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Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review

)
Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2009, Issue 4 http://www.thecochranelibrary.com

Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 3% saline versus 0.9% saline, Outcome 1 Length of hospital stay (days). . . . . . . Analysis 1.2. Comparison 1 3% saline versus 0.9% saline, Outcome 2 Clinical severity score (post-treatment) at day 1. Analysis 1.3. Comparison 1 3% saline versus 0.9% saline, Outcome 3 Clinical severity score (post-treatment) at day 2. Analysis 1.4. Comparison 1 3% saline versus 0.9% saline, Outcome 4 Clinical severity score (post-treatment) at day 3. Analysis 1.5. Comparison 1 3% saline versus 0.9% saline, Outcome 5 Rate of hospitalization. . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 3 3 5 7 8 8 9 10 16 16 17 18 19 19 20 20 20 20 20 21 21

Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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We pooled the data from individual trials using the Cochrane statistical package Review Manager (RevMan). The effect of nebulized hypertonic saline in improving clinical score was greater among outpatients than inpatients. Federal University of Rio Grande. Nebulized hypertonic saline solution may reduce these pathological changes and decrease airway obstruction. University of Alberta. Raúl A Mendoza-Sassi2 .39. Patients treated with nebulized 3% saline had a significantly shorter mean length of hospital stay compared to those treated with nebulized 0. Copyright © 2009 The Cochrane Collaboration.12. 95% CI -1. Faculty of Medicine. Objectives To assess the effects of nebulized hypertonic saline solution in infants with acute viral bronchiolitis. MEDLINE (1966 to November 2007).40. Data collection and analysis Two review authors (ZL. Cochrane Database of Systematic Reviews 2008. Centro.br. Nebulized hypertonic saline solution for acute bronchiolitis in infants. No. 96201-900. Canada Contact address: Linjie Zhang. P = 0. Published by John Wiley & Sons. The 3% saline group also had a significantly lower post-inhalation clinical score than the 0. 95% CI -2. RS. Federal University of Rio Grande. Issue 4.[Intervention Review] Nebulized hypertonic saline solution for acute bronchiolitis in infants Linjie Zhang1 . No adverse events related to 3% saline inhalation were reported. Federal University of Rio Grande. Ltd. Art. 1 .1002/14651858. Rio Grande.pub2. Review content assessed as up-to-date: 12 November 2007. 2 Department of Internal Medicine. and LILACS (November 2007). P = 0.94 days. ABSTRACT Background Airway edema and mucus plugging are the predominant pathological features in infants with acute viral bronchiolitis. Editorial group: Cochrane Acute Respiratory Infections Group. Brazil.9% saline group in the first three days of treatment (day 1: MD -0. MRA) independently performed data extraction and study quality assessment. issue 4).com.0006).00. which contains the Cochrane Acute Respiratory Infections Group Specialized Register.: CD006458. day 3: MD -1. Main results We included four trials involving 254 infants with acute viral bronchiolitis (189 inpatients and 65 outpatients) in this review. 3 Department of Respiratory Medicine. Brazil. OLDMEDLINE (1951 to 1965). 4 Department of Pediatrics. Search strategy We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007. zhanglinjie63@yahoo. 95% CI -1.CD006458. Publication status and date: Edited (no change to conclusions). Wainwright C. EMBASE (1974 to November 2007).9% saline (mean difference (MD) -0. P = 0. Royal Children’s Hospital. Brazil.28. day 2: MD -1. Selection criteria Randomised controlled trials (RCTs) and quasi-RCTs using nebulized hypertonic saline alone or in conjunction with bronchodilators as an active intervention in infants up to 24 months of age with acute bronchiolitis. Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration.38 to -0. RS. published in Issue 4. Klassen TP. 95% CI -1.18. Rio Grande. Terry P Klassen4 1 Faculty of Medicine.57 to 0. 2009. Brisbane.05). Ltd. Mendoza-Sassi RA. Australia. Rio Grande.75.003.48 to -0.02. DOI: 10.97 to -0. P = 0. Published by John Wiley & Sons. Claire Wainwright3 . Citation: Zhang L. Rua Visconde Paranaguá 102. Edmonton.

influenza A and B. but the standard treatment remains supportive care. The combination of airway wall swelling. necrosis and desquamation of ciliated epithelial cells. but not among inpatients (Hartling 2006). a recent Cochrane review showed that nebulized epinephrine for acute bronchiolitis results in a modest short-term improvement in outpatients.There were no adverse effects noted with nebulized hypertonic saline when administered along with bronchodilators. the principal pathological findings include a peribronchial infiltrate of inflammatory cells. gas trapping. Rakshi 1994. fluid intake and feeding of the infant (Panitch 2003. This review was conducted to assess the effects of nebulized hypertonic saline. This drug is thought to exert its major effect by en2 Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. In acute bronchiolitis. Four randomized trials involving 254 infants were included. Other less common pathogens include parainfluenza viruses. Henderson 1979. There is a lack of convincing evidence for any other therapy. Klassen 1997b.Authors’ conclusions Current evidence suggests nebulized 3% saline may significantly reduce the length of hospital stay and improve the clinical severity score in infants with acute viral bronchiolitis. Ltd. However. Shay 1999). proliferation of cuboidal cells and excess mucus secretion (Panitch 1993. has also been tested in hospitalized infants with acute bronchiolitis ( Nasr 2001). In the last decade. human metapneumovirus and Mycoplasma pneumoniae (M. atelectasis and impaired gas exchange. mucosal and submucosal edema. Wohl 2003). Direct fluorescent antibody tests. Inhaled recombinant deoxyribonuclease (rhDNase). Despite the definition of bronchiolitis differing from country to country. any therapeutic modality which can reduce these pathological changes and improve the clearance of airway secretions may be beneficial. pneumoniae) (Garcia-Garcia 2006. PLAIN LANGUAGE SUMMARY Nebulized hypertonic saline solution for acute bronchiolitis in infants Acute viral bronchiolitis is the most common lower respiratory tract infection in infants. Published by John Wiley & Sons. starting as a viral upper respiratory infection (coryza. Description of the condition Acute bronchiolitis is the most frequent lower respiratory tract infection in infants (Klassen 1997a). increased mucus production and impaired secretion clearance eventually leads to airway obstruction. Rose 1987. rhinovirus. Epinephrine has a theoretical effect on acute bronchiolitis because it contains alpha adrenergic properties which lead to vasoconstriction and reduction of airway edema (Wohl 1978). around 40% to 50% develop involvement of the lower respiratory tract and 1% to 2% develop severe disease leading to hospitalization (Meissner 2003. Shay 2001). with the leading cause being the respiratory syncytial virus (RSV). Jacques 2006. adenovirus. Schuh 1992. enzyme immunoassay techniques and cultures of the nasopharyngeal aspirate may be used to identify the causative pathogen. which can increase clearance of mucus. Shay 1999). Most cases are viral in origin. an increasing trend in the rate of hospitalization of children with bronchiolitis has been observed in USA and Canada (Njoo 2001. As airway edema and mucus plugging are the predominant pathological features in acute bronchiolitis. a mucolytic agent. BACKGROUND olitis refers to the first episode of acute wheezing in children less than two years of age. cough or fever) (Panitch 1993). in these patients. Virtually all infants are infected by RSV by the age of two years. These criteria for diagnosis of acute bronchiolitis have also been widely used in clinical trials (Bertrand 2001. . Zhang 2003). Analysis of the pooled data suggests that nebulized 3% saline may significantly reduce the length of hospital stay and improve the clinical severity score in infants with acute viral bronchiolitis. Wainwright 2003. it is generally accepted that acute bronchi- Description of the intervention The standard treatment for acute bronchiolitis remains supportive care and includes ensuring adequate oxygen exchange. The diagnosis of acute bronchiolitis is usually based on clinical grounds. Wohl 1978). sloughing of necrotic debris.

