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\begin{document}

\title{ROX (Respiratory rate-OXygenation) index to predict early response to
high-flow nasal cannula therapy in infants with viral bronchiolitis}



\author[1]{Milesi Christophe}%
\author[1]{Julien Baleine}%
\author[2]{Erika Nogue}%
\author[2]{Lionel Moulis}%
\author[3]{Robin POUYAU}%
\author[1]{Arthur Gavotto}%
\author[4]{David Brossier}%
\author[5]{guillaume mortamet}%
\author[1]{GILLES CAMBONIE}%
\affil[1]{Hopital Arnaud de Villeneuve}%
\affil[2]{Universite de Montpellier Faculte de Medecine Montpellier-Nimes}%
\affil[3]{Centre Hospitalier Lyon-Sud}%
\affil[4]{Centre Hospitalier Universitaire de Caen}%
\affil[5]{CHU Grenoble Alpes Pharmacie}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Introduction} High flow nasal cannula (HFNC) is commonly used as
first step respiratory support in infants with moderate-to-severe acute
viral bronchiolitis (AVB). This device, however, fails to effectively
manage respiratory distress in about a third of patients, and data are
limited on determinants of patient response. The respiratory
rate-oxygenation (ROX) index is a relevant tool to predict the risk for
HFNC failure in adult patients with lower respiratory tract infections.
The primary objective of this study was to assess the relationship
between ROX indexes collected before and 1 hour after HFNC initiation,
and HFNC failure occurring in the following 48 hours in infants with
AVB. \textbf{Method:} This is an ancillary study to the multicenter
randomized controlled trial TRAMONTANE 2, that included 286 infants of
less than 6 months with moderate-to-severe AVB. Collection of
physiological variables at baseline (H0), and 1 hour after HFNC (H1),
included heart rate (HR), respiratory rate (RR), fraction of inspired
oxygen (FiO \textsubscript{2}), respiratory distress score (mWCAS), and
pain and discomfort scale (EDIN). ROX was calculated as SpO
\textsubscript{2}/FiO \textsubscript{2} to RR. Predefined HFNC failure
criteria included increase in respiratory distress score or respiratory
rate, increase in discomfort, and severe apnea episodes. The accuracy of
ROX index to predict HFNC failure was assessed using receiver operating
curve analysis. \textbf{Result:} HFNC failure occurred in 111/286 (39\%)
infants, and for 56 (50\% of the failure) of them within the first 6
hours. The area under the curve of ROX indexes at H0 and H1 were,
respectively, 0.56 (95\% CI 0.48-0.63, p =0.14), 0.56 (95\% CI 0.49-
0.64, p =0.09). HFNC failure was associated with higher mWCAS score at
H1 (p\textless{}0.01) and lower decrease in EDIN scale during the first
hour of HFNC delivery (p = 0.02), but none of the physiological
variables were predictive of HFNC failure. \textbf{Conclusion:} In this
study, neither ROX index, nor physiological variables usually collected
in infants with AVB had early discriminatory capacity to predict HFNC
failure.%
\end{abstract}%



\sloppy


\textbf{ROX (Respiratory rate-OXygenation) index to predict early
response to high-flow nasal cannula therapy in infants with viral
bronchiolitis}

Christophe Milesi\textsuperscript{1}, Julien Baleine\textsuperscript{1},
Erika Nogue\textsuperscript{2}, Lionel Moulis\textsuperscript{2} MD;
Robin Pouyau\textsuperscript{3}; Arthur Gavotto\textsuperscript{1};
David Brosssier\textsuperscript{4}; Guillaume
Mortamet\textsuperscript{5}; Gilles Cambonie\textsuperscript{1}, MD,
PhD; for the GFRUP Respiratory Study Group*.

