Nej Mo a 1301839

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original article

T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

n engl j med 368;24 nejm.org june 13, 20132286

Racemic Adrenaline and Inhalation

Strategies in Acute BronchiolitisHvard Ove Skjerven, M.D., Jon Olav Gjengst Hunderi, M.D.,

Sabine Kristin Brgmann-Pieper, M.D., Anne Charlotte Brun, M.D.,Hanne Engen, M.D., Leif Eskedal, M.D., Ph.D., Marius Haavaldsen, M.D.,

Bente Kvenshagen, M.D., Ph.D., Jon Lunde, M.D., Leif Bjarte Rolfsjord, M.D.,Christian Siva, M.D., Truls Vikin, M.D., Petter Mowinckel, M.Sc.,

Kai-Hkon Carlsen, M.D., Ph.D., and Karin C. Ldrup Carlsen, M.D., Ph.D.

From the Department of Pediatrics, OsloUniversity Hospital (H.O.S., J.O.G.H.,P.M., K.-H.C., K.C.L.C.), and the Instituteof Clinical Medicine, University of Oslo(H.O.S., K.-H.C., K.C.L.C.), Oslo; the De-partment of Pediatrics, stfold HospitalTrust, Fredrikstad, stfold (J.O.G.H.,M.H., B.K., J.L.); the Department of Pedi-atrics, Vestre Viken Hospital Trust, Dram-men, Buskerud (S.K.B.-P.); the Departmentof Pediatrics, Vestfold Hospital Trust,Tnsberg, Vestfold (A.C.B., C.S.); the De-partment of Pediatrics, Telemark HospitalTrust, Skien, Telemark (H.E.); the Depart-ment of Pediatrics, Srlandet Hospital

Trust, Kristiansand, Vest-Agder (L.E.);and the Department of Pediatrics, Inn-landet Hospital Trust, Elverum, Hedmark(L.B.R.), and Lillehammer, Oppland (T.V.) all in Norway. Address reprint requeststo Dr. Skjerven at Oslo University Hospi-tal, Department of Pediatrics, Ullevl,Postboks 4956 Nydalen, 0424 Oslo, Nor-way, or at [email protected].

N Engl J Med 2013;368:2286-93.DOI: 10.1056/NEJMoa1301839

Copyright 2013 Massachusetts Medical Society.

A b s t r a c t

Background

Acute bronchiolitis in infants frequently results in hospitalization, but there is noestablished consensus on inhalation therapy either the type of medication or thefrequency of administration that may be of value. We aimed to assess the effec-tiveness of inhaled racemic adrenaline as compared with inhaled saline and thestrategy for frequency of inhalation (on demand vs. fixed schedule) in infants hos-pitalized with acute bronchiolitis.

Methods

In this eight-center, randomized, double-blind trial with a 2-by-2 factorial design, we compared inhaled racemic adrenaline with inhaled saline and on-demand inha-lation with f ixed-schedule inhalation (up to every 2 hours) in infants (0.1 for all comparisons). On-demand inhalation, as com-pared with fixed-schedule inhalation, was associated with a significantly shorter esti-

mated mean length of stay 47.6 hours (95% confidence interval [CI], 30.6 to 64.6) versus 61.3 hours (95% CI, 45.4 to 77.2; P = 0.01) as well as less use of oxygen supple-mentation (in 38.3% of infants vs. 48.7%, P = 0.04), less use of ventilatory support (in4.0% vs. 10.8%, P = 0.01), and fewer inhalation treatments (12.0 vs. 17.0, P

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Racemic Adrenaline and Inhal ation in Bronchiolitis

n engl j med 368;24 nejm.org june 13, 2013 2287

Acute bronchiolitis in infants, which frequently leads to hospitalization 1,2 and sometimes requires ventilatory sup-port, is occasionally fatal 3 ; it is usually viral inorigin, with respiratory syncytial virus 4 being themost common cause. The clinical disease is char-acterized by nasal flaring, tachypnea, dyspnea,chest retractions, crepitations, and wheezing. 5

