Open Access

Effectiveness of inhaled furosemide for acute asthma exacerbation: a meta-analysis

Critical Care201418:621

https://doi.org/10.1186/s13054-014-0621-y

Published: 24 November 2014

Abstract

No abstract

As the effectiveness of beta-agonists for treating asthma attacks has been established, numerous other supportive treatments for asthma attacks have also been investigated, such as systemic glucocorticoids and magnesium. Among these additional therapies, inhaled furosemide is of particular interest; several studies have evaluated the effects of prophylactic inhaled furosemide in attenuating bronchoconstriction and asthma attacks. To determine the efficacy of inhaled furosemide during asthma attacks, we performed a systematic review using the MEDLINE, EMBASE, Web of Science, and Cochrane Library databases from their inception through 14 March 2014. A meta-analysis was conducted by calculating the standardized mean difference from each study and integrating these means using a random effects model. In addition, subanalyses were performed in the studies that evaluated the peak expiratory flow rate and the forced expiratory volume in 1 second.

We identified six studies using double-blinded, randomized control trial designs that evaluated inhaled furosemide in conjunction with standard treatments in patients experiencing asthma attacks [1]-[6] (Figure 1); a total of 78 patients received inhaled furosemide and 79 patients received a placebo (Tables 1 and 2). The mean age of patients ranged from 8.4 to 47 years [3],[6]. In two studies, patients were administered 40 mg inhaled furosemide [1],[2]; in one study, patients were administered 20 mg inhaled furosemide [6]; and in the three studies that recruited children, patients were administered either 1.0 mg/kg [4],[5] or 10 mg/m2 [3] inhaled furosemide.
Figure 1

Study selection procedure.

Table 1

Trial characteristics

   

Furosemide group

Placebo group

        

Study (year)

Number of randomized patients

Number of patients completing study

Mean patient age (years)

Number of patients (male)

Mean patient age (years)

Number of patients (male)

Smoking

COPD

β-agonist dose

Inhaled furosemide dose

Expiratory airflow assessment time (minutes)

Spirometry measurement used

Severity

Hydrocortisone (mg)

Alshehri and colleagues, 2005 [5]

39

39

8.4

19 (11)

8.5

20 (9)

N/Aa

N/Aa

0.15 mg/kg

1.0 mg/kg

30

PEFR, FEV1.0

Moderate

N/A

González-Sánchez and colleagues, 2002 [4]

20

20

9.8

10 (7)

10

10 (5)

N/Aa

N/Aa

0.15 mg/kg

1.0 mg/kg

30, 60

FEV1.0

Mild or moderate

N/A

Nannini and colleagues, 1992 [1]

20

16

31

7 (N/A)

41

9 (N/A)

N/A

N/A

2.5 mg

40 mg

15, 30

PEFR

N/A

N/A

Nuhoğlu and colleagues, 2006 [3]

32

32

8.6

16 (8)

8.4

16 (12)

N/Aa

N/Aa

0.15 mg/kg

10 mg/m2

N/A

PEFR

Mild or moderate

N/A

Ono and colleagues, 1997b [6]

37

37

47

20 (7)

41

17 (8)

N/A

Exclude

N/A

20 mg

30, 60

PEFR, FEV1.0

Mild to severe

100

Pendino and colleagues, 1998c [2]

42

42

38

6 (N/A)

34

8 (N/A)

Not >10 pack-years

Exclude

2.5 mg

40 mg

15, 30

PEFR

Mild or moderate

300

COPD, chronic obstructive pulmonary disease; FEV1.0, forced expiratory volume in 1 second; N/A, not available; PEFR, peak expiratory flow rate. aSmoking and COPD histories were not available, although no smoking or COPD history was assumed because patients were children. bCombination treatment in all trials was simultaneous administration of a beta-agonist plus furosemide, except for Ono and colleagues, in which patients in both groups received hydrocortisone succinate and aminophylline, followed 30 minutes later by either furosemide or placebo. cOnly subgroup data (pertaining to patients whose exacerbations lasted <8 hours) were available.