\textbf{Affiliations:} \textsuperscript{1}Pediatric Intensive Care Unit,
Arnaud de Villeneuve University Hospital, Montpellier,
France;\textsuperscript{2}Clinical Research and Epidemiology Unit, CHU
Montpellier, Univ Montpellier, Montpellier,
France;\textsuperscript{3}Pediatric Intensive Care Unit,
Woman-Mother-Child University Hospital, Lyon, France;
\textsuperscript{4} Pediatric Intensive Care Unit, University Hospital
Caen-Normandy, France\textsuperscript{5}Pediatric Intensive Care Unit,
Grenoble University Hospital, La Tronche, France;

*The members of the GFRUP Respiratory Study Group are listed in the
acknowledgments.

\textbf{Correspondence:} Christophe Milesi, MD, Department of Neonatal
Medicine and Pediatric Intensive Care, Arnaud de Villeneuve University
Hospital, 371 Avenue Doyen G Giraud, 34295 Montpellier Cedex 5, France.

Tel +33(0)467 336 609, Fax: +33(0)467 336 228,
E-mail:\emph{c-milesi@chu-montpellier.fr}

\textbf{Key words:} bronchiolitis, high-flow nasal cannula, infant,
failure, risk prediction.

\textbf{Word counts:} text: 1758; Abstract: 320; Tables: 2; Figures: 1

\textbf{Conflict of interest statement:} The authors have no financial
relationships and no potential conflicts of interest relevant to this
article to disclose.

\textbf{Abbreviations:}

AUC: area under the curve.

AVB: acute viral bronchiolitis

CPAP: continuous positive airway pressure.

HFNC: high-flow nasal cannula.

EDIN {[}\selectlanguage{ngerman}\emph{Echelle de douleur et d'inconfort du nouveau-né} {]}:
neonatal pain and discomfort scale.

FiO\textsubscript{2}: fraction of inspired oxygen.

HR: heart rate.

mWCAS: modified Wood's clinical asthma score.

pvCO\textsubscript{2}: partial pressure of carbon dioxide.

ROC: receiver operating curve.

ROX: respiratory rate-oxygenation index.

RR: Respiratory rate.

\textbf{ABSTRACT}

\textbf{Introduction}

High flow nasal cannula (HFNC) is commonly used as first step
respiratory support in infants with moderate-to-severe acute viral
bronchiolitis (AVB). This device, however, fails to effectively manage
respiratory distress in about a third of patients, and data are limited
on determinants of patient response. The respiratory rate-oxygenation
(ROX) index is a relevant tool to predict the risk for HFNC failure in
adult patients with lower respiratory tract infections. The primary
objective of this study was to assess the relationship between ROX
indexes collected before and 1 hour after HFNC initiation, and HFNC
failure occurring in the following 48 hours in infants with AVB.

\textbf{Method:}

This is an ancillary study to the multicenter randomized controlled
trial TRAMONTANE 2, that included 286 infants of less than 6 months with
moderate-to-severe AVB. Collection of physiological variables at
baseline (H0), and 1 hour after HFNC (H1), included heart rate (HR),
respiratory rate (RR), fraction of inspired oxygen
(FiO\textsubscript{2}), respiratory distress score (mWCAS), and pain and
discomfort scale (EDIN). ROX was calculated as
SpO\textsubscript{2}/FiO\textsubscript{2} to RR. Predefined HFNC failure
criteria included increase in respiratory distress score or respiratory
rate, increase in discomfort, and severe apnea episodes. The accuracy of
ROX index to predict HFNC failure was assessed using receiver operating
curve analysis.

\textbf{Result:}

HFNC failure occurred in 111/286 (39\%) infants, and for 56 (50\% of the
failure) of them within the first 6 hours. The area under the curve of
ROX indexes at H0 and H1 were, respectively, 0.56 (95\% CI 0.48-0.63, p
=0.14), 0.56 (95\% CI 0.49- 0.64, p =0.09). HFNC failure was associated
with higher mWCAS score at H1 (p\textless{}0.01) and lower decrease in
EDIN scale during the first hour of HFNC delivery (p = 0.02), but none
of the physiological variables were predictive of HFNC failure.

