the study solutions in random order were kept in the ED and assigned to new patients as they entered the study. The placebo/magnesium solutions were identical in appearance. The pharmacy had the only copy of the code, which was not broken until the study was completed and data analysis begun

Probably yes;

Reason: Patients, health care providers and outcome assessors blinded. Data analysist were not blinded

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group. No description of the use of adequate imputation methods

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: The authors did not include all enrolled patients in the statistical analysis. There were 55 asthma episodes meeting inclusion criteria. These episodes represented visits by 42 different patients, with all consenting to participate on all episodes. Patients completed the study protocol in each of the 55 episodes. The following results refer to the first asthma episodes in the 42 study patients (<10% of episodes were excluded).

LOW

Silverman, 2002

Definitely yes;

Reason: Allocation according to a 1:1 ratio randomization table unique for each center

Definitely yes;

Reason: The study pharmacist at each site placed drug or placebo in identically appearing vials, with only the study identification number printed on the label

Probably yes;

Reason: Patients, health care providers and outcome assessors blinded (blinding of data collectors and analysts not reported)

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group. No description of the use of adequate imputation methods

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: The authors did not include all enrolled patients in the statistical analysis. 254 patients were randomized, but 6 patients were inadvertently enrolled twice (<10% of patients were excluded).

LOW

Singh, 2008

Definitely yes;

Reason: Allocation according to a 1:1 ratio randomization table

Definitely yes;

Reason: The individual random numbers were kept in separate envelopes so that concealment could be maintained until the patient was included in the assigned group

Probably yes;

Reason: Patients, health care providers and outcome assessors blinded (blinding of data collectors and analysts not reported)

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group. No description of the use of adequate imputation methods

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: The authors did not include all enrolled patients in the statistical analysis. 75 patients were screened, 5 patients were excluded before randomization, 10 patients randomized had protocol violations (in both groups: n=5) (<10% of patients were excluded).

LOW

Skobeloff, 1989

Definitely yes;

Reason: Allocation according to a randomization list

Definitely yes;

Reason: The placebo/magnesium solutions were pre-packaged in identical vials by the pharmacy and coded from a randomization list

Probably yes;

Reason: Patients, health care providers and outcome assessors blinded (blinding of data collectors and analysts not reported)

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group. No description of the use of adequate imputation methods

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: The authors did not include all enrolled patients in the statistical analysis. 40 patients entered the study, 2 patients were excluded due to protocol violation or entering the study twice (only the first entry was used) (<10% of patients were excluded).

LOW

Montulekast

Camargo, 2010

Definitely yes;

Reason: Allocation according to a computer-generated randomization schedule with a blocking factor of4 provided by the study sponsor

Definitely yes;

Reason: The treatment solution was prepared in a foil-wrapped syringe by a qualified person who was no directly associated with the care of the patients

Probably yes;

Reason: Patients and health care providers blinded (blinding of outcome assessors, data collectors and analysts not reported)

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group. No description of the use of adequate imputation methods

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: The authors did not include all enrolled patients in the statistical analysis. 573/583 randomized patients were included in the statistical analysis (<10%). Excluded from intervention: n=8, control: n=3

LOW

Çýllý, 2003

Probably no;

Reason: Allocation method not described

Definitely no;

Reason: single blinded randomized trial, investigators were not blinded

Probably no;

Reason: Only patients were blinded.

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group. No description of the use of adequate imputation methods

Definitely yes;

Reason: All relevant outcomes were reported

Definitely yes;

Reason: No other problems noted

HIGH

Silverman, 2004

Definitely yes;

Reason: Allocation according to a computer-generated randomization schedule, specific for each site

Probably yes;

Reason: concealment of allocation not described

Probably yes;

Reason: Patients, health care providers and study investigators were blinded

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group.

Definitely yes;

Reason: All relevant outcomes were reported

Definitely yes;

Reason: No other problems noted

LOW

Salbutamol IV

Cheong, 1998

Probably yes;

Reason: Generation of allocation sequence not described

Probably yes;

Reason: sealed envelope system was used, but method not further described.

Probably no;

Reason: blinding not described, but study compared iv salbutamol with nebulised salbutamol. A double dummy design was not specified.

Probably yes;

Reason: Loss to follow-up was infrequent in intervention and control group. No description of the use of adequate imputation methods

Definitely yes;

Reason: All relevant outcomes were reported

Probably yes;

Reason: The authors did not include all enrolled patients in the statistical analysis. 71/76 enrolled patients (<10% of patients were excluded) were included in the statistical analysis. Patients were excluded due to adverse effects or non-response to treatment.

