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Heliox Therapy in Bronchiolitis: Phase III
MulticenterDouble-Blind Randomized Controlled Trial
WHATS KNOWN ON THIS SUBJECT: Bronchiolitis, a leading causeof
infant hospitalization, has few proven treatments. A few
smallstudies have reported the benecial effects of a mixture of
21%oxygen + 79% helium (Heliox). The 2010 Cochrane Review
concludedthat additional large randomized controlled trials were
needed todetermine the therapeutic role of Heliox in
bronchiolitis.
WHAT THIS STUDY ADDS: The Bronchiolitis Randomized
ControlledTrial Emergency-Assisted Therapy with HelioxAn
Evaluation(BREATHE) trial is the largest multicenter randomized
controlledtrial to date to investigate the efcacy of Heliox in
acutebronchiolitis. The delivery method for Heliox therapy was
found tobe crucial to its efcacy.
abstractBACKGROUND AND OBJECTIVE: Supportive care remains the
mainstayof therapy in bronchiolitis. Earlier studies suggest that
helium-oxygentherapy may be benecial, but evidence is limited. We
aimed to compareefcacy of 2 treatment gases, Heliox and Airox (21%
oxygen 1 79%helium or nitrogen, respectively), on length of
hospital treatment forbronchiolitis.
METHODS: This was a multicenter randomized blinded controlled
trial of319 bronchiolitic infant subjects randomly assigned to
either gas; 281 sub-jects completed the study (140 Heliox, 141
Airox), whose data was ana-lyzed. Treatment was delivered via
facemask (nasal cannula, if thefacemask intolerant) 6 continuous
positive airway pressure (CPAP).Severe bronchiolitics received CPAP
from the start. Primary end pointwas length of treatment (LoT)
required to alleviate hypoxia and respira-tory distress. Secondary
end-points were proportion of subjects needingCPAP; CPAP (LoT); and
change in respiratory distress score.
RESULTS: Analysis by intention to treat (all subjects); median
LoT (inter-quartile range, days): Heliox 1.90 (1.083.17), Airox
1.87 (1.113.34), P =.41. Facemask tolerant subgroup: Heliox 1.46
(0.851.95), Airox 2.01 (0.932.86), P = .03. Nasal cannula subgroup:
Heliox 2.51 (1.214.32), Airox 2.81(1.454.78), P = .53. Subgroup
started on CPAP: Heliox 1.55 (1.382.01),Airox 2.26 (1.842.73), P =
.02. Proportion of subjects needing CPAP:Heliox 17%, Airox 19%,
O.R. 0.87 (0.471.60), P = .76. Heliox reduced re-spiratory distress
score after 8 hours (mixed models estimate, 20.1298;P , .001). The
effect was greater for facemask compared with nasalcannula (mixed
models estimate, 0.093; P = .04).
CONCLUSIONS: Heliox therapy does not reduce LoT unless given via
a tight-tting facemask or CPAP. Nasal cannula heliox therapy is
ineffective.Pediatrics 2013;131:661669
AUTHORS: Mina M. Chowdhury, MB, ChB,a Sheila A.McKenzie, FRCP,b
Christopher C. Pearson, FRACP,c SiobhanCarr, FRCPCH,b Caroline Pao,
MRCP,b Arvind R. Shah,FRCPCH,c Elizabeth Reus, MSc,a Joseph
Eliahoo, PhD,e
Fabiana Gordon, PhD,e Hubert Bland, MB, ChB,f and ParvizHabibi,
PhD, FRCP, FRCPCHa
aDepartment of Pediatrics, Wright Fleming Institute,
ImperialCollege, London, United Kingdom; bDepartment of
Pediatrics,Royal London Hospital Whitechapel, London, United
Kingdom;cDepartment of Pediatrics, Womens and Childrens
Hospital,North Adelaide, Australia; dDepartment of Pediatrics,
NorthMiddlesex University Hospital, London, United
Kingdom;eStatistical Advisory Service, Imperial College, London,
UnitedKingdom; and fSurrey Clinical Research Centre, University
ofSurrey, Guildford, United Kingdom
KEY WORDSrandomized controlled trial, heliox, bronchiolitis
ABBREVIATIONSAiroxmixture of 21% oxygen + 79%
nitrogenBREATHEBronchiolitis Randomized Controlled Trial
Emergency-Assisted Therapy with HelioxAn EvaluationCPAPcontinuous
positive airway pressureFiO2fraction of inspired
oxygenFMfacemaskHelioxmixture of 21% oxygen + 79% heliumLoTlength
of treatmentNCnasal cannulaRCTrandomized controlled
trialRSVrespiratory syncytial virusSpO2percutaneous oxygen
saturation
Dr Chowdhury and Dr Habibi designed the study and wrote thetrial
protocol and manuscript; Dr McKenzie, Dr Bland, Dr Carr,Dr Pao, Dr
Shah, and Dr Pearson contributed to the study designand writing of
manuscript; Dr Habibi was the chief investigator;Dr Chowdhury was
the trial coordinating investigator; Dr McKenzie,Dr Carr, Dr Pao,
Dr Shah, and Dr Pearson were principal inves-tigators at
collaborating centers; Dr Habibi, Dr Chowdhury, andMs Reus
coordinated study conduct and data collection at thecenters and
played a major role in supervision of the trialnurses involved in
recruitment; and Dr Eliahoo and Dr Gordonperformed the statistical
analyses and contributed to thewriting and approval of the nal
manuscript.
