The mainstay of treatment for acute bronchiolitis remains supportive care. The objective of this study was to assess the efficacy and safety of nebulized hypertonic saline (HS) in infants with acute bronchiolitis.
Data sources included PubMed and the Virtual Health Library of the Latin American and Caribbean Center on Health Sciences Information up to May 2015. Studies selected were randomized or quasi-randomized controlled trials comparing nebulized HS with 0.9% saline or standard treatment.
We included 24 trials involving 3209 patients, 1706 of whom received HS. Hospitalized patients treated with nebulized HS had a significantly shorter length of stay compared with those receiving 0.9% saline or standard care (15 trials involving 1956 patients; mean difference [MD] −0.45 days, 95% confidence interval [CI] −0.82 to −0.08). The HS group also had a significantly lower posttreatment clinical score in the first 3 days of admission (5 trials involving 404 inpatients; day 1: MD −0.99, 95% CI −1.48 to −0.50; day 2: MD −1.45, 95% CI −2.06 to −0.85; day 3: MD −1.44, 95% CI −1.78 to −1.11). Nebulized HS reduced the risk of hospitalization by 20% compared with 0.9% saline among outpatients (7 trials involving 951 patients; risk ratio 0.80, 95% CI 0.67–0.96). No significant adverse events related to HS inhalation were reported. The quality of evidence is moderate due to inconsistency in results between trials and study limitations (risk of bias).
Nebulized HS is a safe and potentially effective treatment of infants with acute bronchiolitis.
Acute bronchiolitis in infancy, mainly caused by respiratory syncytial virus (RSV), is the most common lower respiratory infection and the leading cause of hospitalization in children younger than 2 years. In the United States, acute bronchiolitis in infancy is responsible for ∼150 000 hospitalizations each year at an estimated cost of $500 million.1,2 From 1992 to 2000, bronchiolitis accounted for ∼1 868 000 emergency department (ED) visits for children younger than 2 years.3 In the United Kingdom, hospital admissions for acute bronchiolitis increased from 21 330 in 2004 and 2005 to 33 472 in 2010 and 2011.4
Globally, it has been estimated that, in 2005, at least 33.8 million episodes of RSV-associated acute lower respiratory infections (ALRIs) occurred in children younger than 5 years, with incidence in developing countries more than twice that of industrialized countries.5 In the same year, RSV-associated severe ALRIs were responsible for ∼3.4 million hospitalizations and 66 000 to 199 000 deaths in young children worldwide, with 99% of these deaths occurring in developing countries.
Despite its high incidence and morbidity, there are few effective therapies for acute bronchiolitis in infancy, and the mainstay of treatment remains supportive care.6,7 Given the theoretical effects of hypertonic saline (HS) in reducing airway edema, unblocking mucus plugging, and improving mucociliary clearance, HS administered via nebulizer has been proposed as a potentially effective therapy for acute bronchiolitis in infants.8 The first randomized trial, published in 2002, showed a significant effect of nebulized 3% saline solution in improving symptom scores among 65 outpatients with acute bronchiolitis, as compared with 0.9% normal saline (NS).9 Over the past decades, a growing number of randomized trials have been undertaken to assess the effects and safety of nebulized HS in infants with acute bronchiolitis.10,–19 The Cochrane review published in 2013 including 11 randomized trials shows that nebulized 3% saline may significantly reduce the length of stay (LOS) in hospitalized infants with acute bronchiolitis and improve the clinical severity score (CSS) in both outpatient and inpatient populations.20 Since then, new trials with conflicting results have been published, and an updated synthesis of the literature is needed.21 We decided to conduct a new systematic review of currently available randomized trials to assess the efficacy and safety of nebulized HS in infants with acute bronchiolitis and to explore possible reasons for inconsistent results across trials. We hypothesize that nebulized HS may be less effective than previously claimed for acute bronchiolitis and effect size of HS may mainly depend on diagnostic accuracy of bronchiolitis and the treatment regimen.
Methods
We followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement for writing this systematic review and meta-analysis.22 The full review protocol is available in the supplementary material. We used different data sources, search strategy, and statistical techniques than that used in the 2013 Cochrane review.20
Data Sources and Search Strategy
We searched PubMed and the Virtual Health Library of the Latin American and Caribbean Center on Health Sciences Information (BIREME), which contains Medline, CENTRAL, LILACS, IBECS, and >20 other databases (www.bireme.br). All databases were searched from inception until May 2015. The search strategy on PubMed was as follows: (bronchiolitis OR “acute wheezing” OR “respiratory syncytial virus” OR RSV OR “parainfluenza virus”) AND (“hypertonic saline” OR “saline solution” OR 3% saline OR 5% saline OR saline). We used the limits of study type: clinical trial, randomized controlled trial (RCT). The search strategy on the Virtual Health Library of BIREME was as follows: bronchiolitis AND “hypertonic saline.” There was no restriction on language of publication. We also conducted a search of the ClinicalTrials.gov trials registry to identify completed but unpublished trials. We checked reference lists of all primary studies and review articles for additional relevant trials.
Study Selection
To be included in this review, studies had to meet all of the following criteria: (1) study design: RCTs or quasi-RCTs; (2) participants: infants up to 24 months of age with diagnosis of acute bronchiolitis; we classified participants into “inpatients” who were admitted to the hospital and “outpatients” who attended at an ambulatory care unit or ED; (3) interventions and comparisons: nebulized HS (≥3%) alone or mixed with bronchodilator, compared with nebulized NS alone or mixed with same bronchodilator, or standard treatment; (4) outcome measures: primary outcomes included LOS in hospital for inpatients defined as time to actual discharge or time taken to be ready for discharge, and admission rate for outpatients, and secondary outcomes included CSSs, rate of readmission to hospital or ED, oxygen saturation, respiratory rate, heart rate, time for the resolution of symptoms/signs, duration of oxygen supplementation, results of pulmonary function tests, radiologic findings, and adverse events (AEs). We excluded studies that included patients who had had recurrent wheezing or were intubated and ventilated, and studies that assessed pulmonary function alone.
Two review authors (RM and LZ) independently assessed the titles and abstracts of all citations identified by the searches. We obtained the full articles when they appeared to meet the inclusion criteria or there were insufficient data in the title and abstract to make a clear decision for their inclusion. The definitive inclusion of trials was made after reviewing the full-text articles. We resolved any disagreements between the 2 review authors about study inclusion by discussion and consensus.
Data Extraction and Management
One review author (LZ) extracted study details from the included trials by using a standardized data extraction form. These were checked by another review author (RM). We resolved any disagreements by discussion and consensus. We extracted the following data: (1) study characteristics: year of publication, and country and setting of study; (2) methods: study design, methods of random sequence generation, allocation concealment and blinding, and description of withdrawal; (3) participants: sample size, age, gender, and inclusion and exclusion criteria; (4) interventions and controls: concentration and volume of saline, type of nebulizer, interval of administration, treatment duration, and cointerventions; (5) outcomes: primary and secondary outcomes as described previously. For continuous outcomes, we extracted sample size, mean (median) and precision of measurements (SD, SE, 95% confidence interval [CI], or interquartile range) of each treatment arm. For dichotomous outcomes, we extracted number of events and total number of participants of each treatment arm. We contacted the principal investigators of 5 trials10,12,18,23,24 for methodological details and additional trial data, of whom 310,12,18 provided the requested data. We used Engauge digitizing software (digitizer.sourceforge.net) to extract the 25th and 75th percentiles of LOS in hospital from the figure of 1 paper.24 For 2 trials,24,25 we estimated mean and SD from median and interquartile range of LOS in hospital by using the method described by Wan et al.26 When the trial recruited multiple groups, we combined them into HS and NS groups.14,15,17,24,27
Assessment of Risk of Bias
Two reviewers (RM and LZ) independently assessed the risk of bias in included trials by examining the 6 key domains according to the recommendations of the Cochrane Collaboration.28 We graded each potential source of bias as yes, no, or unclear, relating to whether the potential for bias was low, high, or unknown. We resolved any disagreements between the 2 review authors by discussion and consensus.
Data Synthesis and Statistical Analysis
We performed meta-analysis for quantitative data synthesis whenever there were available data from the primary studies. For continuous outcomes, we used weighted mean difference (MD) between treatment groups and 95% CI as the metrics of effect size. Dichotomous data were synthesized by using risk ratios (RR) and 95% CIs as the effect measures. We used the random-effects model for meta-analyses.
We assessed heterogeneity in results between studies by using the Cochrane Q test (P < .1 considered significant) and the I2 statistic. The I2 statistic ranges from 0% to 100% and measures the degree of inconsistency across studies, with values of 25%, 50%, and 75% corresponding to low, moderate, and high heterogeneity, respectively.29
We conducted a priori subgroup analysis based on the treatment regimen. We also conducted post hoc subgroup analyses according to diagnosis criteria for bronchiolitis (presence of wheeze as essential diagnostic criteria and availability of virological testing) and risk of bias in the trials. We performed post hoc sensitivity analyses excluding open trials, trials in which mean and SD were estimated from median and interquartile range, trials with high risk of attrition bias (withdrawal rate >20% or data obtained from a part of study sample), and trials that did not use 0.9% saline as the control. All meta-analyses were performed by using Stata version 11.0 (Stata Corp, College Station, TX).
Results
Literature Search and Study Selection
The search strategy identified 97 unique records from PubMed and 125 records from BIREME. After screening the titles and abstracts, we retrieved 26 potentially relevant full-text articles for further evaluation. Five articles were excluded for reasons shown in Fig 1. We obtained the data from clinical trials registry (ClinicalTrials.gov) to assess the eligibility of 3 completed but unpublished trials and all met the inclusion criteria. No additional trials were found by checking the reference lists of primary studies and review articles. Thus, a total of 24 trials4,9,–19,23,–25,27,30,–37 involving 3209 patients were included in the review. All but 2 trials14,35 contributed data to the meta-analyses.