SOME CONCERNS

Reference

Reason for exclusion

Lin AT, Moore-Clingenpeel M, Karsies TJ. Comparison of two continuous nebulized albuterol doses in critically ill children with status asthmaticus. J Asthma. 2020 Sep;57(9):980-986. doi: 10.1080/02770903.2019.1623249. Epub 2019 Jun 12. PMID: 31119958.

no use of systemic corticosteroids

Travers AH, Milan SJ, Jones AP, Camargo CA Jr, Rowe BH. Addition of intravenous beta(2)-agonists to inhaled beta(2)-agonists for acute asthma. Cochrane Database Syst Rev. 2012 Dec 12;12:CD010179. doi: 10.1002/14651858.CD010179. PMID: 23235685.

3 studies included (2 on children, 1 on bedoradrine in adults): does not fit PICO

Travers AH, Rowe BH, Barker S, Jones A, Camargo CA Jr. The effectiveness of IV beta-agonists in treating patients with acute asthma in the emergency department: a meta-analysis. Chest. 2002 Oct;122(4):1200-7. doi: 10.1378/chest.122.4.1200. PMID: 12377842.

heterogenic group (medication and population), only 1 outcome measure of PICO reported, poor methodologic quality

Manning M, Garin M, Jiang B, Sun SX. Impact of Reslizumab on Duration of Exacerbations in Patients with Severe Eosinophilic Asthma. J Allergy Clin Immunol Pract. 2018 Feb;141(2):supp. doi: 10.1016/j.jaci.2017.12.053

abstract only

High-dose zafirlukast in emergency department provides small benefit in acute asthma. J Fam Pract. 2005 Apr;54(4):304-6. PMID: 15833217.

summary of publication of Silverman

Adachi M, Taniguchi H, Tohda Y, Sano Y, Ishine T, Smugar SS, Hisada S. The efficacy and tolerability of intravenous montelukast in acute asthma exacerbations in Japanese patients. J Asthma. 2012 Aug;49(6):649-56. doi: 10.3109/02770903.2012.690479. Epub 2012 Jun 28. PMID: 22742205.

corticosteroids were not usual care

Camargo CA Jr, Smithline HA, Malice MP, Green SA, Reiss TF. A randomized controlled trial of intravenous montelukast in acute asthma. Am J Respir Crit Care Med. 2003 Feb 15;167(4):528-33. doi: 10.1164/rccm.200208-802OC. Epub 2002 Nov 27. PMID: 12456380.

corticosteroids were given as needed

Chaudhury A, Gaude GS, Hattiholi J. Effects of oral montelukast on airway function in acute asthma: A randomized trial. Lung India. 2017 Jul-Aug;34(4):349-354. doi: 10.4103/0970-2113.209234. PMID: 28671166; PMCID: PMC5504892.

effect of oral montelukast on lung function in first 4 weeks after exacerbation

Ferreira MB, Santos AS, Pregal AL, Michelena T, Alonso E, de Sousa AV, Pereira E, Palma-Carlos AG. Leukotriene receptor antagonists (Montelukast) in the treatment of asthma crisis: preliminary results of a double-blind placebo controlled randomized study. Allerg Immunol (Paris). 2001 Oct;33(8):315-8. PMID: 11763721.

no relevant outcome measures

Motamed H, Verki MM, Barzegari H, Shariat S, Hesam, S. Montelukast efficacy for improvement of adult acute phase mild-moderate asthma attack: A clinical trial study. Curr Respir Med Rev. 2020. 16(4): 246-251(6).

no relevant outcome measures

Ramsay CF, Pearson D, Mildenhall S, Wilson AM. Oral montelukast in acute asthma exacerbations: a randomised, double-blind, placebo-controlled trial. Thorax. 2011 Jan;66(1):7-11. doi: 10.1136/thx.2010.135038. Epub 2010 Oct 18. PMID: 20956393.

effect of oral montelukast on lung function in first 4 weeks after exacerbation

Watts K, Chavasse RJ. Leukotriene receptor antagonists in addition to usual care for acute asthma in adults and children. Cochrane Database Syst Rev. 2012 May 16;2012(5):CD006100. doi: 10.1002/14651858.CD006100.pub2. PMID: 22592708; PMCID: PMC7387678.