\textbf{Conclusion:}

In this study, neither ROX index, nor physiological variables usually
collected in infants with AVB had early discriminatory capacity to
predict HFNC failure.

\textbf{INTRODUCTION}

Acute viral bronchiolitis (AVB) is a leading cause of lower respiratory
tract infection and hospitalization in young infants, notably those aged
less than 1 year {[}1{]}. Management of moderate-to-severe AVB is based
on respiratory support, with as the first step administration of a
heated and humidified mixture of air and oxygen with high\selectlanguage{english}-flow nasal
cannula (HFNC) {[}2{]}. While several studies have confirmed HFNC
effectiveness to reduce the work of breathing in AVB {[}3-5{]}, failure
occurs in 30-40\% of these patients {[}6-8{]}. In these infants,
evolving respiratory failure requires escalation in therapeutic
measures, including transition to continuous positive airway pressure
(CPAP), then if necessary to noninvasive ventilation or intubation
{[}9{]}.

Early identification of patients who are most likely to fail with HFNC
is critical for care organization in the pediatric emergency department
{[}10{]}. Indeed, these infants will need to be referred to a pediatric
intensive care unit, necessary for the monitoring of any non-invasive
ventilation technique including CPAP and bilevel positive airway
pressure, while those who will improve with HFNC can potentially be
transferred to a general pediatric ward {[}11{]}. Currently, some
patient characteristics have been individualized as predictors of
respiratory deterioration, notably younger age or initial severity
{[}12, 13{]}. However, neither isolated physiologic parameters, such as
respiratory rate (RR), fraction of inspired oxygen
(FiO\textsubscript{2}), or venous/capillary partial pressure of carbon
dioxide (pvCO\textsubscript{2}), nor clinical scales that incorporate
different vital signs have demonstrated a consistent association with
the risk of HFNC failure and are discriminating enough to be used as
triage tools {[}14-18{]}.

Recently, Roca \emph{et al.} developed a tool to assess the risk for
HFNC failure in adult patients with hypoxemic acute respiratory failure
{[}19{]}. ROX (Respiratory rate-OXygenation) index corresponds to the
ratio of patient oxygenation, which has been associated to HFNC success,
over RR, which has been associated to HFNC failure. Subsequent studies
confirmed it was a good predictor of HFNC failure in lower respiratory
tract infections, including those caused by virus {[}20, 21{]}. In
pediatric patients with acute respiratory failure, ROX index application
24 and 48 hours after hospital admission also appeared a good marker for
predicting the risk of HFNC failure {[}22{]}. In the specific context of
AVB in \textless{}2 years infants managed in a pediatric emergency
department, patients with ROX index in the lowest quartile at HFNC
initiation were three times more likely to require CPAP compared to
those in the highest quartile {[}23{]}. The single-center nature of this
study, with lack of standardization for failure criteria, incited to
test the relevance of ROX index in an homogeneous population of
\textless{}6 months infants requiring HFNC for severe AVB, recruited in
the framework of a multicenter study with predefined HFNC failure
criteria {[}24{]}.

The primary objective of this study was to assess the relationship
between ROX index collected early (\emph{i.e.} before HFNC initiation
and 1 hour after), and HFNC failure occurring in the following 48 hours
in patients admitted for severe AVB.

\textbf{METHODS}

This is an ancillary study to the multicenter randomized controlled
trial TRAMONTANE 2, which compared two settings, (3 versus 2 L/kg/min),
in young infants with severe AVB (defined by a modified Wood's clinical
asthma score (mWCAS) \textgreater{}3) supported with HFNC {[}24{]}. The
study protocol was approved by the South Mediterranean IV Ethics
Committee (2016-A00900-51), and recorded on the National Library of
Medicine registry (NCT02824744). Written authorization was obtained from
the two parents.

The study, performed in 16 French university hospital centers between
November 2016 and March 2017, enrolled 142 infants in the 2 L-group, 144
infants in 3 L-group, and found the same failure rate of 39\% in each
group, allowing to include the 286 TRAMONTANE 2 patients in the current
analysis.

