Pediatrics 2014 Jacobs e8 e13

DOI: 10.1542/peds.2013-1646; originally published online December 16, 2013; 2014;133;e8Pediatrics

Jonathan D. Jacobs, Megan Foster, Jim Wan and Jay Pershad7% Hypertonic Saline in Acute Bronchiolitis: A Randomized Controlled Trial

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7% Hypertonic Saline in Acute Bronchiolitis:A Randomized Controlled Trial

WHATS KNOWN ON THIS SUBJECT: Hypertonic saline (3% and5%), has been shown to improve clinical severity scores andreduce inpatient length of stay, and was associated with a trendtoward lower admission rate in acute bronchiolitis.

WHAT THIS STUDY ADDS: We are not aware of any previous datausing 7% hypertonic saline in bronchiolitis. Our results suggestthat 7% saline does not lower clinical severity of illness,admission rate, or length of stay, when compared with normalsaline.

abstractBACKGROUND: Research suggests that hypertonic saline (HS) mayimprove mucous ow in infants with acute bronchiolitis. Data suggesta trend favoring reduced length of hospital stay and improved pul-monary scores with increasing concentration of nebulized solution to3% and 5% saline as compared with 0.9% saline mixed with epineph-rine. To our knowledge, 7% HS has not been previously investigated.

METHODS: We conducted a prospective, double-blind, randomizedcontrolled trial in 101 infants presenting with moderate to severeacute bronchiolitis. Subjects received either 7% saline or 0.9%saline, both with epinephrine. Our primary outcome was a changein bronchiolitis severity score (BSS), obtained before and aftertreatment, and at the time of disposition from the emergencydepartment (ED). Secondary outcomes measured were hospitalizationrate, proportion of admitted patients discharged at 23 hours, and EDand inpatient length of stay.

RESULTS: At baseline, study groups were similar in demographic andclinical characteristics. The decrease in mean BSS was not statisticallysignicant between groups (2.6 vs 2.4 for HS and control groups, re-spectively). The difference between the groups in proportion of admittedpatients (42% in HS versus 49% in normal saline), ED or inpatient lengthof stay, and proportion of admitted patients discharged at 23 hours wasnot statistically signicant.

CONCLUSIONS: In moderate to severe acute bronchiolitis, inhalation of7% HS with epinephrine does not appear to confer any clinically sig-nicant decrease in BSS when compared with 0.9% saline with epi-nephrine. Pediatrics 2014;133:e8e13

AUTHORS: Jonathan D. Jacobs, MD,a,b Megan Foster,PharmD, BCPS,c Jim Wan, PhD,d and Jay Pershad, MD,MMMa

aDivision of Emergency Medicine, Department of Pediatrics, andDepartments of cPharmacy and dPreventive Medicine,Biostatistics and Epidemiology, University of Tennessee HealthScience Center, Memphis, Tennessee; and bDivision of EmergencyMedicine, Department of Pediatrics, Le Bonheur ChildrensHospital, Memphis, Tennessee

KEY WORDS7% hypertonic saline, acute bronchiolitis

ABBREVIATIONSBSSbronchiolitis severity scoreCIcondence intervalEDemergency departmentHShypertonic saline

Dr Jacobs designed the study and the data collectioninstruments, coordinated and supervised data collection, anddrafted the initial manuscript; Dr Foster assisted withrandomization and masking of study drug in pharmacy; Dr Wancarried out the initial analyses and reviewed and revised themanuscript; Dr Pershad conceptualized the study design andcritically reviewed the manuscript; and all authors approved thenal manuscript as submitted.

This trial has been registered at www.clinicaltrials.gov(identier NCT01871857).

www.pediatrics.org/cgi/doi/10.1542/peds.2013-1646

doi:10.1542/peds.2013-1646

Accepted for publication Sep 19, 2013

Address correspondence to Jay Pershad, MD, Division ofEmergency Medicine, Department of Pediatrics, Le BonheurChildrens Hospital, Memphis, TN 38103. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno nancial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicatedthey have no potential conicts of interest to disclose.

COMPANION PAPER: A companion to this article can be found onpage e213, online at www.pediatrics.org/cgi/doi/10.1542/peds.2013-3250.

