IMPORTANCE Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the effectiveness and safety of these noninvasive respiratory strategies. OBJECTIVE To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure. DESIGN, SETTING, AND PARTICIPANTS A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021. INTERVENTIONS Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475). MAIN OUTCOMES AND MEASURESThe primary outcome was a composite of tracheal intubation or mortality within 30 days. RESULTSThe trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 [95% CI, 56.7 to 58.1] years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, −8% [95% CI, −15% to −1%], P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, −1% [95% CI, −8% to 6%], P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group.CONCLUSIONS AND RELEVANCE Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings.

Background Both continuous positive airway pressure (CPAP) and high-flow nasal oxygenation (HFNO) have been recommended for acute respiratory failure in COVID-19. However, uncertainty exists regarding effectiveness and safety. Methods In the Recovery- Respiratory Support multi-center, three-arm, open-label, adaptive, randomized controlled trial, adult hospitalized patients with acute respiratory failure due to COVID-19, deemed suitable for treatment escalation, were randomly assigned to receive CPAP, HFNO, or conventional oxygen therapy. Comparisons were made between each intervention and conventional oxygen therapy. The primary outcome was a composite of tracheal intubation or mortality within 30-days. Results Over 13-months, 1272 participants were randomized and included in the analysis (380 (29.9%) CPAP; 417 (32.8%) HFNO; 475 (37.3%) conventional oxygen therapy). The need for tracheal intubation or mortality within 30-days was lower in the CPAP group (CPAP 137 of 377 participants (36.3%) vs conventional oxygen therapy 158 of 356 participants (44.4%); unadjusted odds ratio 0.72; 95% CI 0.53 to 0.96, P=0.03). There was no difference between HFNO and conventional oxygen therapy (HFNO 184 of 414 participants (44.4%) vs conventional oxygen therapy 166 of 368 participants (45.1%); unadjusted odds ratio 0.97; 95% CI 0.73 to 1.29, P=0.85). Conclusions CPAP, compared with conventional oxygen therapy, reduced the composite outcome of intubation or death within 30 days of randomisation in hospitalized adults with acute respiratory failure due to COVID-19. There was no effect observed, compared with conventional oxygen therapy, with the use of HFNO. (Funded by the UK National Institute for Health Research; ISRCTN 16912075).

IntroductionNoninvasive ventilation (NIV) improves survival among patients with hypercapnic respiratory failure in hospital, but evidence for its use in domiciliary settings is limited. A patient’s underlying risk of having an exacerbation may affect any potential benefit that can be gained from domiciliary NIV. This is the first comprehensive systematic review to stratify patients based on a proxy for exacerbation risk: patients in a stable state and those immediately post-exacerbation hospitalization.MethodsA systematic review of nonrandomized and randomized controlled trials (RCTs) was undertaken in order to compare the relative effectiveness of different types of domiciliary NIV and usual care on hospital admissions, mortality, and health-related quality of life. Standard systematic review methods were used for identifying studies (until September 2014), quality appraisal, and synthesis. Data were presented in forest plots and pooled where appropriate using random-effects meta-analysis.ResultsThirty-one studies were included. For stable patients, there was no evidence of a survival benefit from NIV (relative risk [RR] 0.88 [0.55, 1.43], I2=60.4%, n=7 RCTs), but there was a possible trend toward fewer hospitalizations (weighted mean difference −0.46 [−1.02, 0.09], I2=59.2%, n=5 RCTs) and improved health-related quality of life. For posthospital patients, survival benefit could not be demonstrated within the three RCTs (RR 0.89 [0.53, 1.49], I2=25.1%), although there was evidence of benefit from four non-RCTs (RR 0.45 [0.32, 0.65], I2=0%). Effects on hospitalizations were inconsistent. Post hoc analyses suggested that NIV-related improvements in hypercapnia were associated with reduced hospital admissions across both populations. Little data were available comparing different types of NIV.ConclusionThe effectiveness of domiciliary NIV remains uncertain; however, some patients may benefit. Further research is required to identify these patients and to explore the relevance of improvements in hypercapnia in influencing clinical outcomes. Optimum time points for commencing domiciliary NIV and equipment settings need to be established.

