The n e w e ng l a n d j o u r na l of m e dic i n e
High-Flow Oxygen Therapy in Infants with Bronchiolitis
To the Editor: In the article by Franklin et al.
(March 22 issue),1 in which infants with bron-
chiolitis were assigned to receive low-flow oxygen
(standard-therapy group) or high-flow oxygen
(high-flow group) through a nasal cannula, the
primary outcomes differed between groups. Treat-
ment failure in the standard-therapy group allowed
patients to be placed in the high-flow group,
whereas failure in the high-flow group resulted
in unknown interventions beyond transfer to an
intensive care unit (ICU). In addition, other mea-
sures of failure (such as transfer or intubation)
did not favor the use of high-flow therapy.
Standard therapy worked well in 566 patients,
suggesting that a large number of patients in the
high-flow group may not have required its use.
The use of high-flow therapy in such patients
increases cost without a clear benefit. Escalation
of therapy in the high-flow group occurred at
significantly higher respiratory rates, suggesting
that provider discomfort with modest levels of
tachypnea drove the escalation of care in the
low-flow group. In addition, in both groups, ap-
proximately the same number of patients who
received high-flow therapy did not benefit, which
implies that there is no real advantage in initi-
ating high-flow therapy early rather than post-
poning it until after standard therapy has failed.
Although high-flow therapy may help some pa-
tients with bronchiolitis and hypoxemia, it is
premature to assume that it should be used
universally.
Sarah D. Meskill, M.D.
Robert H. Moore, M.D.
Baylor College of Medicine
Houston, TX
sdmeskil@​­texaschildrens​.­org
No potential conflict of interest relevant to this letter was re-
ported.
1. Franklin D, Babl FE, Schlapbach LJ, et al. A randomized trial
of high-flow oxygen therapy in infants with bronchiolitis. N Engl
J Med 2018;​378:​1121-31.
DOI: 10.1056/NEJMc1805312
To the Editor: It is worth reflecting on the ef-
ficiency of high-flow therapy. On the basis of the
authors’ primary outcome, efficacy would be a
number needed to treat of 9 patients to prevent
2444 n engl j med 378;25 nejm.org  June 21, 2018
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Copyright © 2018 Massachusetts Medical Society. All rights reserved.
an infant’s condition from worsening given that
all secondary outcomes were equal. Therefore,
efficiency would depend only on the cost differ-
ence between high-flow and low-flow therapy.
Using the probabilities reported by the authors
(Fig. 1), we created a decision-analysis tree and
have concluded that the best approach would be
to initially use low-flow therapy and to use high-
flow therapy only after low-flow therapy has
failed (expected cost, $19.03 per patient).
The difference in the cost of disposable items
alone is $60.07 ($79.10 vs. $19.03), and the dif-
ference in benefit1,2 is 11% (95% confidence in-
terval [CI], 15 to 7). Therefore, the incremental
cost-effectiveness ratio (ICER) to prevent worsen-
ing would be as follows: ICER = cost difference/
benefit difference = $60.07/0.11 = $546.09 (95%
CI, 400.47 to 858.14).
Cost might increase if devices had to be pur-
chased ($2,613.45 per device) or alternative brands
used. In conclusion, considering the elevated cost
of high-flow therapy, we believe it is necessary
to study its efficiency rigorously before general-
izing its use.
Vicent Modesto i Alapont, M.D., Ph.D.
Hospital Universitari Politècnic La Fe
Valencia, Spain
Mireia Garcia Cuscó, M.D.
Bristol Royal Hospital for Children
Bristol, United Kingdom
mireia​.­garciacusco@​­uhbristol​.­nhs​.­uk
Alberto Medina, M.D., Ph.D.
Hospital Universitario Central de Asturias
Oviedo, Spain
No potential conflict of interest relevant to this letter was re-
ported.
1. Heikkilä P, Forma L, Korppi M. High-flow oxygen therapy
is more cost-effective for bronchiolitis than standard treatment:
a decision-tree analysis. Pediatr Pulmonol 2016;​51:​1393-402.
2. Morris S, Devlin N, Parkin D, Spencer A. Economic analysis
in health care. 2nd ed. Chichester, United Kingdom:​John Wiley
& Sons, 2012.
DOI: 10.1056/NEJMc1805312
To the Editor: Franklin et al. reported lower
rates of escalation of care due to treatment fail-
ure in infants with bronchiolitis receiving high-
flow oxygen than in those receiving standard
 Correspondence

Success $HFNC
HFNC

Respiratory Failure
$HFNC
treatment
Success
$LFNC
Success
$LFNC+HFNC
LFNC Failure
Failure
$LFNC+HFNC

Success
$79.10
HFNC 0.880
$79.10
Failure
Respiratory $79.10
treatment 0.120
LFNC: $19.03
Success
$0.84; P=0.770
0.770 Success
$19.03 $79.94; P=0.140
0.610
LFNC Failure
$79.94
0.230 Failure $79.94; P=0.090
0.390

Figure 1. Decision-Tree Analysis — Model and Roll-Back Outcome.

