High-flow nasal oxygen therapy compared with conventional oxygen therapy in hospitalised patients with respiratory illness: a systematic review and meta-analysis

Abstract

Background

High-flow nasal oxygen therapy (HFNO) is used in diverse hospital settings to treat patients with acute respiratory failure (ARF). This systematic review aims to summarise the evidence regarding any benefits HFNO therapy has compared with conventional oxygen therapy (COT) for patients with ARF.

Methods

Three databases (Embase, Medline and CENTRAL) were searched on 22 March 2023 for studies evaluating HFNO compared with COT for the treatment of ARF, with the primary outcome being hospital mortality and secondary outcomes including (but not limited to) escalation to invasive mechanical ventilation (IMV) or non-invasive ventilation (NIV). Risk of bias was assessed using the Cochrane risk-of-bias tool (randomised controlled trials (RCTs)), ROBINS-I (non-randomised trials) or Newcastle-Ottawa Scale (observational studies). RCTs and observational studies were pooled together for primary analyses, and secondary analyses used RCT data only. Treatment effects were pooled using the random effects model.

Results

63 studies (26 RCTs, 13 cross-over and 24 observational studies) were included, with 10 230 participants. There was no significant difference in the primary outcome of hospital mortality (risk ratio, RR 1.08, 95% CI 0.93 to 1.26; p=0.29; 17 studies, n=5887) between HFNO and COT for all causes ARF. However, compared with COT, HFNO significantly reduced the overall need for escalation to IMV (RR 0.85, 95% CI 0.76 to 0.95 p=0.003; 39 studies, n=8932); and overall need for escalation to NIV (RR 0.70, 95% CI 0.50 to 0.98; p=0.04; 16 studies, n=3076). In subgroup analyses, when considering patients by illness types, those with acute-on-chronic respiratory failure who received HFNO compared with COT had a significant reduction in-hospital mortality (RR 0.58, 95% CI 0.37 to 0.91; p=0.02).

Discussion

HFNO was superior to COT in reducing the need for escalation to both IMV and NIV but had no impact on the primary outcome of hospital mortality. These findings support recommendations that HFNO may be considered as first-line therapy for ARF.

PROSPERO registration number

CRD42021264837.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Previous systematic reviews and meta-analyses comparing high-flow nasal oxygen therapy (HFNO) to conventional oxygen therapy (COT) have generated mixed results regarding HFNO’s benefits in reducing mortality rates and the need for escalation to invasive mechanical ventilation (IMV). Most of these studies were conducted within intensive care settings and were conducted prior to or early in the COVID-19 pandemic.

WHAT THIS STUDY ADDS

• This large systematic review and meta-analysis (63 studies (26 randomised controlled trials) n=10 230 participants), which includes all study designs within various hospital settings, suggests that HFNO is superior to COT in reducing the need for escalation to both IMV and non-invasive ventilation, without impacting mortality, in patients with heterogeneous acute respiratory failure.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• These findings support recommendations that HFNO may be a first-line consideration for many patients with heterogeneous acute respiratory failure. The results from this study may support further scrutiny into HFNO’s utility within lower acuity settings outside of the intensive care unit.

Introduction

High-flow nasal oxygen (HFNO) therapy delivers humidified heated oxygen at flow rates of up to 60 L/min.¹ HFNO has several advantages over conventional oxygen therapy (COT) delivered via traditional nasal cannula or face mask for treating acute respiratory failure (ARF), including precise and reliable fraction of inspired oxygen (FiO₂) delivery (compared with COT without oxygen blenders),² improved breathing pattern,³,⁵ increased airway secretion clearance and greater patient comfort.⁶,⁸ Additional physiological benefits of HFNO include upper airway dead space washout and potential generation of positive end-expiratory pressure,² which contribute to decreased work of breathing and improved oxygenation.^{1 7 9}

Although systematic reviews have examined the effects of HFNO compared with COT in patients with ARF in recent years,¹⁰,²⁶ those reviews focused on HFNO use in intensive care units (ICUs) and were conducted prior to, or early in, the COVID-19 pandemic. Many studies comparing HFNO to COT in patients with COVID-19 have since been published.²⁷,⁴² HFNO gained considerable traction during the COVID-19 pandemic. During its peak, there was a global surge in hospital and ICU admissions for COVID-19-related ARF, which saw an impetus to rapidly expand ICU bed capacities and operationalise mechanical ventilatory and non-invasive ventilatory equipment.⁴³ Once HFNO was established to not increase the risk of airborne viral transmission,⁴⁴ many hospitals considered HFNO as an early non-invasive oxygenation strategy for people with COVID-19 and ARF, with generally favourable outcomes. Several centres also employed HFNO within the general ward setting, possibly due to the logistical and technical ease of operating HFNO, against the backdrop of overwhelmed ICUs and high dependency units.⁴⁵

