Table of Contents
- 1 ABSTRACT
- 2 Keywords
- 3 1. Introduction
- 4 2. Methods
- 5 3. Role of the funding source
- 6 4. Results
- 7 5. Discussion
- 8 Funding
- 9 Data sharing statement
- 10 Author contributions
- 11 Declaration of Competing Interest
- 12 Acknowledgments
- 13 Appendix. Supplementary materials
- 14 References
- 15 Article Info
- 16 Permitted
- 17 Not Permitted
ABSTRACT
Background
Continuous positive airway pressure (CPAP) therapy is commonly used for respiratory failure due to severe COVID-19 pneumonitis, including in patients deemed not likely to benefit from invasive mechanical ventilation (nIMV). Little evidence exists demonstrating superiority over conventional oxygen therapy, whilst ward-level delivery of CPAP presents practical challenges. We sought to compare clinical outcomes of oxygen therapy versus CPAP therapy in patients with COVID-19 who were nIMV.
Methods
This retrospective multi-centre cohort evaluation included patients diagnosed with COVID-19 who were nIMV, had a treatment escalation plan of ward-level care and clinical frailty scale ≤ 6. Recruitment occurred during the first two waves of the UK COVID-19 pandemic in 2020; from 1st March to May 31st, and from 1st September to 31st December. Patients given CPAP were compared to patients receiving oxygen therapy that required FiO2 ≥0.4 for more than 12 hours at hospitals not providing ward-level CPAP. Logistic regression modelling was performed to compare 30-day mortality between treatment groups, accounting for important confounders and within-hospital clustering.
Findings
Seven hospitals provided data for 479 patients during the UK COVID-19 pandemic in 2020. Overall 30-day mortality was 75.6% in the oxygen group (186/246 patients) and 77.7% in the CPAP group (181/233 patients). A lack of evidence for a treatment effect persisted in the adjusted model (adjusted odds ratio 0.84 95% CI 0.57-1.23, p=0.37). 49.8% of patients receiving CPAP-therapy (118/237) chose to discontinue it.
Interpretation
No survival difference was found between using oxygen alone or CPAP to treat patients with severe COVID-19 who were nIMV. A high patient-initiated discontinuation rate for CPAP suggests a significant treatment burden. Further reflection is warranted on the current treatment guidance and widespread application of CPAP in this setting.
Keywords
Evidence before this study
We searched PubMed for English language articles up to 27/04/2021 with the terms “continuous positive airway pressure,” “CPAP” or “non-invasive respiratory support” and “COVID-19” or “SARS-COV-2”, and searched the ISRCTN clinicaltrials.gov, and clinicaltrialsregister.eu clinical trial registries. We also searched for relevant clinical guidelines from national and international organisations. One randomised controlled trial comparing continuous positive airway pressure (CPAP) to usual care (RECOVERY-RS) in the critical care setting is still recruiting. We did not find any evidence comparing CPAP to conventional oxygen therapy. Clinical guidelines differ in their view on the role of CPAP in COVID-19, and they acknowledge a paucity of evidence on which to base recommendations.
Added value of this study
This multicentre cohort evaluation is the first, to our knowledge, to compare CPAP to conventional oxygen therapy among patients who are ineligible for invasive mechanical ventilation (nIMV). Mortality rates amongst hypoxic nIMV patients were high and there was no difference between treatment groups, even though baseline patient characteristics were comparable between the groups. We also identified a high rate of CPAP discontinuation according to patient choice, suggesting an associated treatment burden.
Implications of all the available evidence
While CPAP can be delivered outside the critical care setting, its effectiveness amongst nIMV patients with respiratory failure due to COVID-19 is called into question. Further comparative evidence would be of value, including amongst patients who are candidates for invasive mechanical ventilation. Further work to understand and improve patient tolerance of CPAP is also needed.
1. Introduction
,
- Vitacca M
- Nava S
- Santus P
- Harari S.