Bronchodilators are not recommended 6,7 butare often used in the treatment of bronchio-litis, 8-10 as are saline inhalations. Adrenaline re-duces mucosal swelling, 11 giving it an edge overthe 2 -adrenergic agonists, 12 and has led to thefrequent use of inhaled adrenaline, 13 which hasimproved symptoms 12,14-20 and reduced the needfor hospitalization in outpatients with acutebronchiolitis. 12 Among inpatients, however, in-haled adrenaline has not been found to reducethe length of the hospital stay. 12,20-22 Assessmentof the possible influences of age, sex, and status

with respect to an asthma predisposition 23 onthe effect of inhaled adrenaline requires largemulticenter studies. 12,24

Inhaled nebulized solutions can be prescribedfor use on demand or on a fixed schedule. We

were unable to find documentation on the com-parative efficacy of these two strategies in chil-dren with acute bronchiolitis.

We tested the hypothesis that inhaled racemicadrenaline is superior to inhaled saline in thetreatment of acute bronchiolitis in infancy andthat administration on a fixed schedule is supe-rior to administration on demand. We also as-sessed whether age, sex, or status with respect toallergic diseases influenced treatment efficacy.

Methods

Study Design

This multicenter, double-blind, randomized clin-ical trial (the Bronchiolitis All-study, SE-Norway)included infants with acute bronchiolitis who were

admitted to the pediatric departments of eighthospitals in southeastern Norway from January2010 through May 2011. In accordance with a2-by-2 factorial design, children were randomlyassigned to receive inhaled racemic adrenaline orinhaled saline and to receive the assigned treat-ment on demand or on a fixed schedule (Fig. 1).

The study was approved by the Regional Com-mittees for Medical and Health Research Ethicsand by the Norwegian Medicines Agency and isregistered in the Norwegian Biobank Registry.

Written informed consent was obtained from aparent of each child before the start of therapy.The study was audited by the Norwegian Medi-cines Agency in 2011. All authors vouch for theaccuracy and completeness of the reported dataand for the fidelity of the report to the studyprotocol (available with the full text of this ar-ticle at NEJM.org).

The inclusion criteria were clinical signs ofbronchiolitis as defined by Court 5 (see the Sup-plementary Appendix, available at NEJM.org), anage of less than 12 months, and an overallclinical score of at least 4 on a scale of 0 to 10.The clinical score was the sum of points allotted,from 0 (indicating normal findings) to 2 (indi-cating severe illness), for each of the following:general condition, skin color, findings on aus-cultation, respiratory rate, and retractions 15 ,25 (Table S1 in the Supplementary Appendix). Thestudy physicians performing the clinical scoring

were trained at investigator meetings as well ason site by the first author and by local primaryinvestigators. The exclusion criteria were the pres-ence of any serious cardiac, immunologic, neuro-logic, or oncologic disease or any serious pulmo-nary disease other than bronchiolitis; more thanone previous episode of obstructive airway dis-ease; symptoms of disease of the lower airway(e.g., coughing) for more than 4 weeks; and re-ceipt of any glucocorticoid therapy in the preced-ing 4 weeks.

Children were enrolled in the study on admis-sion to the hospital as long as attending person-nel (a physician and a nurse) were available. Clini-cal scoring was performed by a pediatrician.After written informed consent was obtainedfrom a parent, children underwent randomiza-tion, and the assigned study medication wasadministered. The baseline characteristics of thechildren were obtained on admission, and theassessment included a pediatrician-guided, struc-tured interview of one or both parents. Viral

analyses of nasopharyngeal aspirates were per-formed at the largest hospital involved in thestudy (Oslo University Hospital) with the use ofa polymerase-chain-reaction assay for nine com-mon airway viruses. (See the SupplementaryAppendix for further information on the biologicspecimens gathered.)

Randomization was performed centrally inblocks of eight, with assignment to one of thefour study groups, with the use of SAS software,

version 9.3. The randomization codes were com-

The New England Journal of MedicineDownloaded from nejm.org on November 2, 2013. For personal use only. No other uses without permission.

Copyright 2013 Massachusetts Medical Society. All rights reserved.

