Shinshu Med J, 71⑹：403～409, 2023

Predictive Factors for Tracheal Intubation in Patients withCoronavirus Disease 2019 Treated Using a High-flow Nasal Cannula
Yuichi Ikuyama1）＊, Atsuhito Ushiki1）, Jumpei Akahane1）, Yoshitaka Yamazaki2）
Masanobu Kimoto2）, Takashi Ichiyama1）, Yosuke Wada1） and Masayuki Hanaoka1）
1） First Department of Internal Medicine, Shinshu University School of Medicine
2） Center of Infectious Diseases, Nagano Prefectural Shinshu Medical Center

Background : In Japan, patients with coronavirus disease 2019 (COVID-19)＊ requiring a high-flow nasal cannula(HFNC) are often initially treated in non-specialized facilities and transferred to an intensive care unit if tracheal
intubation is required. We aimed to investigate the factors associated with severe respiratory failure requiring
tracheal intubation at an early stage in patients with COVID-19 treated using HFNCs.
Methods : This retrospective cohort study compared the clinical features of consecutively enrolled patients withpolymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus-2 infection admitted totwo centers in Japan between early February 2020 and late June 2021.
Results : A total of 35 patients with COVID-19 treated using HFNCs were included. Treatment success andfailure occurred in 25 and 10 patients, respectively. The oxygen saturation (ROX) index (ratio of oxygen saturation[SpO2] to fraction of inspired oxygen [FiO2] and the respiratory rate) 12 h post-HFNC insertion was a useful predictor of HFNC failure (success group, 8.0 ; failure group, 6.5 : P＝0.0005). Moreover, the time from symptom
onset to respiratory failure was significantly shorter in the failure group than in the success group (3.0 and 5.0
days, P＝0.004).
Conclusions The ROX index and time from symptom onset to respiratory failure were useful predictors of HFNC
failure. Shinshu Med J 71 : 403―409, 2023
(Received for publication March 16, 2023 ; accepted in revised form August 24, 2023)
Key words : high-flow nasal cannula, COVID-19, ROX index, tracheal intubation, oxygen therapy
Abbreviations : COVID-19, coronavirus disease 2019 ; HFNC, high-flow nasal cannula ; SpO2 , oxygen saturation ;FiO2 , fraction of inspired oxygen ; IPPV, invasive positive pressure ventilation ; ICU, intensive care unit ; ROX,
ratio of oxygen saturation ; AUC, area under the curve

Ⅰ Introduction(IPPV), HFNC use minimizes the risk of ventilatorassociated pneumonia. In addition, HFNC use im-

A high-flow nasal cannula (HFNC) can maintain aproves the 90-day mortality rate and the number ofhigh inhaled oxygen concentration by administering

ventilator-free days at 28 days compared with stan-

warmed and humidified oxygen to the patient at adard oxygen therapy or noninvasive ventilation1）.

high flow rate. By reducing the number of patients

Moreover, admission to the intensive care unit (ICU)

who require invasive positive-pressure ventilation

is not always necessary, and medical resources
can be conserved. Therefore, in Japan, patients with＊

Corresponding author : Yuichi IkuyamaFirst Department of Internal Medicine, Shinshu University
School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano
390-8621, Japan
E-mail : ikuyama@shinshu-u.ac.jp

No. 6, 2023

COVID-19 requiring HFNCs are often initially treated in non-specialized facilities without an ICU andare transferred to a facility with an ICU if IPPV is
required.
403

Ikuyama・Ushiki・Akahane et al.

In patients with coronavirus disease 2019 (COVID-

included consecutive patients with polymerase chain19), HFNC use reduced the need for mechanical ven-reaction-confirmed SARS CoV-2 infection who weretilation and improved oxygenation compared withadmitted to these hospitals between early February

2）

that with standard oxygen therapy . Further, in pa-

2020 and late June 2021. Patients who required HFNCs

tients with COVID 19-related acute respiratory fail-after extubation were excluded from the study.

ure, HFNC use increased in the number of ventilator-

We classified patients who received HFNC therapy

free days compared with that with early IPPV

because of deterioration as HFNC success or failure,3）

initiation . Moreover, a previous report showed that

depending on whether intubation could be avoided.

the HFNC application reduced the mortality rate inPatients who died without being intubated because

patients with COVID-19 compared with that withof do-not-intubate orders were classified as cases of

4）

IPPV , and in another study, delayed tracheal intu-

HFNC failure. The ROX index was defined as the5）bation was associated with poor clinical outcomes .

ratio of SpO2 to FiO2 ( ％ ) and the respiratory rate

Therefore, if HFNC treatment fails to improve gas(breaths/min). The median number of days fromexchange and ventilatory function, tracheal intuba-

HFNC application to tracheal intubation was 1 daytion should be performed at the earliest.