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Acute viral bronchiolitis is the mostcommon lower respiratory infection ininfants and young children; the annualinpatient disease burden exceeds thecost of any respiratory disease in theUnited States among children youngerthan2 years (excludingneonatal care).1

From 1980 to 1996, the rate of hospi-talization for bronchiolitis increased inthe United States from 12.9 admissionsper 1000 children to 31.2 admissionsper 1000 children.2 However, a recenttrend among US children between 2000and 2009 suggests a signicant declinein bronchiolitis hospitalizations to 14.9per 1000 children. The use of mechan-ical ventilation and hospital chargesfor bronchiolitis signicantly increasedover this same period.3

Although several treatment strategieshave been investigated, few have beenshown to be effective. The mainstayof treatment remains supportive carewith supplemental oxygen and hydra-tion as needed. Routine use of corti-costeroids or bronchodilators is notrecommended.4 Similarly, in the 2006bronchiolitis guidelines published bythe American Academy of Pediatrics,routine use of bronchodilators is notrecommended, although a trial of bron-chodilators is listed as an option, basedon some evidence that epinephrine maybe more efcacious compared withsalbutamol and placebo in outpatients.5

However, conclusive evidence for ef-cacy of b2-agonist therapy is lacking.

Nebulized hypertonic saline (HS) hasshown promise as an alternative treat-ment option. It has been postulated thataerosolized HS hydrates the airwaysurface liquid, enhances mucociliaryclearance by improving mucus ow,reduces edema of the airway wall byabsorbing water from the mucosa andsubmucosa, and causes sputum in-ductionandcough,whichcanhelpclearsputum and improve small airway ob-struction in acute bronchiolitis.6

A 2008 Cochrane database systematicreview stated that nebulized 3% salinemay signicantly reduce the length ofhospital stay and improve the clinicalseverity score in infantswith acute viralbronchiolitis.7 Since this review, addi-tional studies have evaluated HS ininfants with bronchiolitis: 1 in an am-bulatory setting, 3 in an emergencydepartment (ED), and 5 in hospitalizedpatients.6,816 All of these studies haveshown a reduction in pulmonary se-verity scores and/or a trend towardreduced admission rates in the HSgroup. Of note, all investigations to datehave shown HS to be safe, with nopatients experiencing decreased oxy-gen saturation, apnea, or cyanosis af-ter administration of the medication.

We are unaware of any study examiningthe role of 7% HS in the ED setting fortreating bronchiolitis. Our primary hy-pothesis was that the higher concentra-tion of saline (7% HS) with epinephrineadministered in the ED would confer agreater and more sustained decreasein bronchiolitis severity score (BSS)for infants and young children withacute bronchiolitis and, secondarily,decrease hospitalization rate, increasethe discharge rate after a 23-hour in-patient hospital stay, and decreasehospital length of stay.

METHODS

Study Design

A double-blind, randomized, compara-tive, controlled trial was conducted inthe ED of an urban tertiary care center,with an annual census of 70 000 patientvisits. The institutional review boardapproved the study.

Patient Selection

Informed consent was obtained froma parent or legal guardian of each pa-tient enrolled in thestudy. Patientsage6weeks to#18months presenting to theED between October and March over a

2-year period (20102012) with bron-chiolitis (dened as viral respiratoryillness and rst episode of wheeze) anda BSS of$4 were eligible for the study.Exclusion criteria were a previoushistory of wheezing, any use of bron-chodilators within 2 hours of pre-sentation, gestational age #34 weeks,history of congenital heart disease orchronic pulmonary or chronic renaldisease, oxygen saturation of#85% atthe time of recruitment, severe diseaserequiring ICU admission, or inability toobtain informed consent. Depending onthe availability of the principal inves-tigator (a pediatric emergency medi-cine fellow), a convenience sample wasused to recruit patients. The ED physi-cians and staff were notied of thefellows hours of availability by way of acall schedule that was posted in the ED.

Study Protocol

Eligible patients were randomized to 1of 2 groups in blocks of 10. The controlgroup received an aerosol of 0.5 mL2.25% racemic epinephrine with 3 mL0.9% saline, and the study group re-ceived 0.5 mL 2.25% racemic epineph-rine with 3 mL 7% HS.