This trial has been registered at
http://www.controlled-trials.com/ISRCTN18238432
www.pediatrics.org/cgi/doi/10.1542/peds.2012-1317
doi:10.1542/peds.2012-1317
Accepted for publication Dec 18, 2012
Address correspondence to Parviz Habibi, PhD, FRCP,
FRCPCH,Reader and Consultant in Pediatric Intensive Care
andRespiratory Medicine, Wright Fleming Institute, Imperial
College,Norfolk Place, London W2 1PG, United Kingdom. E-mail:
[email protected]
(Continued on last page)
PEDIATRICS Volume 131, Number 4, April 2013 661
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Acute viral bronchiolitis is a leadingcause of infant
hospitalization, witha rising incidence and health-economicburden
in developed countries.13 Inthe United States, 75 000
respiratorysyncytial virus (RSV)-positive bronchio-litic infants
are hospitalized each year.4,5
Stang et al3 estimated the annual costburden of this to be
between US$365and $585 million. Although there aremany treatments,
few have a strongevidence base or have demonstrateda reduced length
of hospital stay orneed for respiratory support,6 with ox-ygen
being the mainstay of therapy. Amixture of 21% oxygen + 79%
helium(Heliox) is lighter than air or oxygen,promoting laminar ow
in areas ofturbulence or airway narrowing andthus may improve
respiratory distressand wheezing.7 Heliox also reduces re-spiratory
system resistance, hasa higher binary diffusion coefcient forCO2
and O2 and therefore may enhancealveolar gas exchange and lung
re-cruitment, and is an inert gas with anexcellent safety prole.810
Heliox maytherefore be a useful therapy in bron-chiolitis that is
associated with smallairway inammation causing increasedrespiratory
system resistance and in-creased work of breathing. Since 1996when
Paret et al11 successfully treateda bronchiolitic infant in
respiratoryfailure with Heliox, 9 studies (combinedtotal of 172
infants) have investigatedHeliox treatment in
bronchiolitis.7,9,1218
Six of these studies7,9,13,1618 reportedvarious clinical benets,
including im-provement of hypercapnea and re-spiratory distress.
These studies hadsmall sample sizes, used different de-livery
methods for Heliox, and were notalways blinded, and only 1
study16
assessed the effect of Heliox on length oftreatment (LoT) or
hospital stay. Fur-thermore, regardless of clinical efcacy,heliox
must be cost-effective. The cost ofa single bed day on a pediatric
ward is$1947.19,20 Even reducing the hospitalLoT by 0.5 dayswould
save $974,which is
equivalent to 14 cylinders of Heliox ata cost of $70 each.21 In
our experience,only 3 to 5 cylinders per day are con-sumed during
Heliox therapy, thus sup-porting our hypothesis that Heliox maybe
cost-effective if it reduces duration ofhospital treatment. The
2010 CochraneReview concluded that additional largerandomized
controlled trials (RCTs)were needed to investigate the
deliverysystem for Heliox and determine itstherapeutic role in
bronchiolitis.22 Wetherefore report the largest phase III
RCT,called Bronchiolitis Randomized Con-trolled Trial
Emergency-Assisted Therapywith HelioxAn Evaluation
(BREATHE).Results of this work have been pre-viously published as
an abstract.23
METHODS
Setting
A prospective, double-blind RCT wascarried out in the
bronchiolitis seasonsduring 2005 to 2008 across 4 centers inthe
United Kingdom and Australia.