RCTs that fit PICO are separately included

Zhang HP, Jia CE, Lv Y, Gibson PG, Wang G. Montelukast for prevention and treatment of asthma exacerbations in adults: Systematic review and meta-analysis. Allergy Asthma Proc. 2014 Jul-Aug;35(4):278-87. doi: 10.2500/aap.2014.35.3745. PMID: 24992547.

does not fit PICO

Green RH. Asthma in adults (acute): magnesium sulfate treatment. BMJ Clin Evid. 2016 Jan 13;2016:1513. PMID: 26761432; PMCID: PMC4711892.

onvolledige GRADE beoordeling, onduidelijk welke studies geincludeerd en of behandeling met steroiden

Rowe BH, Bretzlaff JA, Bourdon C, Bota GW, Camargo CA Jr. Intravenous magnesium sulfate treatment for acute asthma in the emergency department: a systematic review of the literature. Ann Emerg Med. 2000 Sep;36(3):181-90. doi: 10.1067/mem.2000.105659. PMID: 10969218.

onduidelijk welke studies geincludeerd en of behandeling met steroïden

Rodrigo G, Rodrigo C, Burschtin O. Efficacy of magnesium sulfate in acute adult asthma: a meta-analysis of randomized trials. Am J Emerg Med. 2000 Mar;18(2):216-21. doi: 10.1016/s0735-6757(00)90024-x. PMID: 10750936.

oud, matige kwaliteit,

Dennis RJ, Solarte I, Fitzgerald JM. Asthma in adults. BMJ Clin Evid. 2007 Aug 15;2007:1501. PMID: 19454105.

chronic asthma

Conway J, Friedman B. Intravenous Magnesium Sulfate for Acute Asthma Exacerbation in Adults. Acad Emerg Med. 2020 Oct;27(10):1061-1063. doi: 10.1111/acem.14066. Epub 2020 Aug 14. PMID: 32574392.

No systematic review, unclear study selection

Rodrigo G. Asthma in adults (acute). BMJ Clin Evid. 2011 Apr 4;2011:1513. PMID: 21463536; PMCID: PMC3661228.

No systematic review, unclear study selection

Mohammed S, Goodacre S. Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis. Emerg Med J. 2007 Dec;24(12):823-30. doi: 10.1136/emj.2007.052050. PMID: 18029512; PMCID: PMC2658351.

Most studies also found in our search, low quality SR

Rowe BH, Bretzlaff JA, Bourdon C, Bota GW, Camargo CA Jr. Magnesium sulfate for treating exacerbations of acute asthma in the emergency department. Cochrane Database Syst Rev. 2000;(2):CD001490. doi: 10.1002/14651858.CD001490. PMID: 10796650.

old, 7 studies, no differentiation adults and children

Shan Z, Rong Y, Yang W, Wang D, Yao P, Xie J, Liu L. Intravenous and nebulized magnesium sulfate for treating acute asthma in adults and children: a systematic review and meta-analysis. Respir Med. 2013 Mar;107(3):321-30. doi: 10.1016/j.rmed.2012.12.001. Epub 2013 Jan 3. PMID: 23290189.

Most studies also found in our search, low quality SR

Cheong B, Reynolds SR, Rajan G, Ward MJ. Intravenous beta agonist in severe acute asthma. BMJ. 1988 Aug 13;297(6646):448-50. doi: 10.1136/bmj.297.6646.448. PMID: 3139138; PMCID: PMC1833883.

No relevant outcomes

Zubairi AB, Salahuddin N, Khawaja A, Awan S, Shah AA, Haque AS, Husain SJ, Rao N, Khan JA. A randomized, double-blind, placebo-controlled trial of oral montelukast in acute asthma exacerbation. BMC Pulm Med. 2013 Mar 28;13:20. doi: 10.1186/1471-2466-13-20. PMID: 23537391; PMCID: PMC3616955.

No relevant outcomes

Hirashima J, Yamana H, Matsui H, Fushimi K, Yasunaga H. Effect of intravenous magnesium sulfate on mortality in patients with severe acute asthma. Respirology. 2016 May;21(4):668-73. doi: 10.1111/resp.12733. Epub 2016 Jan 18. PMID: 26781339.

No RCT

Self TH, Abou-Shala N, Burns R, Stewart CF, Ellis RF, Tsiu SJ, Kellermann AL. Inhaled albuterol and oral prednisone therapy in hospitalized adult asthmatics. Does aminophylline add any benefit? Chest. 1990 Dec;98(6):1317-21. doi: 10.1378/chest.98.6.1317. PMID: 2245667.

Does no fit PICO (wrong intervention)