The treatment cost of disposable items per patient is as follows: high-flow nasal cannula (HFNC), $79.10 (Fisher
and Paykel), including $32.07 per interface and $47.03 per circuit, and low-flow nasal cannula (LFNC), $0.84 (Inter‑
surgical). The cost per patient of putting every patient initially on low-flow therapy and escalating to high-flow therapy
only after low-flow therapy has failed is $19.03. The pink line indicates the preferred decision, which is associated
with lower costs, and the short parallel marks indicate the more expensive and therefore less preferable decision.
Cost data were obtained from the National Health Service Supply Chain, April 2018.

treatment. There was no significant difference Fernando Maria de Benedictis, M.D.

between groups on admission to the ICU. The
authors stated that all 167 infants in the stan-
dard-therapy group who had escalation of care,
including 65 in whom high-flow oxygen therapy
was ineffective, were admitted to an ICU. How-
ever, different data for ICU admission (65 of 167)
are shown in Table 3 of the article (available at
NEJM.org). The statistical difference between
groups for this important clinical parameter is
probably destined to change according to the
“true” number of patients to consider.
It is also quite surprising that children who
received high-flow oxygen therapy had a higher
respiratory rate (62.6 breaths per minute) than
those in the standard-treatment group (54.6
breaths per minute) at the time of escalation of
care. There was no significant difference in re-
spiratory rate between the two groups at base-
line (53.1 vs. 52.0), and an increase in respira-
tory rate by any amount since admission was one
of the clinical criteria for escalation of care. The
authors do not explain this point.
Salesi Children’s Hospital Foundation
Ancona, Italy
Paola Cogo, M.D.
S. Maria della Misericordia University Hospital
Udine, Italy
No potential conflict of interest relevant to this letter was re-
ported.
DOI: 10.1056/NEJMc1805312
To the Editor: Franklin et al. show that high-
flow oxygen therapy is successful in preventing
escalation of care in infants with bronchiolitis.
A word of caution regarding escalation of care
in the standard-therapy group is indicated, since
escalation most often resulted in the initiation
of the comparator, high-flow oxygen therapy. Pre-
vention of admission to the pediatric intensive
care unit (PICU) and of mechanical ventilation
are more relevant end points, since both are as-
sociated with substantial complications and high
costs.1-3 High-flow oxygen use may add to the

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 The n e w e ng l a n d j o u r na l of m e dic i n e

The authors reply: Our study was designed to

500
453 452
investigate whether high-flow oxygen can be safe-
450 ly used in general wards, with escalation of care
400
No. of PICU Admissions

due to treatment failure as a primary end point.

350
294 291
312 For pragmatic reasons, patients in the standard-
300
247 therapy group were allowed to cross over to the
250 228 223 231
212
185
high-flow group for rescue therapy. Infants
200
whose condition did not improve in response to
150
100
high-flow oxygen therapy were routinely admit-
50
ted to the ICU, whereas those who did not have a
0 response to standard therapy could be treated on
general wards with high-flow oxygen therapy.
06

07

08

09

10

11

12

13

14

15

16
20

20

20

20

20

20

20

20

20

20

20
Figure 2. Increase in PICU Admissions in the Netherlands from 2006
through 2016.
Data were extracted from a national pediatric intensive care unit (PICU)
registry that reported PICU admissions in which a diagnosis of primary
or secondary bronchiolitis was reported.
alarming increase in PICU admissions for viral
bronchiolitis.3 A trend that is confirmed by pre-
liminary data from the Netherlands in a 10-year
national PICU registry showed an increase in
admissions (Fig. 2). Ironically, as compared with
the standard-therapy group, more children in the
high-flow oxygen group required PICU admis-
sion (65 vs. 87, P = 0.08) and intubation (4 vs. 8).
We suggest that trials that evaluate interventions
in viral bronchiolitis use PICU admission and in-
vasive mechanical ventilation as distinct primary
outcomes.
Rosalie S. Linssen, M.D.
Job B. van Woensel, M.D., Ph.D.
Academic Medical Center
Amsterdam, the Netherlands
r​.­s​.­linssen@​­amc​.­uva​.­nl
Louis Bont, M.D., Ph.D.
University Medical Center
Utrecht, the Netherlands
No potential conflict of interest relevant to this letter was re-
ported.
1. Nishisaki A, Marwaha N, Kasinathan V, et al. Airway man-
agement in pediatric patients at referring hospitals compared
to a receiving tertiary pediatric ICU. Resuscitation 2011;​82:​386-
90.
2. Heikkilä P, Forma L, Korppi M. Hospitalisation costs for
infant bronchiolitis are up to 20 times higher if intensive care is
needed. Acta Paediatr 2015;​104:​269-73.
3. Schlapbach LJ, Straney L, Gelbart B, et al. Burden of disease
and change in practice in critically ill infants with bronchiolitis.
Eur Respir J 2017;​49(6):​1601648.
DOI: 10.1056/NEJMc1805312
In response to Meskill and Moore: we agree
that care for the majority of children with bron-
chiolitis can be managed with standard therapy.
The study was neither powered nor designed to
determine whether late commencement of high-
flow therapy is inferior to early commencement.
De Benedictis and Cogo question the ICU
admission data in the standard-therapy group.
In this group, all 167 patients with treatment
failure who required escalation of therapy were
not automatically admitted to the ICU (65 pa-
tients were admitted). In the high-flow group,
87 were admitted to the ICU. Further, in an un-
blinded study, we cannot exclude the possibility
of a greater bias to tolerate sicker infants in the
high-flow group, which would explain the high-
er respiratory rate at the point of escalation.
Modesto i Alapont et al. are correct that an
understanding of the comparative costs will be an
important consideration in treatment decisions.
An analysis of health care–related economics is
ongoing.
Our study showed that the use of high-flow
oxygen therapy in infants with bronchiolitis can
be accomplished in the general ward. The most
appropriate timing of its deployment remains to
be clarified.
Linssen et al. comment on the upward trend
of bronchiolitis-related ICU admissions in the
Netherlands, which is consistent with previously
published registry data from Australia and New
Zealand.1 In the past, high-flow therapy was
largely restricted to the ICU. Our large random-
ized, controlled trial demonstrates excellent safe-
ty when applying high-flow therapy to hypox-
emic infants with bronchiolitis outside ICUs. In
our study, 308 of 13,454 (2.3%) infants with
bronchiolitis were admitted to ICUs (156 infants
before enrollment and 152 after enrollment).