With an increasing adoption of HFNO across multiple hospital settings (emergency departments (EDs), ward areas, high-dependency units and ICUs) globally,⁴⁶ there is a pressing need to review the evidence for using HFNO in varied hospital settings (ICU, ED and hospital wards). This updated systematic review and meta-analysis aimed to include new data from randomised controlled trials (RCTs), cross-over studies and observational studies for patients with ARF (including acute exacerbations of chronic respiratory illnesses) in varied hospital settings to determine whether HFNO leads to improved clinical outcomes compared with COT.

Methods and materials

Search strategy and study selection

A comprehensive search was performed on 29 June 2021, and subsequently updated on 22 March 2023, for articles within the last 50 years across Embase, Medline via Ovid and CENTRAL databases. The full search strategy and keywords employed can be found in online supplemental table 1A–F. The study protocol was registered with PROSPERO (CRD42021264837).

To meet inclusion criteria, studies had to evaluate HFNO in hospitalised adult patients (≥18 years) with acute respiratory illness necessitating oxygen therapy, indicating ARF. RCTs, cross-over studies and observational studies with an intervention and comparator group were included. Hospitalisation was defined as ED presentation or admission to an ICU or ward. HFNO was defined as flow rates >20 L/min delivered via specialised high-flow devices and nasal cannulae. COT was defined as flow rates ≤15 L/min delivered via standard nasal cannulae, simple face mask, non-rebreather reservoir mask or venturi mask. Illnesses causing ARF (as defined by study authors and with or without hypercapnia) included upper and lower respiratory tract infections, COVID-19, acute respiratory distress syndrome, acute exacerbations of a chronic respiratory illness, pulmonary embolism, pneumothorax, acute lung injury and transfusion-related acute lung injury. Studies examining patients with stable, chronic respiratory illnesses (without a concurrent acute exacerbation), with patients under 18 years old, comparing HFNO to non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV) only or written in languages other than English were excluded.

The primary outcome for this review was hospital mortality rate, with secondary outcomes including short-term mortality (≤30 days), long-term mortality (>30 days), escalation to IMV, escalation to NIV, ICU and hospital length of stay (LOS), changes in partial pressure of carbon dioxide (PaCO₂) levels, disability as defined by study authors (eg, dyspnoea scores) and inpatient admission rates for studies evaluating patients in ED.

Data extraction

Two independent reviewers (DS, YHK, S-WK, AP, DMS, YN or NS) screened abstracts and full-text articles sequentially in pairs for eligible studies. A third reviewer (YHK or NS) resolved disagreements between reviewer pairs by adjudication. For each included study, the risk of bias was assessed independently by two authors (DS, AP or S-WK) with adjudication by a third author (YHK or NS). RCTs and randomised cross-over studies were assessed using the revised Cochrane risk-of-bias tool for randomised trials (RoB 2) while non-randomised interventional studies were assessed using the risk of bias in non-randomised studies of interventions (ROBINS-I) framework. The Newcastle-Ottawa Scale was used for assessments of observational studies.

Data synthesis

Treatment effects were pooled using the random effects model to weigh heterogeneous studies more equally than the fixed effects model, as many studies were clinically and methodologically heterogeneous. The Mantel-Haenszel method was employed for dichotomous outcomes while the inverse variance weighting method was used for continuous outcomes. I² statistic values were used to assess for heterogeneity with the following predefined thresholds: low (25%–49%), moderate (50%– 74%) and high (≥75%).⁴⁷ Treatment effects were expressed as mean difference (with 95% CIs) for continuous outcomes and risk ratio (RR) (with 95% CI) for dichotomous outcomes. Primary analyses included data from both RCTs and observational studies, to greatly expand the available body of evidence and include a wider variety of ARF causes. Secondary analyses examined data from RCT studies only to increase the quality of evidence. Subgroup analyses for different types of respiratory illnesses (COVID-19, acute-on-chronic respiratory illnesses, hypercapnic ARF, chronic obstructive pulmonary disease, COPD and asthma), and sensitivity analyses of studies with low-moderate risk of bias were performed. All meta-analyses were performed by using Review Manager (RevMan, V.5.4; the Cochrane Collaboration).