\textbf{Data collection}

Heart rate (HR), RR, FiO\textsubscript{2}, venous/capillary pH and
pvCO\textsubscript{2}, mWCAS, and the neonatal pain and discomfort scale
(EDIN) were collected at baseline (H0), in the 15 minutes following
admission, while the infant received a blend of air/oxygen using nasal
cannula at a maximal flow rate of 1 L/min. The same physiological
variables, except for capillary blood gas analysis, were collected 1
hour after HFNC initiation at the flow rate allocated by randomization
(H1).

At H0 and H1, ROX was calculated as
SpO\textsubscript{2}/FiO\textsubscript{2} to RR.

Predefined HFNC failure criteria included the occurrence, within 48
hours of randomization, of one or more of the following: increase,
compared to H0, in respiratory distress score (\emph{i.e,} 1 point in
mWCAS) or respiratory rate (\emph{i.e,} \textgreater{}10 breath per min
with RR\textgreater{} 60 bpm), increase in discomfort (1 point in EDIN
score), and severe apnea episodes requiring bag and mask ventilation.

\textbf{Outcome}

The primary study outcome was discriminatory capacity of ROX index
values, at H0 and H1, and their change during the first hour of HFNC
delivery (H1-H0), to predict HFNC failure.

We also tested, as secondary outcomes, the predictive values of the
physiological variables collected at H0 and H1 and their changes between
the 2 time-points.

\textbf{Statistical analyses}

Groups, defined as HFNC failure or success, were compared using Student
or Wilcoxon Mann-Whitney test for continuous variables and Chi-square or
Fisher test for categorical ones.

The accuracy of ROX index and physiological variables to predict HFNC
failure was assessed using receiver operating curve (ROC) analysis. The
area under the curve (AUC) was calculated by the Hanley method and
compared to the value 0.5 using Wilcoxon's W statistic. For the analyses
at H1 and for changes during the first hour of HFNC delivery, all HFNC
failure patients at H1 or before were excluded.

Statistical tests were performed 2-tailed and p-values \textless{}0.05
were considered significant test results. Statistical analyses were
conducted with SAS (version 9.4, SAS Institute, Cary, NC) and R software
(R 2.3.4 for Windows). Patients' characteristics were presented using
mean and standard deviation (SD) for the quantitative variables and
frequencies with proportions for categorical ones.

\textbf{RESULTS}

HFNC failure occurred in 111/286 (39\%) infants, after a mean (SD) delay
of 11.36 (11.98)

hours (Figure 1). In 96/111 (86\%), failure occurred within 24 hours,
including 56 (50\%) within the first six hours.

\textbf{Primary outcome:}

ROX indexes at H0 and H1, and their changes during the first hour were
not different according to HFNC failure or success (Table 1). Their
respective AUC were 0.56 (95\% CI 0.48-0.63, p =0.14), 0.56 (95\% CI
0.49- 0.64, p =0.09), and 0.54 (95\% CI 0.45-0.62, p =0.34) (Table 2).
These results didn't support that early ROX indexes predicted HFNC
failure.

\textbf{Secondary outcome}

HFNC failure was associated with higher mWCAS score at H1
(p\textless{}0.01) and lower decrease in EDIN scale during the first
hour of HFNC delivery (p = 0.02) (Table 1). However, none of the
physiological variables collected at H0 and H1 and their changes during
the first hour of HFNC delivery were predictive of HFNC failure,
according to their respective AUC (Table 2).

\textbf{DISCUSSION}

In this multicentre population of young infants with severe AVB, the
failure rate of HFNC was 39\%. Failure of this first step of respiratory
support occurred early, within 6 hours after HFNC initiation for half of
failing patients and within 24 hours for nearly 90\% of them. Neither
ROX index, nor physiological variables usually collected in infants with
acute respiratory failure had early discriminatory capacity to predict
failure of management with HFNC.

