Combination of ipratropium bromide and salbutamol in children and adolescents with asthma: a meta-analysis

Background A combination of ipratropium bromide (IB) and salbutamol is commonly used to treat asthma in children and adolescents; however, there has been a lack of consistency in its usage in clinical practice. Objective To evaluate the efficacy and safety of IB + salbutamol in the treatment of asthma in children and adolescents. Methods The MEDLINE, Embase, and Cochrane Library as well as other Chinese biomedical databases (including China Biological Medicine Database, Chinese National Knowledge Infrastructure, Chongqing VIP, and Wanfang Chinese language bibliographic database) were systematically searched from the date of database inception to 02/09/2019 for randomized controlled trials in children and adolescents (≤18 years) with asthma who received IB + salbutamol or salbutamol alone. The primary outcomes included hospital admission and adverse events. A random effects model with a 95% confidence interval (CI) was used. Subgroup analysis was performed according to age, severity of asthma, and co-interventions with other asthma controllers. This study was registered with PROSPERO. Results Of the 637 studies that were identified, 55 met the inclusion criteria and involved 6396 participants. IB + salbutamol significantly reduced the risk of hospital admission compared with salbutamol alone (risk ratio [RR] 0.79; 95% CI 0.66–0.95; p = 0.01; I2 = 40%). Subgroup analysis only showed significant difference in the risk of hospital admission in participants with severe asthma exacerbation (RR 0.71; 95% CI 0.60–0.85; p = 0.0001; I2 = 0%) and moderate-to-severe exacerbation (RR 0.69; 95% CI 0.50–0.96; p = 0.03; I2 = 3%). There were no significant differences in the risk of adverse events between IB + salbutamol group and salbutamol alone group (RR 1.77; 95% CI 0.63–4.98). Conclusion IB + salbutamol may be more effective than salbutamol alone for the treatment of asthma in children and adolescents, especially in those with severe and moderate to severe asthma exacerbation. Future prospective research on these subgroup population are needed.


Risk of bias in the included studies
Quality analysis was performed on the basis of aforementioned methods and tools. Details of the risk of bias assessment are provided in Figure 2. Only one study was assessed as being at low risk of bias in all domains 10 . Five studies were considered to be at high risk of bias, one of which was due to random sequence generation 21 , two due to blinding setting 17; 22 and the other two due to selective reporting on predefined outcomes 12; 23 . The remaining 49 studies were considered to be at unclear risk of bias (for details, refer to E-Appendix 5).

Primary outcome
Hospital admission was reported by 16 trials involving 2834 participants 10; 11; 13; 19-22; 24-32 . The meta-analysis was conducted with 15 trials showed that compared with salbutamol alone, the IB + salbutamol group showed a significant reduction in the risk of hospital admission (RR 0.79; 95% CI 0.66-0.95; I 2 = 40%; p = 0.01; Figure 3). One study 21 was not included in the meta-analysis because it reported a number of zero on hospital admission in intervention and comparison groups.
Eight trials (with 1137 participants) reported the number of participants who had adverse events. 28; 31; 33-37 . Three trials reported a number of zero on adverse events in both intervention and comparison groups 33; 37-38 . Based on reporting in the remaining five trials 28; 31; 34-36 , 65 participants had adverse events in the IB + salbutamol group (with 349 participants), and 47 participants had adverse events in the salbutamol alone group (with 348 participants).The results of meta-analysis on these five trials (with 697 participants) 28; 31; 34-36 showed no significant differences on the incidence of adverse events between the compared groups (RR 1.77; 95% CI 0.63-4.98; p = 0.28; I 2 = 77%, Figure 4). The substantial heterogeneity may be explained by the different treatment durations among the five studies in the meta-analysis. In two of the studies 28,31 patients were treated with IB + salbutamol for 60-90 minutes, whereas in the other three studies [34][35][36] , patients were treated for 3-7 days.
The differences in treatment durations may have led to clinical heterogeneity.

Secondary outcome
Pulmonary function was reported in 5 studies (Table 1), among which three reported predicted % FEV 1 at both 60 min and 120 min 19; 28; 30 after treatment, and one reported predicted % FEV 1 at 60min 20 only. Among these four studies, two studies 28; 30 significantly favoring IB + salbutamol therapy at 120 min after treatment. One study 30 significantly favoring IB + salbutamol therapy at 60 min after treatment. Only one study reported absolute % FEV 1 at 60 min and 120 min 40 , favoring IB + salbutamol therapy at 120 min after treatment.
Another study reported respiratory resistance at 60 and 120 min 19 , with no significant difference between IB + salbutamol and salbutamol alone groups.
Nine studies reported clinical scores regarding different symptoms at various timepoints ranging from 15 min to 240 min, with one study did not report treatment duration 43 (E- reported in more than two trials. IB + salbutamol group showed significant reduction on the incidence of nausea compared with salbutamol alone group (RR 0.60; 95% CI 0.39, 0.93; p=0.02; I 2 =0%; seven studies with 763 participants). However, none of the other three IB and salbutamol in children and adolescents with asthma outcomes showed significant differences between the two groups (p > 0.05). In addition, there was also no significant difference in other adverse events (such as abdominal pain, headache, palpitations, etc) between the two groups (p > 0.05) (for details, refer to E-Appendix 8).