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municated directly by the study statistician to thepharmacy, where doses of the two study medica-

tions (10 ml of racemic adrenaline dissolved in0.9% saline to form a solution of 20 mg per mil-liliter or 0.9% saline alone) were prepared inidentical bottles, each labeled with a numericalcode indicating the type of medication and tim-ing of administration (on demand or fixedschedule). The study centers, which were notaware of the randomization block size, wereprovided with a list of study numbers for use inthe consecutive assignment of medication to en-rolled children.

The dose administered was based on the in-fants weight: 0.10 ml for infants weighing less

than 5 kg, 0.15 ml for those weighing 5 to 6.9 kg,0.20 ml for those weighing 7 to 9.9 kg, and0.25 ml for those weighing 10 kg or more. 15 Themedications were diluted in 2 ml of saline be-fore nebulization and were administered througha Sidestream Reusable Nebulizer with a Respi-ronics Facemask (both from Philips Respironics),driven by 100% oxygen at a rate of 6 liters perminute. No other inhaled medications, with theexception of 0.9% inhaled saline (which was anoption in both study groups, to be administered

404 Infants underwent randomization

203 Were assigned

to inhaled RA

201 Were assigned

to inhaled saline

167 Completed inhaled RA

102 Received inhaled RA,on demand

101 Received inhaled RA,fixed schedule

321 Completed study

154 Completed inhaled saline

85 Completed inhaled RA,on demand

82 Completed inhaled RA,fixed schedule

98 Received inhaledsaline, on demand

103 Received inhaledsaline, fixed schedule

78 Completed inhaledsaline, on demand

76 Completed inhaledsaline, fixed schedule

19 Discontinued study12 Had treatment

failure2 Had side effects4 Were withdrawn by

parent1 Was inappropriately

withdrawn


failure1 Had side effects3 Were withdrawn by


withdrawn


failure4 Were withdrawn by

parent2 Were inappropriately

withdrawn


failure5 Were withdrawn by


withdrawn

Figure 1. Randomization of the Study Patients.In five children, the study medication was discontinued because of the following administrative failures: administration of open inhaledracemic adrenaline (RA), suspected pertussis infection, delayed biologic sampling, administration of a dose of the study medication thatwas too high, and insufficient supply of study medication.



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at the discretion of the attending physician),could be administered during the period whenthe infant was participating in the trial. Support-ive therapy and any other treatments were providedin accordance with routine care. In accordance

with national guidelines, glucocorticoids and 2 -adrenergic agonists were not administered. 13

Outcomes

The primary outcome, length of hospital stay, was defined as the time from the f irst study in-halation until discharge from the hospital, asrecorded in the medical record for each patient.Secondary outcomes were the change in the clin-ical score 30 minutes after the first inhalationand the use of nasogastric-tube feeding, oxygensupplementation, or ventilatory support, all of

which were recorded throughout the patients hos-pital stay. Adverse events during hospitalization

were monitored and reported within 24 hours.Clinical scores, oxygen saturation as measured

by pulse oximetry, heart rate, respiratory rate,the use of nasogastric-tube feeding, the use of

ventilatory support, and the time at which eachinhalation occurred were recorded from one tofour times daily during hospitalization (see theSupplementary Appendix for details). Treatment

with supplemental oxygen and the performanceof chest radiography were also recorded.

Statistical Analyses

Continuous data are presented as means (SD),and categorical data are presented as numbersand percentages. Categorical data were assessed

with the use of the Pearson chi-square test. Be-cause data on length of stay had a non-normaldistribution, comparisons between groups wereassessed with the use of a robust, two-samplet-test and Hubers M-estimator, with 95% confi-dence intervals.

Interactions were assessed for inhaled racemicadrenaline versus inhaled saline and on-demand

versus fixed-schedule administration, as well as fortreatment and site, with the use of robust linearregression and Hubers M-estimator. The Jonck-heereTerpstra test was used to assess interactionsbetween age (at 3-month intervals) and interven-tions. Local regression smoothing was appliedto assess the effect of age on length of stay.