In a previous study, Kannikeswaran \emph{et al.} observed an association
between ROX index and HFNC failure, in other words the need for positive
pressure ventilation, in \textless{}2 years infant with bronchiolitis
{[}23{]}. This result was particularly relevant from the perspective of
directing these patients to the most suitable units downstream of the
emergency department. In this perspective, our study aimed to identify a
threshold for this index, associated with actual predictive capacities.
Our AUC results suggested a weak and non-significant relationship
between ROX and HFNC failure, which currently does not confirm the
interest of this tool in a clinical decision rule. The main difference
with studies suggesting that ROX index may be a good marker to predict
the risk of HFNC failure probably comes from different patient's
characteristics {[}22, 23{]}. Our trial involved much younger patients
and, as our results indicate, age is a key risk factor for respiratory
failure in this population {[}12, 13{]}. In addition, the TRAMONTANE 2
study included patients probably affected by more severe forms of the
disease, as mWCAS \emph{\textgreater{}} 3 was required to be eligible,
which signals unambiguous respiratory distress. In Kannikeswaran\emph{et
al.} study, the regression model to estimate the odds ratio of PPV
requirement was based on the highest ROX quartile, suggesting marked
heterogeneity in the severity of bronchiolitis {[}23{]}.

The ROX index takes into account only two characteristics of a
respiratory distress, namely oxygenation and tachypnea. While these
parameters are critical in patients with acute hypoxemic respiratory
failure, they do not take into account all of the determinants of HFNC
failure in AVB. Indeed, AVB present different phenotypes: sometimes as a
restrictive parenchymal disease, but a majority of these infants
demonstrate a severe obstructive lung disease, with markedly increased
work of breathing and frequent apneas {[}4, 5, 25{]}. These two
elements, as well as comfort, are not integrated in the ROX index,
whereas they often intervene in the clinician's decision to upgrade
respiratory support in a patient with AVB.

No variable, observed or calculated, was able to predict HFNC failure in
this work. However, half of failure occurred within 6 hours, which
suggests that such delay may be a relevant criterion for triage. Insofar
as the volume of patients in the emergency room allows it, it may be
consistent to maintain the infant with HFNC and adapted monitoring
during this timeframe before deciding admission to pediatric intensive
care unit.

This study has several strengths, including a large, multicentric and
homogeneous population, in terms of severity and age, of infants with
AVB. In addition, predefined HFNC failure criteria had been validated by
a panel of experts providing from the 16 participating centres in the
trial.

We acknowledge some limitations. Half of the children received a flow
rate of 2 L/min/kg, and the other half 3 L/min/kg, but we are uncertain
whether this affects the interpretation of our results because the
failure rate was exactly the same in the two groups.

The predictive value of the ROX index beyond the first hour of HFNC
delivery could have been evaluated, but it seemed more obvious that the
relevance of an urgent triage tool can hardly exceed 1 to 2 hours.

\textbf{Conclusion:}

In this population of patient with severe AVB supported with HFNC, half
of failures occurred within the first 6 hours. Use of ROX index before
or 1 hour after delivery of this support was not able to predict this
event.

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pneumonia patients with hypoxemic respiratory failure: The utility of
the ROX index. J Crit Care. 2016 Oct;35:200-5. doi:
10.1016/j.jcrc.2016.05.022. Epub 2016 May 31. PMID: 27481760.

20. Roca O, Caralt B, Messika J, Samper M, Sztrymf B, Hernández G,
García-de-Acilu M, Frat JP, Masclans JR, Ricard JD. An Index Combining
Respiratory Rate and Oxygenation to Predict Outcome of Nasal High-Flow
Therapy. Am J Respir Crit Care Med. 2019 Jun 1;199(11):1368-1376. doi:
10.1164/rccm.201803-0589OC. PMID: 30576221.

21. Prakash J, Bhattacharya PK, Yadav AK, Kumar A, Tudu LC, Prasad K.
ROX index as a good predictor of high flow nasal cannula failure in
COVID-19 patients with acute hypoxemic respiratory failure: A systematic
review and meta-analysis. J Crit Care. 2021 Dec;66:102-108. doi:
10.1016/j.jcrc.2021.08.012. Epub 2021 Sep 8. PMID: 34507079; PMCID:
PMC8424061.

