. 2021 Oct 21;28(1):25–50. doi: 10.1097/MCC.0000000000000902

Table 1.

Clinical trials of HFNO in acute hypoxemic respiratory failure of COVID-19 etiology

Publication	PMID	Study design	Setting	Patient Population	Treatment	Intubation Rate	Mortality Rate	Main finding	Secondary findings
Bonnet et al.[47], 2021	33638752	Retrospective multicenter study	ICU	COVID-19 AHRF At admission O2 flow rate 9 lt/min and PaO₂ 69 [63–82]	SOT n = 62 HFNO n = 76	SOT 74% [95% CI 62 to 83] HFNO 51% [95% CI 40 to 62]	SOT 26% [95% CI 17 to 38] HFNO 16% [95% CI 9 to 26]	HFNO oxygen for AHRF due to COVID-19 is associated with a lower rate of invasive mechanical ventilation compared to SOT	Mortality and ICU LOS did not differ. The number of VFD was lower in the HFNO group. A ROX index higher than 4.88 and higher SAPSII were associated with IMV.
Chandel et al.[49], 2021	33328179	Multicentered retrospective study	Mixed population	COVID-19 AHRF PaO₂/FiO₂ not reported ROX index after 2 h of HFNO 4.5 [3.3–6.0]	HFNO n = 272	40% [95% CI 34 to 46]	17% [95% CI 13 to 21]	Prolonged usage of HFNO was not associated with worse clinical outcomes compared with shorter trials in those that ultimately required mechanical ventilation	The ROX index was sensitive for the identification of subjects who were successfully managed with HFNO and a cut off of 3.67 at 12 h was identified
Demoule et al.[31], 2020	32758000	Retrospective study	ICU	COVID-19 AHRF HFNO: PaO₂/FiO₂ 126 [86–189] No-HFNO: PaO₂/FiO₂ 130 [97–195]	Matched sample: HFNO n = 137 no-HFNO n = 137	HFNO 55% [95% CI, 46 to 63] no-HFNO 72% [95% CI, 64 to 79]	HFNO 21%, [95% CI 15 to 29] no-HFNO 22% [95% CI 16 to 30]	HFNO significantly reduces intubation and subsequent invasive mechanical ventilation compared to standard oxygen therapy, but does not affect case fatality
Ehrmann et al.[128^▪▪], 2021	34425070	Prospective collaborative randomized controlled meta trial,	Mixed setting	COVID-19 AHRF SpO₂/FiO₂ awake PP 147.9 (43.9) SpO₂/FiO₂ standard care148.6 (43.1)	Awake PP n = 564 Standard care n = 557 All patients treated with HFNO FiO₂ 0.6 [0.5 – 0.8] Awake PP HFNO flow 50 l/min [40–55] Standard care HFNO flow 40 l/min [40–50]	Treatment failure Awake PP 40% [95% CI 36 to 44] Treatment failure Standard care 46% [95% CI 42 to 50] IMV Awake PP 33% [95% CI 29 to 37] IMV Standard care 40% [95% CI 36 to 44]	Awake PP 21% [95% CI 18 to 24] Standard care 24% [95% CI 20 to 27]	Awake PP reduces the proportion of patients intubated or dying within 28 days of enrolment, 223 (40%) in the awake PP group vs 257 (46%) in the standard of care, P = 0.007, relative risk reduction 0.86 [95% CI 0.75 to 0.98]. Patients that received PP for longer sessions had lower treatment failure rate.	Awake PP significantly improves blood oxygenation, respiratory rate and ROX index during PP. The benefit was maintained after supination.
Franco et al.[67^▪▪], 2020	32747398	Retrospective multicenter study	Non-ICU	COVID-19 AHRF PaO₂/FiO₂ 138 (66)	HFNO n = 163 CPAP n = 330 PEEP 10.2 (1.6) cmH₂O Helmet 149 (99%) Face mask 2 (1%) NIV n = 177 PEEP 9.5 (2.2) cmH₂O Pressure Support 17.3 (3) cmH₂O Helmet 15 (21%) Face mask 57 (79%)	Recieved IMV: HFNO 29% [95% CI 24 to 36] CPAP 25% [95% CI 20 to 30] NIV 28% [95% CI 22 to 35] HFNO Failure 38% [Ci 31 to 47] CPAP Failure 47% [95% CI 42 to 53] NIV Failure 53% [95% CI 46 to 60]	30 day mortality: HFNO 16% [95% CI 11 to 22] CPAP 30% [95% CI 26 to 35] NIV 31% [95% CI 24 to 38] Difference not significant at adjusted analysis	Noninvasive respiratory support outside of ICU is feasibile, and mortality rates compare favourably with previous reports. There was no difference among the interfaces at the adjusted analysis.	Noninvasive respiratory support was associated with risk of staff contamination.
