ABSTRACT 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 ).

BACKGROUND Chronic 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 U.K., domiciliary NIV is considered on health economic grounds in patients after three hospital admissions for acute hypercapnic respiratory failure. OBJECTIVE To assess the clinical effectiveness and cost-effectiveness of domiciliary NIV by systematic review and economic evaluation. DATA SOURCES Bibliographic databases, conference proceedings and ongoing trial registries up to September 2014. METHODS Standard 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. RESULTS Thirty-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. LIMITATIONS Evidence 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. CONCLUSIONS The 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 RECOMMENDATIONS The 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 REGISTRATION This study is registered as PROSPERO CRD42012003286. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Background:Identification of patients who may become hypercapnic, or develop acidotic hypercapnic respiratory failure (AHRF), is important in chronic obstructive pulmonary disease (COPD) to avoid hospital admission and select patients for use of home NIV. This study aimed to identify factors associated with presence and development of hypercapnia.Methods:1224 patients, 637 with COPD and 587 with alpha 1 antitrypsin deficiency (AATD), from 4 previously established patient cohorts, were included in cross-sectional analyses of hypercapnia (PaCO2 ≥ 6.5 kPa or 48.8 mmHg), focusing on phenotypic features of COPD and mortality. Longitudinal associations of rising PaCO2 were also assessed. A second cohort of 160 COPD patients underwent sleep studies and 1-year follow-up, analysing in a similar way, incorporating additional information from their sleep studies if appropriate.Results:Hypercapnia was 15 times more common in usual COPD than AATD (p < 0.01) after adjustment for baseline differences by regression. Independent predictors of hypercapnia in COPD included FEV1 and current use of oxygen; these variables, together with lack of emphysema, explained 11% of variance in CO2. Increasing PaCO2 also associated with higher risk of death (p=0.03). 44/160 patients exhibited sleep disordered breathing. The sleep study cohort also showed an association of low FEV1 with hypercapnia. Prior hospital admission for AHRF was also clinically significant, being a feature of almost double the number of hypercapnic patients in both test and sleep study COPD cohorts.Conclusion:Lower FEV1 and prior AHRF are the main associations of hypercapnia in COPD, which carries a poor prognosis, particularly worsening over time.

Introduction:Noninvasive 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.Methods: A 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.Results: Thirty-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],I 2 =60.4%, n=7 RCTs), but there was a possible trend toward fewer hospitalizations (weighted mean difference -0.46 [-1.02, 0.09], I 2 =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],I 2 =25.1%), although there was evidence of benefit from four non-RCTs (RR 0.45 [0.32, 0.65], I 2 =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. Conclusion:The 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.

Background: Domiciliary non-invasive ventilation may be used in palliative care of patients with chronic obstructive pulmonary disease, although there is uncertainty regarding effect on quality of life. Aim: Explore experiences of domiciliary non-invasive ventilation in chronic obstructive pulmonary disease, to understand decision-making processes and improve future palliative care. Design: Qualitative interview study, based on constructivist grounded theory, and using the framework method for data management and analysis. Participants: 20 chronic obstructive pulmonary disease patients, 4 carers and 15 healthcare professionals. Results: Most patients had very severe chronic obstructive pulmonary disease. Data were categorised into four domains – clinical, technical, socio-economic and experiential. Healthcare professionals felt uncertain regarding clinical evidence, emphasising social support and tolerance as deciding factors in non-invasive ventilation use. Conversely, patients reported symptomatic benefit, which generally outweighed negative experiences and led to continued use. Healthcare professionals felt that patients chose to be on non-invasive ventilation; however, most patients felt that they had no choice as healthcare professionals recommended non-invasive ventilation or their poor health mandated it. Conclusions: 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.

Background and objectiveWe sought to elicit predictors of in-hospital mortality for first and subsequent admissions with acidotic hypercapnic respiratory failure (AHRF) in a cohort of chronic obstructive pulmonary disease patients who have undergone ward-based non-invasive ventilation (NIV), and identify features associated with long-term survival.MethodsAnalysis of prospectively collected data at a single centre on patients undergoing NIV for AHRF between 2004 and 2009. Predictors of in-hospital mortality and intubation were sought by logistic regression and predictors of long-term survival by Cox regression.ResultsInitial pH exhibited a threshold effect for in-hospital mortality at pH7.15. This relationship remained in patients undergoing their first episode of AHRF. In both first and subsequent admissions, a pH threshold of 7.25 at 4h was associated with better prognosis (P=0.02 and P=0.04 respectively). In second or subsequent episodes of AHRF, mortality was lower and predicted only by age (P=0.002) on multivariate analysis.ConclusionsNIV could be used on medical wards for patients with pH7.16 or greater on their first admission, although more conservative values should continue to be used for those with a second or subsequent episodes of AHRF.NIV is increasingly used in patients with COPD exacerbations outside an ICU setting. We show that patients with a lower pre-NIV pH(7.15-7.25) do as well as those with a higher pH, potentially advocating its use in a relatively low intensity setting of a respiratory ward-based NIV unit as opposed to a Critical Care Unit. Future guidelines should to take this into account.

Background: Chronic obstructive pulmonary disease (COPD) remains a significant public health burden. Non-invasive ventilation (NIV) is a method of supported breathing used as standard care for acutely unwell patients in hospital with COPD, but there is uncertainty around the potential benefits of using NIV in the treatment of stable patients in a non-hospital setting. This is a protocol for systematic reviews of the clinical and cost-effectiveness of NIV in this context, being undertaken in support of a model based economic evaluation. Methods/Design: Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction for both the clinical and economic systematic reviews. Bibliographic databases (for example MEDLINE, EMBASE) and ongoing trials registers will be searched from 1980 onwards. The search strategy will combine terms for the population with those for the intervention. Studies will be selected for review if the population includes adult patients with COPD and hypercapnic respiratory failure, however defined. Systematic reviews, randomised controlled trials and observational studies (with n >1) will be included, and quality assessment will be tailored to the different study designs. The primary outcome measures of interest are survival, quality of life, and healthcare utilisations (hospitalisation and Accident and Emergency attendances). Meta-analyses will be undertaken where clinical and methodological homogeneity exists, supported by predefined subgroup analyses where appropriate. A systematic review of the evidence on the cost-effectiveness of non-hospital NIV will be completed, and a model-based cost-utility analysis undertaken to determine the cost-effectiveness of non-hospital-based NIV compared with standard care. Discussion: These reviews will attempt to clarify the clinical effectiveness of non-hospital NIV in COPD patients as well as the cost-effectiveness. The findings may indicate whether NIV in a non-hospital setting should be considered more routinely in this patient group, and what the likely cost implications will be. PROSPERO registration: 2012:CRD42012003286.