Study Characteristics and Risk of Bias
Table 1 summarizes the characteristics of the 24 included trials. All studies were parallel-group RCTs except 1 that was a quasi-RCT.17 The criteria for diagnosis of bronchiolitis were clearly defined by 19 trials. Eighteen trials12,–19,23,24,27,31,–37 defined bronchiolitis as the first episode of wheezing associated with viral respiratory infection in children <2 years of age. In 1 trial,4 bronchiolitis was defined as an apparent viral respiratory tract infection associated with airways obstruction manifest by hyperinflation, tachypnea, and subcostal recession with widespread crepitations on auscultation. Virological investigation was available in 13 trials4,9,–14,16,18,19,24,30,32 and the positive rate for RSV varied from 56% to 88%. The concentration of HS was defined at 3% in all but 5 trials, in which 5%14,27,35 (n = 165), 6%24 (n = 83), and 7%32 saline (n = 52) was used. Treatment regimen of nebulized HS varied across studies, especially outpatient trials (Table 1).
Characteristics of Included Trials
| Study ID and Country | Setting | Inclusion Criteria of Participants | RSV Positivity | Intervention and Control | Treatment Regimen | Outcomes |
|---|---|---|---|---|---|---|
| Al-Ansari 2010,14 Qatar | Outpatient (ED) | Infants ≤18 mo with moderate to severe bronchiolitis, defined as a prodromal history of viral RTI followed by wheezing and/or crackles and Wang CSS of ≥4. | 56.1% (96/171) | −5 mL 3% saline + 1.5 mg epinephrine (n = 58) | Saline solutions given on enrollment and every 4 h thereafter. | - Primary: Wang CSS at 48 h. |
| −5 mL 5% saline + 1.5 mg epinephrine (n = 57) | - Secondary: Wang CSS at 24 and 72 h, LOS in ED, revisit to ED, AEs. | |||||
| −5 mL 0.9% saline + 1.5 mg epinephrine (n = 56) | ||||||
| Anil 2010,15 Turkey | Outpatient (ED) | Infants 6 wk to 24 mo with first episode of bronchiolitis, defined by symptoms of upper RTI and presence of bilateral wheezing and/or crackles on auscultation and Wang CSS between 1 and 9. | NA | −4 mL 3% saline + 1.5 mg epinephrine (n = 39) | Saline solutions given at 0 and 30 min. | - Primary: Wang CSS at 0, 30, 60, 120 min. |
| −4 mL 0.9% saline + 1.5 mg epinephrine (n = 38) | - Secondary: SAO2 in room air and heart rate at 0, 30, 60 and 120 min, AEs. | |||||
| −3% saline + 2.5 mg salbutamol (n = 36) | ||||||
| −4 mL 0.9% saline + 2.5 mg salbutamol (n = 36) | ||||||
| −4 mL 0.9% saline (n = 37) | ||||||
| Everard 2014,4 England and Wales | Inpatient | Children <12 mo with diagnosis of bronchiolitis defined as apparent viral RTI with airway obstruction (hyperinflation, tachypnea, and subcostal recession) and widespread crepitations, needing O2 with SaO2 <92%. | 84% (179/212) | −4 mL 3% saline + standard care (n = 142) | HS given every 6 h until primary outcome achieved. | - Primary: fit for discharge (75% of usual intake and SaO2 ≥92% for 6 h at room air). |
| - Standard care (n = 149) | - Secondary: actual time to discharge, readmission within 28 d from randomization, healthcare usage, duration of respiratory symptoms postdischarge, ITQoL, AEs. | |||||
| Florin 2014,31 USA | Outpatient (ED) | Children <24 mo with first episode of bronchiolitis, defined as first episode of wheezing associated with signs and symptoms of upper RTI and respiratory distress measured by RDAI score between 4 and 15. | NA | −4 mL 3% saline (n = 31) | One dose of saline solutions given at 0 min. | - Primary: RACS at 1 h after inhalation. |
| −4 mL 0.9% saline (n = 31) | - Secondary outcomes: vital signs, SaO2, hospitalization rate, physician clinical impression, parental assessment, AEs. | |||||
| Grewal 2009,13 Canada | Outpatient (ED) | Children 6 wk to 12 mo with diagnosis of bronchiolitis, defined as first episode of wheezing and symptoms of viral RTI, initial SAO2 85%–96% and initial RDAI score ≥4. | 82.2% (37/45) | −2.5 mL 3% saline + 0.5 mL 2.25% racemic epinephrine (n = 24) | One dose saline solutions given at 0 min. | - Primary: RACS 0–120 min, change in SAO2 0–120 min. |
| −2.5 mL 0.9% saline + 0.5 mL 2.25% racemic epinephrine (n = 24) | - Secondary: admission to hospital, return to ED, AEs. | |||||
| Ipek 2011,17 Turkey | Outpatient (ED) | Children <2 y with history of preceding viral upper RTI followed by wheezing and crackles on auscultation and Wang CSS between 4 and 8. | NA | −4 mL 3% saline + 0.15 mg /kg salbutamol (n = 30) | Saline solutions given at 0, 20, 40 min. | - Primary: Wang CSS, use of corticosteroid, hospitalization, clinical assessment 48–72 h. |
| −4 mL 0.9% saline + 0.15 mg /kg salbutamol (n = 30) | - Secondary: SAO2, respiratory rate, heart rate. | |||||
| −4 mL 3% saline (n = 30) | ||||||
| −4 mL 0.9% saline (n = 30) | ||||||
| Jacobs 2014,32 USA | Outpatient (ED) | Children 6 wk to < 18 mo with bronchiolitis defined as viral RTI and first episode of wheezing, Wang CSS ≥4 and SaO2 >85%. | 60.3% (41/68) | −3 mL 7% saline + 0.5 mL 2.25% racemic epinephrine (n = 52) | One dose of saline solutions given at 0 min. | - Primary: Wang CSS before and after treatment and at disposition. |
| −3 mL 0.9% saline + 0.5 mL 2.25% racemic epinephrine (n = 49) | - Secondary: hospitalization rate, proportion of admitted patients discharged at 23 h, LOS, AEs. | |||||
| Kuzik 2007,12 Abu Dhabi and Canada | Inpatient | Children ≤18 mo with history of preceding viral upper RTI, wheezing or crackles on chest auscultation, plus either SaO2 of 94% in room air or significant respiratory distress as measured by RDAI score ≥4. | 68.8% (55/80) | −4 mL 3% saline (n = 47) | 3 doses given every 2 h, followed by every 4 h for 5 doses, followed by every 6 h until discharge. | - Primary: LOS defined as time between study entry and time at which the infant either reached protocol-defined discharge criteria (RDAI score < 4 and SaO2 ≥95% in room air for 4 h) or discharged by attending physician, whichever came first. |
| −4 mL 0.9% saline (n = 49) | - Secondary: AEs. | |||||
| Li 2014,35 China | Outpatient (Ambulatory care unit) | Children 2–18 mo with first episode of bronchiolitis (Wang CSS ≥4). | NA | −2 mL 3% saline (n = 42) | Saline solutions given twice daily for 3 d. | - Primary: Wang CSS 24, 48, 72 h after treatment. |
| −2 mL 5% saline (n = 40) | - Secondary: AEs. | |||||
| −2 mL 0.9% saline (n = 42) | ||||||
| Luo 2010,18 China | Inpatient | Wheezing infants with mild to moderate viral bronchiolitis, measured by Wang CSS. | 69.9% (65/93) | −4 mL 3% saline + 2.5 mg salbutamol (n = 50) | Saline solutions given every 8 h until discharge. | LOS (discharge decided by attending physician), time for resolution of wheezing, cough, pulmonary moist and crackles, Wang CSS, AEs. |
| −4 mL 0.9% saline + 2.5 mg salbutamol (n = 43) | ||||||
| Luo 2011,19 China | Inpatient | Children <24 mo with first episode of wheezing diagnosed as moderate to severe bronchiolitis according Wang CSS. | 73.2% (82/112) | −4 mL 3% saline (n = 57) | 3 doses given every 2 h, followed by every 4 h for 5 doses, followed by every 6 h until discharge. | LOS (discharge decided by attending physician), time for resolution of wheezing, cough, pulmonary moist and crackles, Wang CSS, AEs. |
| −4 mL 0.9% saline (n = 55) | ||||||
| Mandelberg 2003,10 Israel | Inpatient | Children ≤12 mo with clinical presentation of viral bronchiolitis, temperature >38°C and SaO2 ≥85%. | 87% (47/52) | −4 mL 3% saline + 1.5 mg epinephrine (n = 27) | Saline solutions given every 8 h until discharge. | - Primary: LOS (discharge decided by attending physician), Wang CSS. |
| −4 mL 0.9% saline + 1.5 mg epinephrine (n = 25) | - Secondary: radiograph score, AEs. | |||||
| Miraglia 2012,16 Italy | Inpatient | Children under 24 mo with diagnosis of bronchiolitis, defined as first episode of wheezing and clinical symptoms of viral RTI, SAO2 <94% in room air and significant respiratory distress measured by Wang CSS. | 82.1% (87/106) | - ? mL 3% saline + 1.5 mg epinephrine (n = 52) | Saline solutions given every 6 h. | - Primary: LOS defined as time between study entry and time of discharge. |
| - ? mL 0·9% saline + 1.5 mg epinephrine (n = 54) | - Secondary: Wang CSS on each treatment day. | |||||
| Ojha 2014,33 Nepal | Inpatient | Children >6 wk to <24 mo with first episode of bronchiolitis defined as wheezing associated with upper RTI, tachypnea, increased respiratory effort, clinical scoring of respiratory distress ≥4 and SaO2 ≥85%. | NA | −4 mL 3% saline (n = 36) | Saline solutions given every 8 h until discharge. | - Primary: LOS calculated from time of entry to time of discharge (no supplemental O2, feeding adequately, minimal or absent of wheezing, crackles, and retractions, SaO2 ≥95% at room air for 4 h and severity score was < 4). |
| −4 mL 0.9% saline (n = 36) | - Secondary: duration of supplemental O2, clinical scores. | |||||