Participants
Pediatricians in the emergency de-partments or pediatric wards
of par-ticipating hospitals, independent ofthe BREATHE study,
assessed infants(or 12-month corrected age if pre-mature). They
clinically determined ifthe infants had a diagnosis of
bron-chiolitis (history of upper respiratorytract infection
followed by wheezing,coughing, breathing difculty, or chestcrackles
on auscultation) and if theyneeded hospitalization for
respiratorydistress or hypoxia (percutaneousoxygen saturation
[SpO2] , 93% inroom air). Exclusion criteria were asfollows:
imminent intubation; SpO2 ,93% despite 15 L/minute O2 via
non-rebreathing facemask (FM); trache-ostomy; participation in
another studyin the previous 4 weeks; salbutamol,epinephrine, or
ipratropium therapywithin 1 hour or systemic steroidswithin 4 hours
of entry into the study;
and bronchiolitis readmission within24 hours of exit from
BREATHE. Anindependent data committee moni-tored safe conduct
throughout thestudy. The trial was registered in-ternationally and
had independentethics committee approval.
Interventions
Heliox or a mixture of 21% oxygen + 79%nitrogen (Airox), labeled
as gas A or B,was the treatment or control in-tervention with
additional oxygen ti-trated via Y-connection tubing, resultingin 2
gas mixes: A or B 6 additional ox-ygen. Gas delivery was by a
tight-tting3-valve, nonrebreathing facemask (FM;1192;
Intersurgical) or a nasal cannula(NC; BC 2745-20; Fisher &
PaykelHealthcare) if the subject was FM in-tolerant. Gas A or B
drove the continuouspositive airway pressure (CPAP) device(EME
infant ow driver; CareFusion).
Outcome Measures
The primary end point was the total LoTto alleviate hypoxia
(SpO2 $ 93% inroom air) and respiratory distress(minimal work of
breathing). LoT wascalculated from the start to successfulstop of
the trial gas, as dened by clin-ical stability (minimal work of
breathingand SpO2 $ 93%) for 1 hour breathingroom air. Minimal work
of breathingwas qualied as having a normal re-spiratory rate, no
cyanosis, no nasalaring, no tracheal tug or grunting, nohead
bobbing, and no use of accessorymuscles except for mild
intercostalrecessions. Secondary end points wereproportion of each
treatment groupneeding CPAP and the change in re-spiratory distress
over time measuredby the Modied Woods Clinical AsthmaScore (Table
1). We used a scoring toolto assess change in respiratory
distressover time, similar to that used in pre-vious heliox
studies.13,16 The scoring toolwas a modied version of the
originalWoods Clinical Asthma Score.24
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At each assessment period, the type ofdelivery (FM or NC) and FM
tolerancewas prospectively recorded on the trialclinical report
forms to allow analysisof LoT in the FM and NC subgroups. Wealso
recorded the duration of CPAPtherapy (CPAP LoT) in a group of
severebronchiolitic subjects who were com-menced on CPAP from the
beginning oftreatment to compare the impact ofHeliox versus Airox
on duration of CPAP.
Management of bronchiolitis was stan-dardized to a strict
protocol across trialcenters: gas A or B6 oxygen humidiedvia MR850
(Fisher & Paykel Healthcare),minimal handling, attention to
hydrationstatus, and careful airway toilet/suction.Intravenous uids
were preferred overnasogastric feeding in subjects with se-vere
respiratory distress. Bronchodilator,epinephrine, or steroid use
constitutedtrial protocol violations. A team ofBREATHE trial nurses
ensured adherenceto these standards and the trial protocol.
The BREATHE treatment protocol isshown in Fig 1. Subjects had FM
therapyfor 30 minutes. If they were FM in-tolerant, the NC protocol
was used. Ifsubjects were hypoxic despite FM/NC,the CPAP protocol
was started. FM tol-erance was recorded at each assess-ment period,
and FM tolerant wasstrictly dened as mask on all of thetime except
for oronasal suction andfeeding. FM intolerance was dened
asincreasing agitation, distress, shakinghead from side to side,
and pulling theFM off the face for 30 minutes. NC was
started in subjects who remained FMintolerant for 30 minutes.