Hypertonic saline has recently been trialed in patients with acute bronchiolitis (Kuzik 2007.9% saline. we added comparison of nebulized hypertonic saline alone versus nebulized 0.9% saline plus same bronchodilator • Nebulized hypertonic saline plus bronchodilator versus no intervention Given the very limited number of studies that were identified initially. thereby reducing the degree of cross-linking and entanglements and lowering the viscosity and elasticity of the mucus secretion (Ziment 1978). which can help to clear the sputum outside of the bronchi and thus improve airway obstruction (Mandelberg 2003). The above mentioned theoretical benefits provide the rationale for the treatment of acute bronchiolitis with nebulized hypertonic saline solution. Wark 2007). by absorbing water from the mucosa and submucosa. cystic fibrosis. Another widely used approach is chest physiotherapy. The establishment of a therapeutic role for hypertonic saline solution in acute bronchiolitis has relevant clinical implications. This modality may provide a cheap and effective therapy for children with acute bronchiolitis. Types of interventions • Nebulized hypertonic saline alone versus nebulized 0. Ltd. METHODS Criteria for considering studies for this review Types of studies We included randomized controlled trials (RCTs) and quasiRCTs (where there is alternate allocation to treatment and control groups) in this review.9% saline • Nebulized hypertonic saline plus bronchodilator versus nebulized 0. which is thought to assist infants by enhancing the clearance of secretions and reducing ventilatory effort. We excluded studies which included patients who had had recurrent wheezing or were intubated and ventilated. Moreover. rehydrating secretions and improving mucus rheology (Robinson 1997). Hypertonic saline was defined as a concentration of saline greater than or equal to 3%. Kellett 2005. oxygen requirements or improve the clinical severity score in infants with acute bronchiolitis (Perrotta 2006). bronchiectasis. 2) hypertonic saline induces an osmotic flow of water into the mucus layer.9% saline • Nebulized hypertonic saline plus bronchodilator versus nebulized 0. However. hypertonic saline solution can theoretically reduce edema of the airway wall in infants with acute bronchiolitis (Mandelberg 2003. Primary outcomes Length of hospital stay or time taken to be ready for discharge (inpatients). both in inpatients and outpatients. Shoseyov 1998. However. Sarrell 2002. We included studies of inpatients or outpatients. . Hypertonic saline inhalation can also cause sputum induction and cough. or fever). Mandelberg 2003. the current evidence concludes that chest physiotherapy using vibration and percussion techniques does not reduce the length of hospital stay. Types of outcome measures OBJECTIVES To assess the effects of nebulized hypertonic saline solution in infants with acute bronchiolitis. coryza. We excluded patients with recurrent wheezing. How the intervention might work Hypertonic saline solution has been shown to increase mucociliary clearance in normal subjects. Confirmation of viral etiology was not necessary for study inclusion. Sarrell 2002). Published by John Wiley & Sons. The postulated mechanisms of benefit are as follows: 1) hypertonic saline breaks the ionic bonds within the mucus gel. 3 Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. Types of participants Infants up to 24 months of age with the diagnosis of acute bronchiolitis. or rate of hospitalization (outpatients). Why it is important to do this review The hypothesis of this review is that nebulized hypertonic saline solution is beneficial in the management of acute bronchiolitis as assessed by clinically relevant outcomes. 3) hypertonic saline stimulates cilial beat via the release of prostaglandin E2 (Assouline 1977). Tal 2006). no significant effect was observed on clinical severity scores or on the length of hospital stay. and studies which assessed pulmonary function alone. Acute bronchiolitis was defined as the first episode of acute wheezing associated with clinical evidence of a viral infection (cough. and sinonasal diseases (Daviskas 1996.hancing airway secretion clearance. in asthma.

9% saline or nil • Outcomes: primary and secondary outcomes as described previously MEDLINE (OVID) 1 exp Bronchiolitis/ 2 bronchiolit$. and inclusion and exclusion criteria • Intervention: concentration of saline. Data extraction and management One review author (LZ) extracted study details from the included trials using a standardized data extraction form. 13 or/1-12 14 exp Saline Solution. and intention-totreat analysis • Participants: sample size.mp. RAM) independently assessed the titles and abstracts of all studies identified by the searches. These terms were adapted to search CENTRAL. EMBASE (1974 to November 2007). treatment duration.mp. 18 or/14-17 19 exp “Nebulizers and Vaporizers”/ 20 (nebulis$ or nebuliz$). Assessment of risk of bias in included studies Two review authors (LZ. volume of saline. We excluded articles that did not meet the inclusion criteria. OLDMEDLINE (1951 to 1965). 3 exp Respiratory Syncytial Viruses/ 4 exp Respiratory Syncytial Virus Infections/ 5 (respiratory syncytial vir$ or RSV). interval of administration. We entered the extracted data into RevMan 5 (RevMan 2008). vomiting.mp. We resolved any disagreements between the two review authors about study inclusion by discussion. MEDLINE (1966 to November 2007). Data collection and analysis Search methods for identification of studies Selection of studies Two review authors (LZ. proportion of follow up losses. and setting • Methods: method of allocation. age.mp. and cointerventions.Secondary outcomes • Clinical severity scores • Rate of re-admission to hospital • Haemoglobin saturation (oximetry) • Respiratory rate • Heart rate • Time for the resolution of symptoms/signs • Duration of in-hospital oxygen supplementation • Results of pulmonary function tests • Radiological findings • Adverse events (tachycardia. exclusion of participants after randomization. year. 6 exp Parainfluenza Virus 1. Human/ 12 (parainfluenza or adenovirus$ or influenza). .mp.mp.mp. Human/ 7 exp Parainfluenza Virus 2. Electronic searches We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007. We extracted the following data. which contains the Cochrane Acute Respiratory Infections Group Specialized Register. tremor. We noted the reasons for their exclusion (see ’Characteristics of excluded studies’ table). issue 4). 23 exp Aerosols/ 24 aerosol$. Published by John Wiley & Sons. hypertension. Inhalation/ 22 inhal$. nausea. Ltd. 16 exp Sodium Chloride/ 17 saline. We resolved any disagreements by discussion. and LILACS (November 2007). sex. blinding of participants and assessment of outcome. pallor. The following search terms were combined with the highly sensitive search strategy as recommended by the Cochrane Collaboration (Dickersin 1994) to search MEDLINE. Human/ 9 exp Respirovirus Infections/ 10 exp Adenoviridae Infections/ 11 exp Influenza. and acute urinary retention) 21 exp Administration. RAM) independently assessed the methodological quality of all included trials by using the five-point 4 Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. • Study characteristics: publication status.mp. country of study. • Control: nebulized 0. EMBASE and LILACS as required. Hypertonic/ 15 hypertonic saline. Human/ 8 exp Parainfluenza Virus 3. 25 or/19-24 26 13 and 18 and 25 27 from 26 keep 1-79 There were no language or publication restrictions. 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. These were checked by another review author (RAM).