| Pandit 2013,34 India | Inpatient | Children 2–12 mo with acute bronchiolitis defined as short history of cough with or without fever <7 d and first episode of wheezing. | NA | −4 mL 3% saline + 1 mL adrenaline (n = 51) | 3 doses given every 1 h, followed by every 6 h until discharge. | - Primary: LOS (discharge criteria: respiratory rate <60/min, without retractions and wheezing). |
| −4 mL 0.9% saline + 1 mL adrenaline (n = 49) | - Secondary: improvement in RDAI score, respiratory rate, SaO2, heart rate, number of add on treatment, AEs. | |||||
| Sarrel 2002,9 Israel | Outpatient (Ambulatory care unit) | Children ≤24 mo with clinical presentation of mild to moderate bronchiolitis and SaO2 <96%. | 80% (52/65) | −2 mL 3% saline + 5 mg terbutaline (n = 33) | Saline solutions given every 8 h for 5 d. | - Primary: hospitalization rate, Wang CSS. |
| −2 mL 0.9% saline + 5 mg terbutaline (n = 32) | - Secondary: radiograph score, AEs. | |||||
| Sharma 2012,23 India | Inpatient | Children 1–24 mo with moderate (Wang CSS 3–6) acute bronchiolitis defined as first episode of wheezing with prodrome of upper RTI. | NA | −4 mL 3% saline + 2.5 mg salbutamol (n = 125) | Saline solutions given every 4 h until discharge. | - Primary outcome: LOS defined as time from admission to Wang CSS < 3. |
| −4 mL 0.9% saline + 2.5 mg salbutamol (n = 123) | - Secondary: Wang CSS, AEs. | |||||
| Tal 2006,11 Israel | Inpatient | Children ≤12 mo with clinical presentation of viral bronchiolitis leading to hospitalization and SaO2 ≥85%. | 80% (33/41) | −4 mL 3% saline + 1.5 mg epinephrine (n = 21) | Saline solutions given every 8 h until discharge. | - Primary: LOS (discharge decided by attending physician), Wang CSS. |
| −4 mL 0.9% saline + 1.5 mg epinephrine (n = 20) | - Secondary: radiograph score, AEs. | |||||
| Teunissen 2013,24 The Netherlands | Inpatient | Children 0–24 mo with moderate to severe (Wang CSS ≥3) bronchiolitis defined as upper RTI with wheezing, tachypnea, and dyspnea. | 88% (212/241) | −4 mL 3% saline + 2.5 mg salbutamol (n = 84) | Saline solutions given every 8 h until discharge. | - Primary outcome: LOS defined as time between the first dose of medications and clinical decision to discharge (protocol-defined discharge criteria: no supplemental O2, no tube-feeding or intravenous fluids). |
| −4 mL 6% saline + 2.5 mg salbutamol (n = 83) | - Secondary: transfer to ICU, duration of supplemental O2 or tube-feeding, AEs. | |||||
| −4 mL 0.9% saline + .·5 mg salbutamol (n = 80) | ||||||
| Tinsa 2014,27 Tunis | Inpatient | Children 1 to 12 mo with diagnosis of bronchiolitis, defined as first episode of wheezing associated with acute RTI and Wang score ≥3. | NA | −4 mL 5% saline (n = 31) | Saline solutions given every 4 h until discharge. | - Primary: Wang CSS at 30, 60 and 120 min. |
| −2 mL 5% saline + 2 mL epinephrine (n = 37) | - Secondary:: LOS (discharge criteria: no supplemental O2, adequate fluid intake, Wang CSS <3), AEs. | |||||
| −4 mL 0.9% saline (n = 26) | ||||||
| Wu 2014,30 USA | Outpatient (ED) | Children <24 mo with first episode of bronchiolitis during bronchiolitis season. | 62·2% (84/135) | −4 mL 3% saline (n = 211) | Saline solutions given every 20 min to a maximum of 3 doses. Admitted patients: every 8 h until discharge. | - Primary: admission rate, LOS. |
| −4 mL 0.9% saline (n = 197) | - Secondary: RDAI score, need for supplemental therapy, AEs. | |||||
| NCT01276821,36 Nepal | Outpatient (ED) | Children 6 wk to 2 y with bronchiolitis defined as first episode of wheezing and Wang CSS between 1 and 9. | NA | −4 mL 3% saline + 1.5 mg epinephrine (n = 50) | Saline solutions given at 0, 30 min. | - Primary: Wang CSS at 30, 60, 120 min. |
| −4 mL 0.9% saline + 1.5 mg epinephrine (n = 50) | - Secondary: SaO2, respiratory rate, heart rate at 30, 60, 120 min, transfer to ICU, discharge rate after 120 min, revisit to ED within 1 wk, AEs. | |||||
| NCT01488448,25 USA | Inpatient | Children 0–12 mo admitted to hospital with a diagnosis of bronchiolitis. | NA | −4 mL 3% saline (n = 93) | Saline solutions given every 4 h until discharge. | - Primary: LOS. |
| −4 mL 0.9% saline (n = 97) | - Secondary: readmission within 30 d, transfer to ICU, AEs. | |||||
| NCT01238848,37 Argentina | Inpatient | Children 1–24 mo hospitalized for first episode of bronchiolitis, with severity score ≥5 and oxygen saturation ≥97%. | NA | −3 mL 3% saline + albuterol 0·25 mg/kg/day (n = 37) | - Primary: LOS. | |
| −3 mL 0.9% saline + albuterol 0.25 mg/kg/day (n = 45) | - Secondary: duration of supplemental O2, AEs. |
| Study ID and Country | Setting | Inclusion Criteria of Participants | RSV Positivity | Intervention and Control | Treatment Regimen | Outcomes |
|---|---|---|---|---|---|---|
| Al-Ansari 2010,14 Qatar | Outpatient (ED) | Infants ≤18 mo with moderate to severe bronchiolitis, defined as a prodromal history of viral RTI followed by wheezing and/or crackles and Wang CSS of ≥4. | 56.1% (96/171) | −5 mL 3% saline + 1.5 mg epinephrine (n = 58) | Saline solutions given on enrollment and every 4 h thereafter. | - Primary: Wang CSS at 48 h. |
| −5 mL 5% saline + 1.5 mg epinephrine (n = 57) | - Secondary: Wang CSS at 24 and 72 h, LOS in ED, revisit to ED, AEs. | |||||
| −5 mL 0.9% saline + 1.5 mg epinephrine (n = 56) | ||||||
| Anil 2010,15 Turkey | Outpatient (ED) | Infants 6 wk to 24 mo with first episode of bronchiolitis, defined by symptoms of upper RTI and presence of bilateral wheezing and/or crackles on auscultation and Wang CSS between 1 and 9. | NA | −4 mL 3% saline + 1.5 mg epinephrine (n = 39) | Saline solutions given at 0 and 30 min. | - Primary: Wang CSS at 0, 30, 60, 120 min. |
| −4 mL 0.9% saline + 1.5 mg epinephrine (n = 38) | - Secondary: SAO2 in room air and heart rate at 0, 30, 60 and 120 min, AEs. | |||||
| −3% saline + 2.5 mg salbutamol (n = 36) | ||||||
| −4 mL 0.9% saline + 2.5 mg salbutamol (n = 36) | ||||||
| −4 mL 0.9% saline (n = 37) | ||||||
| Everard 2014,4 England and Wales | Inpatient | Children <12 mo with diagnosis of bronchiolitis defined as apparent viral RTI with airway obstruction (hyperinflation, tachypnea, and subcostal recession) and widespread crepitations, needing O2 with SaO2 <92%. | 84% (179/212) | −4 mL 3% saline + standard care (n = 142) | HS given every 6 h until primary outcome achieved. | - Primary: fit for discharge (75% of usual intake and SaO2 ≥92% for 6 h at room air). |
| - Standard care (n = 149) | - Secondary: actual time to discharge, readmission within 28 d from randomization, healthcare usage, duration of respiratory symptoms postdischarge, ITQoL, AEs. | |||||
| Florin 2014,31 USA | Outpatient (ED) | Children <24 mo with first episode of bronchiolitis, defined as first episode of wheezing associated with signs and symptoms of upper RTI and respiratory distress measured by RDAI score between 4 and 15. | NA | −4 mL 3% saline (n = 31) | One dose of saline solutions given at 0 min. | - Primary: RACS at 1 h after inhalation. |
| −4 mL 0.9% saline (n = 31) | - Secondary outcomes: vital signs, SaO2, hospitalization rate, physician clinical impression, parental assessment, AEs. | |||||
| Grewal 2009,13 Canada | Outpatient (ED) | Children 6 wk to 12 mo with diagnosis of bronchiolitis, defined as first episode of wheezing and symptoms of viral RTI, initial SAO2 85%–96% and initial RDAI score ≥4. | 82.2% (37/45) | −2.5 mL 3% saline + 0.5 mL 2.25% racemic epinephrine (n = 24) | One dose saline solutions given at 0 min. | - Primary: RACS 0–120 min, change in SAO2 0–120 min. |
| −2.5 mL 0.9% saline + 0.5 mL 2.25% racemic epinephrine (n = 24) | - Secondary: admission to hospital, return to ED, AEs. | |||||
| Ipek 2011,17 Turkey | Outpatient (ED) | Children <2 y with history of preceding viral upper RTI followed by wheezing and crackles on auscultation and Wang CSS between 4 and 8. | NA | −4 mL 3% saline + 0.15 mg /kg salbutamol (n = 30) | Saline solutions given at 0, 20, 40 min. | - Primary: Wang CSS, use of corticosteroid, hospitalization, clinical assessment 48–72 h. |
| −4 mL 0.9% saline + 0.15 mg /kg salbutamol (n = 30) | - Secondary: SAO2, respiratory rate, heart rate. | |||||
| −4 mL 3% saline (n = 30) | ||||||
| −4 mL 0.9% saline (n = 30) | ||||||
| Jacobs 2014,32 USA | Outpatient (ED) | Children 6 wk to < 18 mo with bronchiolitis defined as viral RTI and first episode of wheezing, Wang CSS ≥4 and SaO2 >85%. | 60.3% (41/68) | −3 mL 7% saline + 0.5 mL 2.25% racemic epinephrine (n = 52) | One dose of saline solutions given at 0 min. | - Primary: Wang CSS before and after treatment and at disposition. |
| −3 mL 0.9% saline + 0.5 mL 2.25% racemic epinephrine (n = 49) | - Secondary: hospitalization rate, proportion of admitted patients discharged at 23 h, LOS, AEs. | |||||
