Study population
The study flow diagram is shown in Figure 1. From 1 March 2020 to 30 April 2021, 522 patients were admitted to our hospital with the diagnosis of COVID-19. Among them, 303 patients were intolerant of conventional oxygen therapy and fulfilled our inclusion criteria. After excluding 121 patients who met the exclusion criteria, we analyzed 81 patients who initially received HFNC (HFNC group) and 101 patients who initially received IMV (IMV group).
Baseline characteristics, comorbidities, respiratory parameters, duration from symptoms to enrollment, SOFA score, and therapeutic interventions in the two groups are shown in Table 1. Age, sex, BMI, and comorbidities were similar between the two groups. The duration from symptoms to enrollment was significantly longer in the HFNC group than that in the IMV group (median, 9 days [interquartile range (IQR), 7–11 days] vs. median, 7 days [IQR, 5–10 days], p=0.010). SOFA score (median, 4 [IQR, 3–4] vs. median, 4 [IQR, 4–6], p=0.001), PaO2/FiO2 ratio (median, 131 [IQR, 115–148] vs. median, 99 [IQR, 82–148], p<0.001), oxygen flow rate (median, 9 L/min [IQR, 8–10 L/min] vs. median, 10 L/min [IQR, 10–15 L/min], p<0.001), and respiratory rate (median, 25 rpm [IQR, 22–29 rpm] vs. median, 27 rpm [IQR, 23–32 rpm], p=0.014) were significantly lower in in the HFNC group than those in the IMV group. Regarding therapeutic interventions, there was no significant difference between the two groups in treatments such as the use of corticosteroids, favipiravir, veno-venous extracorporeal membrane oxygenation, and tracheostomy. The frequency of the use of remdesivir was significantly higher in the HFNC group versus the IMV group (40% vs. 7%, p<0.001). The intubation rate was 53% in the HFNC group.
Table 1
Clinical characteristics and therapeutic interventions in the HFNC and IMV groups
|
HFNC
(n=81)
|
IMV
(n=101)
|
p Value
|
Age, years
|
72 [63, 78]
|
69 [62, 77]
|
0.368
|
Male
|
58 (72)
|
69 (68)
|
0.746
|
Body mass index, kg/m2
|
25 [22, 28]
|
25 [23, 29]
|
0.907
|
Comorbid diseases
|
|
|
|
Hypertension
|
46 (57)
|
53 (53)
|
0.653
|
Diabetes mellitus
|
33 (41)
|
38 (38)
|
0.760
|
Chronic kidney disease
|
8 (9.9)
|
15 (15)
|
0.374
|
End-stage renal disease
|
2 (2.5)
|
6 (5.9)
|
0.302
|
Chronic heart disease
|
9 (11)
|
11 (11)
|
1.000
|
Chronic respiratory disease
|
16 (20)
|
14 (14)
|
0.319
|
COPD
|
13 (16)
|
9 (8.9)
|
0.172
|
Liver disease
|
2 (2.5)
|
0 (0.0)
|
0.197
|
Malignancy
|
3 (3.7)
|
8 (7.9)
|
0.350
|
Duration from symptoms, days
|
9 [7, 11]
|
7 [5, 10]
|
0.010
|
SOFA score
|
4 [3, 4]
|
4 [4, 6]
|
0.001
|
Glasgow Coma Scale, score
|
15 [15, 15]
|
15 [15, 15]
|
0.001
|
PaO2/FiO2 ratio
|
131 [115, 148]
|
99 [82, 148]
|
<0.001
|
Oxygen flow rate, L/min
|
9 [8, 10]
|
10 [10, 15]
|
<0.001
|
Respiratory rate, rpm
|
25 [22, 29]
|
27 [23, 32]
|
0.014
|
Therapeutic interventions
|
|
|
|
Corticosteroids
|
81 (100)
|
99 (98)
|
0.503
|
Remdesivir
|
32 (40)
|
7 (6.9)
|
<0.001
|
Favipiravir
|
35 (43)
|
52 (52)
|
0.298
|
Intubation
|
43 (53)
|
101 (100)
|
<0.001
|
Tracheostomy
|
26 (32)
|
49 (49)
|
0.034
|
VV-ECMO
|
6 (7.4)
|
11 (11)
|
0.456
|
HFNC high-flow nasal cannula, IMV invasive mechanical ventilation, COPD chronic obstructive pulmonary disease, SOFA Sequential Organ Failure Assessment, VV-ECMO veno-venous extracorporeal membrane oxygenation