Results

Of 17 948 abstracts screened, 63 studies (26 RCTs, 13 cross-over studies and 24 observational studies) described in 74 articles, with a total of 10 230 participants were included ³,⁹²⁷ (figure 1).

Figure 1. PRISMA flow chart. ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; COT, conventional oxygen therapy; PRISMA, preferred reporting items for systematic reviews and meta-analyses; RCTs, randomised controlled trials.

Study characteristics and quality

A summary of included study characteristics is shown in online supplemental table 2, with more detailed information available in online supplemental table 3. COVID-19 was the most common cause of ARF (n=3782), followed by pneumonia (n=1583) (figure 1). Definitions of respiratory illnesses, as reported by the included studies, are reflected in online supplemental table 4. Overall, most studies included patients with mild-moderate degrees of hypoxaemia. Of the 17 studies that reported PaO2/FiO2 ratio as an inclusion criteria, 13 studies (76%) included patients with PaO2/FiO2≤300 mm Hg and 4 studies (24%) accepted patients with PaO2/FiO2≤200 mm Hg.

HFNO was most commonly administered via Fisher & Paykel Optiflow system (38 studies, 60%) and initiated at a median initial flow rate of 40 L/min (range 4–60 L/min, 34 studies). COT was initiated at a median initial flow rate of 10 L/min (range 2–15 L/min, 13 studies) and was most commonly delivered via nasal cannula (22 studies, 35%), followed by non-rebreather mask (20 studies, 32%) (table 1).

Table 1. Characteristics of HFNO and COT delivery.

	HFNO delivery	COT delivery
Flow (L/min): median, (range)	Minimum: 18 studies, 30 (20–50)Maximum: 24 studies, 60 (40–60)Initial: 34 studies, 40 (4–60)	Minimum: 16 studies: 3.5 (1–12)Maximum: 15 studies: 10 (4–15)Initial: 13 studies: 10 (2–15)
Duration	<1 hour: 8 studies1–24 hours: 7 studies>24–72 hours: 3 studies>72 hours:2 studiesOther: 7 studiesNot specified: 36 studies	<1 hour: 6 studies1–24 hours: 7 studies>24–72 hours: 2 studies>72 hours: 2 studiesOther: 6 studiesNot specified: 40 studies
Oxygen delivery device*	Fisher & Paykel, Optiflow: 38 studies AIRVO: 2 studies AIRVO 2: 16 studies AIRVO or AIRVO 2: 1 study MR850: 12 studies Other: 3 studiesNot specified: 22 studies	Nasal cannula: 22 studiesFace mask: 19 studiesVenturi mask: 15 studiesNon-rebreather mask: 20 studiesOther: 2 studies (reservoir nasal cannula, high concentration mask)Not specified: 11 studies
Setting(s)	Emergency department: 9 studies, n=460 participantsIntensive care or critical care unit: 34 studies, n=2716 participantsRespiratory ward: 5 studies, n=466 participantsNon-respiratory ward: 1 study, n=51 participantsMixed: 6 studies, n=231 participantsNot specified: 8 studies, n=762 participants	Emergency department: 9 studies, n=422 participantsIntensive care or critical care unit: 34 studies, n=3820 participantsRespiratory ward: 5 studies, n=503 participantsNon-respiratory ward: 1 study, n=49 participantsMixed: 6 studies, n=221 participantsNot specified: 8 studies, n=747 participants
SpO2 target %: median, (range)	≥ 93.5 (91%–96%). (24 studies). SPO2 target for other studies were either expressed as a range or unspecified..

^*More than one system may be used for conventional oxygen therapy.HFNO: High flow nasal oxygen. COT: Conventional oxygen therapy. SpO: Saturation of peripheral oxygen.

COTconventional oxygen therapyHFNOhigh-flow nasal oxygenSpO₂saturation of peripheral oxygen

Risk of bias

Of 26 articles reporting RCTs (25 RCTs and 1 post hoc analysis), 20 (77%) had a moderate risk of bias and 2 (8%) at high risk (online supplemental table 5 and online supplemental figure 1). Five of nine randomised cross-over studies (56%) had a moderate risk of bias, with three (33%) at high risk (online supplemental table 6 and online supplemental figure 2). All five non-randomised interventional studies were of moderate-to-high risk of bias (online supplemental table 7 and online supplemental figure 3). For the 24 included observational studies (including 1 post hoc analysis), the overall risk of bias was low to moderate (online supplemental table 8 and online supplemental figure 4).