The treating clinician in the ED con-tacted the principal investigator whoenrolled theparticipantswithinanhourof an eligible patients arrival. Care-giver consent was obtained before ad-ministration of inhaled therapy. Thepharmacy department maintained a boxin the ED holding sequentially num-bered, previously randomized concealedenvelopes containing either the study(7%HS)orcontrol (0.9%saline)medication.After initial screening and assessmentand after consent was obtained, thepatientwas administered themedicationvia nebulization driven by 6 L per minuteO2 ow. Research personnel, includingthe investigators, the treating physician,and staff who performed the BSS werekept blinded throughout the process.

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BSSs were recorded before, immedi-ately after, and 4 hours after adminis-tering the aerosol. If the patient wasadmitted or discharged before 4 hours,the second posttreatment score wasrecorded at the time of disposition. Thetreating ED clinician determined thenal disposition of the patient.

If admitted, the patient continued toreceive aerosols containing the samedesignated medication every 6 hoursuntil discharge or 24 hours after theadmission. Disposition was ascertainedby reviewing the electronic medicalrecord for the time the order for dis-charge was written by the treatingclinician. Our protocol did not requireany specic criteria for discharge.

A standardized data sheet was com-pletedafterenrollmentandduringeachpatients stay in the ED or inpatientward. Any cointerventions, such as ad-ditional bronchodilators, supplementaloxygen, intravenous uids, or deep nasalsuction, were at the discretion of thetreating clinician. The clinician was freeto withdraw the patient from the studyif clinical deterioration warranted esca-lation of care or if adverse effects re-lated to the medication were observed.

Outcome Measures

The BSS is an objective respiratoryassessment tool that has been pre-viously validated (Table 1).17 We usedamodied BSS, which has been used inour institution since 2006, to assessseverity of illness in acute bronchiolitis(Table 2). A change in the modied BSSwas the primary outcome.

Before study enrollment, we assessedcorrelation between the modied BSSand the BSS published by Wang et al.17

We assumed that these 2 measures arehighly correlated, as high as correla-tion coefcient (r) = 0.85. The null hy-pothesis was that they were not ashighly correlated, and could be r #0.75. Assuming 5% signicance leveland 90% power, the estimated sample

size was 46 patients. The correlationbetween the BSS and the modied BSSwas high, with an r = 0.91 (P, .0001).

Secondaryoutcomemeasures includedhospitalization rate, discharge rate at23 hours (observation status), andlength of hospital stay.

Statistical Analysis

Using retrospective data from patientswith a diagnosis of acute bronchiolitiswho presented to our ED in 2010, wedetermined an SD of 3.4 in BSS. Thesample sizewas calculated on the basisof an anticipated difference in BSS of 2points between the study and controlgroups. Assuming a power of 80%, a of0.05, and a 2-tailed test, estimatedsample size was 47 patients per studygroup. Continuous variables were ex-amined by using Student t test. Di-chotomous variables were examinedby using the x2 or Fisher exact test.

RESULTS

Patient Characteristics

A total of 113 participants were ap-proached for consent. Of these, 101 pa-tientswere enrolled into the study, 52 inthe study group and 49 in the controlgroup (Fig 1). Failure to recruit resultedfrom either refusal to consent or be-cause the guardians primary languagewas other than English. The 2 groupswere similar in all clinical and histori-cal characteristics except that morepatients in the control group hada family history of atopic disease thandid those in the study group (67% vs

46%; Table 3). The difference in pro-portion of patients in the study andcontrol groups who received albuterol(13% vs 18%; P = .5) and/or supple-mental oxygen (12% vs 25%; P = .08) ascointerventions was not statisticallysignicant.

Clinical Outcomes

Although both groups demonstrateda decrease in BSS from baseline to EDdisposition, the difference in BSSs be-tween the 2 groupswas not statisticallysignicant. No difference emerged af-ter 24 hours of inpatient treatment(Table 4).

There was no difference in proportionof patients admitted from the ED, dis-charged at 23 hours after admission, orinpatient length of stay between the 2groups (Table 5). Neither group had anyadverse effects.

Interobserver variability was assessedby having 2 groups of nurses and re-spiratory therapists record a BSS ona sample of 20 patients with bron-chiolitis. The Cohen k statistic for levelof agreement was 0.94.

DISCUSSION

Inhaled 7% HSwith epinephrine was nobetter than normal saline with epi-nephrine in improvement of clinicalscore in patients with moderate to se-verebronchiolitis. Further, theredidnotappear to be a decrease in admissionrate, a lower discharge rate after 23hours observation, or decrease inhospital length of stay.