Gaulton et al.[87], 2020	32984836	Retrospective, multicenter study	ICU	COVID-19 AHRF SpO₂ < 92% with 6l/min nasal cannula Body mass index, kg/m2, mean (sd) = 35.5 (8.6)	Helmet CPAP n = 17 HFNO n = 42 PEEP 5–10 cmH₂O	ETI at 7 days CPAP 18% [6 to 41] HFNO 52% [38 to 67]	Death at 7 days CPAP 6% [1 to 27] HFNO 19% [10 to 33]	Difference in the intubation rate was significant after adjustment for age.	In obese patients Helmet CPAP is effective in reducing the ETI rate.
Geng et al.[37], 2020	32295710	Case series	Non-ICU	COVID-19 AHRF PaO₂/FiO₂ 259.88 (58)	HFNO n = 8	0% [95% CI 0 to 32]	0% [95% CI 0 to 32]	HFNO is safe and effective in mild AHRF of COVID-19 etiology
Grieco et al.[70^▪▪], 2021	33764378	Randomized controlled multicenter trial	ICU	COVID-19 AHRF NIV PaO₂/FiO₂ 105 [83–125] HFNO PaO₂/FiO₂ 102 [80–124]	Helmet NIV n = 54 Continuous treatment PEEP 12 [10–12] cmH₂O Pressure Support 10 [10–12] cmH₂O HFNO n = 55	Helmet NIV 30% [95% CI 19 to 43] HFNO 51% [95% CI 38 to 64]	HFNO 25% [16 to 38] Helmet NIV 24% [95% CI 15 to 37]	Helmet NIV+HFNO or HFNO alone do not affect respiratory support free days.	Helmet NIV reduces rate of ETI and increases invasive VFD at day 28.
Hernandez-Romieu et al.[30], 2020	32804790	Retrospective study	ICU	COVID-19 AHRF PaO₂/FiO₂ not reported for the overall cohort. At intubation, PaO₂/FiO₂ 148 [111–205]	HFNO n = 109 Only IMV n = 97	72% [95% CI 62 to 79]	HFNO 22% [95% CI 15 to 31] Only IMV 40% [95% CI 31 to 50]	A trial of noninvasive respiratory support, including HFNO, in an attempt to avoid intubation, is not associated with increased mortality.	Use of noninvasive respiratory support is not associated with worse pulmonary compliance and oxygenation, among those who eventually require mechanical ventilation.
Liu et al.[40^▪▪], 2021	33573999	Retrospective multicentre study	ICU	COVID-19 AHRF PaO₂/FiO₂ HFNO 116 [66–252] PaO₂/FiO₂ NIV 113 [68–183]	HFNO n = 366 NIV n = 286 Type and setting of NIV is not reported	HFNO 56% [95% CI 51 to 61] NIV 74% [95% CI 68 to 78]	HFNO 49% [95% CI 44 to 54] NIV 62% [95% CI 56 to 67]	The nomogram and online calculator are simple to use and able to predict the risk of failure in patients with covid-19 treated with HFNO and NIV	Age, number of comorbidities, ROX index, Glasgow coma scale score, and use of vasopressors on the first day of noninvasive respiratory support were independent risk factors for noninvasive respiratory support failure
Mellado-Artigas et al.[33], 2021	33573680	Prospective observational study	ICU	COVID-19 AHRF Only IMV PaO₂/FiO₂ 117 (51) HFNO PaO₂/FiO₂ 121 (49)	HFNO n = 61 Only IMV n = 61	38% [95% CI 27 to 50]	Only IMV 21% [95% CI 13 to 33] HFNO 15% [95% CI 8 to 26]	HFNO was associated with an increase in VFDs at 28 days when compared with early IMV and with reduction in ICU length of stay.	Mortality was not different in the patients that were intubated early and in the patients that failed HFNO.
Montiel et al.[30], 2020	32990864	Prospective observational study	ICU	COVID-19 AHRF PaO₂/FiO₂ 83 (± 22)	HFNO n = 21	Not reported	Not reported	A surgical mask placed on patient's face already treated by a HFNO device would offer an advantage in terms of oxygenation in COVID-19 patients admitted in ICU with severe AHRF.	The oxygenation improvement is associated with neither a clinically significant change in the PaCO₂ nor subjective patient complaints.