Outcomes

Table 2 provides a summary of all key outcomes for hospitalised patients, including the primary analyses of all study designs and secondary analyses of RCTs only. A more detailed summary can be found in online supplemental table 9.

Table 2. Summary of clinical outcomes.

Outcome	Results
	All study designs	RCTs only
Hospital mortality	RR=1.08 (95% CI 0.93 to 1.26; p=0.29)17 studies, n=5887	RR=0.97 (95% CI 0.85 to 1.10; p=0.63)8 studies, n=3031
Short-term mortality	RR=0.94 (95% CI 0.81 to 1.09; p=0.42)20 studies, n=6022	RR=1.00 (95% CI 0.86 to 1.17; p=1.00) 10 studies, n=3371
Long-term mortality	RR=0.96 (95% CI 0.83 to 1.10; p=0.55)10 studies, n=5209	RR=0.96 (95% CI 0.84 to 1.09; p=0.50)6 studies, n=2676
Overall need for IMV escalation	RR=0.85 (95% CI 0.76 to 0.95; p=0.003)39 studies, n=8932	RR=0.85 (95% CI 0.76 to 0.95; p=0.004)23 studies, n=5046
Need for IMV escalation at 24 hours	RR=0.58 (95% CI 0.31 to 1.09; p=0.09)4 studies, n=487	RR=0.41 (95% CI 0.10 to 1.59; p=0.20)3 studies, n=400
Need for IMV escalation at 28 days	RR=0.80 (95% CI 0.74 to 0.87; p<0.0001)8 studies, n=2857	RR=0.83 (95% CI 0.75 to 0.92; p=0.0004) 6 studies, n=2368
Need for IMV escalation at 72 hours	RR=0.66 (95% CI 0.42 to 1.03; p=0.07)4 studies, n=276	RR Not estimable (no IMV escalations), 2 studies, n=71
Overall need for NIV escalation	RR=0.70 (95% CI 0.50 to 0.98; p=0.04)16 studies, n=3076	RR=0.69 (95% CI 0.49 to 0.99; p=0.04)15 studies, n=2974
Hospital admission	RR=0.92 (95% CI 0.85 to 0.99; p=0.03)3 studies, n=198	RR=0.88 (95% CI 0.53 to 1.45; p=0.61)2 studies, n=77
ICU admission	RR=1.04 (95% CI 0.94 to 1.16; p=0.45)9 studies, n=1948	RR=1.05 (95% CI 0.89 to 1.25; p=0.53)5 studies, n=1571
ICU mortality	RR=1.05 (95% CI 0.86 to 1.28; p=0.64)12 studies, n=4977	RR=0.98 (95% CI 0.79 to 1.22; p=0.87)6 studies, n=2379
Hospital LOS	MD=−0.30 days (95% CI −1.16 days to 0.56 days; p=0.50)22 studies, n=6488	MD=−0.32 days (95% CI −0.81 days to 0.17 days; p=0.20)13 studies, n=4140
ICU LOS	MD=0.45 days (95% CI −0.34 days to 1.24 days; p=0.27)18 studies, n=5199	MD=0.23 days (95% CI −0.85 days to 1.31 days; p=0.68)11 studies, n=3084
ED LOS	MD=−1.31 hours (95% CI −2.87 hours to 0.25 hours; p=0.10)3 studies, n=442	MD=−0.99 hours (95% CI −2.78 hours to 0.79 hours; p=0.28)2 studies, n=340

COTconventional oxygen therapyEDEmergency departmentHFNOhigh-flow nasal oxygenICUintensive care unitIMVinvasive mechanical ventilationLOSlength of stay MDmean differenceNIVnon-invasive mechanical ventilationRCTsrandomised controlled trialsRRrisk ratio

Mortality

Mortality outcomes were reported in 17 studies (8 RCTs), with 5887 participants, for in-hospital mortality830 32 33 42 49 51,^{53 56}; 20 studies (10 RCTs), with 6022 participants, for short-term (≤30 days) mortality²⁷,³²³⁴ and 10 studies (6 RCTs), with 5209 participants for long-term (>30 days) mortality.^{827 28 30},32 51 52 54 84 For short-term (≤30 days) mortality, 17 studies (85%) reported mortality at 28 days²⁷,³²³⁴ and 3 studies (15%) at 30 days.^{40 42 50} For long-term (>30 days) mortality, 7 studies (70%)^{8 30 32 51 52 54 84} reported mortality at 90 days and 3 studies (30%)^{27 28 31} at 60 days.