Sensitivity analysis
In sensitivity analysis omitting enrolled studies in turn, the results remained consistent across different analyses, which suggested that the findings were reliable and robust (for details, refer to E-Appendix 9).

Publication bias
Publication bias of the studies was assessed using funnel plots for hospital admission and relapse rates. No obvious asymmetry was observed in all groups (E-Appendix 10).

Discussion
There is a lack of consistency in clinical practice regarding the treatment of asthma exacerbation in children and adolescents. Since the last systematic review published in 2013 14 , a considerable number of new studies evaluating the efficacy and safety of IB + salbutamol compared with those of salbutamol alone for the treatment of asthma exacerbation in children and adolescents have been published. This systematic review was conducted to update the findings on this topic and provide clinicians with the most current information to aid in the decision-making process involved in determining the best treatment options for the pediatric population presenting with acute asthma exacerbation.
This systematic review supported the benefits of IB + salbutamol for the treatment of asthma in children and adolescents according to the reduction in hospital admission (RR 0.79; 95% CI 0.66-0.95). We performed subgroup analysis to determine whether age, severity of asthma, and co-intervention influenced the effect of IB + salbutamol treatment on hospital admission.
Although the subgroup analyses might have contained overlap and non-randomized participants, the result could probably suggest the benefits in children and adolescents with severe asthma exacerbation (RR 0.71; 95% CI 0.60-0.85) and moderate-to-severe asthma exacerbation (RR 0.69; 95% CI 0.50-0.96), which is consistent with the results of a previous systematic review 14 . Consistent with the findings of Castro-Rodriguez (2015) 48 , patient age did not alter the effect of IB + salbutamol on reduction of the risk of hospital admission.
However, contrary to the findings of Griffiths (2013) 14 , IB + salbutamol showed no significant reduction in the risk of hospital admission in patients with co-intervention of glucocorticoid.
A possible explanation is the difference in interventions between the present review and Griffiths' (2013) 14 review. The previous review reported a wider range of intervention that IB and salbutamol in children and adolescents with asthma included all types of combined inhaled anticholinergics and SABAs, which may have included studies focused on terbutaline. However, the present review only included IB + salbutamol as an intervention treatment. Therefore, studies with a focus on terbutaline were excluded.
Another explanation could be the updated search date. Compared with the review by Griffiths Consistent with previous systematic reviews 14,48 , IB + salbutamol could significantly improve the predicted % and absolute % change in FEV 1 at both 60 and 120 minutes after treatment compared with salbutamol alone. Contrary to the review by Griffiths (2013) 14 , the increase in lung function observed with the combined treatment was not associated with an increase in oxygen saturation. A possible explanation for this is that the pervious review 14 used oxygen saturation < 95% instead of percentage of oxygen saturation as the outcome indicator.
Consistent with previous systematic review 14 , nausea, vomiting, and tremors were listed as secondary outcomes because of the direct treatment-related effects of salbutamol or ipratropium bromide. Although the combination of IB and salbutamol was previously found to result in fewer tremors and less nausea compared with salbutamol alone 16,17 , we found consistent results in nausea (RR 0.60; 95% CI 0.39-0.93) but did not identify any significant difference in the other three adverse events between the two groups. Possible explanations could be what has mentioned previously for subgroup results.
The present review found that most Chinese studies reported a clinical response as an outcome after treatment using IB + salbutamol or salbutamol alone in children and 13 IB and salbutamol in children and adolescents with asthma adolescents. However, because the clinical response was not clearly defined in the original studies, it was not included as a secondary outcome in the present review.
A key contribution of this present review is the update of evidence that appeared between 2013 and 2019. To our knowledge, no relevant systematic review has been published after 2013. The result, again, verified the clinical benefits of using a combination of SABA and IB in children and adolescents with asthma compared with using SABA alone and provided an evidence-base for clinical practice. However, this systematic review has several limitations. Firstly, because of the different diagnostic criteria of childhood asthma, the external validity of the studies is quite poor. Secondly, original research protocols were not always well described, which resulted in low quality of evidence. As such, there were some missing details for certain studies, which limited our ability to interpret the data. Thirdly, the applicability of results from the present review should be concluded with caution. The analyses of patients' age, severity of asthma, and co-interventions were conducted with subgroup data from original studies and resulted consistent conclusion with 2013 review 14 . In addition, because of insufficient data, we were unable to perform subgroup analyses of other factors of interest, such as dosage regimens and frequency. Moreover, the treatment durations across the included studies varied. The differences may also affect the applicability of the present review results. Although data extrapolation from the non-randomized subgroup population should be cautious, the current conclusion of our meta-analysis may provide new ideas and directions to identify the clinical beneficiaries of combination therapy of IB + salbutamol.
Further well-conducted and adequately powered RCTs with standardized outcome measures are needed to explore the most appropriate treatment dosage and duration for children and adolescents with asthma.
In conclusion, the results indicate that IB + salbutamol can significantly reduce the risk of hospital admission in children and adolescents, and this combined therapy may have significant clinical benefits in children with severe and moderate-to-severe asthma exacerbation. Future prospective randomized controlled trials are needed to evaluate the clinical benefits of combining IB and salbutamol in asthma children and adolescent in different age, severity of asthma, and co-interventions subgroups.