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NIHR Signal Inhaling a saline mist did not reduce the time in hospital for babies with bronchiolitis

Published on 28 October 2015

doi: 10.3310/signal-000139

In this NIHR-funded trial babies with a viral chest infection (acute bronchiolitis) were treated either with a strong saline mist (nebulised 3% hypertonic sodium chloride) with standard care or standard care alone. The stronger than usual, hypertonic saline mist had no effect on the time it took for babies to be ready for discharge, nor did the trial demonstrate any other benefit from its use. The treatment itself caused some minor side effects in a few babies, such as excessive coughing and a fall in blood oxygen levels. It was also not cost-effective at usual NHS thresholds. The results of the trial should be directly relevant to the UK context.

The authors also conducted their own systematic review, combining the results of 15 trials including their own trial. These combined results showed a small reduction in length of stay in hospital (just over 8 hours) and was in agreement with a 2013 Cochrane review of 11 trials that concluded hypertonic saline significantly reduced length of stay in hospital by just over a day. However the results of both reviews should be treated with caution.

The results are in line with 2015 NICE guidelines that say hypertonic saline should not be used in these babies.

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Why was this study needed?

Bronchiolitis is a common respiratory tract infection affecting about 1 in 3 babies. About 2% to 3% of these babies develop more severe symptoms, such as breathing difficulties, needing hospital treatment. The number of hospital admissions for bronchiolitis has been increasing over the last ten years, from 21,330 admissions in England in 2004 to 30,451 in 2011.

A 2013 Cochrane systematic review of 11 trials found that the use of nebulised hypertonic saline (3% sodium chloride), might significantly reduce the length of time spent in hospital with bronchiolitis compared with using nebulised normal saline (0.9% sodium chloride), but there has been doubt about the conclusion.

The NIHR funded this large randomised controlled trial (called SABRE) to find out whether treatment with nebulised hypertonic saline in addition to standard care would reduce the time babies with bronchiolitis needed to stay in hospital.

What did this study do?

This was a pragmatic randomised controlled trial including 317 babies admitted to ten UK hospitals with bronchiolitis. About half received standard care including treatment with oxygen. The other half received standard care plus treatment with 4ml nebulised 3% hypertonic saline every six hours. The final analysis included 290 children as 26 were ineligible and the notes of one child were lost. The primary outcome was the time until babies were assessed as being fit for discharge.

An economic evaluation and a systematic review of 15 trials including the SABRE trial were also conducted.

What did it find?

  • There was no difference between the two groups in the time to being declared fit for discharge (hazard ratio [HR] 0.95, 95% Confidence Interval [CI] 0.75 to 1.20). The average (median) time until a baby in the saline group was fit for discharge was 75.6 hours compared with 75.9 hours in the standard care group.
  • There was no difference for the secondary outcome of actual time to discharge (HR 0.97, 95% CI 0.76 to 1.23). The median time for the saline group to be discharged was 88.5 hours compared with 88.7 hours.
  • The systematic review found that hypertonic saline reduced the mean length of stay in hospital by about eight hours (difference 0.36 days, 95% CI 0.22 to 0.50 days). However, the results showed a wide variability in treatment effectiveness which means that the pooled estimate of effects should be treated with caution. The authors say that the estimate will not be a useful basis for decision-making.
  • The cost utility analysis found that nebulised saline was not cost-effective at usual thresholds. It included underlying costs and benefits that were themselves highly uncertain.

What does current guidance say on this issue?

The 2015 NICE guideline on bronchiolitis recommends that nebulised hypertonic saline should not be used to treat bronchiolitis in children. The guideline recommends giving oxygen supplementation.

What are the implications?

This trial provided strong evidence that using nebulised hypertonic saline added no benefit to standard care for the treatment of bronchiolitis in babies and was not cost-effective. This is in accordance with the 2015 NICE guideline.

The results of the SABRE study should be reliable and generalisable to the UK as it was conducted in ten UK hospitals, including both teaching and district general hospitals, with a typical spectrum of disease and standard treatments.

Citation

Everard ML, Hind D, Ugonna K, et al. Saline in Acute Bronchiolitis RCT and Economic evaluation: hypertonic saline in acute bronchiolitis - randomised controlled trial and systematic review. Health Technol Assess. 2015;19(66).

This project was funded by the National Institute for Health Research Health Technology Assessment (HTA) programme (project number 09/91/22).

Bibliography

Chen YJ, Lee WL, Wang CM, et al. Nebulized hypertonic saline treatment reduces both rate and duration of hospitalization for acute bronchiolitis in infants: an updated meta-analysis. Pediatr Neonatol. 2014 Dec;55(6):431-8.

Zhang L, Mendoza-Sassi RA, Wainwright C, et al. Nebulised hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2013;(7). Art. No.: CD006458.