The power analysis was based on the lengthof stay of approximately 450 children hospital-ized at the main study site during a 12-monthperiod before the start of the study. Assuming

that clinically relevant improvement would beindicated by a length of stay that was reduced byat least 5 hours in the group receiving inhaledracemic adrenaline, 26 we calculated that a totalof 176 children in each medication group wouldprovide a power of at least 80% at a two-sidedalpha level of 0.05. Owing to the inclusion ofsecondary outcomes and subgroup analyses, weincreased the enrollment target to a total of 500children. The level of significance was set at0.05, and analyses were performed with the useof SAS software, version 9.3, and IBM SPSS soft-

ware, version 19.

R e s u l t s

Study Patients

The study included 404 children (59.4% of whom were boys) with a mean age of 126 days(4.2 months) (Table 1). The number of childrenenrolled at each study center ranged from 22 to136 (mean, 51) (Table S2 in the SupplementaryAppendix). The study medication was discontin-ued in 83 children (20.5%) for the reasons listedin Figure 1.

The mean (SD) length of stay for all infants was 8067 hours; most children were dischargedbetween 8 a.m. and 11 p.m. (Fig. S1 in the Sup-plementary Appendix). Baseline characteristicsdid not differ signif icantly among the four studygroups ( Table 1 ).

Routine respiratory viral assays were per-formed in 123 of the 136 children admitted toOslo University Hospital; 99 of those 123 chil-dren (80.5%) were positive for respiratory syncy-tial virus and 21 of 123 children (17.1%) werepositive for another virus; 5 of 123 (4.1%) chil-dren were positive for two viruses.

Racemic Adrenaline versus Saline

There was no significant difference in length ofhospital stay between children treated with in-

haled racemic adrenaline and those treated withinhaled saline (P = 0.43) (Table 2 and Fig. 2A).There were also no significant between-groupdifferences in the use of nasogastric-tube feeding,supplemental oxygen, or ventilatory support;clinical scores before and after the first inhala-tion of the study medication; or the number ofchildren in whom the study medication was dis-continued (36 children in the group receivinginhaled racemic adrenaline and 47 in the groupreceiving inhaled saline) (Table 2).



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On-Demand versus Fixed-Schedule

Administration

The mean length of the hospital stay was signifi-cantly shorter for children in the group receivingtreatment on demand than in the group receiv-ing treatment on a fixed schedule (P = 0.01) (Ta-ble 2 and Fig. 2B). Children in the on-demandgroup received a mean of 5.0 (30%) fewer inhala-tions than those in the fixed-schedule group

(P

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T a b

l e 2 . L e n g t

h o f

S t a y a n

d U s e o f S u p p o r

t i v e

T h e r a p y

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d i n g

t o M e d

i c a t

i o n

a n d I n h a l a t

i o n

S t r a t e g y .

V a r

i a b l e

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R a c e m

i c A d r e n a l

i n e

( N =

2 0 3 )

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i n e

( N =

2 0 1 )

D i f f e r e n c e o r

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R a t

i o

( 9 5 %

C I ) *

P V a l u e

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d

( N =

2 0 0 )

F i x e

d S c h e d u

l e

( N =

2 0 4 )

D i f f e r e n c e o r

R a t e R a t

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( 9 5 %

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P V a l u e

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t h o f s t a y h

r

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7 8 . 7

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8 6 . 5

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t o 9 1 . 0

6 4 . 6 t o 8 3 . 2

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t o 9 5 . 8

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l e n g

t h o f s t a y h

r

M e a n

6 3 . 6

6 8 . 1

4 7 . 6

6 1 . 3

R a n g e

4 6 . 2

t o 8 1 . 0

4 9 . 8

t o 8 6 . 4

3 0 . 6 t o 6 4 . 6

4 5 . 4

t o 7 7 . 2

M e a n

d i f f e r e n c e

4 . 5 ( 6 . 5 t o 1 5 . 5

)

0 . 4 2

1 3 . 7 (

2 . 9 t o 2 4 . 4

)