TABLE 1 BSS

Score 0 1 2 3

Respiratory rate,breaths/min

,30 3145 4660 .60

Wheezing None Terminal expiratory oronly with stethoscope

Entire expiration oraudible on expirationwithout stethoscope

Inspiration and expirationwithout stethoscope

Retraction None Intercostals only Tracheosternal Severe with nasal aringGeneral condition Normal Irritability, lethargy,

poor feeding


Our results are mixed when comparedwith other studies evaluating lowerconcentrations of nebulized HS to treatbronchiolitis. Most showed a reductionin either respiratory distress scoresor hospital length of stay in the HSgroup6,8,12,16; others failed to show anystatistical difference between the 2groups in terms of their primaryoutcomes.6,9,10,12,16 Two of these stud-ies, albeit underpowered, demon-strated a difference that favored HSbut did not reach statistical signi-cance.10,12 When limiting the compar-ison with studies initiated in the ED,Al-Ansari et al8 evaluated 5% HS andshowed a lower mean severity scoreat 48 hours compared with normalsaline (NS) (3.69 6 1.09 vs 4.12 6

1.11, P = .04; difference, 0.43; 95%condence interval [CI] for the dif-ference 0.02 to 0.88). In contrast,Grewal et al10 demonstrated no changein mean respiratory score from base-line to 120 minutes (study group 4.39versus control group 5.13; difference0.74; CI 1.45 to 2.93).

Our results seem to be consistent withprevious data on use of HS in patientswith cystic brosis.18 Studies of infantswith cystic brosis have shown that 7%HS is well tolerated and safe in this agegroup, although ineffective in reducingpulmonary exacerbations or improvinglung function.

Although higher concentrations of sa-line have shown promise in a dose re-sponsepattern for improvingmucociliary

clearance and maintaining lung func-tion in patients with cystic brosis, thesafety and efcacy of inhaled therapy inpatients younger than 6 years has beenestablished only with 7% HS.19 Hence,we elected to study the role of 7% HS inour trial.

The variable results from studies con-ducted in the ED and outpatient settingwith HS may be related to frequency ofadministration of the study drug andduration of therapy. We speculate thatthis may also explain the failure of ourstudy to demonstrate a difference frombaseline to ED disposition or after 24hours of inpatient treatment with 7%HS. This hypothesis is supported byinpatient studies that showed a de-crease in either severity scores and/orhospital length of stay when HS wasgiven more frequently from admissionuntil discharge.6,11,16 However, in bothinpatient and outpatient studies, animprovement in clinical scores was ob-served by study day 1.15,16,20 Moreover,because bronchiolitis tends to be a self-limiting illness, we felt that any im-provement noted after 24 hours ofsupportive care might reect the natu-ral course of disease. The challenge incomparing these trials with our resultsis the heterogeneity of study design,respiratory assessment tools, and fre-quency and duration of inhaled therapy.

Our study had several limitations. Weelected to evaluate change in bron-chiolitis score as our primary outcome.Asothers have suggested, it is unclear ifthis is a pertinent outcome in thecontext of a disease like viral bron-chiolitis.21 Although we also compared

TABLE 2 Modied BSS

0 Points 1 Point 2 Points 3 Points

Respiratory rate, breaths/minute ,40 4050 5060 . 60Breath sounds Clear End-expiratory wheeze/crackles Full expiratory wheeze/crackles Inspiratory/expiratory

wheeze/cracklesWork of breathing None/mild Subcostal, intercostal Subcostal, intercostal, supraclavicular GlobalOxygen saturation $95% on room air 92% to 94% on room air 90% to 95% on ,40% FIO2 , 90% on .40% FIO2Mental status Awake and alert Fussy but consolable Fussy and inconsolable Lethargic

FIO2, fraction of inspired oxygen.

FIGURE 1Encounter ow diagram.

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admission rate, discharge rate at 23hours, hospital length of stay, andsafety prole, our study was not pow-ered for these outcomes.

Thedecisiontodischargethepatientwasat the discretion of the treating clinician.Our protocol did not require that thepatientmeet specic discharge criterianordidwespecicallyaddressreadinessto discharge versus actual departuretime. This may have led to variability intiming of patient disposition.