NHS Choices. Bronchiolitis. London: Department of Health; 2013

NICE. Bronchiolitis in children. NG9. London: National Institute for Health and Care Excellence; 2015.

Why was this study needed?

Bronchiolitis is a common respiratory tract infection affecting about 1 in 3 babies. About 2% to 3% of these babies develop more severe symptoms, such as breathing difficulties, needing hospital treatment. The number of hospital admissions for bronchiolitis has been increasing over the last ten years, from 21,330 admissions in England in 2004 to 30,451 in 2011.

A 2013 Cochrane systematic review of 11 trials found that the use of nebulised hypertonic saline (3% sodium chloride), might significantly reduce the length of time spent in hospital with bronchiolitis compared with using nebulised normal saline (0.9% sodium chloride), but there has been doubt about the conclusion.

The NIHR funded this large randomised controlled trial (called SABRE) to find out whether treatment with nebulised hypertonic saline in addition to standard care would reduce the time babies with bronchiolitis needed to stay in hospital.

What did this study do?

This was a pragmatic randomised controlled trial including 317 babies admitted to ten UK hospitals with bronchiolitis. About half received standard care including treatment with oxygen. The other half received standard care plus treatment with 4ml nebulised 3% hypertonic saline every six hours. The final analysis included 290 children as 26 were ineligible and the notes of one child were lost. The primary outcome was the time until babies were assessed as being fit for discharge.

An economic evaluation and a systematic review of 15 trials including the SABRE trial were also conducted.

What did it find?

  • There was no difference between the two groups in the time to being declared fit for discharge (hazard ratio [HR] 0.95, 95% Confidence Interval [CI] 0.75 to 1.20). The average (median) time until a baby in the saline group was fit for discharge was 75.6 hours compared with 75.9 hours in the standard care group.
  • There was no difference for the secondary outcome of actual time to discharge (HR 0.97, 95% CI 0.76 to 1.23). The median time for the saline group to be discharged was 88.5 hours compared with 88.7 hours.
  • The systematic review found that hypertonic saline reduced the mean length of stay in hospital by about eight hours (difference 0.36 days, 95% CI 0.22 to 0.50 days). However, the results showed a wide variability in treatment effectiveness which means that the pooled estimate of effects should be treated with caution. The authors say that the estimate will not be a useful basis for decision-making.
  • The cost utility analysis found that nebulised saline was not cost-effective at usual thresholds. It included underlying costs and benefits that were themselves highly uncertain.

What does current guidance say on this issue?

The 2015 NICE guideline on bronchiolitis recommends that nebulised hypertonic saline should not be used to treat bronchiolitis in children. The guideline recommends giving oxygen supplementation.

What are the implications?

This trial provided strong evidence that using nebulised hypertonic saline added no benefit to standard care for the treatment of bronchiolitis in babies and was not cost-effective. This is in accordance with the 2015 NICE guideline.

The results of the SABRE study should be reliable and generalisable to the UK as it was conducted in ten UK hospitals, including both teaching and district general hospitals, with a typical spectrum of disease and standard treatments.

Citation

Everard ML, Hind D, Ugonna K, et al. Saline in Acute Bronchiolitis RCT and Economic evaluation: hypertonic saline in acute bronchiolitis - randomised controlled trial and systematic review. Health Technol Assess. 2015;19(66).

This project was funded by the National Institute for Health Research Health Technology Assessment (HTA) programme (project number 09/91/22).

Bibliography

Chen YJ, Lee WL, Wang CM, et al. Nebulized hypertonic saline treatment reduces both rate and duration of hospitalization for acute bronchiolitis in infants: an updated meta-analysis. Pediatr Neonatol. 2014 Dec;55(6):431-8.

Zhang L, Mendoza-Sassi RA, Wainwright C, et al. Nebulised hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2013;(7). Art. No.: CD006458.

NHS Choices. Bronchiolitis. London: Department of Health; 2013

NICE. Bronchiolitis in children. NG9. London: National Institute for Health and Care Excellence; 2015.

Saline in Acute Bronchiolitis RCT and Economic evaluation: hypertonic saline in acute bronchiolitis - randomised controlled trial and systematic review

Published on 22 August 2015

Everard, M. L.,Hind, D.,Ugonna, K.,Freeman, J.,Bradburn, M.,Dixon, S.,Maguire, C.,Cantrill, H.,Alexander, J.,Lenney, W.,McNamara, P.,Elphick, H.,Chetcuti, P. A.,Moya, E. F.,Powell, C.,Garside, J. P.,Chadha, L. K.,Kurian, M.,Lehal, R. S.,MacFarlane, P. I.,Cooper, C. L.,Cross, E.