(range, 0.5-2.5 days) in the failure group. Because

The wave of severe acute respiratory coronavirus-2

data at 6 h after HFNC introduction were missing,(SARS CoV-2) infection in Japan was substantially

we investigated the ROX index at 12 h in this study.

large, and intensive medical care resources were se-This study was performed in accordance with theverely limited. Therefore, it was important to identi-

Declaration of Helsinki and was approved by our In-fy cases with poor therapeutic effects of HFNC at an

stitutional Review Board (approval number 5228, July

early stage and conserve medical resources.

15th, 2021). The requirement for written informed

In previous studies, the ratio of the oxygen satura-consent was waived because of the use of de-identified

tion (ROX) index at 6 h, 12 h, and 72 h was used as adata collected retrospectively. Furthermore, this re-

simple, non-invasive, and promising tool for predict-search used an opt-out consent model, which meanting HFNC discontinuation : it could be used for thethat patients could opt out at any time and have theirassessment of progress and risk of intubation in

information deleted from the registry.

patients with COVID-19 presenting with pneumo6）-9）

HFNC use raises concerns regarding the increased. The ROX index refers to the combination ofrisk of viral transmission due to aerosol dispersion10）11）.

the ratio of oxygen saturation (SpO2) to the fraction

In this study, staff providing COVID-19 medical careof inspired oxygen (FiO2) and the respiratory rate.

services underwent training for personal protective

Although useful, it requires some time for calcula-equipment donning and doffing. The medical caretion. Moreover, the ROX index can be calculated after

staff donned personal protective equipment, including

introducing HFNC. Therefore, a simple indicator for

long-sleeved gowns, gloves, N95 masks, surgicaltracheal intubation is required. Accordingly, thismasks with face shields, and hair caps, while attending

study aimed to identify suitable indicators that can

to patients receiving HFNC or conventional oxygen

predict tracheal intubation earlier than the ROX

therapy. Nosocomial infections in healthcare workers

index in patients with severe respiratory failure.

were not reported during the study period.

niaⅡMaterials and Methods

Ａ

Data analysis

Continuous data are presented as median (inter-

We retrospectively reviewed the medical records

quartile range [IQR], 25th quartile, 75th quartile). Theof patients with COVID-19 who received conventionalt-test and Mann-Whitney U-test were used to com-oxygen therapy through HFNCs at the Shinshu Uni-

pare continuous data with normal and non-normal

versity Hospital (Matsumoto, Japan) and Nagano Pre-

distributions, respectively. Categorical variables were

fectural Shinshu Medical Center (Suzaka, Japan). We

compared using the chi-square test or Fisher’s exact

404

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Predictive factors for tracheal intubation with a high-flow nasal cannula in patients with COVID-19
Table 1

Demographic and clinical characteristics of the patient groups
All patients(n＝35)

Characteristic
Age, median (IQR) years≥ 65, n (％)
Number of comorbidities, n (IQR)
Heart disease
Cerebrovascular disease
Hypertension
Diabetes mellitus
Kidney disease
Respiratory disease
Malignant tumor under treatment
BMI, median (IQR) kg/m2
Sex, male, n (％)
Brinkman index, median (IQR)
SpO2 on room air, median (IQR) ％Patients treated with methylprednisolone pulse therapy (500-1000 mg/
day three times per week)
Initial steroid dose※

HFNC success(n＝25)

HFNC failure(n＝10)

P-value(HFNC successvs. HFNC failure)

67.0 (58.0, 82.0)
21 (60 ％)1.6 (1, 2)
4 (11 ％)
3 (9 ％)
17 (49 ％)
15 (43 ％)
3 (9 ％)
7 (20 ％)
3 (9 ％)