]. Subsequently it gained traction as an intervention that could be delivered outside of the intensive therapy unit (ITU) and high-dependency unit (HDU) [
Scottish Intercollegiate Guidelines Network (SIGN). COVID-19 position statement: CPAP for COVID-19 related respiratory failure [Internet]. 2020 [updated 2020 Sept, cited 2021 July]. Available from http://www.sign.ac.uk.
, ,
World Health Organisation (WHO). Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance [Internet]. 2019 [updated 2020 Mar, cited 2021 Jul]. Available from: https://apps.who.int/iris/handle/10665/331446.
].
- Perkins GD
- Couper K
- Connolly B
- et al.
]. Patients considered unlikely to benefit from IMV with a ward-level treatment escalation plan (hereafter termed nIMV) comprise the majority of hospitalised patients with COVID-19 and have greatest mortality and morbidity [
- Docherty AB
- Harrison EM
- Green CA
- et al.
]. At the time of writing no registered trials of CPAP were found investigating its use in patients who are nIMV. Moreover, the current evidence base, upon which the use of CPAP is predicated, focuses on its role in patients suitable for IMV [
- Vaschetto R
- Barone-Adesi F
- Racca F
- et al.
,
- Aliberti S
- Radovanovic D
- Billi F
- et al.
,
- Franco C
- Facciolongo N
- Tonelli R
- et al.
].To date, evidence generated during this pandemic comprises single-arm observational studies, or where early IMV, HFNO and CPAP were delivered simultaneously at study hospitals based solely upon clinician judgement, obscuring treatment effect [
,
- Vaschetto R
- Barone-Adesi F
- Racca F
- et al.
,
- Aliberti S
- Radovanovic D
- Billi F
- et al.
,
- Franco C
- Facciolongo N
- Tonelli R
- et al.
,
- Ashish A
- Unsworth A
- Martindale J
- et al.
,
- Burns GP
- Lane ND
- Tedd HM
- et al.
]. Evidence prior to COVID-19 consists of small observational studies in viral pneumonitis or is extrapolated from trials of CPAP in surgery-associated acute respiratory distress syndrome [
- Faria DAS
- da Silva EMK
- Atallah ÁN
- Vital FMR.
,
,
- Vdoushkina E
- Chernogayeva G
- Povalyaeva L
- Borodulina E.
]. Of the few studies to report mortality in patients who are nIMV the largest cohort in Italy (n=140) shows high mortality (73% 60-day mortality) [
- Vaschetto R
- Barone-Adesi F
- Racca F
- et al.
]. No study that focuses on patients who are nIMV has a control comparison group [
- Ashish A
- Unsworth A
- Martindale J
- et al.
,
- Burns GP
- Lane ND
- Tedd HM
- et al.
,
- Bradley P
- Nixon J
- Wilson J
- et al.
].
Scottish Intercollegiate Guidelines Network (SIGN). COVID-19 position statement: CPAP for COVID-19 related respiratory failure [Internet]. 2020 [updated 2020 Sept, cited 2021 July]. Available from http://www.sign.ac.uk.
, ,
World Health Organisation (WHO). Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance [Internet]. 2019 [updated 2020 Mar, cited 2021 Jul]. Available from: https://apps.who.int/iris/handle/10665/331446.
,
ANZICS COVID-19 Guidelines.
]. Practice has varied within the North-West region of England; some hospitals did not offer CPAP to patients who were nIMV, whilst others did. This was due to clinical equipoise, given the weakness of the quality of available evidence for CPAP benefit, and practical considerations regarding aerosol generation and infection control principles, nursing availability, availability of CPAP machines and oxygen pipeline capacity. Additional to the resource burden of delivering CPAP is the potential burden on individual patients.
