EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNALEvid.-Based Child Health 5: 1276–1278 (2010)Published online in Wiley Online Library (onlinelibrary.wiley.com). DOI: 10.1002/ebch.577

Commentary

Commentaries on ‘Nebulized hypertonic saline solutionfor acute bronchiolitis in infants’Steve Cunningham1* and Brian A. Kuzik2* *1Department of Respiratory and Sleep Medicine, Royal Hospital for Sick Children, Edinburgh, UK.2Department of Paediatrics, Royal Victoria Hospital of Barrie, Ontario, Canada.

These are commentaries on a Cochrane review, published in this issue of EBCH, first published as:Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulized hypertonic saline solution for acutebronchiolitis in infants. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD006458.DOI: 10.1002/14 651 858.CD006458.pub2.

Further information for this Cochrane review is available in this issue of EBCH in the accompanying Summaryarticle.

Commentary by Steve Cunningham:Nebulized Hypertonic Saline Solution forAcute Bronchiolitis in Infants: What,Where, When and How?

Bronchiolitis of infancy is a common and miserabledisease with no effective treatment. When needed,supportive care in hospital is to help with feeding andsupplementing low arterial oxygen. Any therapeuticoption to improve the lot of infants with bronchiolitisis welcome.

The authors of this review have brought togetherthe current randomized experience with hypertonicsaline. Use of nebulized hypertonic saline in otherdiseases with mucus plugging (1) has been asso-ciated with clinically relevant improvements, so theapplication to acute bronchiolitis is appropriate toinvestigate.

The review concludes that pooled results compar-ing nebulized 3% hypertonic saline to 0.9% normalsaline identified an important and statistically signif-icant reduction in length of stay in hospital. Infantswent home almost 24 h earlier than their placebopeers. Earlier discharge could make family life easierand winter bed logistics more manageable. For thatreason we are recommended by the review authorsto use nebulized hypertonic saline for patients withbronchiolitis.

But, what, where, when and how hypertonic salineworks remain important questions with incompleteanswers.

*Correspondence to: Steve Cunningham,E-mail: Steve.Cunningham@luht.scot.nhs.uk**Correspondence to: Brian A. Kuzik,E-mail: briankuzik@hotmail.com

What is it to be given?

The review authors conclude that hypertonic salineshould be given together with bronchodilator. Why?Although stronger concentrations of hypertonic saline(i.e. 6–7%) used in cystic fibrosis (1) are regularlyassociated with bronchoconstriction, the frequencywith which 3% hypertonic saline induces bronchocon-striction is poorly described. There is good evidencefrom the review to assume it may not be unduly com-mon. In the study by Kuzik et al. (2), clinicians caringfor study infants were requested to use 3% hypertonicsaline without bronchodilator. Many did, but manyothers couldn’t resist adding bronchodilator; 34% ofnebulized 3% hypertonic saline doses were mixed withbronchodilator, 41% for placebo. As similar numbersof patients in active and placebo arms had bronchodila-tor added, and there were similar reported side effectsin both limbs of the study, possibly 3% hypertonicsaline is not an important cause of bronchoconstric-tion. In which case future trials should not burden chil-dren and staff with unnecessary medicines that maycause irritability and tachycardia. Another ‘What’ isstrength. The rationale for all current reported random-ized trials in bronchiolitis to choose 3% hypertonicsaline isn’t entirely clear; 6% has been the norm inother diseases reporting clinical effect (1). A betterrationale for 3% hypertonic saline or a factorial studydesign to incorporate differing saline strengths wouldhelp answer this question for infants with bronchiolitis.

Where is it to be given?

Outpatient or inpatients or both? Studies in the reviewhad limited overall power, even when combined,but the emergency department/out patient study wasparticularly limited by sample size. Reducing hospital

Copyright 2010 John Wiley & Sons, Ltd.

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admissions by the use of nebulized hypertonic salinein the emergency department and/or home nebulizationwould be a significant advance to disease managementand logistics. Adequately powered studies in bothclinical areas are required.

When is it to be given?

The range of dosing frequency in four studies fromtwo centres was large. Practicability would be impor-tant, but a rapid airway clearance approach (hourlyfor 4–6 h) vs steady clearance design (6–8 hourly)during in patient treatment would be good strategiesto explore. Another ‘when’ is when in the phase ofillness is hypertonic saline most effective; the earlyphase with relatively little mucus plugging in a pre-ventative fashion, or later in the disease to relieveplugging already present. In the paper by Mandel-berg (3), infants in the active 3% saline limb wereat a later stage in their illness at randomization (3.9vs 3.0 days), and this may have influenced responseto treatment (or possibly time to discharge irrespectiveof treatment).