| Kuzik 2007,12 Abu Dhabi and Canada | Inpatient | Children ≤18 mo with history of preceding viral upper RTI, wheezing or crackles on chest auscultation, plus either SaO2 of 94% in room air or significant respiratory distress as measured by RDAI score ≥4. | 68.8% (55/80) | −4 mL 3% saline (n = 47) | 3 doses given every 2 h, followed by every 4 h for 5 doses, followed by every 6 h until discharge. | - Primary: LOS defined as time between study entry and time at which the infant either reached protocol-defined discharge criteria (RDAI score < 4 and SaO2 ≥95% in room air for 4 h) or discharged by attending physician, whichever came first. |
| −4 mL 0.9% saline (n = 49) | - Secondary: AEs. | |||||
| Li 2014,35 China | Outpatient (Ambulatory care unit) | Children 2–18 mo with first episode of bronchiolitis (Wang CSS ≥4). | NA | −2 mL 3% saline (n = 42) | Saline solutions given twice daily for 3 d. | - Primary: Wang CSS 24, 48, 72 h after treatment. |
| −2 mL 5% saline (n = 40) | - Secondary: AEs. | |||||
| −2 mL 0.9% saline (n = 42) | ||||||
| Luo 2010,18 China | Inpatient | Wheezing infants with mild to moderate viral bronchiolitis, measured by Wang CSS. | 69.9% (65/93) | −4 mL 3% saline + 2.5 mg salbutamol (n = 50) | Saline solutions given every 8 h until discharge. | LOS (discharge decided by attending physician), time for resolution of wheezing, cough, pulmonary moist and crackles, Wang CSS, AEs. |
| −4 mL 0.9% saline + 2.5 mg salbutamol (n = 43) | ||||||
| Luo 2011,19 China | Inpatient | Children <24 mo with first episode of wheezing diagnosed as moderate to severe bronchiolitis according Wang CSS. | 73.2% (82/112) | −4 mL 3% saline (n = 57) | 3 doses given every 2 h, followed by every 4 h for 5 doses, followed by every 6 h until discharge. | LOS (discharge decided by attending physician), time for resolution of wheezing, cough, pulmonary moist and crackles, Wang CSS, AEs. |
| −4 mL 0.9% saline (n = 55) | ||||||
| Mandelberg 2003,10 Israel | Inpatient | Children ≤12 mo with clinical presentation of viral bronchiolitis, temperature >38°C and SaO2 ≥85%. | 87% (47/52) | −4 mL 3% saline + 1.5 mg epinephrine (n = 27) | Saline solutions given every 8 h until discharge. | - Primary: LOS (discharge decided by attending physician), Wang CSS. |
| −4 mL 0.9% saline + 1.5 mg epinephrine (n = 25) | - Secondary: radiograph score, AEs. | |||||
| Miraglia 2012,16 Italy | Inpatient | Children under 24 mo with diagnosis of bronchiolitis, defined as first episode of wheezing and clinical symptoms of viral RTI, SAO2 <94% in room air and significant respiratory distress measured by Wang CSS. | 82.1% (87/106) | - ? mL 3% saline + 1.5 mg epinephrine (n = 52) | Saline solutions given every 6 h. | - Primary: LOS defined as time between study entry and time of discharge. |
| - ? mL 0·9% saline + 1.5 mg epinephrine (n = 54) | - Secondary: Wang CSS on each treatment day. | |||||
| Ojha 2014,33 Nepal | Inpatient | Children >6 wk to <24 mo with first episode of bronchiolitis defined as wheezing associated with upper RTI, tachypnea, increased respiratory effort, clinical scoring of respiratory distress ≥4 and SaO2 ≥85%. | NA | −4 mL 3% saline (n = 36) | Saline solutions given every 8 h until discharge. | - Primary: LOS calculated from time of entry to time of discharge (no supplemental O2, feeding adequately, minimal or absent of wheezing, crackles, and retractions, SaO2 ≥95% at room air for 4 h and severity score was < 4). |
| −4 mL 0.9% saline (n = 36) | - Secondary: duration of supplemental O2, clinical scores. | |||||
| Pandit 2013,34 India | Inpatient | Children 2–12 mo with acute bronchiolitis defined as short history of cough with or without fever <7 d and first episode of wheezing. | NA | −4 mL 3% saline + 1 mL adrenaline (n = 51) | 3 doses given every 1 h, followed by every 6 h until discharge. | - Primary: LOS (discharge criteria: respiratory rate <60/min, without retractions and wheezing). |
| −4 mL 0.9% saline + 1 mL adrenaline (n = 49) | - Secondary: improvement in RDAI score, respiratory rate, SaO2, heart rate, number of add on treatment, AEs. | |||||
| Sarrel 2002,9 Israel | Outpatient (Ambulatory care unit) | Children ≤24 mo with clinical presentation of mild to moderate bronchiolitis and SaO2 <96%. | 80% (52/65) | −2 mL 3% saline + 5 mg terbutaline (n = 33) | Saline solutions given every 8 h for 5 d. | - Primary: hospitalization rate, Wang CSS. |
| −2 mL 0.9% saline + 5 mg terbutaline (n = 32) | - Secondary: radiograph score, AEs. | |||||
| Sharma 2012,23 India | Inpatient | Children 1–24 mo with moderate (Wang CSS 3–6) acute bronchiolitis defined as first episode of wheezing with prodrome of upper RTI. | NA | −4 mL 3% saline + 2.5 mg salbutamol (n = 125) | Saline solutions given every 4 h until discharge. | - Primary outcome: LOS defined as time from admission to Wang CSS < 3. |
| −4 mL 0.9% saline + 2.5 mg salbutamol (n = 123) | - Secondary: Wang CSS, AEs. | |||||
| Tal 2006,11 Israel | Inpatient | Children ≤12 mo with clinical presentation of viral bronchiolitis leading to hospitalization and SaO2 ≥85%. | 80% (33/41) | −4 mL 3% saline + 1.5 mg epinephrine (n = 21) | Saline solutions given every 8 h until discharge. | - Primary: LOS (discharge decided by attending physician), Wang CSS. |
| −4 mL 0.9% saline + 1.5 mg epinephrine (n = 20) | - Secondary: radiograph score, AEs. | |||||
| Teunissen 2013,24 The Netherlands | Inpatient | Children 0–24 mo with moderate to severe (Wang CSS ≥3) bronchiolitis defined as upper RTI with wheezing, tachypnea, and dyspnea. | 88% (212/241) | −4 mL 3% saline + 2.5 mg salbutamol (n = 84) | Saline solutions given every 8 h until discharge. | - Primary outcome: LOS defined as time between the first dose of medications and clinical decision to discharge (protocol-defined discharge criteria: no supplemental O2, no tube-feeding or intravenous fluids). |
| −4 mL 6% saline + 2.5 mg salbutamol (n = 83) | - Secondary: transfer to ICU, duration of supplemental O2 or tube-feeding, AEs. | |||||
| −4 mL 0.9% saline + .·5 mg salbutamol (n = 80) | ||||||
| Tinsa 2014,27 Tunis | Inpatient | Children 1 to 12 mo with diagnosis of bronchiolitis, defined as first episode of wheezing associated with acute RTI and Wang score ≥3. | NA | −4 mL 5% saline (n = 31) | Saline solutions given every 4 h until discharge. | - Primary: Wang CSS at 30, 60 and 120 min. |
| −2 mL 5% saline + 2 mL epinephrine (n = 37) | - Secondary:: LOS (discharge criteria: no supplemental O2, adequate fluid intake, Wang CSS <3), AEs. | |||||
| −4 mL 0.9% saline (n = 26) | ||||||
| Wu 2014,30 USA | Outpatient (ED) | Children <24 mo with first episode of bronchiolitis during bronchiolitis season. | 62·2% (84/135) | −4 mL 3% saline (n = 211) | Saline solutions given every 20 min to a maximum of 3 doses. Admitted patients: every 8 h until discharge. | - Primary: admission rate, LOS. |
| −4 mL 0.9% saline (n = 197) | - Secondary: RDAI score, need for supplemental therapy, AEs. | |||||
| NCT01276821,36 Nepal | Outpatient (ED) | Children 6 wk to 2 y with bronchiolitis defined as first episode of wheezing and Wang CSS between 1 and 9. | NA | −4 mL 3% saline + 1.5 mg epinephrine (n = 50) | Saline solutions given at 0, 30 min. | - Primary: Wang CSS at 30, 60, 120 min. |
| −4 mL 0.9% saline + 1.5 mg epinephrine (n = 50) | - Secondary: SaO2, respiratory rate, heart rate at 30, 60, 120 min, transfer to ICU, discharge rate after 120 min, revisit to ED within 1 wk, AEs. | |||||
| NCT01488448,25 USA | Inpatient | Children 0–12 mo admitted to hospital with a diagnosis of bronchiolitis. | NA | −4 mL 3% saline (n = 93) | Saline solutions given every 4 h until discharge. | - Primary: LOS. |
| −4 mL 0.9% saline (n = 97) | - Secondary: readmission within 30 d, transfer to ICU, AEs. | |||||
| NCT01238848,37 Argentina | Inpatient | Children 1–24 mo hospitalized for first episode of bronchiolitis, with severity score ≥5 and oxygen saturation ≥97%. | NA | −3 mL 3% saline + albuterol 0·25 mg/kg/day (n = 37) | - Primary: LOS. | |
| −3 mL 0.9% saline + albuterol 0.25 mg/kg/day (n = 45) | - Secondary: duration of supplemental O2, AEs. |
ITQoL, Infant Toddler Quality of Life; NA, not applicable; RACS, Respiratory Assessment Change Score; RTI, respiratory tract infection; SaO2, oxygen saturation.
All trials were double-blind except 3 open trials,4,34,37 in which performance bias and detection bias might occur (Supplemental Table 5). All trials but 117 were stated as randomized; however, 11 trials9,–12,15,16,18,25,30,35,37 did not describe the methods for random sequence generation and/or allocation concealment. Attribution bias might occur in 3 trials25,32,37 because of high and unbalanced withdrawal rate after randomization.