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 Correspondence

Among the 1472 infants who were randomly as-

signed to the study, 12 (0.8%) were intubated, a 1600
rate that is lower than that previously reported

ICU Admission for Bronchiolitis

1400
by Hasegawa et al. (2.3%).2 The latest figures 1200
provided in the Australia and New Zealand reg- 1000
istry show a decrease in ICU admissions (Fig. 3),

(per yr)
800
possibly because of more frequent use of high-
flow oxygen in general wards. We disagree that 600

ICU care should be used as the primary out- 400

come, since ICU admission depends not only on 200
the physiological status of the patient but also 0
on local thresholds and practices. Risk-adjusted

11

12

13

14

15

16

17
20

20

20

20

20

20

intubation rates that varied by a factor of 6 were
reported in infants with bronchiolitis who were
admitted to ICUs in Australia and New Zealand.3
Donna Franklin, B.N., M.B.A.
Mater Research Institute, University of Queensland
Brisbane, QLD, Australia
20
Figure 3. ICU Admissions for Infants with Bronchiolitis in Australia
and New Zealand between 2010 and 2017.
Data are from the Australian and New Zealand Pediatric Intensive Care
(ANZPIC) Registry.1

Franz E. Babl, M.D., M.P.H. 1. Australian and New Zealand Paediatric Intensive Care
Murdoch Children’s Research Institute (ANZPIC) Registry (http://www​.anzics​.com​.au/​w ww​.anzics​.com​
Melbourne, VIC, Australia .au/​pages/​CORE/​A NZPICR-registry​.html).
2. Hasegawa K, Tsugawa Y, Brown DF, Mansbach JM, Camargo
Andreas Schibler, M.D. CA Jr. Trends in bronchiolitis hospitalizations in the United
Centre for Children’s Health Research States, 2000–2009. Pediatrics 2013;​132:​28-36.
South Brisbane, QLD, Australia 3. Schlapbach LJ, Straney L, Gelbart B, et al. Burden of disease
a​.­schibler@​­uq​.­edu​.­au and change in practice in critically ill infants with bronchiolitis.
Eur Respir J 2017;​49(6):​1601648.
Since publication of their article, the authors report no fur-
ther potential conflict of interest. DOI: 10.1056/NEJMc1805312

Are We Prepared for Nuclear Terrorism?

To the Editor: Gale and Armitage (March 29
issue)1 provide detailed scenarios of intentional
exposure of the public to ionizing radiation. Such
an incident of any size would be a disaster, and
the detonation of an improvised nuclear device
would be catastrophic. The authors wisely note
the importance of efforts to avoid these incidents
and the need for education, prevention, prepared-
ness, planning, and necessary resources.
After the 9/11 World Trade Center and an-
thrax terrorist attacks in 2001, the U.S. govern-
ment and many nongovernmental organizations
launched a concerted effort to develop resources
and capabilities based on advances in science and
and links to other organizations’ resources for
first responders.
Many programs are run by staff members
who continue to work every day on this massive
task of preparedness to respond to a radiologic
disaster. Health care workers and response plan-
ners must endeavor to work together without
being overwhelmed by the task at hand.
Dennis Confer, M.D.
National Marrow Donor Program
Minneapolis, MN
Nelson Chao, M.D., M.B.A.
Duke University
Raleigh, NC

technology. Key resources include the Radiation Cullen Case, Jr., M.P.A.
Emergency Medical Management website (www​. National Marrow Donor Program
Minneapolis, MN
remm​.­nlm​.­gov/​­), which offers medical care pro- ccase@​­nmdp​.­org
viders information on response and prepared- No potential conflict of interest relevant to this letter was re-
ness, just-in-time training, educational materials, ported.

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