The optimumow rate for trial gas was based on ti-tration against
oxygen to achieve SpO2$ 93% using the minimum ow of ad-ditional
oxygen. For FM therapy, themaximum combined ow rate (gas A/B+
oxygen) was 10 L/minute and for NCtherapy it was 3 L/minute based
onconsensus of practice.25 CPAP was star-ted if subjects were
hypoxic (SpO2 ,93%) despite oxygen.4 L/minute via FMor .2 L/minute
via NC. CPAP was dis-continued once subjectswereweaned to1 to 2
cmH2O pressure and were nolonger hypoxic in fraction of
inspiredoxygen (FiO2) , 0.4 for 1 hour. CPAPfailure was dened as
hypoxia (SpO2,93%) despite 9 cmH2O pressure and FiO20.6, whereupon
subjects exited the trial.
Those subjects with severe
bronchiolitisatpresentation,whorequiredimmediatecommencement of
CPAP driven by gas Aor B, followed the CPAP protocol (Fig 1).
Sample Size
Sample size calculation (using nQueryAdvisor v4.0) was based on
an unpairedt test with 80% power for a 2-sided a of5% to detect a
0.75-day LoT reduction. Abaseline mean LoT for bronchiolitis of2.7
days (SD= 2.3 days)was assumed.26,27
The calculation showed that 298 sub-jects would be needed to
achieve areduction in total LoT by 0.75 days.Three-quarters of a
day duration wasselected both from the point of viewof feasibility
of recruitment and also
representing a clinically importantthreshold (eg, a 0.75-day LoT
reductionin a center that treats 100 infants wouldsave 75 bed-days
and was considereda positive impact on health economics).
Randomization and Blinding
After written informed consent wasobtained from parents,
patients wereenrolled and allocated to Gas A or B bytelephone using
computer-stratiedblock-randomization. Parents/legal guard-ians and
clinical/study personnel wereblinded to randomization sequence
andallocation. Randomization codes re-mained secure until the end
of the trial.For blinding, identical cylinders markedGas A or B and
identical equipment andconnectionswereused. TheCPAPoxygendial was
blanked off and FiO2 was reg-ulated by the LED display. The air
inlet tothe CPAP device was modied to deliverGas A or B using
identical connectors.
Statistical Methods
The primary endpoint (LoT) was ana-lysed blind, for all
subjects, based onintention to treat, in order to determineany
difference in LoT between treat-ment groups known as gas A and gas
B.Subgroup LoT data was analyzed forFM, NC subjects and for CPAP
subjectswho were severe enough to warrantCPAP from the start. The
Mann-Whitneytest was used to compare LoT betweentreatment groups
(as data wasskewed), with results summarized asmedians with
interquartile ranges
TABLE 1 Modied Woods Clinical Asthma Score
SCORE 0 1 2Pulse oximetry SpO2 . 93%: Room Air SpO2 , 94%: Room
Air SpO2 , 94%: 40% FiO2Accessory muscle use NONE of:
Recessions Head bobbing Nasal aring Tracheal tug
ANY one of: Recessions Head bobbing Nasal aring Tracheal tug
ALL four of: Recessions Head bobbing Nasal aring Tracheal
tug
Cyanosis No Yes In room air Yes In 40% FiO2Cerebral function
Normal Depressed or Agitated ComaBreath sounds Normal Unequal
Decreased or absentExpiratory wheezing None Yes
Maximum score = 11.
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FIGURE 1BREATHE treatment protocol.
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(IQR). Fishers exact test was used tocompare proportions
progressing toCPAP in the two groups. All analyseswere two tailed
with an alpha level setat 005. STATA 10 and SPSS 17 wereused for
analysis. Change in respira-tory distress over time measured
byMWCAS was analyzed for all subjectsas well FM and RSV positive
(RSV1)subgroups. Mixed Models methodologywas used since it takes
into accountcorrelatedmeasures (gas type, gender,birth gestation,
age, weight, virus sta-tus, temperature, heart rate, re-spiratory
rate, SpO2). Due to the nature
of the data, the square root trans-formation of MWCAS was used
as thedependant variable for the modelling.The modelling and
estimation of theeffects of interest was carried out bythe
PROCMIXED routine in SPSS version17, with a signicance level set at
5%.