22. Yildizdas D, Yontem A, Iplik G, Horoz OO, Ekinci F. Predicting nasal
high-flow therapy failure by pediatric respiratory rate-oxygenation
index and pediatric respiratory rate-oxygenation index variation in
children. Eur J Pediatr. 2021 Apr;180(4):1099-1106. doi:
10.1007/s00431-020-03847-6. Epub 2020 Oct 19. PMID: 33078280.

23. Kannikeswaran N, Whittaker P, Sethuraman U. Association between
respiratory rate oxygenation index and need for positive pressure
ventilation in children on high flow nasal cannula for bronchiolitis.
Eur J Pediatr. 2022 Nov;181(11):3977-3983. doi:
10.1007/s00431-022-04607-4. Epub 2022 Sep 14. PMID: 36102995; PMCID:
PMC9525568.

24. Milési C, Pierre AF, Deho A, Pouyau R, Liet JM, Guillot C, Guilbert
AS, Rambaud J, Millet A, Afanetti M, Guichoux J, Genuini M, Mansir T,
Bergounioux J, Michel F, Marcoux MO, Baleine J, Durand S, Durand P,
Dauger S, Javouhey E, Leteurtre S, Brissaud O, Renolleau S, Portefaix A,
Douillard A, Cambonie G; GFRUP Respiratory Study Group. A multicenter
randomized controlled trial of a 3-L/kg/min versus 2-L/kg/min high-flow
nasal cannula flow rate in young infants with severe viral bronchiolitis
(TRAMONTANE 2). Intensive Care Med. 2018 Nov;44(11):1870-1878. doi:
10.1007/s00134-018-5343-1. Epub 2018 Oct 21. PMID: 30343318.

25. Cambonie G, Milési C, Jaber S, Amsallem F, Barbotte E, Picaud JC,
Matecki S. Nasal continuous positive airway pressure decreases
respiratory muscles overload in young infants with severe acute viral
bronchiolitis. Intensive Care Med. 2008 Oct;34(10):1865-72. doi:
10.1007/s00134-008-1201-x. Epub 2008 Jul 8. PMID: 18607564.

