The online version of this article (doi:10.1186/s13054-014-0621-y) contains supplementary material, which is available to authorized users.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
RI and AA drafted the initial manuscript. YA contributed to the manuscript composition. RI and AA both independently screened the studies. YA performed the statistical analyses. NY critically reviewed the manuscript. All authors provided written consent for publication. All authors read and approved the final manuscript.
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.
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.
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 (I2 = 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.
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.
Acknowledgements
The authors are grateful to Dr Masao Iwagami (The London School of Hygiene & Tropical Medicine, London, UK) for his assistance.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
RI and AA drafted the initial manuscript. YA contributed to the manuscript composition. RI and AA both independently screened the studies. YA performed the statistical analyses. NY critically reviewed the manuscript. All authors provided written consent for publication. All authors read and approved the final manuscript.