There was no significant difference between in the primary outcome of hospital mortality for patients receiving HFNO compared with COT (RR 1.08, 95% CI 0.93 to 1.26; p=0.29; 17 studies, n=5887, I²=37%) (figure 2). Secondary analysis of data from RCTs only showed similar lack of difference between the two groups for in-hospital mortality (RR 0.97, 95% CI 0.85 to 1.10; p=0.63; 8 studies, n=3031 participants; I²=0%)^{8 32 42 49 51 56 83 84} (online supplemental figure 5).

Figure 2. Hospital mortality. COT, conventional oxygen therapy; HFNO, high-flow nasal oxygen therapy; M-H, Mantel-Haenszel.

Similarly, there were no significant differences in short-term mortality at ≤30 days (RR 0.94, 95% CI 0.81 to 1.09; p=0.42; 20 studies, n=6022, I²=53%) or long-term mortality at >30 days (RR 0.96, 95% CI 0.83 to 1.10; p=0.55; 10 studies, n=5209, I²=39%) between patients receiving HFNO compared with COT (online supplemental figure 6–7). Secondary analysis of pooled data from RCT only revealed a similar lack of difference between HFNO and COT for short-term (RR 1.00, 95% CI 0.86 to 1.17; p=1.00; 10 studies, n=3371 participants; I²=16%)^{3132 35},37 42 48 50 51 59 and long-term (RR 0.96, 95% CI 0.84 to 1.09; p=0.50; 6 studies, n=2676 participants; I²=0%)^{8 31 32 51 54 84} mortality outcomes.

IMV escalation

Need for escalation from HFNO or COT to IMV was reported at variable illness time points (ranging from within 2 hours to the end of hospital admission) in 39 studies (23 RCTs) with 8932 participants^{68 27},^{37 42 48} (figure 3). Therefore, the overall need for IMV was defined as the need for IMV escalation at any time point during the study period. Most studies (n=21, 54%) reported IMV escalation at the end of hospitalisation or did not specify the time point(s) where IMV escalation was assessed. Eight studies (21%) reported IMV escalation at 28 days,^{2731 32 34},^{36 51 54} four studies (10%) at 24 hours,^{8 67 72 81} four studies (10%) at 72 hours,^{50 56 57 72} one study (3%) at 30 days,⁴² one study (3%) at 48 hours⁶ and one study (3%) at 2 hours.⁶⁰

Figure 3. Overall need for escalation to invasive mechanical ventilation (IMV). COT, conventional oxygen therapy; HFNO, high-flow nasal oxygen therapy; M-H, Mantel-Haenszel.

Pooled data from all study designs demonstrated a significant reduction in overall need for IMV escalation for HFNO when compared with COT (RR 0.85, 95% CI 0.76 to 0.95 p=0.003; 39 studies, n=8932, I²=56%) (figure 3 and online supplemental figure 8). For studies that reported specific assessment time points, a significant difference was observed (in favour of HFNO compared with COT) for IMV escalation at 28 days (RR 0.80, 95% CI 0.74 to 0.87 p<0.0001; 8 studies, n=2857, I²=0%) (online supplemental figure 9). No significant differences were seen for IMV escalation at 24 hours (RR 0.58, 95% CI 0.31 to 1.09 p=0.09; 4 studies, n=487, I²=0%) and at 72 hours (RR 0.66, 95% CI 0.42 to 1.03 p=0.07; 4 studies, n=276, I²=0%); however, these sample sizes were small (online supplemental figure 10–11).

Secondary analysis of data from RCTs only demonstrated similar results (in favour of HFNO compared with COT) in reducing the overall need for IMV escalation (RR 0.85, 95% CI 0.76 to 0.95 p=0.004; 23 studies, n=5046, I²=19%).68 31 32 35,37 42 48 49 51 52 54 56 59 60 62 67 76 77 81 83 84

NIV escalation

Need for escalation to NIV was reported in 16 studies (15 RCTs).68 31 32 35 37 48 54 56 60,62 67 77 83 84 Timing of NIV escalation was either reported at 24 hours (2 studies, 13%),^{8 67} at 28 days (3 studies, 19%)^{31 35 54} or unspecified (11 studies, 69%). Only one study (6%) defined NIV escalation as either non-invasive positive pressure ventilation (NIPPV) (bilevel support) or continuous positive airway pressure (CPAP).⁸ Four studies (25%) specified escalation to NIPPV only.^{31 32 54 84} The remaining 11 studies (69%) did not elaborate on NIV modality.