\textbf{FIGURE TABLE}

Figure 1. Cumulative number of failures according to time in infants
with acute viral bronchiolitis included in the TRAMONTANE 2 trial.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Table 1. Characteristics of the study population, ROX index and
physiological variables at baseline (H0) and 1 hour after HFNC
initiation (H1).\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Total Population N= 286\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
HFNC Success N= 175\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
HFNC Failure N= 111\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Study population\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Study population\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Study population\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Study population\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Study population\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Male (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
170 (59.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
100 (57.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
70 (63.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.32\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age, days (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
54 (54)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
58 (42)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
47 (68)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Weight, g (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4460 (1137)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4547 (1147)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4324 (1112)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.09\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Born preterm (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
42 (15)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27 (15)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15 (14)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.66\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Baseline (H0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Baseline (H0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Baseline (H0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Baseline (H0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Baseline (H0)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
ROX index (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 250 6.6 (3.3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 158 6.6 (2.8)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 92 6.4 (4.1)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.14\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
mWCAS (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 286 4.5 (1.1)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 175 4.3 (1.0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 111 4.7 (1.3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
EDIN (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 279 5 (3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 173 5 (3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 106 5 (3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.60\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
pH (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 231 7.3 (0.1)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 143 7.3 (0.1)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 88 7.3 (0.1)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.46\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
RR, bpm (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 286 58 (16)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 175 57 (15)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 111 59 (18)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.42\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
HR, bpm (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 286 161 (20)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 175 161 (19)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 111 162 (21)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.35\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
FiO\textsubscript{2}, \% (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 250 32 (13)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 158 31 (13)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 92 33 (13)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.07\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
PCO\textsubscript{2}, mmHg (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 234 58 (13)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 145 58 (13)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 89 60 (12)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.28\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 hour after HFNC initiation (H1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 hour after HFNC initiation (H1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 hour after HFNC initiation (H1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 hour after HFNC initiation (H1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 hour after HFNC initiation (H1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
ROX index (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 261 7.4 (3.3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 175 7.7 (3.4)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 86 7.0 (2.8)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.09\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
mWCAS (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 258 3.5 (1.2)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 175 3.3 (1.0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 83 4.0 (1.5)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textless{} 0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
EDIN (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 256 3 (2.3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 173 2.9 (2.2)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 83 3.3 (2.5)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.30\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
RR, bpm (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 261 51 (14)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 175 50 (13)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 86 54 (17)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
HR bpm (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 261 155 (19.4)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 175 153 (20.3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 86 158 (16.9)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.03\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
FiO\textsubscript{2}, \% (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 261 29.6 (8.5)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 175 29.4 (8.9)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 86 30.0 (7.8)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.28\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Change during the first hour of HFNC delivery (H1-H0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Change during the first hour of HFNC delivery (H1-H0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Change during the first hour of HFNC delivery (H1-H0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Change during the first hour of HFNC delivery (H1-H0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Change during the first hour of HFNC delivery (H1-H0)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
ROX index (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 230 0.8 (3.3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 158 1.0 (3.3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 72 0.5 (3.4)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.34\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
mWCAS (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 258 -0.9 (1.0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 175 -1.0 (1.0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 83 -0.7 (1.0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.07\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
EDIN (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 252 -2.0 (2.4)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 171 -2.2 (2.4)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 81 -1.5 (2.3)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.02\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
RR, bpm (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 261 -6.3 (\selectlanguage{ngerman}± 14.4)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 175 -7.1 (\selectlanguage{ngerman}± 14.4)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 86 -4.7 (\selectlanguage{ngerman}± 14.2)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.31\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
HR, bpm (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 261 -6.4 (\selectlanguage{ngerman}± 20.0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 175 -8.0 (\selectlanguage{ngerman}± 19.8)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 86 -3.2 (\selectlanguage{ngerman}± 20.2)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.17\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
FiO\textsubscript{2}, \% (\selectlanguage{ngerman}±SD)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 247 -1.9 (12.5)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 158 -1.6 (12.2)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
N= 89 -2.4 (13.0)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.94\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Values are mean (SD) or numbers (\%).

BPD: Bronchopulmonary dysplasia; EDIN: neonatal pain and discomfort
scale; HR: Heart rate; mWCAS: modified Wood's Clinical Asthma Score;
ROX: Respiratory rate OXygenation index; RR: Respiratory rate.

Table 2. Area under the receiver operating curve for ROX index and
physiological variables at baseline (H0), 1 hour after HFNC initiation
(H1), and their change during the first hour (H1-H0), to predict the
risk of HFNC failure in infants with acute viral bronchiolitis.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
AUC (95\% CI)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
H0\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
p\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
H1\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
p\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
H1-H0\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ROX index\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.56 (0.48-0.63)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.14\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.56 (0.49-0.64)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.09\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.54 (0.46-0.62)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.34\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
mWCAS\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.57 (0.50-0.64)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.05\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.64 (0.57-0.72)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.57 (0.49-0.65)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.07\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
EDIN\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.52 (0.45-0.59)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.60\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.54 (0.46-0.62)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.30\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.59 (0.51-0.66)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.02\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
RR\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.53 (0.46-0.60)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.39\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.57 (0.50-0.65)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.05\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.54 (0.46-0.61)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.31\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HR\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.53 (0.46-0.60)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.35\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.59 (0.51-0.66)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.02\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.55 (0.48-0.63)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.17\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

AUC: Area under the receiver operating curve; CI: confidence intervals;
EDIN: neonatal pain and discomfort scale; HR: Heart rate; mWCAS:
modified Wood's Clinical Asthma Score; ROX: Respiratory rate OXygenation
index; RR: Respiratory rate.

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