Panadero et al.[44], 2020	32983456	Retrospective study	Non-ICU	COVID-19 AHRF SpO₂/FiO₂ in HFNO success 103.0 (3.4) ROX index in HFNO success 4.0 (1.4) SpO₂/FiO₂ in HFNO failure 101.4 (5.1) ROX index in HFNO failure 3.7 (1.0)	HFNO n = 40	52% [95% CI 37 to 67]	22% [95% CI 12 to 37]	HFNO therapy is a useful treatment in ARDS in order to avoid ETI or as a bridge therapy, and no increased mortality was observed secondary to delayed intubation	After initiating HFNO, a ROX index below 4.94 predicts the need for intubation.
Rosén et al.[127^▪], 2021	34127046	Multicenter randomized clinical trial	Non-ICU	COVID-19 AHRF Standard care n = 39 PaO₂/FiO₂ standard care 115 [94–130] Prone n = 36 PaO₂/FiO₂ prone 115 [86–130]	HFNO standard care n = 29 HFNO prone n = 31 NIV standard care n = 27 PEEP 8 [6–8] NIV prone n = 21 PEEP 7 [6–10]	Standard care group 33% [95% CI 20 to 49] Prone group 33% [95% CI 20 to 50]	Control group 8% [95% CI 3 to 20] Prone group 17% [95% CI 8 to 22]	The implemented protocol for awake PP increased duration of awake PP but did not reduce the rate of intubation in patients with AHRF due to COVID-19 compared to standard care.	Nine patients (23%) in the control group had pressure sores compared with two patients (6%) in the prone group, P = 0.03, there were no difference in the use of NIV, vasopressors, continuous renal-replacement therapy, ECMO, VFD, hospital and ICU length of stay and mortality among the two groups.
Suliman et al.[43], 2021	33471350	Diagnostic research	Mixed population	COVID-19 AHRF At intubation PaO₂/FiO₂ 91 [60–110]	HFNO n = 69	59% [95% CI 48 to 70]	Not reported	ROX index is a simple noninvasive promising tool for predicting discontinuation of high-flow oxygen therapy and could be used by clinicians in the assessment of progress and the risk of intubation in COVID-19 patients with pneumonia	The ROX index on the 1st day of admission was significantly associated with the presence of comorbidities, COVID-19 clinical classification, CT findings and intubation
Vega et al.[34], 2021	34049831	Retrospective analysis of prospectively collected data	Non-ICU	COVID-19 AHRF SpO₂/FiO₂ 155 [106–190]	HFNO n = 120	29% [95% CI 21 to 38]	7.5% [95% CI 4 to 14]	ROX index with cut off of 5.99 may be useful in guiding clinicians in their decision to intubate patients (especially in moderate acute respiratory failure) treated outside ICU	Among the components of the index SpO₂/FiO₂ had greater predictive value
Vianello et al.[35], 2020	32703883	Retrospective study	ICU	COVID-19 AHRF PaO₂/FiO₂ 108 [52–296]	HFNO n = 28 Rescue NIV n = 9 NIV settings, interfaces, and whether CPAP is codified as NIV is not reported	HFNO failure 32% [95% CI 18 to 51] Rescue NIV failure 56% [95% CI 27 to 81] ETI 18% [95% CI 8 to 36]	11% [95% CI 4 to 27]	HFNO can be considered an effective and safe means to improve oxygenation in less severe forms of AHRF secondary to COVID-19 not responding to conventional oxygen therapy	Severity of hypoxemia and C reactive protein level were correlated with HFNO failure
Wang et al.[41], 2020	32232685	Retrospective study	Mixed population	COVID-19 AHRF PaO₂/FiO₂ 209 [179–376] in success patients PaO₂/FiO₂ 142 [130–188] in failure patients	HFNO n = 17 only IMV n = 1 first line NIV n = 9 rescue NIV n = 7	HFNO failure and rescue NIV 41% [95% CI 22 to 64] HFNO 12% [95% CI 3 to 34] First line NIV failure 11% [2 to 42] Rescue NIV failure 29% [8 to 64]	Not reported	HFNO was the most common ventilation support for patients, and rescue NIV was often used in case of HFNO failure	Patients with lower PaO₂/FiO₂ were more likely to experience HFNO failure
Wang et al.[39], 2020	32267160	Retrospective study	ICU	SpO₂/FiO₂ in the overall cohort 279 [157–328]	HFNO n = 35 NIV n = 34 IMV n = 100	HFNO 66% [95% CI 49 to 79] HNFO failure 77% [95% CI 61 to 88] NIV failure 79% [95% CI 63 to 90]	HFNO 80% [95% CI 64 to 90] NIV 77% [95% CI 61 to 88] IMV 97% [95% CI 92 to 99]	Older patients with comorbidities are at increased risk of mortality. Real-time monitoring of SpO₂/FiO₂ and regular measurements of lymphocyte count and inflammatory markers may be essential to disease management.	A total of 128 out of 145 (88.3%) patients who developed ARDS died at or before 28 days.