There was a statistically significant reduction in overall need for NIV escalation for HFNO compared with COT (RR 0.70, 95% CI 0.50 to 0.98; p=0.04; 16 studies, n=3076, I²=56) (online supplemental figure 12). Secondary analysis of pooled RCT data only yielded similar results favouring HFNO (RR 0.69, 95% CI 0.49 to 0.99; p=0.04; 15 studies, n=2974, I²=59).^{6 8 31 32 35 37 48 54 56 60 62 67 77 83 84}

Inpatient admission rates

There was a small but significant reduction in the risk of needing inpatient admission for patients receiving HFNO in the ED compared with COT (RR 0.92, 95% CI 0.85 to 0.99; p=0.03; 3 studies, n=198; I²=0%)^{55 62 81} (online supplemental figure 13). This is likely due to the dominance (97.3% weightage) of an observational study⁵⁵ which compared HFNO to COT in patients with PaO2<60 mm Hg in the ED setting. This small difference was not observed in the secondary analysis when data from RCTs only were pooled together instead (RR 0.88, 95% CI 0.53 to 1.45; p=0.61; 2 studies, n=77; I²=4%).^{62 81}

Other hospitalisation-related outcome

Meta-analyses of all studies for all other outcomes, including ICU admission rates, ICU mortality, ED LOS, ICU LOS and hospital LOS, were not significantly different between patients who received either HFNO or COT (online supplemental figures 14–18). The statistical significance of these outcomes remained unchanged for secondary analysis of combined data from RCTs only.

Physiological and disability outcomes

Meta-analysis was not performed for change in PaCO₂ on arterial blood gases or disability scores (including dyspnoea, comfort and dryness scores) due to high methodological heterogeneity between studies. Of 31 studies (n=2019 participants) reporting a change in PaCO₂ levels between HFNO and COT, only nine studies (29%, n=766 participants)^{6 49 68 72 74 77 79 80 83} reported a significantly lower change in PaCO₂ levels in favour of HFNO compared with COT (online supplemental table 10).

Dyspnoea scores were most commonly measured using the Borg scale and visual analogue scale. 14 (56%), with 1601 participants, of 25 (n=3005 participants) studies731 32 49 54 61,65 68 74 78 81 reported significantly lower dyspnoea scores in patients receiving HFNO compared with COT (online supplemental table 11). Comfort scores were mostly reported using Visual Analogue Scale. 11 (46%), with 1088 participants, of 24 studies (n=3667 participants) reported significantly higher comfort or lower discomfort levels in the HFNO group compared with COT.^{6 7 35 37 54 62 64 67 69 77 81} The remaining 13 (64%, n=2579) reported no significant differences between the two groups^{5 8 31 32 48 49 51 60 61 63 66 70 80} (online supplemental table 12).

Subgroup analyses: types of respiratory illness

Online supplemental table 13 provides an overview of subgroup analyses results for different types of respiratory illnesses. In patients with ARF due to COVID-19, there were no significant differences between HFNO and COT in the primary outcome of hospital mortality (RR 1.06; 95% CI 0.87 to 1.30; p=0.54; 4 studies, n=2842 participants; I²=38%),^{30 32 33 42} short-term mortality (RR 0.87, 95% CI 0.73 to 1.04; p=0.12; 13 studies, n=4462 participants; I²=55%),²⁷,³²³⁴ or long-term mortality (RR 0.90; 95% CI 0.68 to 1.19; p=0.45; 5 studies, n=2923 participants; I²=58%)^{2728 30},³² (online supplemental figures 19 A–C). However, HFNO therapy significantly reduced the overall need for IMV escalation compared with COT (RR 0.81, 95% CI 0.73 to 0.89; p<0.001; 12 studies, n=4384 participants; I²=34%)²⁷,³⁷⁴² (online supplemental figure 19 D). In the secondary analysis of pooled RCT data only, there were no significant differences noted for all mortality outcomes and a non-significant trend towards reduction in the need for overall IMV escalation in favour of HFNO (RR 0.84, 95% CI 0.71 to 1.00; p=0.05; 6 studies, n=2297 participants; I²=35%).^{3132 35},^{37 42} There were no significant differences between HFNO and COT for all other outcomes (including need for NIV escalation and LOS outcomes) in both primary and secondary analyses for patients with COVID-19 ARF (online supplemental figure 19 E–I).