Data on CPAP efficacy compared to ward-level oxygen delivery for patients who are nIMV with severe COVID-19 pneumonitis are urgently needed, both in countries with established consensus guidelines and resource-restricted countries with critical decisions on resource allocation. This multi-centre retrospective cohort evaluation had the objective of describing, evaluating and comparing the effect of treating patients who are nIMV with conventional ward-based oxygen or CPAP treatment. Primary outcomes of 30-day mortality and secondary outcomes of survival to discharge and survivor length of stay are compared between treatment groups. This study provides outcomes for the largest ward-level (not treated in ITU or HDU) cohort of patients who received CPAP therapy and considered unlikely to benefit from IMV. It is, as far as we are aware, the first comparison with an independent control group.
2. Methods
2.1 Study design
Seven hospitals participated across the North West of England, representing varying local practice in the management of hypoxia in COVID-19. Two hospitals did not offer CPAP or HFNO to patients who were nIMV, while the other hospitals provided CPAP or CPAP with HFNO as second line therapy. The time periods captured were during ‘wave 1’ and ‘wave 2’ of the COVID-19 pandemic in the UK, taken as 1st March to 31st May 2020 and 1st September to 31st December 2020 respectively. The primary outcome measure was all-cause 30-day mortality. Secondary outcome measures were time to death and time from inclusion to discharge (termed time to discharge) in survivors.
Scottish Intercollegiate Guidelines Network (SIGN). COVID-19 position statement: CPAP for COVID-19 related respiratory failure [Internet]. 2020 [updated 2020 Sept, cited 2021 July]. Available from http://www.sign.ac.uk.
,].
Diagnosis of COVID-19 was either proven with polymerase chain reaction (PCR) testing for SARS-CoV-2 or considered likely according to clinical judgement, which was based upon radiological changes seen on chest radiographs and occasionally computed tomography imaging, consistent with COVID-19 pneumonitis, combined with typical signs or symptoms of COVID-19. All COVID-19 inpatients at the seven hospitals within the study inclusion dates were screened to see if they met inclusion criteria.
2.2 Data collection
Data collection was performed retrospectively by interrogation of clinical records. Records were reviewed at least 30 days from the date each patient met inclusion criteria to capture mortality. Baseline data collected includes patient age, ethnicity, obesity (body mass index (BMI) ≥ 30kg/m2) and comorbidities. Blood results for urea and C-reactive protein (CRP) were recorded at the time-point patients met the inclusion criteria. All patients had the vital signs of pulse oximetry (SpO2), FiO2 and respiratory rate (RR) recorded from observations captured prior to inclusion. Additionally, initial and maximum CPAP pressures, and maximum FiO2, were recorded. CPAP machines included Respironics A40 (Phillips, USA), ResMed Airsense (ResMed, Aus) and Sleepcube (DeVilbiss, UK) that utilised entrained oxygen across three hospitals and Trilogy 202 (Phillips, USA) that utilised blended oxygen across two hospitals. It was recorded when CPAP treatment was discontinued due to patient wishes; when this was not the case, CPAP discontinuation is categorised as clinician-decided, whether due to successful weaning or futility. Provision of palliative care interventions and/or specialist consultation was recorded.
2.3 Statistical analysis
Unadjusted associations between 30-day mortality and explanatory variables, including treatment, were assessed with univariable logistic regression modelling. A Kaplan-Meier curve was created to illustrate the overall survival by treatment group and the survival difference tested using a log-rank test. Within the CPAP-group descriptive analysis was performed and then stratified by (i) 30-day mortality, and (ii) decision to discontinue CPAP treatment.
- Zeger SL
- Liang K-Y
- Albert PS.
]. This method assumes that patients within a hospital are equally correlated with each other, and as a marginal model it provides a population average interpretation: the effect on mortality rate of treating the whole eligible cohort with CPAP. A saturated multivariable model was fitted and then refined using the following principles: retention of key demographics (age, sex); retention of study inclusion criteria dependent variables (FiO2, CFS); retention of any unadjusted variable identified as significant (p
- Zeger SL
- Liang K-Y
- Albert PS.
,
]. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) are reported.