RESULTS
Participant Flow, Recruitment,Baseline Characteristics,
andNumbers Analyzed
Infants presenting with any respira-tory signs or symptoms were
screened
between the period of 2005 to 2008. Atotal of 361 patients with
clinically di-agnosed bronchiolitis were consideredfor eligibility.
Consent was obtained for319 subjectswhowere randomized andenrolled
into the study. The consortowchart (Fig 2) shows that 3
subjectswere excluded (2 withdrawal of con-sent and 1 screening
failure); there-fore, 316 subjects were allocated totreatments. An
additional 35 subjectswere excluded because of protocol vi-olation,
consent withdrawal, screeningfailure, hospital clinicians decision,
orpremature disruption of therapy. Thus,
FIGURE 2Consort owchart.
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281 subjects (140 Heliox and 141 Airox)with similar baseline
characteristics(Table 2) completed the study, and theirdata was
analyzed. The results aresummarized in Table 3. There were
nohospital readmissions for subjectswho had completed or exited the
trial.
Length of Treatment
Analysis of data from all 281 subjectsshowed no difference in
median LoTbetween treatment groups [Heliox 1.90days (interquartile
range 1.083.17)compared to Airox 1.87 days (inter-quartile range
1.113.34), P 5 .41].However, LoTwas signicantly reducedin favor of
Heliox for FM-tolerant sub-jects [Heliox, 1.46 days
(interquartilerange 0.851.95); Airox, 2.01 days
(interquartile range 0.932.86) P = .03].A more notable reduction
in LoT wasseen in RSV+ subjects [Heliox, 1.31 days(interquartile
range 0.611.91); Airox,2.18 days (interquartile range 1.402.95) P =
.004]. There was no differencein LoT for NC subjects [Heliox 2.51
days(interquartile range1.214.32), Airox2.81 days (interquartile
range 1.454.78) P = .53].
Averting Need for CPAP
Analysis of data from all 281 subjectsshowed no reduction in
proportion ofcases progressing to CPAP [24 of 140Heliox subjects
(17%) vs 27 of 141 Airoxsubjects (19%); odds ratio 0.87 (0.471.60),
P 5 .76]. However, for FM toler-ant RSV1 subjects there was a
66%
reduction in proportions requiring CPAPin favor of Heliox, at
borderline signi-cance [3 of 27 Heliox subjects (11%) vs10 of 31
Airox subjects (32%); odds ratio0.26 (.071.02), P5 .76]
Impact on CPAP Efcacy
Heliox signicantly reducedmedian LoTfor severe bronchiolitic
subjects whowere started directly onto CPAP [Heliox1,55 days
(interquartile range 1.382.01), Airox 2.26 days (interquartilerange
1.842.73); P = .02].
Impact on Respiratory Distress
Heliox reduced respiratory distress inall 281 subjects across
all time pointsand statistically signicant at 8 hoursonwards. MWCAS
(mixed models esti-mate = 20.1298; 95% condence in-terval 20.202 to
20.057, P , .001).Regardless of gas type, FM was moreeffective than
NC (mixed models esti-mate5 0.093; 95% condence interval0.005 to
0.181, P = .04).
Adverse Events
Six subjects required intubationfor different reasons. In one
casethere was CPAP equipment malfunc-tion which precipitated
emergency
TABLE 2 Baseline Characteristics of Subjects in the Study
Baseline Characteristics Units Heliox (N = 140) Airox (N =
141)
Gender male:female ratio 1:1.59 1:1.52Gestation at birth wk 39.0
(38.0240.0) 40.0 (38.0240.0)Age at presentation wk 10.90
(5.85225.50) 17.70 (6.80229.40)Weight at presentation kg 5.65
(4.3427.70) 5.70 (4.4027.70)NPA +ve at presentation N (% of cases)
111 (79.3%) 116 (82.3%)Temperature C 37.0 (37.0238.0) 37.0
(37.0238.0)Heart rate beats per min 152.0 (136.02165.0) 148.5
(133.52168.0)Respiratory rate breaths per min 56.0 (44.0262.0) 53.0
(47.0263.5)SpO2 in room air % 92.0% (89.0295.0) 91.0%
(89.0294.0)Modied Woods Clinical
Asthma ScoreMaximum score of 11 3.0 (2.023.0) 3.0 (2.024.0)
Values are medians and IQRs. NPA, nasopharyngeal aspirate virus
detection.