scoring system proposed by Jadad (Jadad 1996). For inpatients. followed by every four hours for five doses. these were not undertaken because of the limited number of included trials. The duration of the treatment was five days for outpatients. in which ultrasonic nebulizers were utilized. Patients with a previous wheezing episode were excluded in all four trials. we identified seven papers as being potentially relevant. The mean age of participants varied from 2. 5 Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. The volume of saline for each inhalation was 4 ml in three trials (Kuzik 2007. This clinical score was initially described by Wang (Wang 1992). by attending physicians. blinding. . We calculated the Risk Ratio (RR) and 95% CI for one categorical outcome (rate of hospitalization). Tal 2006) and 2 ml in one trial (Sarrell 2002). Mandelberg 2003. which were reviewed in full text. double-blind. Virological investigation was available in all four trials and the positive rate for respiratory syncytial virus (RSV) varied from 69% to 87%. Four The concentration of hypertonic saline was defined at 3% in all four trials. The same clinical severity score was used by two trials as the secondary outcome measure. Mandelberg 2003. We used fixed-effect models for outcomes without heterogeneity and random-effects models for outcomes with heterogeneity. Inhaled therapies were delivered at eight-hour intervals in three trials (Mandelberg 2003.5 months (range: 10 days to 24 months). Included studies All four studies were randomized. This method evaluates the reported quality of randomization. albuterol was added in 37% of the treatments and racemic epinephrine was added in 23% of the treatments. However. We resolved any disagreements between the review authors by discussion. In one trial (Kuzik 2007) the study protocol did not require or encourage the co-administration of bronchodilators with the study solution. Interventions RESULTS Description of studies See: Characteristics of included studies.6 to 12. Tal 2006) used length of hospital stay as the primary outcome measure. Tal 2006). The criteria for diagnosis of viral bronchiolitis were clearly defined only by one trial (Kuzik 2007). parallel-group. Data synthesis We combined outcomes from individual trials using the Cochrane statistical package RevMan 5 (RevMan 2008). retraction. the treatment was delivered until discharge. Sensitivity analysis We planned sensitivity analyses and examination for publication bias. two used 1. Two numerical outcomes (length of hospital stay and clinical severity score) were suitable for meta-analysis. Oxygen-driven nebulizers were used for drug deliveries in all but one trial (Tal 2006). controlled trials.5 mg of epinephrine ( Mandelberg 2003. We performed subgroup analysis according to patient status (outpatient versus inpatient). Tal 2006). Bronchodilators were added to the study solution in three trials. the treatment was administered every two hours for three doses. grading respiratory rate. wheezing. and then every six hours. Tal 2006). Two review authors (LZ. In one trial (Kuzik 2007). We assessed homogeneity of effect size between the studies being pooled by visual inspection of graphical presentations and the I2 statistic (Higgins 2003 ). Ltd. However. Characteristics of excluded studies. The other three studies were conducted by the same group of investigators in Israel (Mandelberg 2003. Participants Outpatients were recruited in one trial (Sarrell 2002) and inpatients were recruited in the other three trials (Kuzik 2007. Outcome measures All three inpatient trials (Kuzik 2007. One study was a multi-center trial involving one hospital in the United Arab Emirates and two hospitals in Canada (Kuzik 2007). Sarrell 2002. RAM) also independently ranked quality of allocation concealment by using the Cochrane approach: Grade A: adequate concealment Grade B: uncertain Grade C: clearly inadequate concealment Assessment of heterogeneity Due to the small number of included studies the Chi2 test was not appropriate to detect heterogeneity. trials met all the criteria for study selection for this review (see ’ Characteristics of included studies’ table). and description of withdrawals and drop-outs. Tal 2006) and one used 5 mg of terbutaline (Sarrell 2002). Published by John Wiley & Sons. We calculated the mean difference (MD) and 95% confidence intervals (CI) to estimate the pooled treatment effect. Mandelberg 2003. Results of the search The search of electronic databases retrieved a total of 261 citations. Sarrell 2002. After reviewing the titles and abstracts.

4. None of the four trials had described allocation concealment. This trial failed to demonstrate the efficacy of nebulized 3% saline in reducing the risk of hospitalization (RR 0.28. Tal 2006) used clinical severity score as an outcome. P = 0. All three trials compared the post-inhalation clinical scores between infants treated with nebulized 3% saline and those treated with nebulized 0. the two inpatient trials (n = 71) (Mandelberg 2003.64 (95% CI -3. However. demonstrated a benefit of nebulized 3% saline in reducing the duration of hospitalization. Side effects associated with inhaled therapies were reported in all four trials.9% saline group.and general condition from 0 to 3.9% reduction from the mean length of hospital stay in the 0.38 to -0. Mandelberg 2003. Sarrell 2002. P = 0. Ltd. Tal 2006). Sarrell 2002) reported that pulse rate did not differ. the authors were requested to provide details regarding the method of randomization and they were judged as adequate. but statistically significant between the two groups among 89 inpatients (Mandelberg 2003. between the 3% saline group and the 0. P = 0.9% saline group.0001). 3. This represents a 25.06). The pooled results from these two trials demonstrate benefit of nebulized 3% saline in reducing the post-inhalation clinical score on the third day of treatment.12 to 3. one outpatient trial (n = 65) ( Sarrell 2002) showed a lower post-inhalation clinical score in the 3% saline group.0 (95% CI -2.18 (95% CI -1. One trial (Kuzik 2007) used analysis on an intention-to-treat basis. 2.48 (95% CI -1. Although one trial (Kuzik 2007) reported that five infants were withdrawn at the parents’ request 6 Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. P < 0.12.75 (95% CI -1. Adverse events No adverse events related to 3% saline inhalation were reported in any of the four trials. 95% CI -2. with a MD of -2.42 to -0. Two trials (Mandelberg 2003.43.85 to -1. the results are of borderline statistical significance (MD -1.0001). one outpatient trial (n = 65) (Sarrell 2002) showed that the 3% saline group had a statistically significant lower post-inhalation clinical score compared to the 0. For outpatients (Sarrell 2002) rate of hospitalization and clinical severity score were used as the outcome measures.69.28 (95% CI -1.92 to -0. with a MD of -1. In the other three trials ( Mandelberg 2003.9% saline on the first three days of treatment. with a total of 189 infants. P = 0. with a MD of -2. with increased severity receiving a higher score.13). 95% CI 0. The baseline clinical scores were comparable between the two groups in all three trials. Effects of interventions Four RCTs involving 254 infants with viral bronchiolitis (189 inpatients and 65 outpatients) compared nebulized 3% saline to nebulized 0. P = 0. P < 0. The pooled results from the three trials demonstrate a significantly lower post-inhalation clinical score favoring treatment with nebulized 3% saline over nebulized 0. However. Tal 2006). This difference represents a 20% reduction from the mean clinical score in the 0.003).9% saline group. Length of hospital stay All three inpatient trials (Kuzik 2007. with a MD of -0. Risk of bias in included studies The method of randomization was explicitly described and was adequate in one trial (Kuzik 2007). On the second day of treatment. Published by John Wiley & Sons.14. P = 0. The pooled results show that infants treated with nebulized 3% saline had a statistically significant shorter mean length of hospital stay compared to those treated with nebulized 0. one outpatient trial (n = 65) ( Sarrell 2002) showed a lower post-inhalation clinical score in the 3% saline group compared to the 0.9% saline on the first day of treatment. 95% CI -1. Tal 2006).48 to -0. the differences between the two groups did not reach statistical significance for 93 inpatients included in two trials (Mandelberg 2003. On the third day of treatment.00.9% saline group. Clinical severity score One outpatient (Sarrell 2002) and two inpatient trials ( Mandelberg 2003. P = 0.65). Tal 2006). .10 to 0.85 (95% CI -1.9% saline group. 1. However.02). On the first day of treatment. The Jadad score was five for all four trials. The methods for doubleblinding and the description of withdrawals/drop-outs were described and were appropriate in all four trials. with a MD of -0. allocation concealment was judged to be adequate in all four trials.0006).004). P < 0. The pooled results from these three trials demonstrate benefit of nebulized 3% saline in reducing the post-inhalation clinical score on the second day of treatment. One trial (Mandelberg 2003) did not find a significant difference between the two groups in terms of room air saturation of oxyhemoglobin throughout the study period.40.94 days (95% CI -1.92 to -1.97 to -0. This difference represents a 11.39.04.2% reduction from the mean clinical score in the 0. We obtained the original data on clinical severity score of these three trials from the trial authors.57 to 0. with a MD of -0.75.05).28. Rate of hospitalization One outpatient trial (n = 70) (Sarrell 2002) used the rate of hospitalization as an outcome.9% saline group.9% saline. with a MD of -0.08.9% saline.64. The difference was smaller.67. P = 0.42 to 0. with a MD of -1. Tal 2006) failed to show a statistically significant difference between the two groups in terms of post-inhalation clinical score (MD -0. on any day of the treatment. After assessing information provided on request by the trial authors.0001).