How does it work?

If it works, does it really matter how? The answer ismore than just an academic ‘yes’. Whilst good theoret-ical reasons are provided for the effect of hypertonicsaline in the bronchiolitic airway, the very importantreductions in length of stay demonstrated by pooledresults (24.7%) are not adequately supported by clin-ical outcomes. In the single out-patient study (4),whilst large differences were seen in clinical scoresbetween the two groups, we are told this did not influ-ence admission to hospital (a major aim of the studybut not reported); it is not clear therefore what valueclinical scores have in identifying infants who requiresupportive care (feeding and/or supplemental oxygen).For the three in-patient studies, there was no clearpooled benefit to clinical scores (small improvementon day 2, but not day 1 or 3) and no effect on arte-rial oxygen saturation. Unfortunately, feeding support,despite being a major reason for hospital care, was notreported. So if infants are eligible to go home 24.7%earlier with nebulized hypertonic saline, then why? Weare aware that oxygen supplementation is the principalreason for prolonged hospital admission in the major-ity of infants with bronchiolitis (5), and so earlierdischarge without effect on arterial oxygen saturationrequires explanation.

Studies to date have been rather cluttered by theaddition of therapies with no proven benefit in bronchi-olitis. This review succinctly identifies the potentiallygenerous effect of this simple intervention, providingsupportive evidence for a pure and simple study ofnebulized hypertonic saline in infants with acute viralbronchiolitis, adhering to Consort standards for doubleblind randomized controlled trials.

Declaration of Interest

None.

References

1. Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP,Marks GB, et al. A controlled trial of long-term inhaled hypertonicsaline in patients with cystic fibrosis. N Engl J Med 2006; 354(3):229–240.

2. Kuzik BA, Al-Qadhi SA, Kent S, Flavin MP, Hopman W, Hotte S,et al. Nebulized hypertonic saline in the treatment of viralbronchiolitis in infants. J Pediatr 2007; 151(3): 70 e1 266–70.

3. Mandelberg A, Tal G, Witzling M, Someck E, Houri S, Balin A,et al. Nebulized 3% hypertonic saline solution treatment inhospitalized infants with viral bronchiolitis. Chest 2003; 123(2):481–487.

4. Sarrell EM, Tal G, Witzling M, Someck E, Houri S, Cohen HA,et al. Nebulized 3% hypertonic saline solution treatment inambulatory children with viral bronchiolitis decreases symptoms.Chest 2002; 122(6): 2015–2020.

5. Unger S, Cunningham S. Effect of oxygen supplementation onlength of stay for infants hospitalized with acute viral bronchiolitis.Pediatrics 2008; 121(3): 470–475.

Commentary by Brian A. Kuzik

Viral bronchiolitis is the most common reason for hos-pital admission of infants (1) and has been studiedextensively for decades. Despite this attention fromthe medical profession, it remains an enigma withouta universally accepted definition and without (perhapsuntil now) a confirmed effective therapy. Intuitively,the wheezing in these infants should respond well tobronchodilators, but doesn’t (2); the airway inflamma-tion should respond to steroids, but doesn’t (3), andthe airway plugging should respond to chest physio-therapy, but doesn’t (4) – and yet these discreditedtherapies continue to be commonly used (5) perhapsout of our need to ‘do something’.

This Cochrane Review by Zhang et al. provides anexcellent analysis of the small but growing literatureon a promising new therapy. The Review concludesthat the use of inhaled 3% hypertonic saline (HS) isassociated with a clinically relevant and statisticallysignificant decrease in length-of-stay in infants hos-pitalized with viral bronchiolitis. In outpatients, theuse of HS leads to significant improvement in clinicalscores but currently available studies have been under-powered to demonstrate an ability to reduce admis-sions. Although this is very welcome news for thosewho struggle with how to treat these very symptomaticinfants – it raises as many questions as it answers.