Health Technol Assess Volume 19 , 2015

BACKGROUND: Acute bronchiolitis is the most common cause of hospitalisation in infancy. Supportive care and oxygen are the cornerstones of management. A Cochrane review concluded that the use of nebulised 3% hypertonic saline (HS) may significantly reduce the duration of hospitalisation. OBJECTIVE: To test the hypothesis that HS reduces the time to when infants were assessed as being fit for discharge, defined as in air with saturations of > 92% for 6 hours, by 25%. DESIGN: Parallel-group, pragmatic randomised controlled trial, cost-utility analysis and systematic review. SETTING: Ten UK hospitals. PARTICIPANTS: Infants with acute bronchiolitis requiring oxygen therapy were allocated within 4 hours of admission. INTERVENTIONS: Supportive care with oxygen as required, minimal handling and fluid administration as appropriate to the severity of the disease, 3% nebulised HS every +/- 6 hours. MAIN OUTCOME MEASURES: The trial primary outcome was time until the infant met objective discharge criteria. Secondary end points included time to discharge and adverse events. The costs analysed related to length of stay (LoS), readmissions, nebulised saline and other NHS resource use. Quality-adjusted life-years (QALYs) were estimated using an existing utility decrement derived for hospitalisation in children, together with the time spent in hospital in the trial. DATA SOURCES: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and other databases from inception or from 2010 onwards, searched ClinicalTrials.gov and other registries and hand-searched Chest, Paediatrics and Journal of Paediatrics to January 2015. REVIEW METHODS: We included randomised/quasi-randomised trials which compared HS versus saline (+/- adjunct treatment) or no treatment. We used a fixed-effects model to combine mean differences for LoS and assessed statistical heterogeneity using the I (2) statistic. RESULTS: The trial randomised 158 infants to HS (n = 141 analysed) and 159 to standard care (n = 149 analysed). There was no difference between the two arms in the time to being declared fit for discharge [median 76.6 vs. 75.9 hours, hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.75 to 1.20] or to actual discharge (median 88.5 vs. 88.7 hours, HR 0.97, 95% CI 0.76 to 1.23). There was no difference in adverse events. One infant developed bradycardia with desaturation associated with HS. Mean hospital costs were pound2595 and pound2727 for the control and intervention groups, respectively (p = 0.657). Incremental QALYs were 0.0000175 (p = 0.757). An incremental cost-effectiveness ratio of pound7.6M per QALY gained was not appreciably altered by sensitivity analyses. The systematic review comprised 15 trials (n = 1922) including our own. HS reduced the mean LoS by -0.36 days (95% CI -0.50 to -0.22 days). High levels of heterogeneity (I (2) = 78%) indicate that the result should be treated cautiously. CONCLUSIONS: In this trial, HS had no clinical benefit on LoS or readiness for discharge and was not a cost-effective treatment for acute bronchiolitis. Claims that HS achieves small reductions in LoS must be treated with scepticism. FUTURE WORK: Well-powered randomised controlled trials of high-flow oxygen are needed. STUDY REGISTRATION: This study is registered as NCT01469845 and CRD42014007569. FUNDING DETAILS: This project was funded by the NIHR Health Technology Assessment (HTA) programme and will be published in full in Health Technology Assessment; Vol. 19, No. 66. See the HTA programme website for further project information.

Bronchiolitis is a common lower respiratory tract infection that affects babies and young children under two years old. The majority of cases are caused by respiratory syncytial virus. Most children get better without treatment in about two weeks, but some develop more severe symptoms that require admission to hospital and supplementary oxygen treatment. Some children may have trouble feeding and they may need to be fed using a tube.

Expert commentary

Every winter, epidemics of acute bronchiolitis cause large numbers of infants (most previously healthy) to be admitted to hospital and even intensive care. Treatment hitherto has been supportive, until recent reviews (see Bibliography) suggested that nebulised 3% hypertonic saline would be beneficial. Since then, further large and important trials, reviewed here, have shown no benefit. 3% hypertonic saline is not indicated in acute bronchiolitis, and the Cochrane recommendations need to be updated to this effect. The present article should change the practice of giving 3% hypertonic saline to these babies.

Professor Andrew Bush

Professor of Paediatrics and Head of Section (Paediatrics), Imperial College, Professor of Paediatric Respirology, National Heart and Lung Institute, Consultant Paediatric Chest Physician, Royal Brompton & Harefield NHS Foundation Trust

Expert commentary

Clinicians should take on board the focussed message from this trial that hypertonic saline does not work in infants with acute bronchiolitis, either from a cost or health perspective. Managing a condition with no treatment is clinically frustrating and the temptation is always to try new therapies. This trial challenges clinicians to do nothing in preference to doing something that is ineffective. Watchful waiting requires clinical confidence and is not easy in those who are acutely unwell, but for infants with bronchiolitis leaving them to get better without disturbance seems to be the best thing.

Dr Steve Cunningham, Consultant & Honorary Reader in Paediatric Respiratory Medicine, Royal Hospital for Sick Children, Edinburgh