Published by John Wiley & Sons. between outpatients and inpatients. One two month old male infant was withdrawn because of vigorous crying during his third inhalation (3% saline alone) and again at his fifth inhalation (3% saline + racemic epinephrine). There are two clinical severity scoring systems more commonly used by randomized trials involving infants with viral bronchiolitis. Therefore. The pooled results from these three trials demonstrate that nebulized 3% saline could produce a reduction of 0. there was approximately a one-day reduction in the duration of hospitalization. In three trials (Mandelberg 2003. The other scoring system. The potential side effects.9% saline group. nebulized 3% saline produced a greater reduction in clinical severity score than nebulized 0. Given the high prevalence of viral bronchiolitis in infants and the tremendous burden of this illness related to hospitalization. . A greater severity of illness was postulated as the possible factor contributing to a smaller treatment effect size among inpatients with viral bronchiolitis. In contrast. the benefit of nebulized 3% saline in improving clinical score on the third day of treatment was of borderline statistical significance. the effect sizes of the treatment with 3% saline inhalation reported by three independent studies (Kuzik 2007. Ltd. providing a score ranging from 0 to 12. Given the possibility of acute bronchospasm induced by hypertonic saline in asthmatics and the difficulty in distinguishing between asthma and viral bronchiolitis in infants. this reduction may be considered clinically relevant and may potentially have a positive economic impact. Despite differences in inhalation mixture and delivery intervals across the studies. has recently been reported in another Cochrane review of 143 cystic fibrosis patients (Wark 2007). principally acute bronchospasm.because of perceived adverse effects of the therapy. Mandelberg 2003. assesses respiratory rate. the effect size of treatment with 3% saline inhalation was smaller among inpatients and the reduction in clinical score reached statistical significance only on the second day of treatment. Moreover. This represents a 25. it would seem reasonable to administer hypertonic saline in conjunction with bronchodilators to avoid any possible bronchoconstrictive effect. with a higher score indicating more severe respiratory distress (Lowell 1987). This study showed a 33% reduction in the risk of hospitalization among outpatients treated with 3% saline inhalation compared to those treated with 0. This review included 128 infants receiving 3% saline in repeated doses and no significant adverse events were reported. Sarrell 2002. In one trial (Kuzik 2007). with increased severity receiving a higher score (Wang 1992). However. The safety of nebulized hypertonic saline. the patients received hypertonic saline inhalation in conjunction with bronchodilators. but not on the first and the third days of treatment.9% saline on each of the first three days of treatment. In this review. Low statistical power due to a small sample size may have contributed to this negative result. even in higher concentration (5% to 7%). but bronchodilators were added into the study solution in 60% of the treatments by attending physicians. this review could not provide valid evidence regarding the safety of nebulized 3% saline alone in infants with viral bronchiolitis. remain a concern with nebulized hypertonic saline. this reduction was not statistically significant. The benefit of nebulized hypertonic saline in reducing the rate of hospitalization was assessed by one outpatient trial (Sarrell 2002). There were no other associated changes in respiratory status or clinical condition in these two infants and they were eventually discharged on day six and day two. The pooled results from these three trials (one outpatient and two inpatient) demonstrate a statistically significant lower mean postinhalation score among infants treated with 3% saline inhalation compared to those treated with 0.9% saline inhalation in the first two days of treatment. The magnitude of reduction in the severity score produced by 3% saline inhalation may be considered clinically relevant because it represents a reduction of up to 20% from the mean clinical score in the 0. retraction. However. Tal 2006). and general condition. DISCUSSION Summary of main results In this review. and provides a score ranging from 0 to 17. One is a Respiratory Distress Assessment Instrument (RDAI) which assesses chest retractions and auscultary findings. Clinical score is generally considered a relatively objective instrument to assess the severity of illness. wheezing.94 days in the mean length of hospital stay. only two of these infants were treated with 3% saline inhalation. initially described by Wang. three trials utilized the clinical severity score system proposed by Wang. Tal 2006) were similar.9% reduction from the mean length of hospitalization in the normal saline group. the study protocol defined the use of nebulized 3% saline alone. The other three month old female infant was withdrawn because of agitation after her second inhalation (3% saline + albuterol). 7 Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. which attributed the good safety profile of the therapy to the co-administration of hypertonic saline with bronchodilators. A less favorable treatment response among inpatients than among outpatients was also observed in another Cochrane review which evaluated the efficacy of nebulized epinephrine in infants with viral bronchiolitis (Hartling 2006). the subgroup analysis showed significant heterogeneity. regarding effect sizes of treatment with 3% saline inhalation. That is. Among outpatients. the length of hospital stay was defined as the primary outcome to measure the efficacy of nebulized hypertonic saline among inpatients with viral bronchiolitis. Low statistical power due to insufficient sample size may have contributed to this finding.9% saline inhalation. Further large RCTs are required to evaluate the efficacy of nebulized 3% saline in preventing hospitalization among outpatients with viral bronchiolitis.