TABLE 3 Summary of BREATHE Findings
Impact on LoT Intervention N Mean LoT (95% Condence Interval),
days Median LoT (Interquartile Range), days P
All subjects Heliox 140 2.268 (1.993 to 2.544) 1.902
(1.08323.173) .41Airox 141 2.487 (2.180 to 2.794) 1.865
(1.11423.344)
NC (6CPAP) Heliox 40 2.952 (2.335 to 3.569) 2.505 (1.21024.315)
.53Airox 47 3.296 (2.643 to 3.948) 2.810 (1.45024.780)
FM (6CPAP) Heliox 44 1.538 (1.234 to 1.841) 1.464 (0.85221.947)
.03Airox 40 2.236 (1.744 to 2.728) 2.006 (0.92822.859)
FM (6CPAP), RSV+ Heliox 27 1.411 (0.982 to 1.841) 1.310
(0.60821.906) .004Airox 31 2.456 (1.868 to 3.044) 2.179
(1.39622.951)
CPAP LoT Heliox 9 1.619 (1.301 to 1.934) 1.552 (1.38022.013)
.02Airox 12 2.380 (1.773 to 2.986) 2.258 (1.84422.727)
Proportion of cases needing CPAP Percent Odds Ratio (95%
Condence Interval)All cases Heliox 24/140 17% 0.87 .78
Airox 27/141 19% (0.4721.60)FM, RSV+ Heliox 3/27 11% 0.26
.07
Airox 10/31 32% (0.0721.02)
Impact on MWCAS Comparison Estimate of Fixed Effects (95%
Condence Interval)Results are Heliox effect relative
to Airox over timeAll patients 20.1298 (20.202 to 20.057)
,.001FM relative to NC 0.093 (0.005 to 0.181) .04
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intubation. Two subjects suffered re-current apnoeas immediately
followingenrolment (i.e. screening failure). Onesubject due to
receive CPAP was intu-bated and transferred out because nohigh
dependency bed available whileone subject was intubated because
ofdelay in high dependency bed avail-ability. One subject had a
previouslyundetected patent ductus arteriosusand was therefore
referred to thecardiologists.
DISCUSSION
Bronchiolitis is a leading cause of infanthospitalization
worldwide yet, to date,oxygen and supportive care are themainstay
of treatment for the vastmajority of patients. The excellent
safetyprole and unique physical properties ofHeliox position it as
a potentially usefultherapy for acute bronchiolitis. TheBREATHE
study found the deliverymethodof Heliox to be crucial to its
efcacy: itwas only benecial if given by a tight-tting FM or by
CPAP. Thus, if deliveredeffectively, Heliox therapy
signicantlyreduced length of hospital treatment atdifferent points
of care (ward, PICU). TheBREATHE study was powered to detecta
0.75-day reduction in LoT. However,the statistically signicant
nding ofa 0.55-day reduction in LoT in FM-tolerantpatients is still
a clinically useful nd-ing, given the very signicant pressureon
hospital beds every winter imposedby bronchiolitis. Furthermore,
given theneedto justify thehealth-economiccostofHeliox, the results
of the subgroup anal-ysis support the rational use of Heliox inRSV+
patients who showed a greaterreduction in LoT (0.87 day).
Heliox rapidly reduced respiratory dis-tress, making it a
potentially usefulstabilization tool in emergency care. Theeffect
was greater when consideringRSV+ subjects (archetypical
bronchiol-itis), consistent with Martinon-Torresndings on his group
of RSV+ subjects.16
However, the authors of that study found
Heliox shortened the length of hospitalstay. Because many other
variables canaffect the length of hospital stay, wechose to measure
total LoT as the pri-mary end point, because it is directlylinked
to therapy.
We found Heliox conferred no benetover oxygen when delivered by
NC atow rates of #3 L/minute. We believethe difference in efcacy
between FMand NC is caused by several factors. Atight-tting FM is
used in clinical sit-uations when the highest FiO2 needs tobe
delivered with minimal air entrain-ment. Delivering a high
concentrationof helium must also be very importantfor Heliox
therapy, and our previousndings28,29 also provide support foruse of
the nonrebreathing FM. The useof an NC is subject to signicant
airentrainment, and thus variable FiO2, asdemonstrated by Sung et
al.30 The dis-advantages of the NC would be magni-ed when using
Heliox, a much lightergas. Furthermore, in small infants,nasal
prongs may also increase re-sistance to nasal airow and work
ofbreathing. It is not surprising thereforethat NC therapy with
Heliox at conven-tional ow rates is ineffective.