The extent to which the findings in this Review canbe generalized to all infants with bronchiolitis is ham-pered by the lack of a universally accepted definitionof this illness. Viral bronchiolitis has been describedas an episode of viral-induced wheezing restricted toinfants under the age of 6 months (6) or (as in thisReview) up to 1 or 2 years. Presumably to distinguish

Copyright 2010 John Wiley & Sons, Ltd. Evid.-Based Child Health 5: 1276–1278 (2010)DOI: 10.1002/ebch.577

1278 S. Cunningham

it from other wheezing phenotypes, most bronchioli-tis studies (including the ones in this Review) excludeinfants with a past history of wheezing whereas manyothers do not (2). There is no compelling evidence,however, to justify why treatment of the initial episodeof viral-induced wheezing should be distinguishedfrom subsequent episodes within the first 2 years oflife or indeed if it is practical or reliable to identify apast history of wheezing based on parental reporting.Recent authors have raised this point and simply referto wheezing in infancy according to its trigger (viral,allergic, or other) and likelihood to be the harbingerof future asthma with no special significance givento whether any episode is the first, second, etc. (7).In support of this, Mansbach et al. (8) in a largemulti-center study of infants under 24 months withbronchiolitis, revealed that a past history of wheez-ing did not affect the risk for admission. Furthermore,it seems that there now exists a debate as to whetheran infant with viral triggered wheezes and crackles isa separate entity from one who is only wheezing (9).Until further study clarifies these issues, we will con-tinue to face the dilemma of not knowing if the therapysupported in this Review is applicable to other infantswith a nearly identical clinical picture – but with theirsecond or third episode.

The authors correctly point out that comparing theseearly studies on inhaled 3% HS is compromised bysignificant variability in the doses used (ranging from4 ml every 2 h to 2 ml three times per day) as well asthe episodic co-administration of one of three differ-ent bronchodilators (salbutamol, epinephrine or terbu-taline) or none at all. In addition, the tonicity studied(3%) is much less than the 7% shown to safely andeffectively improve airway clearance in infants withcystic fibrosis (10). These are not insurmountableproblems, however, and future research will undoubt-edly clarify these points and thereby optimize therapy.In the meantime, this Review gives us encouragementthat we may be seeing a paradigm shift in the approachto treating this very common condition in infants.

Regrettably, medical advances are typically asso-ciated with significant increases in medication costs.

Treatment with HS, however, is likely to be much lessexpensive than any currently used or previously pro-moted medical options. It is therefore refreshing thatthis new treatment may be available to even less welldeveloped healthcare systems worldwide that, in thepast, had to watch from the sidelines as new (but moreexpensive) therapies were released. We are very grate-ful to the authors of this Review for helping us to findour way.

Declaration of Interest

Dr Kuzik was the lead author for a trial included inthe Cochrane systematic review.

References

1. Leader S, Kohlhase K. Recent trends in severe respiratorysyncytial virus among US infants, 1997–2000. J Pediatr 2003;143: S127–132.

2. Gadomski AM, Bhasale AL. Bronchodilators for bronchiolitis.Cochrane Database Syst Rev 2003; Issue 3.

3. Patel H, Platt R, Lozano JM, et al. Glucocorticoids for acute viralbronchiolitis in infants and young children. Cochrane DatabaseSyst Rev 2007; Issue 4.

4. Perrotta C, Ortiz Z, Roque Figulis M. Chest physiotherapy foracute bronchiolits in paediatric patients between 0 and 24 monthsold. Cochrane Database Syst Rev 2007; Issue 1.

5. Plint AC, Johnson DW, Wiebe N, et al. Practice variation amongpediatric emergency departments in the treatment of bronchiolitis.Acad Emerg Med 2004; 11: 353–360.

6. Ho L, Collis G, Landau LI, et al. Effect of salbutamol on oxygensaturation in bronchiolitis. Arch Dis Child 1991; 118: 1061–1064.

7. Brand PLP, Baraldi E, Bisgaard H, et al. Definition, assessmentand treatment of wheezing disorders in preschool children: anevidence-based approach. Eur Respir J 2008; 32: 1096–1110.

8. Mansbach JM, Clark S, Christopher NC, et al. Prospectivemulticenter study of bronchiolitis: Predicting safe discharges fromthe emergency department. Pediatr 2008; 121: 680–688.

9. Wainwright C. Acute viral bronchiolitis in children – a verycommon condition with few therapeutic options. Paed Resp Rev2010; 11: 39–45.

10. Subbarao P, Balkovec S, Solomon M, et al. Pilot study of safetyand tolerability of inhaled hypertonic saline in infants with cysticfibrosis. Ped Pulmonol 2007; 42: 471–476.

Copyright 2010 John Wiley & Sons, Ltd. Evid.-Based Child Health 5: 1276–1278 (2010)DOI: 10.1002/ebch.577