0 . 0 1

C h a n g e i n c l i n i c a l s c o r e a f t e r

1 i n h a l a t i o n

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6

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8

1 . 1

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R a n g e

1 . 4

4 t o 1 . 0

8

1 . 2

3 t o 0 . 9 2

1 . 3

5 t o 1 . 0

2

1 . 3

3 t o 0 . 9

8

N o . o f

i n h a l a t i o n s

M e a n

1 3 . 9

1 5 . 2

1 2 . 0

1 7 . 0

R a n g e

1 2 . 1

t o 1 5 . 7

1 3 . 2 t o 1 7 . 2

1 0 . 3 t o 1 3 . 6

1 5 . 0 t o 1 9 . 1

S u p p o r t i v e t h e r a p y n

o . /

t o t a l n o . ( % )

O x y g e n

8 3 / 1 9 2 ( 4 3 . 2 )

8 3 / 1 8 9 ( 4 3 . 9 )

0 . 9 8 ( 0 . 7

8 t o 1 . 2 4 )

7 2 / 1 8 8 ( 3 8 . 3 )

9 4 / 1 9 3 ( 4 8 . 7 )

0 . 7 9 ( 0 . 6

2 t o 0 . 9 9 )

0 . 0 4

N a s o g a s

t r i c -

t u b e f e e d

i n g

5 7 / 2 0 1 ( 2 8 . 4 )

5 9 / 1 9 9 ( 2 9 . 6 )

0 . 9 6 ( 0 . 7

0 t o 1 . 3 0 )

5 2 / 1 9 8 ( 2 6 . 3 )

6 4 / 2 0 2 ( 3 1 . 7 )

0 . 8 3 ( 0 . 6

1 t o 1 . 1 3 )

V e n t

i l a t o r y s u p p o r

t

1 5 / 2 0 3 ( 7 . 4

)

1 5 / 2 0 1 ( 7 . 5 )

0 . 9 9 ( 0 . 5

0 t o 1 . 9 7 )

8 / 2 0 0 ( 4 . 0

)

2 2 / 2 0 4 ( 1 0 . 8 )

0 . 3 7 ( 0 . 1

7 t o 0 . 8 1 )

0 . 0 1

D i s c o n t

i n u e

d t r e a t m e n

t n

o . /

t o t a l n o .

( % )

3 6 / 2 0 3 ( 1 7 . 7 )

4 7 / 2 0 1 ( 2 3 . 4 )

0 . 7 6 ( 0 . 5

2 t o 1 . 1 2 )

3 7 / 2 0 0 ( 1 8 . 5 )

4 6 / 2 0 4 ( 2 2 . 5 )

0 . 8 2 ( 0 . 5

6 t o 1 . 2 1 )

* R a t e r a

t i o s a r e s h o w n

f o r s u p p o r t i v e

t h e r a p y .

T h e m e a n g i v e n

f o r

L e n g

t h o f s t a y w a s a n u n w e i g h

t e d m e a n .

T h e m e a n g i v e n

f o r

E s t i m a t e d

l e n g

t h o f s t a y

w a s a w e i g h

t e d m e a n e s

t i m a t e d w

i t h t h e u s e o f r o

b u s t l

i n e a r r e g r e s s

i o n a n a l y s

i s .

T h e r e w e r e

3 7 7 c h

i l d r e n w

i t h c l

i n i c a l s c o r i n g

b e f o r e a n

d a f

t e r t

h e f i r s t

i n h a l a t i o n a t

t h e

t i m e o f s t u d y e n r o

l l m e n

t .



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as compared with that of inhaled saline. In the youngest children only, inhalations given on de-mand were associated with a significantly short-er hospital stay than were inhalations given on afixed schedule (Table S3 in the SupplementaryAppendix). Status with respect to a history of

atopic eczema or wheezing, status with respectto a family history of atopic disease, and sex were not found to have a significant inf luenceon treatment response.

Adverse Events

No serious adverse events were reported. Threechildren (including one who was receiving in-haled saline) discontinued treatment because ofmoderate tachycardia, which may have been dueto the study medication.

Discussion

In infants with acute bronchiolitis, treatment with inhalations of racemic adrenaline was notassociated with a shorter hospital stay than treat-ment with inhaled saline. However, the adminis-tration of inhalations on demand was found tobe superior to administration on a f ixed schedulein reducing the length of stay and in reducing theuse of ventilatory support, supplemental oxygentherapy, and nasogastric-tube feeding. There wasan interaction between age and either medica-tion type or inhalation strategy.