Efficacy of Nebulized HS in Inpatients
LOS in Hospital
Among 14 inpatient trials, 139,–12,16,18,19,23,–25,33,34,37 used LOS as the primary outcome and 127used LOS as the secondary outcome. One ED trial30 involving 408 patients provided the data of LOS among 145 hospitalized patients. We included the data of these 145 inpatients in the meta-analysis. The pooled results of 15 trials with a total of 1956 inpatients showed a statistically significant shorter mean LOS among infants treated with HS compared with those treated with 0.9% saline or standard care (MD of −0.45 days, 95% CI −0.82 to −0.08, P = .01) (Fig 2). There was significant heterogeneity in results between studies (I2 statistic = 82%). The data were suitable for conducting 5 subgroup analyses (Table 2). Nine trials4,10,–12,16,18,19,24,30 in which virological investigation was available showed significant effects of HS on reducing LOS, whereas 6 trials23,25,27,33,34,37 in which such testing was not available did not show significant benefits (P = .02 for subgroup comparison). The effect size of HS on LOS appeared to be greater in trials10,–12,16,18,25,30,37 with unclear or high risk of selection bias, compared with trials4,19,23,–25,27,33 with low risk of selection bias. However, the difference between subgroups was not statistically significant.
Subgroup Analyses on LOS (Inpatients) and Admission Rate (Outpatients)
| Subgroups | LOS, d | Admission rate, % | ||||||
|---|---|---|---|---|---|---|---|---|
| Trial, n | Patients, n | Effect Size: MD (95% CI) | Subgroup Comparison,a P Value | Trial, n | Patients, n | Effect Size: RR (95% CI) | Subgroup Comparison,a P Value | |
| Virological investigation | .02 | .06 | ||||||
| Available | 9 | 1183 | −0.74 (−1.32 to −0.16) | 4 | 620 | 0.71 (0.58–0.88) | ||
| Not available | 6 | 773 | 0.01 (−0.17–0.19) | 3 | 331 | 1·04 (0.75–1.44) | ||
| Wheeze as diagnostic criteria | .42 | — | ||||||
| Yes | 11 | 1427 | −0.40 (−0.84–0.04) | 5 | 478 | 0.92 (0.72–1.16) | ||
| No | 1 | 291 | −0.03 (−0.80–0.74) | 0 | 0 | — | ||
| HS mixed with bronchodilatorb | .80 | .71 | ||||||
| Yes | 9 | 1019 | −0.42 (−0.89–0.05) | 5 | 481 | 0.76 (0.55–1.06) | ||
| No | 7 | 937 | −0.52 (−1.18–0.14) | 2 | 470 | 0.85 (0.52–1.40) | ||
| Treatment regimenc | .79 | .07 | ||||||
| A | 6 | 840 | −0.52 (−1.14–0.09) | 4 | 358 | 0.93 (0.73–1.20) | ||
| B | 9 | 1116 | −0.41 (−0.93–0.10) | 3 | 593 | 0.67 (0.52–0.87) | ||
| Selection bias | .31 | .13 | ||||||
| Low | 7 | 1151 | −0.26 (−0.82–0.30) | 3 | 209 | 0.91 (0.68–1.23) | ||
| Unclear/high | 8 | 805 | −0.65 (−1.14 to −0.15) | 4 | 742 | 0.68 (0.52–0.87) | ||
| Subgroups | LOS, d | Admission rate, % | ||||||
|---|---|---|---|---|---|---|---|---|
| Trial, n | Patients, n | Effect Size: MD (95% CI) | Subgroup Comparison,a P Value | Trial, n | Patients, n | Effect Size: RR (95% CI) | Subgroup Comparison,a P Value | |
| Virological investigation | .02 | .06 | ||||||
| Available | 9 | 1183 | −0.74 (−1.32 to −0.16) | 4 | 620 | 0.71 (0.58–0.88) | ||
| Not available | 6 | 773 | 0.01 (−0.17–0.19) | 3 | 331 | 1·04 (0.75–1.44) | ||
| Wheeze as diagnostic criteria | .42 | — | ||||||
| Yes | 11 | 1427 | −0.40 (−0.84–0.04) | 5 | 478 | 0.92 (0.72–1.16) | ||
| No | 1 | 291 | −0.03 (−0.80–0.74) | 0 | 0 | — | ||
| HS mixed with bronchodilatorb | .80 | .71 | ||||||
| Yes | 9 | 1019 | −0.42 (−0.89–0.05) | 5 | 481 | 0.76 (0.55–1.06) | ||
| No | 7 | 937 | −0.52 (−1.18–0.14) | 2 | 470 | 0.85 (0.52–1.40) | ||
| Treatment regimenc | .79 | .07 | ||||||
| A | 6 | 840 | −0.52 (−1.14–0.09) | 4 | 358 | 0.93 (0.73–1.20) | ||
| B | 9 | 1116 | −0.41 (−0.93–0.10) | 3 | 593 | 0.67 (0.52–0.87) | ||
| Selection bias | .31 | .13 | ||||||
| Low | 7 | 1151 | −0.26 (−0.82–0.30) | 3 | 209 | 0.91 (0.68–1.23) | ||
| Unclear/high | 8 | 805 | −0.65 (−1.14 to −0.15) | 4 | 742 | 0.68 (0.52–0.87) | ||
Subgroup comparison using χ2 test (degrees of freedom = 1) with P < .1 considered as statistically significant.
One trial had 2 interventions compared with NS: HS mixed with epinephrine and HS alone. We included 2 comparisons, splitting the number of NS group in half for each comparison.
For inpatients: regimen A, every 4 h or 3 initial doses given every 1–2 h followed by every 4–6 h; regimen B, every 6–8 h. For outpatients: regimen A, 1 to 2 doses; regimen B, multiple doses (≥3).
Improvement in CSSs
Eleven inpatient trials used bronchiolitis severity scores as outcome measure. Two trials12,34 used Respiratory Distress Assessment Instrument (RDAI)38 scores based on wheezing and retractions, but 112 did not report the results and the other34 reported RDAI scores only on day 1 of admission. One trial33 used a clinical score based on respiratory rate, wheezing, retractions, and oxygen saturation. This trial did not find a significant difference between HS and NS groups in clinical scores through day 1 to day 4 of admission. All the remaining 8 trials used Wang’s clinical scores,39 grading respiratory rate, wheezing, retractions, and general condition from 0 to 3. However, only 5 trials10,11,16,18,19 with a total of 404 patients provided suitable data for the meta-analysis, showing a significant effect of HS in improving clinical scores on day 1 (MD of −0.99, 95% CI −1.48 to −0.50, P < .0001, I2 statistic = 67%), day 2 (MD of −1.45, 95% CI −2.06 to −0.85, P < .0001, I2 statistic = 79%), and day 3 of admission (MD of −1.44, 95% CI −1.78 to −1.11, P < .0001, I2 statistic = 53%).
Other Efficacy Outcomes
Three trials24,33,37 used duration of in-hospital oxygen supplementation as efficacy outcome. Other efficacy outcomes used by at least 1 trial included duration of tube feeding, time for the resolution of respiratory symptoms and signs, radiograph scores, measurement of respiratory rate, heart rate and oxygen saturation, readmission within 28 days from randomization, and infant and parental quality-of-life questionnaire. Two trials18,19 reported a shorter duration of respiratory symptoms and signs (cough, wheezing, and crackles) in patients treated with HS compared with those receiving NS. None of the trials showed significant effects of HS on other previously mentioned outcomes.
Efficacy of Nebulized HS in Outpatients
Admission Rate
Seven outpatient trials with a total of 951 patients assessed the efficacy of nebulized 3% saline on reducing the risk of hospitalization. The pooled RR was 0.80 (95% CI 0.67–0.96, P = .01) (Fig 3). There was no significant heterogeneity in results between studies (I2 statistic = 2%). The data were available for conducting 4 subgroup analyses (Table 2). The effect size of HS on the risk of hospitalization was significantly greater in trials9,13,30,32 in which virological investigation was available and in trials9,17,30 in which multiple doses (≥3) of saline solutions were administered, compared with trials15,17,31 in which virological testing was not available and trials13,15,31,32 by using only 1 to 2 doses of saline solutions, respectively. Four trials9,15,17,30 with unclear or high risk of selection bias showed significant effects of HS on reducing the risk of hospitalization, whereas 3 trials13,31,32 with low risk of selection bias did not show significant benefits of HS; however, the difference between subgroups was not statistically significant.
Effects of nebulized HS on reducing the risk of hospitalization among outpatients.
Effects of nebulized HS on reducing the risk of hospitalization among outpatients.
Improvement in CSSs
All 10 outpatient trials used bronchiolitis severity scores as the outcome measure. Variation in scoring methods and time points of assessment makes it inappropriate to conduct meta-analyses. Thus, we narratively summarized the main results of 9 trials in terms of effects of HS on improving clinical scores (Table 3). These trials did not show significant effects of nebulized HS in improving clinical scores, except 3 of the trials. One9 showed significant benefits of 3% saline compared with NS on each of 3 treatment days, the second14 showed consistent trend favoring 5% saline compared with 3% and 0.9% saline solutions from 8 to 72 hours after randomization, and the third34 showed the superiority of both 5% and 3% saline solutions over NS on each of 3 treatment days, but no significant difference was found between 5% and 3% saline groups.