Continuous variables are expressed as median [interquartile range] and categorical variables as absolute value (%)
|
Effect on primary and secondary outcomes
In-hospital mortality tended to be lower in the HFNC group compared to that in the IMV group, but the difference was not statistically significant (19% in the HFNC group vs. 25% in the IMV group, p=0.37, Table 2). The Kaplan-Meier survival curves were not significantly different between the groups (p=0.374, log rank test, Figure 2). Similarly, the univariate analysis showed that initial use of HFNC was associated with relatively lower mortality, which was not statistically significant (OR, 0.69; CI, 0.34–1.42; p=0.31, Figure 3). After adjusting the baseline imbalances by IPTW, initial use of HFNC was not associated with either an increase or decrease in mortality compared to the initial use of IMV (OR, 1.01; CI, 0.37–2.77; p=0.984, Figure 3). This association was confirmed not to be materially affected by the other models: a multivariable logistic regression analysis adjusted by propensity score for a confounder showed no significant association between the initial use of HFNC and mortality (OR, 0.97; CI, 0.39–2.43; p=0.945, Figure 3).
Table 2
Primary and secondary outcomes
|
HFNC
(n=81)
|
IMV
(n=101)
|
p Value
|
Primary outcome
|
|
|
|
In-hospital mortality
|
15 (19)
|
25 (25)
|
0.370
|
Secondary outcomes
|
|
|
|
Ventilator-free days within 28 days
|
22 [2, 28]
|
14 [0, 20]
|
<0.001
|
ICU-free days within 28 days
|
23 [0, 28]
|
15 [0, 20]
|
<0.001
|
HFNC high-flow nasal cannula, IMV invasive mechanical ventilation, ICU intensive care unit, Continuous variables are expressed as median [interquartile range] and categorical variables as absolute value (%)
|
Ventilator-free days within 28 days were significantly longer in the HFNC group than those in the IMV group (median, 22 days [IQR, 2–28 days] vs. median, 14 days [IQR, 0–20 days], p<0.001, Table 2). ICU-free days within 28 days were significantly longer in the HFNC group than those in the IMV group (median, 23 days [IQR, 0–28 days] vs. median, 15 days [IQR, 0–20 days], p<0.001, Table 2). Respiratory failure days were relatively shorter in the HFNC group, but the difference was not statistically significant (p=0.071, Gehan-Breslow-Wilcoxon test, Figure 2).
Subgroup analysis of the patients intubated and receiving IMV in both groups
Among the 81 patients in the HFNC group, 43 patients (53%) were secondarily intubated after the initiation of HFNC and categorized into the HFNC to IMV group. Baseline characteristics, therapeutic interventions, and outcomes in the subgroups are shown in Table S1. Sex, age, and BMI were not significantly different between the groups. The prevalence of chronic obstructive pulmonary disease (COPD) was significantly different between the groups; the HFNC to IMV group had a higher ratio of COPD compared to those in the other two groups.
The Kaplan-Meier survival curves are shown in Figure S1. The in-hospital mortality in the HFNC to IMV group was 30% (13 of 43 patients) and higher than that in the other two groups. Both the ventilator-free days and ICU-free days were significantly different between groups and were remarkably shorter in the HFNC to IMV group. The Kaplan-Meier curves for the lengths of respiratory failure days also showed them to be remarkably longer in the HFNC to IMV group (Figure S1).