Sarrell 2002. with Jadad scores of five. Further studies are required to compare the efficacy of nebulized hypertonic saline delivered by different nebulizers in infants with viral bronchiolitis. On the one hand. However. The optimal delivery intervals and concentration of saline. especially Liz Dooley. The mechanism of action of nebulized hypertonic saline in patients with viral bronchiolitis also needs to be addressed by further studies. three trials (Mandelberg 2003. Sree Nair and Meenu Singh. among infants hospitalized with viral bronchiolitis.9% reduction (0. Avigdor Mandelberg. and the most effective delivery devices remain to be determined. This review also might not have enough power to assess the efficacy of nebulized hypertonic saline in preventing hospitalization among outpatients with viral bronchiolitis. Tal 2006). which may affect their therapeutical efficacies. AUTHORS’ CONCLUSIONS Implications for practice Nebulized 3% saline produces a 25. for ongoing assistance. The delivery interval of nebulized hypertonic saline was eight hours in three trials (Mandelberg 2003. Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. Implications for research Further large RCTs. This analysis strategy aims to maintain the unbiased group comparison afforded by randomization and to deal with the problem of non-compliance and protocol deviation. Ltd. Given the clinically relevant benefit and good safety profile. nebulized 3% saline used in conjunction with bronchodilators should be considered an effective and safe treatment for infants with viral bronchiolitis. some methodological limitations should be taken into account in the interpretation of the results of this review. Federico Martinón Torres. Tal 2006) did not use analysis on an intention-to-treat basis. 8 . but more frequent deliveries were administrated in one trial (Kuzik 2007). the lack of application of an intention-to-treat principle was unlikely to cause significant bias. jet nebulizers generate aerosols with smaller aerodynamic mass median diameter which may more easily reach smaller bronchi and bronchioles. On the other hand. regarding effect sizes of treatment with 3% saline inhalation delivered at different intervals. Firstly. ultrasonic nebulizers induce sputum more efficiently than jet nebulizers. The authors wish to thank the following people for commenting on the draft review: Hayley Edmonds. Secondly. However.94 days) in the mean length of hospital stay. the optimal delivery intervals of nebulized hypertonic saline in infants with viral bronchiolitis still need to be established by further studies. As the number of patients withdrawn after randomization was small in these three trials. Sarrell 2002. However. Published by John Wiley & Sons. Thanks also to Libby Lissiman for assistance in the early stages of this review and to the Cochrane ARI Group. the sample size of this review was relatively small and the statistical power of the study might be sufficient for some but not for other outcome measures. Quality of the evidence All four included trials had high overall quality.The inhalation therapy was administrated via jet nebulizers in all but one trial (Tal 2006). principally to verify the benefit of this therapy in improving clinical score among inpatients and in reducing the risk of hospitalization among outpatients. This review could not provide direct evidence regarding the impact of the physical properties of aerosols generated by different types of nebulizers. on the reduction of length of hospital stay. are still required to evaluate the effectiveness of nebulized hypertonic saline in infants with viral bronchiolitis. there are some differences in the physical properties of aerosols produced by jet nebulizers and ultrasonic nebulizers. at least one trial (Tal 2006) demonstrated that both jet nebulizers and ultrasonic nebulizers are an efficient method of delivery of hypertonic saline in these patients. This therapy also significantly reduces clinical severity score. Theoretically. hypertonic saline in reducing the length of hospital stay but failed to demonstrate consistently the benefit of this therapy in improving the clinical severity score in the first three days of treatment. preferably multi-centered. No significant difference was observed between the studies. compared to nebulized normal saline. in which ultrasonic nebulizers were used. on the efficacy of inhaled hypertonic saline in infants with viral bonchiolitis. This limitation may explain why this review could confirm the efficacy of nebulized ACKNOWLEDGEMENTS Thanks to Ruth Foxlee and Sarah Thorning for help in defining the search strategy and in running the literature search. principally among outpatients with viral bronchiolitis. among inpatients with viral bronchiolitis.

Strouse PJ. Nebulized 3% saline effective for viral bronchiolitis. Witzling M. Wheezing in infants: the response to epinephrine.Assessing the quality of reports of randomized clinical trials: Is blinding necessary?. Klassen 1997b Klassen TP. Calvo C. Balin A. Cesar K. Houri S. Nasr 2001 Nasr SZ.123:481–7. McCarthy P. Tal G. Senior RJ. Acosta B. Measuring inconsistency in meta-analysis. Dickersin 1994 Dickersin K. Hypertonic saline/epinephrine treatment in hospitalized infants with viral bronchiolitis reduces hospitalization stay: 2 years experience. Pediatric Clinics of North America 1997. European Journal of Pharmacology 1977. Higgins 2003 Higgins JPT. Wiebe N. Epinephrine for bronchiolitis. E3016. 9 References to studies excluded from this review Amirav 2005 {published data only} Amirav I. Identifying relevant studies for systematic reviews.327:557–60. Guomo 2007 {published data only} Guomo R.41(9):863–71. Canciani M.Nebulized 3% hypertonic saline solution treatment in hospitalized infants with viral bronchiolitis. European Respiratory Journal 1996. Cossettini M. Recent advances in the treatment of bronchiolitis and laryngitis. [DOI: 10.120(1):203–8. Danon A. Controlled Clinical Trials 1996. Vol. Cohen HA. Jenkinson C. Garcia-Garcia 2006 Garcia-Garcia ML. Ltd. Efficacy of nebulized epinephrine versus salbutamol in hospitalized infants with bronchiolitis. Oron A. Journal of Pediatrics 1997. Cochrane Database of Systematic Reviews 2006.95: 183–90. et al. Sanchez I. Houri S.31(4):284–8.122:2015–20.Association of respiratory picornaviruses with acute bronchiolitis in French infants.Nebulized 3% hypertonic saline solution treatment in ambulatory children with viral bronchiolitis decreases symptoms. Stimulation of prostaglandin output from rat stomach by hypertonic solution. Daviskas 1996 Daviskas E. Collier AM. et al. Pediatrics 1987.25(4):463–6.44(1):249–61.Nebulized hypertonic saline in the treatment of viral bronchiolitis in infants. Bouscambert-Duchamp M. Efficacy of hypertonic saline solution in infants with acute bronchiolitis. Journal of Clinical Virology 2006. Someck E. Hartling 2006 Hartling L. The Israel Medical Association Journal 2006. Journal of Pediatrics 1979. Klassen TP. Hopman W. Houri S. Denny FW. Bertrand 2001 Bertrand P. Guerrera T. Journal of Pediatrics 2007. Ballin A.147(5):627–31. et al. Mandelberg 2003 {published data only} Mandelberg A.CD003123. 30. Pediatric Infectious Disease Journal 2003. Rubin BK. Kellett 2005 Kellett F.52(5):359–60. et al. Cesar K. controlled trial. Patel H.The etiologic and epidemiologic spectrum of bronchiolitis in pediatric practice. et al. Clyde WA Jr. Soskoline E. Maxvold NJ. Carquin J.9(4):725–32.99(1):27–31. Carroll D. Witzling M.. Watters LK. Chest 2003.309:1286–91. Tal G. Ballin A. Journal of Pediatrics 2005.8:169–73. Brodard V. Prevalence and clinical characteristics of human metapneumovirus infections in hospitalized infants in Spain. issue Suppl:51. Perez-Brena P. Meissner 2003 Meissner HC. Measuring inconsistency in metaanalysis. Al Qaghi SA. Russell K. Selected populations at increased risk from respiratory syncytial virus infection.151:266–70. Kent S. Sheaffer CI. Lina B. BMJ 1994. Wells GA. Reynolds DJ. Pediatric Pulmonology 2001. De Cea JM. Jadad 1996 Jadad A. Fasoli L. Additional references Assouline 1977 Assouline G. Moret H. Thompson SG. Castro E.Inhalation of hypertonic saline aerosol enhances mucociliary clearance in asthmatic and healthy subjects. Chest 2001. Redfern J. Lowell 1987 Lowell DI. Deeks JJ. Sarrell 2002 {published data only} Sarrell EM. Eberl S.130:191–6. Leibson V. Allen UD. Aranibar H. Meikle S. Issue 1. Tal G.Aerosol delivery in RSV bronchiolitis: hood or face-mask?. Niven RM.44:271–3. et al. Houri S. Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. Respiratory Medicine 2005.Efficacy of recombinant human deoxyribonuclease I in the hospital management of respiratory syncytial virus bronchiolitis. Saretta F. Tal 2006 {published data only} Tal G. Published by John Wiley & Sons. Mandelberg A.87:939–45. Casas I. Dexamethasone in salbutamol-treated in patients with acute bronchiolitis: a randomized. Sutcliffe T. Moore AR. Klassen 1997a Klassen TP. et al. Li MM.pub2] Henderson 1979 Henderson FW. Garver KA. Seale JP. et al. Tribastone 2003 {published data only} Tribastone AD. Scherer R. Evaluation of nebulised hypertonic saline (7%) as an adjunct to physiotherapy in patients with stable bronchiectasis.22(2 Suppl):S40–4. Von Kloss H. Chest 2002. Lister G. Altman DG. Someck E. Gonda I. Oron A. BMJ 2003. Jacques 2006 Jacques J. Hotte S.17:1–12. .REFERENCES References to studies included in this review Kuzik 2007 {published data only} Kuzik BA. European Respiratory Journal 2007. Anderson SD. Gavaghan DJ. Lefebvre C. et al. Flavin MP.1002/14651858. The Journal of Family Practice 2003. Pediatric Pulmonology 2006.