Narrative Summary of the Main Findings of 10 Outpatient Trials in Terms of Effects of HS on Improving Clinical Scores
| Trial | Scoring Methods | Main Findings |
|---|---|---|
| Al-Ansari 201014 | Wang score | - Mean scores (SD) 24 h after randomization: 5% saline vs 0.9% saline: 3.75 (1.27) vs 3.97 (1.40), P > .05; 3% saline vs 0.9% saline: 4.0 (0.98) vs 3.75 (1.27), P > .05. |
| - Mean scores (SD) 48 h after randomization: 5% saline vs 0.9% saline: 3.69 (1.09) vs 4.12 (1.11), P = .04; 3% saline vs 0.9% saline: 4.0 (1.22) vs 4.12 (1.11), P > .05. | ||
| - Consistent trend favoring 5% saline from 8 to 72 h after randomization. | ||
| Anil 201015 | Wang score | There was no significant difference between 3% and 0·9% saline groups in terms of clinical scores at 30, 60, and 120 min of assessment. |
| Florin 201431 | RDAI score | - Mean RDAI scores (95% CI) 1 h after saline administration: 3% saline vs 0.9% saline: 6.6 (5.5–7.6) vs 5.1 (4.1–6.2), P = .05. |
| - Mean RACS scores (95% CI) 1 h after saline administration: 3% saline vs 0.9% saline: −1.5 (−3.1–0.2) vs −4.0 (−5.3 to −2.7), P = .01. | ||
| Grewal 200913 | RDAI score | Mean RACS scores (95% CI) from 0 to 120 min: 3% saline vs 0.9% saline: 4.39 (2.64–6.13) vs 5.13 (3.71–6.55), P > .05. |
| Ipek 201117 | Wang score | There was no significant difference between 3% and 0.9% saline groups in terms of clinical scores at 60 min of assessment. |
| Jacobs 201432 | Wang score | - Mean change in scores (SD) at ED disposition: 7% saline vs 0.9% saline: 2.6 (1.9) vs 2.4 (2.3), P = .21. |
| - Mean change in scores (SD) after first nebulization in ED disposition: 7% saline vs 0.9% saline: 2.06 (1.7) vs 2.0 (1.9), P = .06. | ||
| Li 201435 | Wang score | Median scores (interquartile range): 5%, 3% vs 0.9% saline. |
| −24 h after treatment: 6 (1), 6 (1) vs 7 (1); P < .05 (5% vs 0.9%; 3% vs 0.9%). | ||
| −48 h after treatment: 5 (1), 5 (1) vs 6 (0.2), P < .05 (5% vs 0.9%). | ||
| −72 h after treatment: 3.5 (1), 4 (1) vs 7 (0), P < 0·05 (5% vs 0.9%; 3% vs 0.9%). | ||
| Sarrell 20029 | Wang score | Mean scores differed significantly, in favor of 3% saline compared with 0.9% saline, on each of the treatment days. |
| Wu 201430 | RDAI score | Mean scores (SD): 3% saline vs 0.9% saline: 5.32 (3.14) vs 4.88 (2.95), P > .05. |
| NCT 0127682136 | Wang score | Mean change in scores (SD) after 2 sessions of nebulization: 3% saline vs 0.9% saline: 3.52 (1.41) vs 2.26 (1.15) |
| Trial | Scoring Methods | Main Findings |
|---|---|---|
| Al-Ansari 201014 | Wang score | - Mean scores (SD) 24 h after randomization: 5% saline vs 0.9% saline: 3.75 (1.27) vs 3.97 (1.40), P > .05; 3% saline vs 0.9% saline: 4.0 (0.98) vs 3.75 (1.27), P > .05. |
| - Mean scores (SD) 48 h after randomization: 5% saline vs 0.9% saline: 3.69 (1.09) vs 4.12 (1.11), P = .04; 3% saline vs 0.9% saline: 4.0 (1.22) vs 4.12 (1.11), P > .05. | ||
| - Consistent trend favoring 5% saline from 8 to 72 h after randomization. | ||
| Anil 201015 | Wang score | There was no significant difference between 3% and 0·9% saline groups in terms of clinical scores at 30, 60, and 120 min of assessment. |
| Florin 201431 | RDAI score | - Mean RDAI scores (95% CI) 1 h after saline administration: 3% saline vs 0.9% saline: 6.6 (5.5–7.6) vs 5.1 (4.1–6.2), P = .05. |
| - Mean RACS scores (95% CI) 1 h after saline administration: 3% saline vs 0.9% saline: −1.5 (−3.1–0.2) vs −4.0 (−5.3 to −2.7), P = .01. | ||
| Grewal 200913 | RDAI score | Mean RACS scores (95% CI) from 0 to 120 min: 3% saline vs 0.9% saline: 4.39 (2.64–6.13) vs 5.13 (3.71–6.55), P > .05. |
| Ipek 201117 | Wang score | There was no significant difference between 3% and 0.9% saline groups in terms of clinical scores at 60 min of assessment. |
| Jacobs 201432 | Wang score | - Mean change in scores (SD) at ED disposition: 7% saline vs 0.9% saline: 2.6 (1.9) vs 2.4 (2.3), P = .21. |
| - Mean change in scores (SD) after first nebulization in ED disposition: 7% saline vs 0.9% saline: 2.06 (1.7) vs 2.0 (1.9), P = .06. | ||
| Li 201435 | Wang score | Median scores (interquartile range): 5%, 3% vs 0.9% saline. |
| −24 h after treatment: 6 (1), 6 (1) vs 7 (1); P < .05 (5% vs 0.9%; 3% vs 0.9%). | ||
| −48 h after treatment: 5 (1), 5 (1) vs 6 (0.2), P < .05 (5% vs 0.9%). | ||
| −72 h after treatment: 3.5 (1), 4 (1) vs 7 (0), P < 0·05 (5% vs 0.9%; 3% vs 0.9%). | ||
| Sarrell 20029 | Wang score | Mean scores differed significantly, in favor of 3% saline compared with 0.9% saline, on each of the treatment days. |
| Wu 201430 | RDAI score | Mean scores (SD): 3% saline vs 0.9% saline: 5.32 (3.14) vs 4.88 (2.95), P > .05. |
| NCT 0127682136 | Wang score | Mean change in scores (SD) after 2 sessions of nebulization: 3% saline vs 0.9% saline: 3.52 (1.41) vs 2.26 (1.15) |
Rate of Readmission to Hospital or ED
Five outpatient trials reported the rate of readmission to hospital and/or the ED 24 hours to 1 week after discharge. The meta-analysis did not show significant effects of HS in reducing the risk of readmission to hospital (4 trials13,–15,31 with 428 patients, RR of 1.45, 95% CI 0.67–3.14, P = .34, I2 statistic = 1%) and to ED (5 trials13,–15,31,36 with 523 patients, RR of 0.78, 95% CI 0.46–1.32, P = .36, I2 statistic = 29%).
Other Efficacy Outcomes
Oxygen saturation was used as an efficacy outcome by 4 trials.13,15,17,31 Other efficacy outcomes used by at least 1 trial included duration of oxygen supplementation, measurement of respiratory rate and heart rate, radiograph scores, and parental perception of improvement. None of the trials showed beneficial effects of HS on previously mentioned outcomes.
Safety of Nebulized HS
Of 24 trials included in this review, 21 reported safety data among 2897 participants, 1557 of whom received HS (3% saline: n = 1257; 5% saline: n = 165; 6% saline: n = 83; 7% saline: n = 52). Fourteen trials9,–11,14,15,18,23,25,27,31,32,34,36,37 did not find any significant AEs among a total of 1548 participants, of whom 828 received nebulized HS (mixture with bronchodilators: n = 673, 81.3%; HS alone: n = 155, 18.7%). In the remaining 7 trials4,12,13,19,24,30,35 involving 1324 participants of whom 729 received nebulized HS (mixture with bronchodilators: n = 190, 26%; HS alone: n = 539, 74%), at least 1 AE was reported. Variation in reporting and in outcomes precluded the possibility of conducting meta-analysis of safety data. We narratively summarized the safety data of 7 trials (Table 4). Various AEs were reported in both HS and control groups. In most of cases, AEs were mild and resolved spontaneously. Only 1 inpatient trial4 involving 142 patients receiving 3% saline alone without bronchodilator reported 1 serious AE (bradycardia and desaturation) possibly related to HS inhalation but resolved the following day.
Narrative Summary of AEs of Treatment Reported by 7 Trials
| Trial | HS (n) vs Controls (n) | Main Findings |
|---|---|---|
| Everard 20144 | 3% saline (n = 142) vs standard care (n = 143) | Six AEs were possibly related to saline treatment, including 1 serious AE (SAE), bradycardia and desaturation, which resolved the following day. The remaining 5 non-SAEs were bradycardia (self-correcting), desaturation, coughing fit, and increased respiratory rate (all of which were resolved within 1 d), and a chest infection that resolved after 6 d. |
| Grewal 200913 | 3% saline + epinephrine (n = 23) vs 0.9% saline + epinephrine (n = 23) | AEs were noted in 4 infants (vomiting, 3; diarrhea, 1); all were enrolled in the HS group. No additional bronchodilators were given to any enrolled patient during the study period. |
| Kuzik 200712 | 3% saline (n = 47) vs 0.9% saline (n = 49) | No infants were withdrawn by the medical staff due to AEs, although 5 infants were withdrawn at parents’ request because of perceived AEs, only 2 from the HS group, of whom 1 presented with vigorous crying and another with agitation. |
| Li 201435 | 5% saline (n = 40), 3% saline (n = 42) vs 0.9% saline (n = 42) | No AEs were observed in the 3% and 0.9% saline groups. Four patients from the 5% saline group presented with paroxysmal cough during saline inhalation. |
| Luo 201119 | 3% saline (n = 57) vs 0.9% saline (n = 55) | No infants were withdrawn by the medical staff because of AEs. Coughing and wheezing never worsened during saline inhalation, although 5 infants had hoarse voices, only 2 from the HS group, and the symptom disappeared after 3–4 d. |
| Teunissen 201424 | 3%, 6% saline + salbutamol (n = 167) vs 0.9% + salbutamol (n = 80) | A substantial number of AEs (eg, cough, bronchospasm, agitation, desaturation) were noted in all treatment groups. Except for cough, which occurred significantly more in the HS groups (P = .03), no differences were found between groups. Withdrawals due to AEs did not differ between groups (4.3%, 6.1% and 7.9% in the 3%, 6% and 0.9% saline groups, respectively, P = .59). |
| Wu 201430 | 3% saline (n = 211) vs 0.9% saline (n = 197) | Three patients in the NS group and 4 in the HS group withdrew owing to parent request. Of these parent requests, 1 in the NS group and 2 in the HS group were attributed to worsening cough. For these 3 patients, pretreatment and posttreatment vital signs and RDAI score were the same or improved, and no intervention or additional treatment was necessary. |
| Trial | HS (n) vs Controls (n) | Main Findings |
|---|---|---|
| Everard 20144 | 3% saline (n = 142) vs standard care (n = 143) | Six AEs were possibly related to saline treatment, including 1 serious AE (SAE), bradycardia and desaturation, which resolved the following day. The remaining 5 non-SAEs were bradycardia (self-correcting), desaturation, coughing fit, and increased respiratory rate (all of which were resolved within 1 d), and a chest infection that resolved after 6 d. |
| Grewal 200913 | 3% saline + epinephrine (n = 23) vs 0.9% saline + epinephrine (n = 23) | AEs were noted in 4 infants (vomiting, 3; diarrhea, 1); all were enrolled in the HS group. No additional bronchodilators were given to any enrolled patient during the study period. |
| Kuzik 200712 | 3% saline (n = 47) vs 0.9% saline (n = 49) | No infants were withdrawn by the medical staff due to AEs, although 5 infants were withdrawn at parents’ request because of perceived AEs, only 2 from the HS group, of whom 1 presented with vigorous crying and another with agitation. |
| Li 201435 | 5% saline (n = 40), 3% saline (n = 42) vs 0.9% saline (n = 42) | No AEs were observed in the 3% and 0.9% saline groups. Four patients from the 5% saline group presented with paroxysmal cough during saline inhalation. |
| Luo 201119 | 3% saline (n = 57) vs 0.9% saline (n = 55) | No infants were withdrawn by the medical staff because of AEs. Coughing and wheezing never worsened during saline inhalation, although 5 infants had hoarse voices, only 2 from the HS group, and the symptom disappeared after 3–4 d. |
| Teunissen 201424 | 3%, 6% saline + salbutamol (n = 167) vs 0.9% + salbutamol (n = 80) | A substantial number of AEs (eg, cough, bronchospasm, agitation, desaturation) were noted in all treatment groups. Except for cough, which occurred significantly more in the HS groups (P = .03), no differences were found between groups. Withdrawals due to AEs did not differ between groups (4.3%, 6.1% and 7.9% in the 3%, 6% and 0.9% saline groups, respectively, P = .59). |
| Wu 201430 | 3% saline (n = 211) vs 0.9% saline (n = 197) | Three patients in the NS group and 4 in the HS group withdrew owing to parent request. Of these parent requests, 1 in the NS group and 2 in the HS group were attributed to worsening cough. For these 3 patients, pretreatment and posttreatment vital signs and RDAI score were the same or improved, and no intervention or additional treatment was necessary. |
Discussion
This new systematic review and meta-analysis shows a modest but statistically significant benefit of nebulized 3% saline in reducing LOS in infants hospitalized for acute bronchiolitis. The review also shows that nebulized HS could reduce the risk of hospitalization by 20% compared with normal saline among outpatients with bronchiolitis.