66.0 (57.5, 76.0)
13 (52 ％)
2 (1, 2)4 (16 ％)
3 (12 ％)
14 (56 ％)
11 (44 ％)
2 (8 ％)
4 (16 ％)
2 (8 ％)

67.0 (62.0, 82.0)
8 (80 ％)
2 (1, 2)0 (0 ％)
0 (0 ％)
3 (30 ％)
4 (40 ％)
1 (10 ％)
3 (30 ％)
1 (10 ％)

0.22
0.13
0.37
0.30
0.54
0.26
1.0
1.0
0.38
1.0

26.5 (23.2, 30.5)
23 (67.7 ％)
200 (0, 600)

28.1 (24.5, 30.8)
15 (71.4 ％)
20 (0, 550)

24.2 (23.8, 28.2)
6 (60.0 ％)
470 (85, 1050)

0.15
0.82
0.70

91.5 (88.3, 94.0)
9 (26 ％)

92.0 (87.5, 94.5)
6 (24 ％)

91.5 (87.3, 93.5)
3 (30 ％)

0.36
0.13

44 (40-88)

44 (40-88)

50 (45.5-87.5)

0.31

28 (80 ％)
4 (11 ％)
3 (9 ％)

20 (80 ％)
2 (8 ％)
3 (12 ％)

8 (80 ％)
2 (20 ％)
0

0.22
0.18
－

Antiviral drugs
Remdesivir
Favipiravir
Lopinavir and Ritonavir

HFNC, high-flow nasal canula ; IQR, interquartile range ; BMI, body mass index.
※ In case patients who received steroid pulse therapy, dose after steroid pulse therapy.

test, as appropriate (expected value＜0.05 in one cell).

tients in this study received corticosteroids and anti-

The ability of each risk score and biomarker tovirals, and none were vaccinated. The frequency of

discriminate between patients with HFNC successsteroid pulse and initial corticosteroid dose was not

and HFNC failure was evaluated by calculating thesignificantly different between the HNFC success andarea under the curve (AUC) of the receiver operating

failure groups (in case patients who received steroid

characteristic and its 95 ％ confidence interval. The

pulse therapy, describe the dose after steroid pulse

optimal cutoff values to assess HFNC failure weretherapy)n.

evaluated using Youden’s index. Statistical analysis

Ｂ Comparison of clinical data between the HFNC

was performed using Windows-compatible software

success and failure groups(StatFlex version 7 : Artech Co. Ltd., Osaka, Japan).

The HFNC success and failure groups included 25

Statistical significance was set at P ＜ 0.05.
Ⅲ Results
Ａ

Baseline characteristics

and 10 patients, respectively. There were no significant differences in age, sex, body mass index, or thenumber of complications, which are risk factors forsevere COVID-1912）-14）, between the HFNC successAmong the patients with COVID-19 treated during

and failure groups. Further, the laboratory test results

the study period, 35 patients met the inclusion criteria.

were not significantly different between the two

The median age was 67.0 (IQR, 58.0, 82.0) years, andgroups (Table 2). The median period from symptom

21 (67.7 ％) patients were men. The baseline charac-

onset to respiratory failure was significantly shorter

teristics of the patients are listed in Table 1. All pa-

in the HFNC failure group than in the HFNC successNo. 6, 2023

405

Ikuyama・Ushiki・Akahane et al.
Table 2

WBC, /μL
Lym, /μL
LDH, IU/L
BUN, mg/dL
Cre, mg/dL
BUN/Cre, mg/dL
CRP, mg/dL
KL-6, U/L
Ferritin, μg/L
D-dimer, μg/mL

Laboratory findings at admission
P-value

All patients(n＝35)

HFNC success(n＝25)

HFNC failure(n＝10)