Sensitivity analyses are conducted to test the stability and robustness of the final candidate explanatory model. This included: (i) excluding patients in the oxygen-group with maximum FiO2 < 0.60, (ii) excluding patients in the CPAP-group with duration of use < 24 hours, (iii) excluding any patients with prolonged time from admission to inclusion, (iv) including an obesity-age interaction term (Supplementary 8 a-e).
Selection bias was minimised by (i) aligning inclusion criteria at oxygen-group sites with CPAP-group sites and national guidelines, (ii) selecting oxygen-group and CPAP-group patients from sites only offering that treatment (avoiding clinician bias) (iii) multiple study sites, (iv) employing a modelling approach that adjusts for important predictors of mortality, and recognises the clustering by hospital site, and (v) performing sensitivity analyses to account for differences in baseline characteristics and model selection.
- Docherty AB
- Harrison EM
- Green CA
- et al.
,
- Sablerolles RSG
- Lafeber M
- van Kempen JAL
- et al.
,
- Knight SR
- Ho A
- Pius R
- et al.
]. Variables are assessed for collinearity using correlation matrices (Supplementary 3). Statistical tests were two-tailed with statistical significance defined at 5%. Data analysis was performed in R (version 4.0.3) using R Studio (version 1.4.1103) with the ‘geepack’ package [
R: A language and environment for statistical computing.
,
- Højsgaard S
- Halekoh U
- Yan J.
,
].
3. Role of the funding source
No funding source had any role in the design, collection, analysis, interpretation or preparation of the manuscript.
4. Results
Table 1Study population demographics stratified by oxygen treatment and CPAP treatment. 1n (%); Median (IQR). 2Fisher’s exact test; Wilcoxon rank sum test. Abbreviations used: HIV, human immunodeficiency virus; CFS, clinical frailty scale; CRP, C-reactive protein; FiO2, fraction of inspired oxygen; RR, respiratory rate; SpO2, pulse oximetry.
4.1 Baseline characteristics
4.2 Analysis of survival: unadjusted model
Figure 130 day mortality unadjusted odds ratios (OR, left) of variables and final Generalised Estimating Equations (GEE) model with estimated 30-day mortality adjusted odds ratios (aOR, right). Variables coloured grey were not included in the final GEE model. An OR>1 represents increased occurrence of 30 day mortality. Abbreviations used: FiO2, fraction of inspired oxygen; RR, respiratory rate; SpO2, pulse oximetry; CRP, C-reactive protein; BMI, body mass index; CFS, clinical frailty scale. Blue variables were subsequently used in the final adjusted OR model.
We included 171 patients from wave 1 and 308 from wave 2. There was no significant difference in 30-day mortality (OR 1.04, 95% CI 0.68-1.58, p=0.87) or in survival time (p=0.55, Supplementary 4) between the first two waves of the UK pandemic. Hospital site conferred no significant association with 30-day mortality, time to discharge or time to death (p=0.18, Supplementary 5).
4.3 Effect of treatment on survival
Figure 2a) 30-day survival curve analysis stratified by treatment (unadjusted) with log-rank test p-value. There was no censored data at any time-point, b) Box and whisker plot showing time from inclusion to discharge of survivors (days). Boxes are bound by the upper and lower quartiles, whilst whiskers are bounded by these ± 1.5x the interquartile range.
- Sablerolles RSG
- Lafeber M
- van Kempen JAL
- et al.
,
- Knight SR
- Ho A
- Pius R
- et al.
]. Findings did not change in any sensitivity analysis conducted (Supplementary figure 8 a-f).
4.4 CPAP treatment: characterisation and experience
Table 2Patient Characteristics of CPAP treatment and subgroups. 1n (%); Median (IQR). 2Pearson’s Chi-squared test; Wilcoxon rank sum test; Fisher’s exact test. Abbreviations used: FiO2, fraction of inspired oxygen; RR, respiratory rate; SpO2, pulse oximetry; CFS, clinical frailty scale.