The lack of effect of inhaled racemic adrena-line on length of hospital stay confirms similarfindings on length of stay for albuterol and sa-line21 and for albuterol alone. 22 There was asimilar lack of effect of these medications on theclinical score and oxygen saturation accordingto a Cochrane meta-analysis, 12 including thefindings in 292 patients from two trials 20,21 re-

viewed in the meta-analysis.Our data show that inhalations given on de-

mand are superior to those administered on afixed schedule in children younger than 12 monthsof age, with the mean length of stay 13.7 hoursshorter for those receiving inhalations on de-mand. This difference was both clinically andstatistically significant and has substantial f inan-cial implications. Although not previously shown,the possibility that saline may have a broncho-constrictive effect in the youngest infants (young-er than 3 months of age) cannot be ruled out.Thus, the superiority of the on-demand sched-ule, in which fewer inhalations were adminis-tered, supports the goal of minimal handling(allowing infants to sleep, with minimal inter-ruption) 27 in acutely ill infants.

The significant interaction we noted betweenage and inhaled racemic adrenaline is of inter-est. The tendency for the youngest infants receiv-ing inhaled racemic adrenaline to have a longer

hospital stay does not support the reported ef-fectiveness of inhaled racemic adrenaline for re-ducing vascular engorgement and edema in chil-dren with asthma. 11 Also unlike the findings inchildren with asthma, 28 in our study populationof children with bronchiolitis, status with respectto a parental history of allergic disease, status

with respect to atopic eczema, and sex were notassociated with symptomatic treatment efficacy.

Our study of two inhalation solutions wassufficiently powered to allow detection of a

P r o p o r t

i o n o

f I n f a n

t s R e m a i n

i n g

i n H o s p

i t a l

1.00

0.80

0.60

0.40

0.20

0.000 100 200 300 400

Length of Stay (hr)

B On Demand vs. Fixed Schedule

A Inhaled RA or Inhaled Saline

RA

Saline

P r o p o r t

i o n o

f I n f a n

t s R e m a

i n i n g

i n H o s p

i t a l

1.00

0.75

0.50

0.25

0.000 100 200 300 400

Length of Stay (hr)

On demand

Fixed schedule

P=0.43

P=0.01

Figure 2. Length of Hospital Stay According to Study Treatment and Sched-

ule of Administration.KaplanMeier plots show the proportion of infants remaining in the hospi-tal according to whether they were treated with inhaled racemic adrenalineor inhaled saline (Panel A) and according to whether the inhalations wereadministered on demand or on a fixed schedule (Panel B).



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5-hour difference in length of stay and to per-form subgroup analyses for the major outcomes.The study included a nationally representativepatient cohort with the expected patterns of viralinfection. 4 In addition, the study was managedin accordance with local and national guide-lines, and the baseline characteristics were sim-ilar in all four treatment groups (Table S1 in theSupplementary Appendix).

Despite the limited power of the study to de-tect an interaction between the interventions, theobserved interaction was approximately one thirdof the 5-hour length of stay selected a priori asa clinically relevant difference. 26 The initiallyplanned end point for length of stay, which wasthe time at which the child was deemed readyfor discharge, was not recorded for 83 children(Fig. 1). We therefore used the actual time of dis-

charge for all children. The results were similar with the use of these two end points (Table S5in the Supplementary Appendix).

In conclusion, our study showed that for hos-pitalized infants with acute bronchiolitis, inhaledracemic adrenaline was not superior to inhaledsaline with regard to length of hospital stay, useof supportive treatment, or clinical score. How-ever, the administration of inhalations on demand,as compared with a fixed schedule of inhalations,

was associated with a shorter hospital stay and with a reduced need for supportive treatment.

Supported by Medicines for Children, a publicly funded bodyadministered by Haukeland University Hospital.

Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.

We thank the nurses and pediatricians at all the participatinghospitals for their invaluable contribution to this project.

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