Patients with acute exacerbations of chronic respiratory illnesses were identified in 12 studies (6 RCTs, 3 cross-over studies and 3 observational studies).⁷³,⁸⁴ Pooled data from all study designs demonstrated a significant reduction in-hospital mortality (RR 0.58, 95% CI 0.37 to 0.91; p=0.02; 4 studies, n=485 participants, I²=0%)⁷³⁸²,⁸⁴ for participants receiving HFNO compared with COT (online supplemental figure 20 A). This difference in-hospital mortality was not observed when pooled data were restricted to RCTs only (RR 0.39, 95% CI 0.06 to 2.54; p=0.32; 2 studies, n=375 participants, I²=0%).^{83 84} A significant reduction was also seen for ICU LOS (mean difference=−1.58 days, 95% CI −2.28 days to −0.89 days; p<0.0001; 1 RCT and one observational study, n=85 participants, I²=0%)^{82 83} (online supplemental figure 20 B). There were no significant differences between HFNO and COT for all other outcomes including need for IMV escalation, the need for NIV escalation and hospital LOS (online supplemental figure 20 C–E).

There were no significant differences between HFNO and COT in any outcomes for meta-analyses using the small number of studies limited to patients with acute hypercapnic respiratory failure, or patients with exacerbations of COPD or asthma (online supplemental figures 21–23).

Sensitivity analyses: studies of low risks of bias

Sensitivity analyses were performed excluding studies with an overall high risk of bias, defined as RCTs and randomised cross-over studies with a ‘high’ risk of bias using the ROB2 framework, non-randomised interventional studies with a serious risk of bias using the ROBINS-I framework or observational studies with scores <6 using the Newcastle-Ottawa Scale.

Using only pooled data from studies not at high risk of bias yielded the same findings for the primary outcome of hospitality mortality (RR 1.09, 95% CI 0.93 to 1.26; p=0.28; 16 studies, n=5817 participants; I²=40%),830 32 33 42 49 51,^{53 56} short-term mortality (RR 0.96, 95% CI 0.83 to 1.12; p=0.60; 18 studies, n=5915 participants; I²=52%)²⁷,³²³⁴ and long-term mortality (RR 0.96, 95% CI 0.83 to 1.10; p=0.55; 10 studies, n=5209 participants; I²=52%).^{827 28 30},32 51 52 54 84

Discussion

In this systematic review, which included a large number of studies (of mixed design) from diverse countries around the world, there were no significant differences in the primary outcome of hospital mortality, or other mortality outcomes between HFNO and COT in patients with heterogeneous ARF. However, HFNO significantly reduced the overall need for IMV escalation and overall need for NIV escalation compared with COT. These results were similar for both primary analyses of all study designs, as well as the secondary analyses of RCT studies only. Findings regarding change in PaCO₂, dyspnoea scores and comfort for the two treatments varied between studies. For disease-specific causes of ARF, patients with COVID-19 who received HFNO experienced a significant reduction in need for IMV escalation, but no need for NIV escalation or mortality outcomes, compared with COT. Patients with acute-on-chronic respiratory illness who received HFNO compared with COT demonstrated a significant reduction in-hospital mortality and ICU LOS, although the sample sizes were small, and these differences were not significant when considering RCT data only. Among all included studies in this review, most patients had mild-moderate ARF, with PaO2/FiO2 ratios <300 or <200, which was appropriate for the initial oxygenation strategy of HFNO or COT. By contrast, severe ARF (PaO2/FiO2<100) may indicate the urgent need for IMV.

Recent meta-analyses comparing IMV escalation needs in patients with ARF have generated mixed results with no significant differences between HFNO and COT in some reviews^{10 25 26} and significant reductions in IMV escalation for HFNO in others.^{11 21 24} The 2021 European Respiratory Society clinical practice guidelines recommend HFNO over COT in patients with acute hypoxaemic respiratory failure, based on pooled data from 12 RCTs and 4 randomised cross-over studies showing a trend but not statistically significant reduction in escalation to IMV with the use of HFNO.²⁶ Our meta-analysis supports the utilisation of HFNO over COT in hospitalised patients with ARF, with a statistically significant reduction in overall need for IMV escalation in the HFNO group. Importantly, similar to previous systematic reviews, we found no significant differences between HFNO and COT in terms of mortality benefit,^{1112 16 18},²⁵ ICU admission rates¹² or ICU LOS¹¹¹⁷,19 21 24 25 in all patients with ARF. Notably, the studies included in our review were very heterogeneous in terms of patient populations, administration of interventions and outcome measurements. 15 studies administered HFNO for less than 24 hours and 36 did not report this information. Therefore, it is debatable whether HFNO genuinely has no impact on mortality or whether this finding may be attributed to inadequate treatment utilisation.