Table 2

Trial results

 

Furosemide

Placebo

 

PEFR

FEV1.0

PEFR

FEV 1.0

Study (year)

Baseline airflow

SD

Post-treatment airflow

SD

Baseline airflow

SD

Post-treatment airflow

SD

Baseline airflow

SD

Post-treatment airflow

SD

Baseline airflow

SD

Post-treatment airflow

SD

Alshehri and colleagues, 2005 [5]

59.0

22.0

84.9

14.0

58.5

14.5

80.2

13.9

57.2

25.4

80.7

17.4

56.7

17.3

77.8

19.1

Nuhoğlu and colleagues, 2006 [3]

178

65.9

222

66.1

N/A

N/A

183

51.7

218

60.3

N/A

N/A

    
 

Baseline airflow

SD

Net airflow improvement above baseline

SD

Baseline airflow

SD

Net airflow improvement above baseline

SD

Baseline airflow

SD

Net airflow improvement above baseline

SD

Baseline airflow

SD

Net airflow improvement above baseline

SD

González-Sánchez and colleagues, 2002 [4]

N/A

N/A

0.820

0.460

0.910

0.067

N/A

N/A

0.850

0.340

0.980

0.078

    

Nannini and colleagues, 1992 [1]

147

68.0

269

89.7

N/A

N/A

234

82.0

316

56.2

N/A

N/A

    

Ono and colleagues, 1997 [6]

171

20.0

205

45.1

1.18

0.13

 

178

25.0

198

21.3

1.32

0.74

N/A

  

Pendino and colleagues, 1998 [2]

200

71.0

426

98.0

N/A

N/A

209

68.0

337

73.2

N/A

N/A

    

FEV1.0, forced expiratory volume in 1 second; N/A, not available; PEFR, peak expiratory flow rate; SD, standard deviation.

Integrating the standardized mean difference in each study, a random effects model showed that inhaled furosemide had a significant positive effect on asthma attacks (Z = 2.70; 95% confidence interval, 0.14 to 0.85; P = 0.007) with a negligible heterogeneity (I 2 = 16.82) (Figure 2 and Table 3). Subanalyses of the studies reporting the peak expiratory flow rate (Z = 2.23; P = 0.026; n = 68/70, inhaled furosemide/placebo) and the forced expiratory flow in 1 second (Z = 1.84; P = 0.066; n = 49/46, inhaled furosemide/placebo) values confirmed the significant effectiveness of inhaled furosemide for asthma attacks (Table 3). Jackknife sensitivity analyses confirmed the replicability of these findings (P <0.028) (Figure 3). No adverse events associated with furosemide inhalation were reported.
Figure 2

Meta-analysis of randomized clinical trial studies. A random effects model demonstrated significant effectiveness of inhaled furosemide for asthma attacks [1]-[6]. CI, confidence interval; Std, standard.

Table 3

Meta-analyses of randomized controlled trials

 

Number of studies

Furosemide group ( n )

Placebo group ( n )

Lower 95% CI

Upper 95% CI

Z value

P value

I 2

Whole studies

6

78

79

0.14

0.85

2.70

0.007

16.8

PEFR

5

68

70

0.058

0.90

2.23

0.026

30.4

FEV1.0

3

49

46

-0.027

0.83

1.84

0.066

8.16

CI, confidence interval; FEV1.0, forced expiratory volume in 1 second; PEFR, peak expiratory flow rate.

Figure 3

Jackknife sensitivity analysis, excluding one study at a time. All sensitivity analyses preserved the significant effectiveness of inhaled furosemide for asthma attacks [1]-[6]. CI, confidence interval; Std, standard.

These results thus reveal a statistically significant improvement in airflow obstruction with no evident adverse events when inhaled furosemide was used as an adjunctive treatment for acute asthma exacerbation. The present study provides evidence supporting the addition of inhaled furosemide to conventional treatment in clinical situations.

Declarations

Acknowledgements

The authors are grateful to Dr Masao Iwagami (The London School of Hygiene & Tropical Medicine, London, UK) for his assistance.

Authors’ Affiliations

(1)
Department of Emergency and Critical Care Medicine, The University of Tokyo Hospital
(2)
Department of Emergency Medicine, JR General Hospital
(3)
Department of Psychiatry, Tokyo Metropolitan Health and Medical Treatment Corporation, Ebara Hospital
(4)
Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo

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Copyright

© Inokuchi et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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