The BREATHE study is the only RCT thusfar to investigate the
rate of CPAP use inbronchiolitis. However, the observed66%
reduction only reached borderlinestatistical signicance, which may
bebecauseoftherelativelysmallnumberofCPAP subjects (n = 58).
Martinon-Torreset al17 in their Heliox-CPAP study dem-onstrated a
reduction in work ofbreathing and improved CO2 clearance.The
BREATHE study also enabled as-sessment of the impact of Heliox
onCPAP efcacy. We analyzed data forsubjects who were started on
CPAPfrom the beginning of the trial becausetheir pathophysiology
had not yet beenaltered by previous therapy. We foundthat CPAP
duration was signicantlyreduced if Heliox was the driving gas
forCPAP. The numbers of subjects totaled
only 21, so we cannot draw any strongconclusions. However, if
the nding ofreduced treatment time was to be rep-licated in a
larger CPAP study, thiswouldrepresent a signicant
health-economicbenet for using Heliox to drive CPAP incases of
severe bronchiolitis.
We did not select patients based onclinical severity but
screened consec-utive infants presenting with any re-spiratory
signs or symptoms and found361 patients with clinically
diagnosedbronchiolitis. We could not rule out thepossibility that
some patientsmay havehad asthma. However, any cases
ofasthma-bronchiolitis overlap wouldhave been balanced out between
the 2treatment groups through the processof randomization. Virus
detection fromnasopharyngeal aspirate was carriedout by the
hospitals on 281 of the en-rolled patients. We found 227 of
281(80%) were virus positive, with RSVaccounting for the vast
majority. Thecenters routinely assayed only for RSV,para-inuenza,
adenovirus, Flu A/B,and rhinovirus. Therefore, the 80% vi-rus
positive rate (Table 2) was mostlikely an underestimate and we
arecondent that our clinical selectioncriteria captured mostly
viral bron-chiolitis.
The BREATHE study is the largest phaseIII, multicenter,
double-blinded RCT ofHeliox in bronchiolitis. It attempted
toresolve the challenges of blinding. Theuse of special
hosingmaterial, identicalin appearance for Heliox and Airox
en-sured that there was no difference insound generation that could
havealerted the investigator to identify thestudy gas.
The BREATHE study linked efcacy to themode of delivery: CPAP or
tight-ttingnonrebreathing FM. However, thelarge number of subjects
treated by NCmeant that the positive ndings in favorofHelioxwere
limited toonly84subjectswho tolerated the FM. Although the useof
the FM was a major limitation of this
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study, we chose it as the delivery in-terface because it is
readily available,and others13,16 had reported effectiveHeliox
delivery by FM. Our previousresearch28,29 also found that a
tight-tting 3-valve, nonrebreathing FMwould deliver the highest
concentra-tion of oxygen and helium. However,FMs are generally
poorly tolerated inyoung children, and this was also ourexperience.
To maximize FM compli-ance in their study, Martinn-Torreset al16
used swaddling to comfort-ably restrain subjects with the FM
heldagainst the face by soft elasticizedtube netting applied over
the head. Weused a bonnet to allow a tighter-ttingFM and help
prevent the elastic bandfrom slipping down, used swaddling,and
encouraged staff and mothers tomaximize compliance. Despite ourbest
efforts, many subjects did nottolerate the FM, and it proved
impos-sible to apply it continuously. Maskintolerance was
highlighted after re-cruitment of the rst few subjects intothe
trial when we found nursing staffwishing to use an NC, the
commonlyused mode of oxygen delivery forinfants. It was considered
unethical towithhold a trial gas treatment if sub-jects had already
started to improve.We therefore considered delivery oftrial gas via
NC because Williamset al31 successfully used NC with Helioxin
infants, and oxygen is already con-ventionally administered via NC.
There-fore, NC was included as a protocolamendment for subjects who
were FMintolerant.