Wendel Garcia et al.[36], 2021	34034782	Retrospective subanalysis of data	ICU	COVID-19 AHRF PaO₂/FiO₂ 123 [92, 167]	SOT n = 87 HFNO n = 87 NIV n = 87 MV n = 92	SOT 64% [95% CI 53 to 63] HFNO 52% [95% CI 41 to 62] NIV 49% [95% CI 39 to 60]	SOT 18% [95% CI 11 to 27] HFNO 20% [95% CI 13 to 29] NIV 37% [27 to 47]	A trial of HFNO appeared to be the most balanced initial respiratory support strategy.	Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality P = 016 and should be avoided.
Xia et al.[46], 2020	32826432	Retrospective multicenter study	Mixed population	COVID-19 AHRF PaO₂/FiO₂ available in only 12 patients: 122 (51)	HFNO n = 43	30% [95% CI 19 to 45] HFNO failure 47% [95% CI 33 to 61]	32% [95% CI 20 to 48]	Early HFNO may be an effective respiratory support modality for COVID-19 patients with mild to moderate AHRF, most severe cases need IMV or NIV	Male and lower oxygenation at admission were the two strongest predictors of HFNO failure.
Yang W. et al.[39], 2020	32267160	Retrospective study	ICU	COVID-19 AHRF SpO₂/FiO₂ in the overall cohort 279 [157–328]	HFNO n = 35 NIV n = 34 IMV n = 100	HFNO 66% [95% CI 49 to 79] HNFO failure 77% [95% CI 61 to 88] NIV failure 79% [95% CI 63 to 90]	HFNO 80% [95% CI 64 to 90] NIV 77% [95% CI 61 to 88] IMV 97% [95% CI 92 to 99]	Older patients with comorbidities are at increased risk of mortality. Real-time monitoring of S/F and regular measurements of lymphocyte count and inflammatory markers may be essential to disease management.	A total of 128 out of 145 (88.3%) patients who developed ARDS died at or before 28 days.
Yang X. et al.[66], 2020	32105632	Retrospective study	ICU	PaO₂/FiO₂ 100 [66.6–126.7] in survivors PaO₂/FiO₂ 62 [52–74] nonsurvivors	Overall cohort n = 52 HFNO n = 33 NIV n = 29 IMV n = 22	The progression among the interfaces is not reported	HFNO 48% [95% CI 32 to 65] NIV 79% [95% CI 62 to 90] IMV 86% [95% CI 67 to 95]	Among 52 critically ill patients with COVID-19 infection, 32 (61.5%) patients had died at 28 days.	Older patients (>65 years) with comorbidities and ARDS are at increased risk of death.
Zhou et al.[37], 2020	32171076	Retrospective multicenter study	Mixed Population	PaO₂/FiO₂ at enrollment is not reported	HFNO n = 41 NIV n = 26 IMV n = 32 NIV settings, interfaces, and whether CPAP is codified as NIV is not know	Not reported	HFNO 80% [CI66 to 90] NIV 92% [95% CI 96 to 98] IMV 97% [95% CI 84 to 99]	Older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage.	Noninvasive respiratory support and invasive mechanical ventilation have high mortality rate.
Zucman et al.[42], 2020	32671470	Retrospective study	ICU	COVID-19 AHRF FiO₂ at admission 0.8 [0.6–1] Median SpO₂ 96% [94–98]	HFNO n = 60	65% [95% CI 52 to 76]	17% [9 to 28]	Early application of NHF as first-line ventilatory support during COVID-19-related AHRF may have obviated the need for intubation in up to a third of cases.	The ROX index measured within the first 4 h after NHF initiation could be an easy-to-use marker of early ventilatory response.

Values are displayed as means (SD) or medians [Interquartile range].

Failure was defined as either intubation, death while still on noninvasive respiratory support, or escalation to other noninvasive respiratory support to avoid endotracheal intubation. AHRF, acute hypoxemic respiratory failure; ARDS, acute respiratory distress syndrome; awake PP, awake prone position; CPAP, continuous positive end-expiratory pressure; FiO₂, fraction of inspired oxygen; HFNO, high-flow nasal oxygen; ICU, intensive care unit; IQR, interquartile range; NIV, noninvasive ventilation; PaO₂, partial pressure of arterial oxygen; PEEP, positive end-expiratory pressure; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment; SpO₂, peripheral capillary oxygen saturation; VFD, Ventilatory Free Days.