5. Discussion
This multi-centre evaluation is the first to report outcomes in patients not likely to benefit from invasive mechanical ventilation (nIMV) treated with conventional ward-level oxygen compared to CPAP therapy for COVID-19 respiratory failure. We found no significant association between 30-day mortality and treatment group, even after adjustment for important confounders. Given the resources required to provide CPAP it raises the question as to whether it should be provided to patients who are nIMV, which has been commonplace during the COVID-19 pandemic. Importantly, however, we found no evidence of worsened outcomes in patients treated with CPAP.
Patient-initiated CPAP discontinuation rate was high across all study hospitals (50.2% range 44-60%) despite being delivered by respiratory specialist teams experienced in providing CPAP, alongside readily available palliative care interventions. Patients who discontinued their CPAP treatment did so after a reasonable duration of use (median 2 days, IQR 1-4) and reached therapeutic maximal pressures. Sensitivity analyses were further conducted to exclude patients with a short CPAP treatment duration (< 24 hours): there was still no association between treatment and mortality. This suggests that patient discontinuation of CPAP is unlikely to be the reason for a lack of superiority. Furthermore, the high patient-discontinuation rate implies a high treatment burden which requires further research.
- Vaschetto R
- Barone-Adesi F
- Racca F
- et al.
,
John C, Crickett R, Owen W, et al. P58 Reviewing the role of continuous positive airway pressure (CPAP) in patients with severe COVID-19: a multi-site observational study. 2021. DOI:10.1136/thorax-2020-btsabstracts.203.
]. Our study population demographics are broadly similar to those reported in other large UK studies [
- Docherty AB
- Harrison EM
- Green CA
- et al.
]. Additional reassurance in the study design and model used is provided by finding that several variables predictive of mortality, included in the ISARIC 4C study and mortality risk score, had their association with mortality replicated here [
- Knight SR
- Ho A
- Pius R
- et al.
].
Although treatments were provided at separate hospitals, patient demographics were similar between treatment groups, and measures have been taken to account for within-hospital clustering (GEE model). Furthermore, for any variables that had significantly different distribution between treatment groups (p < 0.1), analysis was undertaken both with and without these variables in the adjusted OR model, with no substantive differences in findings. Using a pragmatic study design, data were obtained from routinely recorded clinical information; consequently our findings are reflective of real-world practice.
- Sablerolles RSG
- Lafeber M
- van Kempen JAL
- et al.
]. This is mirrored in other acute illnesses where over-65 year-old patient cohorts with CFS 4-5 have been shown to have poor predictive value in 6- and 12-month mortality [
- Chong E
- Chan M
- Tan HN
- Lim WS.
]. This has raised concern regarding the use of CFS to weight treatment decisions in this patient group during the COVID-19 pandemic [
- Chong E
- Chan M
- Tan HN
- Lim WS.
].
The difference in RR and FiO2 between treatment groups at inclusion is likely to represent pragmatic differences in the initiation of CPAP and oxygen. Conventional oxygen therapy is generally escalated reflexively in response to desaturation below a predetermined target SpO2. In practice, CPAP initiation does not happen as quickly: the decision to initiate CPAP is made by a senior physician after clinical review following deterioration; at times there may be an inclination to delay CPAP once FiO2 0.4 is reached, giving them a period of further observation in the hope of improvement; and setting up CPAP requires the practicalities of preparing equipment and often moving a patient to a suitable bedspace where it can be delivered. We observed only 9/246 patients in the oxygen treatment group with a maximal FiO2 < 0.60, indicating that this group did not disproportionately capture patients with mild disease. Sensitivity analysis, when excluding patients in the oxygen group with maximal FiO2 < 0.60, showed no significant difference in treatment effect to that presented in the final model.