We prospectively studied a cohort ofclinically diagnosed
bronchiolitic in-fants, regardless of severity and viraletiology,
enabling us to identify a treat-ment for bronchiolitis that can be
usedacross different modalities (FM andCPAP) and points of care
(emergencydepartment, ward, and PICU). Nonethe-less, this approach
to recruitmentresulted in a smaller proportion of
severe cases, making it difcult to con-clusively study outcomes
such as CPAP.The latter is very important becauseCPAP compared with
standard treat-ment has been shown to improve ventila-tion, with a
reduction in hypercapnea,32
with growing consensus that CPAP ther-apy prevents deterioration
and need formechanical ventilation.
We did not collate data on length of staybut rather focused on
length of treat-ment. The study was powered for thelatter because
LoT was a clear anddenitive endpoint in the disease pro-cess.
The BREATHE study was not powered toinvestigate intubation
rates, whichwould also have been informative. Only8 of 316 (2.8%)
needed intubation.Therefore, amuch larger sample size ora moderate
number of a more selectedsevere group of patients would beneeded to
investigate the impact ofHeliox on intubation rates. The
BREATHEprotocol (part B, not yet carried out)had originally been
designed to in-vestigate intubation rate in a moresevere subgroup
of bronchiolitics (de-ned as already requiring CPAP). Abaselinegure
of 35%was assumed forthe bronchiolitis intubation rate (de-ned as
CPAP failure) derived fromdatafor our PICU at St Marys hospital.
Thepower calculation showed that a totalof 86 severe bronchiolitics
on CPAPwould need to be recruited to detecta reduction in the
intubation rate from35% to 10% with 80% power.
The BREATHE study has highlighted theneed to review our approach
to re-spiratory care in general: use of FM hastolerance issues, and
NC (at conven-tional ow rates) has limited efcacy.Although NC
delivery of Heliox at owrates ,3 L/minute was ineffective,
wetheorize that at higher ow rates (tol-erated based on our
anecdotal experi-ence), Heliox therapy by nasal cannulamay be
effective. A well-designed RCTcomparing 3-valve nonrebreathing
FM
versus high-ow NC therapy is neededto identify the optimal
method of de-livery. Furthermore, a sufciently pow-ered RCT of
Heliox-driven versusconventional Airox-driven CPAP woulddetermine
whether Heliox reduces theneed for mechanical ventilation.
In the meantime, the clinical practicerecommendations arising
from theBREATHE study ndings are as follows:
Heliox therapy should be startedfor bronchiolitic infants who
re-quire hospital admission for treat-ment of hypoxemia or
respiratorydistress.
If the use of Heliox therapy needsto be rationalized, it could
be tar-geted to those who are RSV posi-tive.
Heliox therapy should only be de-livered via a tight-tting
nonre-breathing FM or CPAP, as per theprotocol outlined in the
BREATHEstudy.
CONCLUSIONS
The BREATHE study showed that thedeliverymethodofHeliox is
critical to itsefcacy. Heliox is effective if deliveredvia a
tight-tting nonrebreathing FM orCPAP but not via a NC at
conventionalowrates.With effective delivery, Helioxreduces the LoT,
alleviates respiratorydistress, improves CPAP efcacy, andmay reduce
the need for CPAP. A moreacceptable patient interface for
effec-tive delivery remains the challenge forindustry if Heliox is
to be more widelyused in pediatric respiratory care.
ACKNOWLEDGMENTSWe thank the patients, families, andnursing,
medical, and other healthcarestaff across all the hospitals,
whosecooperation and support allowed usto undertake the BREATHE
trial. We es-pecially thank the BREATHE team
mem-berswhosemeticulousattention to trialconduct ensured the rigor
of this study.
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(Continued from rst page)
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
Copyright 2013 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: Dr Bland was a Clinical Director of
British Oxygen Company (BOC) Medical during the period of conduct
of this trial; the other authorshave indicated they have no nancial
relationships relevant to this article to disclose.
FUNDING: Supported by a research grant from BOC Medical and
equipment support from Fisher and Paykel Healthcare, EME
(Electro-Medical Equipment)Carefusion, and Covidien Nellcor.
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DOI: 10.1542/peds.2012-1317; originally published online March
18, 2013; 2013;131;661Pediatrics
Hubert Bland and Parviz HabibiCaroline Pao, Arvind R. Shah,
Elizabeth Reus, Joseph Eliahoo, Fabiana Gordon,
Mina M. Chowdhury, Sheila A. McKenzie, Christopher C. Pearson,
Siobhan Carr,Randomized Controlled Trial
Heliox Therapy in Bronchiolitis: Phase III Multicenter
Double-Blind
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