282(15):1440–6. Spika L. Wohl 2003 Wohl ME. Kovesi T. Zhang 2003 Zhang L. [DOI: 10. Davila NE. Bronchiolitis in children. Schidlow DV. American Review of Respiratory Diseases 1978. Thorax 1997. Nebulised hypertonic saline for cystic fibrosis. Johnson D. controlled trial of nebulized epinephrine in infants with acute bronchiolitis. ∗ Indicates the major publication for the study Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. Treatment with hypertonic saline versus normal saline nasal wash of pediatric chronic sinusitis. New England Journal of Medicine 2003. Faria CS. Published by John Wiley & Sons.A multicenter.118:759–81. Chest physiotherapy for acute bronchiolitis in paediatric patients between 0 and 24 months old. Respiratory disease in Canada. Chernick V. Schuh 1992 Schuh S. Jensen WA.90:920–3. Pediatric Infectious Disease Journal 2003. Holman RC. Cheney M. New England Journal of Medicine 2003. Journal of Infectious Diseases 2001. Journal of Allergy and Clinical Immunology 1998. Respiratory pharmacology and therapeutics. Ahoseyov N. 1978. Shai P. Holman RC. American Review of Respiratory Diseases 1992. Issue 4. Anderson LJ. et al. Liu LL. Wang 1992 Wang EE. Pediatrics 1992.22(Suppl):83–8. Archives of Disease in Childhood 1994. Milner RA. Hemming A. Navas L. Couriel JM. Callahan CW. 5.8:405–18. Price D. Health Canada and Statistics Canada 2001:65–87. Bibi H.CD004873. Bronchiolitis hospitalizations.101(5):602–5. Bailey D. 145(1):106–9. Hurvitz H. The Cochrane Collaboration. Observer agreement for respiratory signs and oximetry in infants hospitalized with lower respiratory infections. Shields M. Auler MI. Wainwright 2003 Wainwright C. [DOI: 10. double-blind.0.349:27–35. et al. Anderson LJ. Viral infection of the lower respiratory tract.pub2] Wohl 1978 Wohl MEB.71(5):463–9.Efficacy of adding nebulized ipratropium bromide to nebulized albuterol therapy in acute bronchiolitis. JAMA 1999. Management of acute bronchiolitis. Wark 2007 Wark PAB. Roosevelt GE. Copenhagan: The Nordic Cochrane Centre. Ltd. Clinical Chest Medicine 1987.1002/14651858. Rose 1987 Rose RM. et al. Roque M. Pelletier L. Panitch 1993 Panitch HB. The Cochrane Collaboration.39:548–51. Clinics in Chest Medicine 1993. Altamirano L. Pinkston P. O’Donnell C. Shoseyov 1998 Shoseyov D.Njoo 2001 Njoo H. Shay 1999 Shay DK. Wong A. Clarke MJ. et al. RevMan 2008 The Nordic Cochrane Centre. McDonald V. Review Manager (RevMan). Panitch 2003 Panitch HB. Shay 2001 Shay DK. Journal of Paediatrics and Child Health 2003. Cochrane Database of Systematic Reviews 2006.Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis. Bonfanti T.CD001506. 2008. Barber S. Ortiz Z.349:82–3. 10 . Philadelphia: WB Saunders. Maj H. Perrotta 2006 Perrotta C. Ziment 1978 Ziment I. Jones AP. Respiratory syncytial virus bronchiolitis: supportive care and therapies designed to overcome airway obstruction. Chernick VC. Issue 1. Shazberg G.Long and short-term effect of prednisolone in hospitalized infants with acute bronchiolitis. Newman RD. Stout JW. randomized. Bronchiolitis-associated mortality and estimates of respiratory syncitial virus-associated deaths among US children 1979-1997. Ottawa: Canadian Institute for Health Information. Treatment of acute bronchiolitis. Canny G. Reisman J. Regnis J. State of the art: bronchiolitis. 52(10):900–3. Bautotvich GJ. Cheney J. Robinson 1997 Robinson M.183:16–22.14(4):715–31.1002/14651858.pub3] Rakshi 1994 Rakshi K. Ferruzzi E. Cochrane Database of Systematic Reviews 2007.

or head box. 1 in United Arab Emirates and 2 in Canada Eligible: not stated Randomized: 47 HS group. 11 . Jadad score: 5 Participants Setting: inpatient wards of 3 regional tertiary care hospitals. double-blind. All inhaled therapies were delivered to a settled infant from a standard oxygen-driven hospital nebulizer through a tight-fitting face-mask. controlled trial Randomization: computer-based randomization program Blinding: double-blind Withdrawals/drop-outs: 2 patients from the hypertonic saline (HS) group and 3 from the normal saline (NS) group were withdrawn at parental request because of perceived adverse effects of therapy.7 months. which required a history of a preceding viral upper respiratory infection.CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID] Kuzik 2007 Methods Design: randomized. or premature birth (gestational age <= 34 weeks) Interventions Test group: nebulized 3% hypertonic saline (4 ml) Control group: nebulized 0. chronic cardiopulmonary disease or immunodeficiency. The treatment was given every 2 hours for 3 doses. parallel-group. range 10 days to 18 months Inclusion criteria: infants with diagnosis of moderately severe bronchiolitis. the presence of wheezing or crackles on chest auscultation. followed by every 6 hours until discharge. 49 NS group Completed: 45 HS group. 46 NS group Gender (male): 59% Age: mean age 4. followed by every 4 hours for 5 doses. Ltd. Published by John Wiley & Sons.9% normal saline (4 ml). whichever was better tolerated by the infant Outcomes Notes Risk of bias Length of hospital stay Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. the use of nebulized HS within the previous 12 hours. plus either an oxygen saturation of < 94% in room air or RDAI score of >= 4 Exclusion criteria: previous episode of wheezing. critical illness at presentation requiring admission to intensive care.

All inhaled treatments were delivered using a nebulizer (Aeromist Nebulizer Set 61400.9% saline group).5 to 12 months Inclusion criteria: infants with clinical presentation of viral bronchiolitis with temperatures > 38ºC that lead to hospitalization Exclusion criteria: cardiac disease. 27 NS group Gender (male): 57. B&F Medical by Allied.5 mg epinephrine. Toledo. OH) connected to a source of pressurized oxygen at a flow rate of 5 L/min Outcomes Length of hospital stay Change in clinical severity score Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. 30 (3% saline group) Completed: 25 HS group. controlled trial Randomization: randomization in blocks of 4. until the patient was ready for discharge. Published by John Wiley & Sons. Ltd. 8 because of parental refusal (3 from the 3% saline group and 5 from the 0.9% saline group) and 1 because of clinical deterioration (from the 0.5 mg epinephrinene Control group: nebulized 0. the Edith Wolfson Medical Center.9% saline group). previous wheezing episode.adequate Mandelberg 2003 Methods Design: randomized.7% Age: mean age 2. and/or progressive respiratory failure requiring mechanical ventilation Interventions Test group: nebulized 3% saline solution (4 ml) plus 1. chronic respiratory disease. The treatment was given 3 times/day at intervals of 8 hours. range 0.9% saline solution (4 ml) plus 1. using an online randomizer Blinding: double-blind Withdrawals/drop-outs: 9 patients were withdrawn.Kuzik 2007 (Continued) Item Allocation concealment? Authors’ judgement Yes Description A . obtunded consciousness. Jadad score: 5 Participants Setting: inpatient ward. 12 . oxygen saturation < 85% in room air.9 months. Israel Eligible: 61 Randomized: 31 (0. age > 12 months. double-blind. parallel-group.