The results of this new review confirmed our hypothesis that nebulized HS may be less effective than previously claimed for infants with acute bronchiolitis. The effect size of nebulized HS on reducing LOS in hospitalized patients shown by the present review is only approximately one-third of that shown by the 2013 Cochrane review,20 which included 6 inpatient trials involving 500 patients (MD −1.15 days, 95% CI −1.49 to −0.82 days). It is interesting to note that all 8 trials4,23,–25,27,30,33,34 published in 2013 and thereafter, including 2 European multicenter studies4,24 with relatively large sample size, did not find significant effects of nebulized HS on LOS among inpatients with bronchiolitis. For outpatients, this new review showed a 20% reduction on the risk of hospitalization associated with nebulized HS in contrast with a 37% non–statistically significant reduction shown by the 2013 Cochrane review,20 which included 4 outpatient trials involving 380 participants (RR 0.63, 95% CI 0.37–1.07).
We conducted subgroup analyses to explore potential effect modifiers and sources of heterogeneity in the results across studies. We found that trials in which virological investigation was available showed a significantly greater effect size of nebulized HS than trials without such testing in both inpatients and outpatients, measured by reduction of LOS and risk of hospitalization. These data suggest that diagnostic accuracy of bronchiolitis may affect the treatment outcomes with HS. The number and frequency of saline inhalations may also appear to influence the effect size of HS. Trials undertaken in an outpatient setting in which multiple doses (≥3) of saline solutions were administrated showed a significantly greater reduction on the risk of hospitalization compared with trials that used 1 to 2 doses of saline solutions. However, for inpatients, no significant difference was observed in reduction of LOS between trials that used more frequent saline inhalations (3 initial doses given every 1–2 hours, followed by every 4–6 hours) and those in which saline solutions were given every 6 to 8 hours. Another factor that could possibly influence the effect size of HS was risk of selection bias. Trials with unclear or high risk of selection bias showed significant effects of HS on reducing LOS and risk of hospitalization, whereas trials with low risk of selection bias did not show significant benefits of HS on these outcomes. This does cast some doubt on the overall effect estimates of HS; however, the difference between subgroups was not statistically significant. A tight seal between the mask and the infant’s face is crucial for an effective drug delivery with nebulizer.40 The performance of the nebulizer may also affect drug delivery.41 Thus, variability in drug delivery could be considered one of the potential sources of heterogeneity across studies; however, lack of data from primary studies did not allow us to include this important factor for subgroup analyses.
Clinical score is generally considered a relatively objective measure to assess the severity of illness. Eleven inpatient trials used bronchiolitis severity scores as the efficacy outcome, but only 5 trials that used Wang’s clinical scores provided suitable data for meta-analysis. The pooled results of these 5 trials showed a significant effect of HS in improving clinical scores through day 1 to day 3 of admission. However, the inability to include another 6 inpatient trials in the meta-analysis may have affected the results of the analysis. Seven of 10 outpatient trials did not show significant effects of nebulized HS in improving clinical scores.
Potential adverse effects of intervention with nebulized HS, such as acute bronchospasm, remain a potential concern. In this review, there were 14 trials involving 828 patients receiving nebulized HS that did not report any significant AEs. In 81.3% of these patients, saline solutions were mixed with bronchodilators. In contrast, there were 7 trials involving 729 patients treated with nebulized HS of which 74% received HS alone and reported at least 1 AE. Most AEs were mild and resolved spontaneously. These results suggest that nebulized HS is a safe treatment in infants with bronchiolitis, especially when administered in conjunction with a bronchodilator.
This systematic review included trials conducted in both high-income and low-income countries and in different settings (inpatient, ambulatory care unit, and ED). Thus, evidence derived from the review may have a wide applicability. However, the quality of evidence could be graded only as moderate, mainly due to inconsistency in the results between studies and risk of bias in some trials, according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria.42 Moreover, all but 3 trials excluded patients requiring mechanical ventilation, intensive care, or having an oxygen saturation reading <85% on room air, so caution should be taken when extrapolating the findings of this review to infants with more severe bronchiolitis. The underlying airway pathologic changes may vary between infants with different severity of bronchiolitis, so different responses to treatments with HS may be expected in more severe cases. The results of meta-analysis for effects of HS on clinical scores among inpatients may be biased because only 5 of 11 trials measuring this outcome were included in the analysis. The number of trials and patients in outpatient settings is limited, and 1 trial30 with a relatively large sample size has contributed 43% of weight to the overall summary estimate of effects of HS on reduction of risk of hospitalization. All but 1 trial4 used NS as the comparison. The use of NS allows the trial to be double-blind; however, NS is not technically a placebo, as high-volume NS inhalation could potentially have physiologic effects by improving airway mucociliary clearance, which may have beneficial effects on acute bronchiolitis.8 Use of NS as the control may tend to minimize the effect size of HS.
In conclusion, this new systematic review shows that nebulized HS is associated with a mean reduction of 0.45 days (∼11 hours) in LOS among infants admitted for acute bronchiolitis and a mean reduction of 20% in the risk of hospitalization among outpatients. This review also suggests that nebulized HS is a safe treatment in infants with bronchiolitis, especially when administered in conjunction with a bronchodilator. Given the high prevalence of bronchiolitis in infants and huge burden on health care systems throughout the world, benefits of nebulized HS shown by this review, even though smaller than previously estimated, may still be considered clinically relevant. Moreover, good safety profile and low cost make nebulized HS a potential attractive therapeutic modality for bronchiolitis in infants. However, further large multicenter trials are still warranted to confirm benefits of nebulized HS in both inpatients and outpatients with bronchiolitis, given the limited number of available trials, the small sample sizes of most previous trials, and conflicting results across studies. Further trials should use the most widely accepted clinical criteria and virological investigation for diagnosis of bronchiolitis. When LOS in hospital and admission rate are used as the primary efficacy outcomes, well-defined admission and discharge criteria should be used. Multiple doses of saline inhalations should be administered in outpatients; however, the optimal treatment regimen of nebulized HS for infants with bronchiolitis remains to be determined by further trials in both inpatients and outpatients.
- AEs
adverse events
- ALRIs
acute lower respiratory infections
- BIREME
Latin American and Caribbean Center on Health Sciences Information
- CI
confidence interval
- CSS
clinical severity score
- ED
emergency department
- GRADE
Grading of Recommendations, Assessment, Development and Evaluations
- HS
hypertonic saline
- LOS
length of stay
- MD
mean difference
- NS
normal saline
- RACS
respiratory assessment change score
- RCTs
randomized controlled trials
- RDAI
respiratory distress assessment instrument
- RR
risk ratio
- RSV
respiratory syncytial virus
- RTI
respiratory tract infection
Dr Zhang conceptualized and designed the study, participated in trial selection, quality assessment, data collection and data analysis, and drafted the protocol and the review article; Dr Mendoza-Sassi provided input for study design, critically reviewed the protocol and the review article, and participated in trial selection, quality assessment, and data collection; Drs Klassen and Wainwright provided input for study design, and critically reviewed the protocol and review article; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
Comments
RE: Too much hype for nebulized hypertonic saline for bronchioitis
We thank Drs Silver, Rinke and O'Connor for their comments. We performed a post hoc subgroup analysis based on the mean LOS of the control group for patients hospitalized with bronchiolitis. This subgroup analysis included 11 trials with 3 or more days LOS showed significant effects of HS on reduction of LOS (MD of -0.78 days, 95% CI -1.16 to -0.40), whereas the 4 trials with fewer than 3 days LOS did not show significant benefits (MD of 0.15 days, 95% CI -0.10 to 0.39) (P < 0.0001 for subgroup comparison). Given that the mean LOS in the control group reflects mainly the severity of bronchiolitis, this subgroup analysis may suggest that patients hospitalized with more severe bronchiolitis appear to benefit most from the effects of HS. However, we recommend caution when interpreting these results given the small number of trials with LOS less than 3 days and indirect comparison using subgroup analysis. Caution should also be taken in interpreting the results of other subgroup analyses in this review.