To ensure the rigour of the study findings, the stability and robustness of the final candidate explanatory model was tested with a sensitivity analysis that excludes any important patient groups that may result in underestimating the effect of CPAP therapy. This included: (i) excluding patients in the oxygen group with maximum FiO2 < 0.60, a proportion of whom may not have been included in the CPAP treatment group if they did not exhibit increased respiratory effort; (ii) excluding patients with a short duration of CPAP therapy, as they may not have achieved any potential CPAP efficacy; (iii) excluding any patients with time from admission to inclusion > 7 days, as prolonged admission to inclusion time may indicate hospital acquired infection; (iv) the authors noted the presence of a relatively younger and more obese group of patients in the CPAP group with favourable survival. To account for any potentially significant impact of obesity on the relationship between treatment group and 30-day mortality, an obesity-age interaction term is included. The lack of change in treatment effect aOR in all the sensitivity analyses conducted indicates the model is robust when stressed.
Scottish Intercollegiate Guidelines Network (SIGN). COVID-19 position statement: CPAP for COVID-19 related respiratory failure [Internet]. 2020 [updated 2020 Sept, cited 2021 July]. Available from http://www.sign.ac.uk.
,,
ANZICS COVID-19 Guidelines.
]. Devices used to deliver CPAP include those that provide entrained oxygen, as detailed in the methods, which are capable of delivering a lower theoretical maximal FiO2 than others within the study that provide blended oxygen. This represents the machines available at the time in this real-world study and did not appear to have a large impact upon mortality at sites that predominantly used one type of machine.
- Coppadoro A
- Benini A
- Fruscio R
- et al.
].
Shah A, Naidu S, Saigal A, Hurst J, Lipman M, Mandal S. P56 Higher body mass index (BMI) is associated with improved continuous positive airway pressure (CPAP) outcomes in patients with hypoxic respiratory failure secondary to COVID-19. 2021. DOI:10.1136/thorax-2020-btsabstracts.201.
,
- Helvaci N
- Eyupoglu ND
- Karabulut E
- Yildiz BO.
]. Whilst obesity is a significant factor in improved unadjusted mortality in our data (OR 0.54, CI 0.36-0.87, p
- Helvaci N
- Eyupoglu ND
- Karabulut E
- Yildiz BO.
,
Parikh R, Garcia MA, Rajendran I, et al. ICU outcomes in Covid-19 patients with obesity. Therapeutic Advances in Respiratory Disease. 2020; 14. DOI:10.1177/1753466620971146.
].
In summary, this study shows no evidence of a survival advantage from CPAP treatment as a ceiling of care in severe COVID-19 pneumonitis when compared to conventional oxygen therapy amongst patients who were nIMV. CPAP administration in the ward setting has been demonstrated to be feasible, but it has high mortality and may bring a significant treatment burden to patients. This invites pause for reflection on whether the current treatment guidance and widespread application of CPAP in this setting is appropriate.
Funding
L Pearmain is supported by the MRC (MR/R00191X/1). TW Felton is supported by the NIHR Manchester Biomedical Research Centre.
Data sharing statement
Data requests will be considered and should be addressed to the corresponding author. Any request would be subject to institutional approval.
Author contributions
PB, LP & JN conceived and designed the study. PB, JW, JN, JR, PW, LP, MG, KK, AH, PD, CW, RCR, CL, ND, DSHM, JC, MSD, SR, MM, HA, KS, MH, DG acquired data. PB, JW, LP, PW, TG, AA, JN,TB verified underlying data. JW, PB, LP, JN, PB TB, TG, TWF, NC, AA, EN, AB contributed to data interpretation. JW, LP, PB & RT designed and conducted the analysis. LP, JW and PB drafted the manuscript and LP, PB, JW, NC, TWF, TG, TB and AB edited the manuscript. All authors reviewed and approved the final manuscript.
Declaration of Competing Interest
AB reports fees for speaking/session chair for Fisher and Paykel webinars (high nasal flow cannulae). AB is an advisory board member for Sanofi Genzyme (respiratory management of Pompe disease). All other authors have nothing to declare.
Acknowledgments
The authors would like to acknowledge the NWCORR for providing the platform enabling this collaboration. Additionally, we would like to thank the staff in all study hospitals for their dedication and care towards our patients. Finally, we would like to take the opportunity to remember our patients included in this work, many of whom are sadly no longer with us.
Appendix. Supplementary materials
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