4600 (3200, 6900)
1100 (875, 1338)
325 (265, 458)
13.7 (12.8, 16.9)
0.89 (0.74, 1.03)
17.4 (13.0, 19.6)
5.0 (2.3, 11.9)
386 (247, 484) (n＝13)
630 (291, 921) (n＝17)
1.0 (0.5, 1.7)5150 (3697, 7125)
1000 (800, 1100)
358 (298, 456)
14.1 (12.8, 16.9)
0.94 (0.74, 1.07)
17.3 (13.9, 18.2)
5.7 (2.4, 12.1)
328 (247, 440) (n＝9)
642 (330, 921) (n＝13)
0.9 (0.5, 1.6)4885 (3055, 7720)
1210 (1159, 1458)
287 (215, 535)
13.6 (13.0, 16.9)
0.85 (0.61, 0.91)
18.9 (14.2, 21.3)
7.1 (1.8, 11.8)
457 (344, 548) (n＝4)
507 (507, 782) (n＝4)
1.1 (1.0, 4.6)

(HFNC successvs. HFNC failure)
0.76
0.29
0.96
0.61
0.07
0.22
0.71
0.46
0.86
0.42

All values are presented as median (interquartile range).
HFNC, high-flow nasal canula : WBC, white blood cell count ; Lym, lymphocyte count ; LDH, lactate dehydrogenase ;BUN, blood urea nitrogen ; Cre, creatinine ; CRP, C-reactive protein ; KL-6, sialylated carbohydrate antigen Krebs vonden Lungen-6.
Table 3Comparison of the clinical courses and outcomes between the HFNC success and failure groups
HFNC success(n＝25)

HFNC failure(n＝10)

P-value(HFNC successvs. HFNC failure)

Duration between diagnosis and respiratory 2.0 (0.0, 3.0)
failure, median (IQR) days

2.0 (0.0, 3.5)

2.5 (0.8, 3.5)

0.87

Number of days from diagnosis to HFNC
initiation, median (IQR)

5.0 (1.0, 7.0)

5.0 (2.0, 7.0)

5.0 (1.0, 7.5)

0.59

Duration between respiratory failure and 2.0 (1.0, 4.75)
HFNC application, median (IQR) days

2.0 (1.0, 4.5)

1.0 (0.5, 4.0)

0.68

Duration between symptom onset and respiratory failure, median (IQR) days

4.0 (3.0, 6.0)

5.0 (4.0, 6.5)

3.0 (3.0, 4.5)

0.044

Intubation, n (％)

7 (20 ％)

0 (0 ％)

7 (70 ％)

Death, n (％)

3 (8.6 ％)0 (0 ％)

3 (30 ％)

Variable

All patients(n＝35)

HFNC, high-flow nasal canula ; IQR, interquartile range.

group (Table 3). Three patients in the HFNC failure

Ｄ Receiver operating characteristic analysis andgroup died.

comparison of predictive ability for HFNC failureＣ Comparison of the ROX index between the HFNC

Fig. 1 shows the AUC according to the ROX index

success and failure groups

at 12 h, and median duration from symptom onset to

The duration of HFNC use was significantly longer

respiratory failure. The AUCs (± standard error) of

in the HFNC success group than in the failure group

the ROX index at 12 h and duration between symptom(8.0 [IQR, 7.0, 11.0] and 2.0 [IQR, 0.8, 3.0] days, respec-

onset and respiratory failure were 0.91 (± 0.05) andtively) (Table 4). The ROX index at 12 h was signifi-

0.73 (± 0.09), respectively. The optimal cutoff values

cantly higher in the HFNC success group than in theto assess HFNC failure using Youden’s index were

HFNC failure group (8.0 [IQR, 7.5, 8.9] and 6.5 [IQR,

7.0 and 3.5 days for the ROX index at 12 h and time

5.8, 7.3], respectively) (Table 4).

between symptom onset and respiratory failure, re-406

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Predictive factors for tracheal intubation with a high-flow nasal cannula in patients with COVID-19
Table 4

Clinical parameters after HFNC initiation

All patients(n＝35)

Parameter
HFNC duration, days
Maximum FiO2O2 Flow, L/min
ROX index at 12 h

HFNC success(n＝25)

HFNC failure(n＝10)

P-value(HFNC successvs. HFNC failure)

7.0 (3.0, 10.0)

8.0 (7.0, 11.0)

2.0 (0.8, 3.0)

0.004

0.60 (0.53, 0,73)
40 (40, 50)
8.0 (6.8, 9.0)

0.60 (0.50, 0.60)
40 (40, 50)
8.0 (7.5, 8.9)0.80 (0.65, 0.80)
40 (29, 40)
6.5 (5.8, 7.3)

0.004
0.59
0.0005All values are presented as median (interquartile range).
HFNC, high-flow nasal cannula : ROX, ratio of oxygen saturation

Fig. 1 Receiver operating characteristic curves for the ratio of oxygen saturation(ROX) index (12 h) (solid line) and median time from symptom onset torespiratory failure in patients with coronavirus disease 2019 (dotted line)

useful predictor of HFNC failure in patients with

spectively.
Ⅳ Discussion

COVID-19 who received HFNCs6）. Similar results
were obtained in this study.