using an online randomizer Blinding: double-blind Withdrawals/drop-outs: 5 patients were withdrawn. chronic respiratory disease. previous wheezing episode.Mandelberg 2003 (Continued) Others: pulse rate. and need for hospitalization Interventions Test group: nebulized 3% saline solution (2 ml) plus 5 mg (0. 13 .9% saline solution (2 ml) plus 5 mg (0. controlled trial Randomization: randomization in blocks of 4. and number of add-on treatments Notes Risk of bias Item Allocation concealment? Authors’ judgement Yes Description A .5 months.9% saline group). oxygen saturation < 96% on room air. and tremor Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. age >= 24 months. but the reasons were not stated Jadad score: 5 Participants Setting: The Pediatrics and Adolescent Ambulatory Community Clinic of General Health Services of Petach-Tikva. Ltd. Published by John Wiley & Sons. saturation on room air. parallel-group.5 ml) terbutaline. 33 (3% saline group) Gender (male): 59% Age: mean age 12.Adequate Sarrell 2002 Methods Design: randomized. The treatment was given 3 times/day at intervals of 8 hours for 5 days Outcomes Change in clinical severity score Hospitalization rate Others: radiograph assessment score. pulse rate. double-blind. radiograph assessment score. Israel Eligible: not stated Randomized: 70 Completed: 32 (0.5 ml) terbutaline Control group: nebulized 0. range 3 to 24 months Inclusion criteria: infants with clinical presentation of mild-to-moderate viral bronchiolitis Exclusion criteria: cardiac disease.

1 because of clinical deterioration and another because of parental refusal. 21 (3% saline group) Gender (male): 56. Published by John Wiley & Sons. Ltd. 14 . All inhaled treatments were delivered using an ultrasonic nebulizer (Omron UI. range 1 to 5 months Inclusion criteria: infants with clinical presentation of viral bronchiolitis that led to hospitalization Exclusion criteria: cardiac disease. using an online randomizer Blinding: double-blind Withdrawals/drop-outs: 2 patients from the 0.5 mg epinephrine.1% Age: mean age 2. oxygen saturation < 85% on room air. until the patient was ready for discharge. controlled trial Randomization: randomization in blocks of 4. OMRON Matsusaka Co. double-blind.6 months. the Wolfson Medical Center. age > 12 months. Japan) Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration.9% saline group).9% saline group were withdrawn.. parallel-group.9% saline group). 22 (3% saline group) Completed: 20 (0.9% saline solution (4 ml) plus 1. Jadad score: 5 Participants Setting: inpatient ward. obtunded consciousness. and/or progressive respiratory failure requiring mechanical ventilation Interventions Test group: nebulized 3% saline solution (4 ml) plus1. previous wheezing episode. Israel Eligible: unclear Randomized: 22 (0.Adequate Tal 2006 Methods Design: randomized. 1 patient from the 3% saline group was withdrawn because of protocol violation. The treatment was given 3 times/day at intervals of 8 hours. Ltd.5 mg epinephrinene Control group: nebulized 0. chronic respiratory disease.Sarrell 2002 (Continued) Notes Risk of bias Item Allocation concealment? Authors’ judgement Yes Description A .

Published by John Wiley & Sons. Ltd. 15 .Adequate HS = hypertonic saline NS = normal saline Characteristics of excluded studies [ordered by study ID] Amirav 2005 Guomo 2007 Tribastone 2003 Study of drug delivery (hood versus face-mask) Abstract only Summary of Sarrell 2002 Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration.Tal 2006 (Continued) Outcomes Length of hospital stay Change in clinical severity score Notes Risk of bias Item Allocation concealment? Authors’ judgement Yes Description A .

-0.1 % 31.64] -0.86.18 [-1. -0. -0. Random.DATA AND ANALYSES Comparison 1.92.13 ] -0.43] -0.42 (P = 0. Random. Fixed.00063) -4 -2 0 2 4 Favors 3% saline Favors 0.98).5 (1.90 [ -1.00 [ -1.Fixed. 0. Outcome 1 Length of hospital stay (days).38.95% CI Weight Mean Difference IV. of studies 3 3 1 2 3 1 2 3 1 2 1 No.28 [-1. 95% CI) Effect size -0.9) 3.03.9% saline N 25 20 49 Mean(SD) 4 (1. 0.2) 2. Random. 95% CI) Risk Ratio (M-H.4) 2. -0. Random. 3% saline versus 0.6 (1.88.97.48.64 [-3.9% saline Outcome or subgroup title 1 Length of hospital stay (days) 2 Clinical severity score (posttreatment) at day 1 2.28] Not estimable -2. Random.75 [-1.Fixed.6 (1.90 [ -1.42. Published by John Wiley & Sons.08 ] Total (95% CI) 95 94 100.0% Test for overall effect: Z = 3.9% saline Outcome: 1 Length of hospital stay (days) Study or subgroup 3% saline N Mean(SD) 3 (1.2 Inpatients 3 Clinical severity score (posttreatment) at day 2 3.67 [0. -1. 3. Random.1 Outpatients 4. Random.48.6 % 30. Random. 95% CI) Mean Difference (IV.92.1 Outpatients 3. 0.12. 95% CI) Mean Difference (IV.9% saline. df = 2 (P = 0.40] -0.00 [-2.85 [-1. 95% CI) Mean Difference (IV.0 % -0. 95% CI) Mean Difference (IV.3 % -1. Ltd.40 ] Heterogeneity: Chi2 = 0. 95% CI) Mean Difference (IV.87.42.2 Inpatients 5 Rate of hospitalization No.10. Review: Nebulized hypertonic saline solution for acute bronchiolitis in infants Comparison: 1 3% saline versus 0.1 Outpatients 2.75] Analysis 1.9) 0. 95% CI) Mean Difference (IV. -0.14] -1.12] -1.85. -1.5 (2.1.95% CI Mandelberg 2003 Tal 2006 Kuzik 2007 27 21 47 38.39] 0.08] -0. Fixed.94 [ -1. of participants 189 158 65 93 154 65 89 136 65 71 70 Statistical method Mean Difference (IV. I2 =0. -0.9% saline Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. Comparison 1 3% saline versus 0. 95% CI) Mean Difference (IV.06 ] -0. 95% CI) Mean Difference (IV.94 [-1. 0. 95% CI) Mean Difference (IV.9) Mean Difference IV.04] 0. Random. -0.7) 3.48 [-1. 16 .2 Inpatients 4 Clinical severity score (posttreatment) at day 3 4.69 [-1.