We planned to exclude the trials including patients with previous wheeze, but we erroneously included one unpublished trial (NCT01488448) which did include such patients. Exclusion of this trial from the meta-analysis does not significantly affect the results of HS on LOS (MD of -0.51 days, 95% CI -0.91 to -0.11).
In the subgroup analysis based on availability of virological testing, we misclassified this unpublished trial into the group without virological testing because the results of testing were not posted on ClinicalTrials.gov from which we extracted the trial data and we did not contact the principal investigator for additional data. A new subgroup analysis in which NCT01488448 trial was classified into the group with viriological testing yielded similar results to that shown in the review.
In one of 4 post hoc sensitivity analyses, we excluded 3 trials including NCT01488448 trial classified as having a high risk of attrition bias due to a relatively high withdrawal rate, as shown in the supplementary table of risk of bias. Given that all trials included in this review were short-term, we used 15% of withdrawal rate rather than 20% used in another systematic review of long-term trials (1) as the cut-off for high risk of attrition bias. We realize that we have made a mistake in the review text describing 20% as the cut-off.
We thank Drs Silver, Rinke and O'Connor for their concern on the data accuracy of this review. We have subsequently rechecked all the extracted data and we did not find any other disagreements between extracted data in the review and the data shown in the trials.
Publication bias is a major threat to the validity of systematic reviews and inclusion of unpublished trials may help to overcome this problem (2). However, obtaining the data from unpublished trials is a challenge due to incomplete or no standard reporting.
References
1. Zhang L, Prietsch SOM, Ducharme FM. Inhaled corticosteroids in children with persistent asthma: effects on growth.Cochrane Database Syst Rev.2014, Issue 7. Art. No.: CD009471. DOI: 10.1002/14651858.CD009471.pub2.
2. McAuley L, Pham B, Tugwell P, Moher D. Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses? Lancet. 2000;256(9237):1228-31.
RE: Too much hype for nebulized hypertonic saline for bronchioitis
Dear Editor,
Drs. Zhang, Mendoza-Sassi, Klassen and Wainwright have provided a well-written and comprehensive systematic review (SR) on the use of hypertonic saline (HS) for acute bronchiolitis.[1] Additional details about the generalizability of these results and the studies included in the SR may be of interest.
When examining the data, there are a subgroup of patients with length of stay (LOS) >3 days who appear to benefit most from the effects of HS. This potential LOS subgroup effect is mentioned in the most recent bronchiolitis Clinical Practice Guidelines endorsed by the American Academy of Pediatrics and published before the SR. [2] While we applaud the authors’ efforts to conduct several subgroup analyses, it would be of interest to perform an analysis based on 3 or more days LOS which may influence generalizability of the SR’s results. This analysis is particularly important to U.S. practitioners where the average LOS is shorter than many of the studies performed abroad and two U.S. clinical trials demonstrated no effect of HS on LOS, both with and without the use of concomitant bronchodilators [3][4]. This SR finds utility in HS treatment of acute bronchiolitis. We would challenge this broad conclusion for the majority of routine inpatient cases of bronchiolitis in the U.S. population until LOS subgroup analyses are performed.
Additionally, as the authors of one included trial in this SR, [3] (NCT 01488448), we are concerned about several inaccuracies with respect to our study. First, the SR excludes studies that included patients with previous wheeze, yet our study included those patients and was included in this review. Second, the SR performed a sensitivity analyses excluding trials with a high risk of attrition (defined as >20%), yet our study, with an attrition rate <20%, was excluded from this analysis. These data were available for our study on the Clinicaltrials.gov website before the SR’s submission. A third concern is that the authors compared the effect of HS in trials with and without available virological testing. As above, our study was included in the group without virological testing, yet our study was done with virological testing. We concede this was not part of the preliminary results on ClinicalTrials.gov, but we were not contacted by the authors to discuss these details which we would have happily clarified. These methodological inaccuracies which suggest a lack of SR precision with respect to our study raise concerns about misrepresentations of other included studies as well.
It is well-known that many clinicians look to SRs for an appraisal of available evidence and to make evidence-based practice decisions, so we recommend caution when interpreting the results and generalizability of this SR.
Sincerely,
Drs. Alyssa H Silver, Michael L Rinke and Katherine O’Connor
References
1. Zhang L, Mendoza-Sassi RA, Klassen TP, Wainwright C. Nebulized Hypertonic Saline for Acute Bronchiolitis: A Systematic Review. Pediatrics, 2015; 136(4):687-701.
2. Ralston SL, Lieberthal AS, Meissner HC, Alverson BK, et al. Clinical Practice Guideline: The Diagnosis, Management, and Prevention of Bronchiolitis. Pediatrics, 2014;134(5):e1474-e1502.
3. Silver AH, Esteban-Cruciani N, Azzarone G, Douglas LC, et al. 3% Hypertonic Saline versus Normal Saline in Inpatient Bronchiolitis: A Randomized Controlled Trial. Pediatrics. 2015. [In Press]
4. Wu S, Baker C, Lang ME, Schrager SM, et al. Nebulized hypertonic saline for bronchiolitis: a randomized clinical trial. JAMA Pediatr. 2014;168(7):657-63.
Re:Nebulized hypertonic solution in acute bronchiolitis: a descending parabola
We thank Cozzi G, et al for their comments on our paper. The review conclusion stating that "nebulized hypertonic solution is safe and potentially effective for children with acute bronchiolitis" was based on the data of all available randomized trials up to May 2015. A good safety profile of nebulized hypertonic saline (HS) has been reported by 21 trials with a total of 1557 infants receiving HS solution. Cozzi G et al cited one recently published trial (1) to support their "completely disagreement" with the review conclusion on the safety of nebulized HS. However, this trial reported only excessive rhinorrhoe and coughing related to nebulized HS and the authors stated that "exacerbation of rhinorrhoe and cough could be explained by physiological effects of HS and should not be considered a negative effect". In fact, coughing induced by nebulized HS has been postulated as one of the mechanisms by which HS could improve mucocillary clearance (2). As regard to the effects of HS on reduction of length of stay (LOS) among inpatients with bronchiolitis, we have called attention to the fact that all 8 trials published in 2013 and thereafter did not find significant benefits of HS. The subgroup analyses showed that diagnostic accuracy of bronchiolitis and the risk of selection bias might affect the effect size of nebulized HS. Cozzi G et al pointed out some methodological weakness of trials published before 2013, such as no uniform bronchiolitis definition, heterogeneity of interventions or clinical scoring and the inclusion of children older than 12 months. However, above-mentioned "methodological weakness" occurred also in the trials published after 2013. We classified the risk of selection bias of a large emergency department trial (3) as "unclear" but not "high" as Cozzi G et al described in the letter. Nebulized HS for infants with acute bronchiolitis remains an open topic of debate and further large multicenter trials are still warranted.
References
1. Flores P, Mendes AL, Neto AS. A randomized trial of nebulized 3% hypertonic saline with salbutamol in the treatment of acute bronchiolitis in hospitalized infants. Pediatr Pulmonol. 2015; Sep 3. doi: 10.1002/ppul.23306. [Epub ahead of print]. 2. Mandelberg A, Amirav I. Hypertonic saline or high volume normal saline for viral bronchiolitis: mechanisms and rationale. Pediatr Pulmonol. 2010;45(1):36-40. 3. Wu S, Baker C, Lang ME, et al. Nebulized hypertonic saline for bronchiolitis: a randomized clinical trial. JAMA Pediatr. 2014;168(7):657-663.
Conflict of Interest:
None declared
Nebulized hypertonic solution in acute bronchiolitis: a descending parabola
We read the paper by Zhang et al (Sept 2015) (1). We are very surprised by the Authors' conclusion stating that: "nebulized hypertonic solution is safe and potentially effective for children with acute bronchiolitis". Since 2013, all the published trials, without any exception, showed that treatment with nebulized hypertonic solution did not reduce the length of stay in hospital (LOS) of children with acute bronchiolitis (2,3). Trial published before 2013 were flawed by significant methodological weakness e.g. no uniform bronchiolitis definition, heterogeneity of interventions or clinical scoring and, above all, the inclusion of children older than 12 months (4). Nevertheless, considering all trials, the supposed reduction of the LOS is nearly of 11 hours only. Since 2013, only one trial, identified by the review's Authors as at high risk of patients' selection bias, showed a benefit of this treatment to reduce the risk of hospitalization of these children. Furthermore we completely disagree with the Authors' statement that treatment with nebulized hypertonic solution is safe and without any significant side effects. A recent trial highlights well that nebulized hypertonic solution may be very annoying for children with acute bronchiolitis (3) as already shown with epinephrine inhalation as well (5). The most recent and better methodologically designed trials do not support the use of nebulized hypertonic solution in children with acute bronchiolitis. We believe that available evidence does not allow to consider hypertonic solution potentially effective and well tolerated for acute bronchiolitis neither does justify its routinely use in clinical practice.
References
1) Zhang L, Mendoza-Sassi RA, Klassen TP, Wainwright C. Nebulized Hypertonic Saline for Acute Bronchiolitis: A Systematic Review. Pediatrics. 2015; 136: 687-701. 2) Legg JP, Cunningham S. Hypertonic saline for bronchiolitis: a case of less is more. Arch Dis Child. 2015 Jul 27. doi: 10.1136/archdischild-2014- 308039. [Epub ahead of print] 3) Flores P, Mendes AL, Neto AS. A randomized trial of nebulized 3% hypertonic saline with salbutamol in the treatment of acute bronchiolitis in hospitalized infants. Pediatr Pulmonol. 2015 Sep 3. doi: 10.1002/ppul.23306. [Epub ahead of print] 4) Barbi E, Neri E, Ventura A. Nomina sunt consequential rerum: time for a change in the definition of bronchiolitis? Arch Pediatr Adolesc Med. 2004; 158: 403. 5) Skjerven HO, Hunderi JO, Br?gmann-Pieper SK et al. Racemic adrenaline and inhalation strategies in acute bronchiolitis. N Engl J Med. 2013; 368: 2286-93.
Conflict of Interest:
None declared