Additionally, our results suggest that some patient populations may be more responsive to HFNO than others, such as those with COVID-19 ARF. The results for COVID-19 ARF are consistent with another recent systematic review (six RCTs)⁸⁹ which showed a significant reduction in IMV, without any difference in mortality, in patients with COVID-19 ARF receiving HFNO compared with COT. The pathological processes driving hypoxaemia in people with COVID-19 and ARF are complex with large ventilation perfusion mismatches arising that necessitate higher oxygen flows and fractions of inspired oxygen delivery.^{90 91} Compared with COT, HFNO provides higher oxygen flows to match COVID-19 patients increased respiratory flow demands.⁹² Moreover, HFNO provides a greater reduction in inspiratory effort than COT,^{3 92} which could reduce the extent of lung injury seen in COVID-19 ARF.^{92 93}

Strengths, limitations and future research recommendations

This is the largest systematic review to explore the impacts of HFNO compared with COT on morbidity and mortality in patients with a broad range of respiratory illnesses. Limitations of this review include heterogeneous timing of outcome measurements, particularly the need for IMV escalation, as this varied depending on the time of treatment failure. Additionally, there was significant heterogeneity between studies in terms of administration of HFNO and COT, which were delivered in different countries and hospital clinical settings, using widely ranging flows and for varying amounts of time. Importantly, there was suboptimal reporting of information regarding the administration of HFNO (flow, time of usage, etc). Thus, it is not clear if the lack of change for many clinical outcomes was due to the intervention or suboptimal utilisation.

Second, the overall pooled population was small for certain outcomes, such as hospital admission rates. Third, the risk of bias was moderate for most studies and there was high heterogeneity for some outcomes such as hospital and ICU LOS. Thus, large, high-quality RCTs are required to further increase the power of meta-analyses to address several key clinical questions that remain unanswered. Fourth, it is challenging to blind participants and outcome assessors to the intervention (given the different sensation and delivery devices required for HFNO and COT), thus introducing bias, particularly for more subjective outcomes such as dyspnoea. Importantly, reporting regarding the causes of ARF in individual studies was suboptimal, with 3035 of 10 230 participants (30%) having no specified acute respiratory illness reported. Therefore, we were unable to better characterise the results by specific causes of ARF, which is crucial for understanding which patient populations with ARF are most likely to benefit from HFNO. It must also be highlighted that some of the meta-analyses were dominated by a few studies, including those performed for hospital and ICU admission rates, and the weaknesses of these dominant studies should be considered when interpreting the overall pooled results. Lastly, data from patients with a broad spectrum of respiratory conditions were pooled together to reflect real-world hospital settings for generalisability. While this introduces heterogeneity within the study population, it is important to examine HFNO’s clinical benefits compared with COT for patients with ARF secondary to heterogeneous causes as HFNO becomes more universally adopted.

Future studies that aim to determine which patient populations are most likely to respond to HFNO, measure outcomes at more standardised times, provide HFNO for longer durations and consider cost-effectiveness compared with COT are required.

Conclusion

This systematic review and meta-analysis, which includes pragmatic research conducted during the pandemic, suggests that HFNO administered in various hospital settings around the world is superior to COT in reducing the need for escalation to both IMV and NIV but has no impact on the primary outcome of hospital mortality or other mortality outcomes, in hospitalised patients with ARF due to heterogeneous respiratory illnesses (low certainty evidence with moderate-low heterogeneity). These findings support recommendations that HFNO may be considered as a first-line treatment for many patients with heterogeneous ARF. Recent studies on ARF suggest that HFNO can be safely deployed in low acuity care settings outside of the ICU, thus minimising resources.^{45 94 95} Given the physiological and clinical benefits of high-flow oxygenation and humidity,² there is a potential for HFNO to be used within low-income and middle-income countries as a less resource-intensive treatment for ARF. Further research is needed to better understand which patients benefit most and if a longer duration of HFNO use is more effective.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.