7 (1.Random.5 % -0. df = 2 (P = 0.64 (1. I2 =32% Test for overall effect: Z = 1.75 [ -1.10. Published by John Wiley & Sons. 0. Ltd. Outcome 2 Clinical severity score (post-treatment) at day 1.14 ] Heterogeneity: Tau2 = 0.Analysis 1.1) 25 20 7.5 % -1. I2 =59% Test for overall effect: Z = 2. Review: Nebulized hypertonic saline solution for acute bronchiolitis in infants Comparison: 1 3% saline versus 0.019) -10 -5 0 5 10 Favors 3% saline Favors 0.0 % 35.34 (P = 0. -0.5 % -0.5) 6. -0.9% saline Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration.49) 7 (1) 29.28 [ -1.0 % -0. -0.70 ] -0.9% saline N Mean(SD) Mean Difference IV. 17 . df = 1 (P = 0.95% CI 1 Outpatients Sarrell 2002 33 4.93. -0.92.5 % -1.48 [ -1.52 (P = 0.64 ] Subtotal (95% CI) Heterogeneity: not applicable 33 32 35.54) 35. Chi2 = 1.90 (P = 0.23).95% CI Weight Mean Difference IV.11 ] Subtotal (95% CI) 48 45 64.12 ] Heterogeneity: Tau2 = 0.Random.06.64 ] Test for overall effect: Z = 3.36 (1.000095) 2 Inpatients Mandelberg 2003 Tal 2006 27 21 7. Chi2 = 4.13) Total (95% CI) 81 77 100.92.92.9% saline.05) 32 5.46.08).38. 0.2.9% saline Outcome: 2 Clinical severity score (post-treatment) at day 1 Study or subgroup 3% saline N Mean(SD) 0. Comparison 1 3% saline versus 0.39.11 [ -0.81 (1.75 [ -1.28 [ -1.25 (1.18.

01.82.92.35 (1.62) 6.08 ] Subtotal (95% CI) Heterogeneity: not applicable 33 32 30.39 ] Heterogeneity: Tau2 = 0.31) 30. 0.53.06).30).18 [ -1. df = 2 (P = 0.2 % -0.0036) Total (95% CI) 77 77 100. -0.08 ] Test for overall effect: Z = 4.85 [ -1.000018) 2 Inpatients Mandelberg 2003 Tal 2006 24 20 6.00 [ -2. I2 =8% Test for overall effect: Z = 2.4) 5.36.9% saline Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration.9% saline.41 (1. Review: Nebulized hypertonic saline solution for acute bronchiolitis in infants Comparison: 1 3% saline versus 0.95% CI Weight Mean Difference IV.28 ] Heterogeneity: Tau2 = 0.10 [ -1.0 % -1. df = 1 (P = 0.77 (2.9% saline N Mean(SD) Mean Difference IV. Published by John Wiley & Sons.97.92.00 [ -2. 18 .0033) -10 -5 0 5 10 Favors 3% saline Favors 0. Comparison 1 3% saline versus 0.92 (1.Random.5 % -0. Outcome 3 Clinical severity score (post-treatment) at day 2.28 (P = 0. -0.42.3.45 (1) 32.51 [ -1.91 (P = 0. Chi2 = 5. I2 =64% Test for overall effect: Z = 2.3) 25 20 6. -1.08.8 % -2.7 % 36.34 ] -1. Chi2 = 1.3) 32 4. Ltd.9% saline Outcome: 3 Clinical severity score (post-treatment) at day 2 Study or subgroup 3% saline N Mean(SD) 0.Random.95% CI 1 Outpatients Sarrell 2002 33 2.8 % -2.Analysis 1.38 ] Subtotal (95% CI) 44 45 69.31. -1.93 (P = 0.77 (1. -0.

42. Outcome 5 Rate of hospitalization. df = 1 (P = 0.3 % -1.37.72 (1) 6.08 (2.86 (P = 0.01. Review: Nebulized hypertonic saline solution for acute bronchiolitis in infants Comparison: 1 3% saline versus 0.1 % 33. I2 =1% Test for overall effect: Z = 1.4 % -0.9% saline N Mean(SD) Mean Difference IV. 19 .27 [ -1.43 ] Test for overall effect: Z = 4.85.68) 14 23 5.Random.33.81 (1.95% CI Weight Mean Difference IV. Chi2 = 8.95% CI Sarrell 2002 2/35 100. Review: Nebulized hypertonic saline solution for acute bronchiolitis in infants Comparison: 1 3% saline versus 0.77 (2. Published by John Wiley & Sons.Analysis 1.85. Chi2 = 1.7 (1.9% saline.57) 31.28 (P = 0.9% saline Outcome: 4 Clinical severity score (post-treatment) at day 3 Study or subgroup 3% saline N Mean(SD) 0.04 ] Heterogeneity: Tau2 = 0. Outcome 4 Clinical severity score (post-treatment) at day 3.9% saline) Test for overall effect: Z = 0.46 (P = 0.75 ] Total (95% CI) Heterogeneity: not applicable 35 35 100.050) -10 -5 0 5 10 Favors 3% saline Favors 0. I2 =76% Test for overall effect: Z = 1.98.9% saline.9% saline Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. Ltd.000019) 2 Inpatients Tal 2006 Mandelberg 2003 13 21 4.9% saline n/N 3/35 Risk Ratio M-H.063) Total (95% CI) 67 69 100.4.00. 3.83 ] Subtotal (95% CI) 34 37 68. 3.95% CI Weight Risk Ratio M-H.Fixed. 0.Random.6 % -2.9% saline Outcome: 5 Rate of hospitalization Study or subgroup 3% saline n/N 0.4) 32 4.00 ] Heterogeneity: Tau2 = 0.02).05 ] -0.12. df = 2 (P = 0.9% saline Analysis 1.0 % -1. -0.Fixed.0 % 0.96 (P = 0.5) 5.12.03) 35. -1. Comparison 1 3% saline versus 0.41 (2.64 [ -3.28 [ -2.67 [ 0.67 [ 0.02 0.99.57. Comparison 1 3% saline versus 0. 3 (0.65) 0. 0.43 ] Subtotal (95% CI) Heterogeneity: not applicable 33 32 31.02 [ -1.6 % -2.64 [ -3.75 ] Total events: 2 (3% saline).0 % 0.1 1 10 50 Favors 3% saline Favors 0.95% CI 1 Outpatients Sarrell 2002 33 1. 0.32). -1.69 [ -1.5.

SOURCES OF SUPPORT Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. HISTORY Protocol first published: Issue 2. The final version of the review was approved by all authors. LZ and Raúl A Mendoza-Sassi (RAM) were responsible for study selection. 2008 13 May 2009 18 February 2008 13 November 2007 Amended Amended New search has been performed No changes . 20 . 2007 Review first published: Issue 4.republished to fix technical problem. 6 August 2009 Amended Contact details updated. data collection and data analysis. RAM. Published by John Wiley & Sons. Ltd.WHAT’S NEW Last assessed as up-to-date: 12 November 2007. Searches conducted. Claire Wainwright (CW) and Terry P Klassen (TPK) provided input for writing the protocol and review. Converted to new review format. CONTRIBUTIONS OF AUTHORS Linjie Zhang (LZ) conceived the idea and wrote the draft protocol and review. quality assessment. DECLARATIONS OF INTEREST None known.

Viral [∗ therapy]. Published by John Wiley & Sons. Infant Nebulized hypertonic saline solution for acute bronchiolitis in infants (Review) Copyright © 2009 The Cochrane Collaboration. Ltd. 21 .9% saline. Bronchiolitis.Internal sources • Departamento Materno-Infantil. Nebulizers and Vaporizers. Randomized Controlled Trials as Topic. External sources • No sources of support supplied DIFFERENCES BETWEEN PROTOCOL AND REVIEW Given the very limited number of studies that were identified initially. we added comparison of nebulized hypertonic saline alone versus nebulized 0. Bronchodilator Agents [administration & dosage]. INDEX TERMS Medical Subject Headings (MeSH) Acute Disease. We also clarified the population according to the age and changed the title to specify infants. Hypertonic saline was defined as a concentration of saline greater than or equal to 3%. Hypertonic [∗ administration & dosage] MeSH check words Humans. Saline Solution. Brazil. Universidade Federal do Rio Grande.

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