It hasbeensuggested thatbycombiningHS with inhaled epinephrine, the pres-ence of a confounding bronchodilatormay have resulted in drug interactionthat couldmask the benets of HS.21 We

elected to include epinephrine becauseof its proven efcacy in acute bron-chiolitis and to mitigate against thetheoretical risk of exacerbating bron-chospasm with the higher concentra-tion of HS. Further, most of the previousstudies in bronchiolitis have used sim-ilar models, by using HS combined witha bronchodilator to demonstrate a clin-ical improvement.810,15,16,21 However,HS appears to be safe when used aloneto treat infants with bronchiolitis.11,12,22

Another limitation is that the modiedBSS is not widely used and has not beenexternally validated.8 However, it hasbeen an established respiratory as-sessment tool in our institution for

more than 7 years and incorporates allthe major criteria used by other scor-ing systems for bronchiolitis, includingoxygen saturation. Further, it demon-strated good interobserver agreementand was highly correlated with the BSSpreviously published.

Although we intended to recruit infantswith severe bronchiolitis, our study pop-ulationprimarily included childrenwithmoderate disease. Hence, our studycannot exclude potential benet of in-haled 7% HS in infants with severe ill-ness. We also did not specify previouscorticosteroid use as an exclusion cri-terion. Because corticosteroids havenot been shown to be benecial inbronchiolitis, and because patients withasthma or recurrent wheezing (a sub-group that may benet from steroids)weresystematically excluded,wedonotbelieve that this was a signicant con-founder. Of note, none of the partic-ipants inour studyhad received inhaledor oral corticosteroids.

Although informed consent was ob-tained before administration of inhaledtherapy, we were unable to providecomparative information on time fromadmission to enrollment. Finally, al-though randomization ensured that the2 groups were similar, because a con-venience sample was assessed, wecannot exclude enrollment bias.

CONCLUSIONS

Our study demonstrated no addi-tional clinical benet from inhaled 7%HS with epinephrine when comparedwith normal saline with epinephrine.Although 7% HS appears safe, future,larger studies should focus on the safetyand efcacy of HS when adminis-tered alone versus when combinedwith epinephrine.

TABLE 3 Baseline Patient Characteristics

HS, n = 52 Normal Saline, n = 49

Age, mo, mean 6 SD 6.0 6 3.9 5.6 6 3.3Gender, male 36/52 (69%) 28/49 (57%)Weight, kg, mean 6 SD 7.5 6 2.1 7.4 6 2.0Duration of symptoms, d, mean 6 SD 3.4 6 1.7 3.4 6 1.6RSV positive 26/38 (68%) 15/30 (50%)Baseline BSS score, mean 6 SD 5.8 6 1.5 5.7 6 1.8Albuterol use 7/52 (13%) 9/49 (18%)Supplemental oxygen 6/52 (12%) 12/48 (25%)Family history of atopy 24/52 (46%) 33/49 (67%)Eczema 13/52 (25%) 13/49 (27%)

RSV, respiratory syncytial virus.

TABLE 4 Primary Outcomes

HS, 7% Normal Saline, 0.9% Difference, P Value (95% CI)

Change in BSS at ED disposition(mean 6 SD)

2.6 6 1.9 2.4 6 2.3 0.21,P = .61 (0.61 to 1.03)

Change in BSS after rstnebulized treatment in EDdisposition (mean6 SD)

2.06 6 1.7 2.0 6 1.9 0.06,P = .87 (0.67 to 0.78)

Change in BSS for admitted patientsat 24 h (mean6 SD)

3.1 6 2.5 3.7 6 1.9 20.6,P = .37 (2.0 to 0.78)

TABLE 5 Secondary Outcomes

HS, n = 52 Normal Saline, n = 49 P Value (95% CI)

Length of stay in ED, h, mean 6 SD 4.1 6 0.9 3.9 6 4.0 .8Proportion of patients admitted 22/52 (42%) 24/49 (49%) OR = 0.76 (0.351.7)Proportion of patients discharged at 24 h 3/21 (14%) 3/23 (13%) OR = 1.1 (0.26.2)

OR, odds ratio.


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DOI: 10.1542/peds.2013-1646; originally published online December 16, 2013; 2014;133;e8Pediatrics

Jonathan D. Jacobs, Megan Foster, Jim Wan and Jay Pershad7% Hypertonic Saline in Acute Bronchiolitis: A Randomized Controlled Trial

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