In this study, tracheal intubation was avoided in 25

The present study revealed that the period fromout of 35 patients (71.4 ％). This result was better thansymptom onset to respiratory failure was significantly

that reported previously (8 out of 15 patients, 53.3 ％)shorter in the HFNC failure group than in the HFNC

in Japan15）

and may be related to the advances insuccess group (3.0 [IQR, 3.0, 4.5] and 5.0 [IQR, 4.0, 6.5]

treatment, such as the use of corticosteroids and an-days, respectively). This suggests that among patientstiviral drugs.

with HFNCs, tracheal intubation is more likely to be

In a previous study, the ROX index at 12 h was a
No. 6, 2023

required in those exhibiting a shorter period from407

Ikuyama・Ushiki・Akahane et al.

symptom onset to respiratory failure. To the best of

COVID-19 variants. This study was conducted

our knowledge, this association has not been reported

between February 2020 and June 2021. This is thepreviously. This allows for predicting the outcome atperiod from the first confirmation of COVID-19 to

HFNC initiation and is highly valuable in clinicalthe fourth wave in Japan. B.1.1.7 was prevalent in thepractice.

fourth wave in Japan16）. Thus, differences results may

The ROX index can be calculated after HFNC application. In contrast, the median time from symptom

be obtained in patients infected with the current
variants of SARS CoV-2.

onset to respiratory failure can be evaluated earlier.

Ｖ

Although the AUC of the receiver operating charac-

Conclusions

teristic for the median time from symptom onset to

Delay in tracheal intubation may increase the risk

respiratory failure was smaller than that for the ROXof mortality, and it is important to use the ROX index

index, it is known before HFNC application. There-

and time from symptom onset to respiratory failure

fore, the median time from symptom onset to respi-

simultaneously to ensure that patients requiring

ratory failure is an important indicator that can helptransition from HFNC to tracheal intubation are notconserve medical resources and ensure cooperation

missed. The time from symptom onset to respiratory

between hospitals.

failure, which can be determined upon admission, has

In patients exhibiting a shorter period between
symptom onset and respiratory failure, oxygen satu-

a predictive value comparable with that of the ROX
index.

ration should be monitored more carefully and IPPV

Acknowledgments

should be initiated if the respiratory condition worsens. Furthermore, it may be necessary to consider

The authors would like to thank the following

the possibility of ventilator management in patients

members at the First Department of Internal Medi-with rapid respiratory failure.

cine, Shinshu University School of Medicine for pro-

Despite these novel findings, this study had someviding clinical data, advice, and experience : Kitaguchi

limitations. First, this was a retrospective study con-

Yoshiaki, Masamichi Komatsu, Kazuhisa Urushihata,

ducted at two facilities, possibly resulting in selection

Kei Sonehara, Kazunari Tateishi, and Hiroshi Yama-

bias, and the severity may have been different be-

moto. We would also like to thank Editage (www.

tween facilities. Second, in many cases, tracheal intu-

editage.com) for English language editing.

bation was considered when the FiO2 was consistent-

Fundingly ≥ 0.6 : however, a well-defined protocol for HFNC
initiation was lacking. Thus, the treatment results

This study received no specific grant from any

could have varied depending on the judgment of in-

funding agency in the public, commercial, or not-for-dividual physicians. Third, the ROX index at 6 h is

profit sectors.

more useful than that at 12 h in patients with COVID-

Conflict of interest

19 with hypoxemia9）. However, in this study, somedata on the ROX index at 6 h were missing : therefore,

The authors declare no conflicts of interest.

it was not used. Fourth, this study could not examine
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