Our study identifies 'adapting to non-invasive ventilation' as the central process enabling long-term use in palliative care, although the way in which this is approached by healthcare professionals and patients does not always converge. We present ideas emerging from the data on potential interventions to improve patient experience and adaptation.

BackgroundChronic obstructive pulmonary disease (COPD) is a chronic progressive lung disease characterised by non-reversible airflow obstruction. Exacerbations are a key cause of morbidity and mortality and place a considerable burden on health-care systems. While there is evidence that patients benefit from non-invasive ventilation (NIV) in hospital during an acute exacerbation, evidence supporting home use for more stable COPD patients is limited. In the UK, domiciliary NIV is considered on health economic grounds in patients after three hospital admissions for acute hypercapnic respiratory failure.ObjectiveTo assess the clinical effectiveness and cost-effectiveness of domiciliary NIV by systematic review and economic evaluation.Data sourcesBibliographic databases, conference proceedings and ongoing trial registries up to September 2014.MethodsStandard systematic review methods were used for identifying relevant clinical effectiveness and cost-effectiveness studies assessing NIV compared with usual care or comparing different types of NIV. Risk of bias was assessed using Cochrane guidelines and relevant economic checklists. Results for primary effectiveness outcomes (mortality, hospitalisations, exacerbations and quality of life) were presented, where possible, in forest plots. A speculative Markov decision model was developed to compare the cost-effectiveness of domiciliary NIV with usual care from a UK perspective for post-hospital and more stable populations separately.ResultsThirty-one controlled effectiveness studies were identified, which report a variety of outcomes. For stable patients, a modest volume of evidence found no benefit from domiciliary NIV for survival and some non-significant beneficial trends for hospitalisations and quality of life. For post-hospital patients, no benefit from NIV could be shown in terms of survival (from randomised controlled trials) and findings for hospital admissions were inconsistent and based on limited evidence. No conclusions could be drawn regarding potential benefit from different types of NIV. No cost-effectiveness studies of domiciliary NIV were identified. Economic modelling suggested that NIV may be cost-effective in a stable population at a threshold of £30,000 per quality-adjusted life-year (QALY) gained (incremental cost-effectiveness ratio £28,162), but this is associated with uncertainty. In the case of the post-hospital population, results for three separate base cases ranged from usual care dominating to NIV being cost-effective, with an incremental cost-effectiveness ratio of less than £10,000 per QALY gained. All estimates were sensitive to effectiveness estimates, length of benefit from NIV (currently unknown) and some costs. Modelling suggested that reductions in the rate of hospital admissions per patient per year of 24% and 15% in the stable and post-hospital populations, respectively, are required for NIV to be cost-effective.LimitationsEvidence on key clinical outcomes remains limited, particularly quality-of-life and long-term (> 2 years) effects. Economic modelling should be viewed as speculative because of uncertainty around effect estimates, baseline risks, length of benefit of NIV and limited quality-of-life/utility data.ConclusionsThe cost-effectiveness of domiciliary NIV remains uncertain and the findings in this report are sensitive to emergent data. Further evidence is required to identify patients most likely to benefit from domiciliary NIV and to establish optimum time points for starting NIV and equipment settings.Future work recommendationsThe results from this report will need to be re-examined in the light of any new trial results, particularly in terms of reducing the uncertainty in the economic model. Any new randomised controlled trials should consider including a sham non-invasive ventilation arm and/or a higher- and lower-pressure arm. Individual participant data analyses may help to determine whether or not there are any patient characteristics or equipment settings that are predictive of a benefit of NIV and to establish optimum time points for starting (and potentially discounting) NIV.Study registrationThis study is registered as PROSPERO CRD42012003286.FundingThe National Institute for Health Research Health Technology Assessment programme.