The role of CPAP as a potential bridge to invasive ventilation and as a ceiling-of-care for patients hospitalized with Covid-19—An observational study

Jonathan Walker; Shaman Dolly; Liji Ng; Melissa Prior-Ong; Kalpana Sabapathy

doi:10.1371/journal.pone.0244857

. 2020 Dec 31;15(12):e0244857. doi: 10.1371/journal.pone.0244857

The role of CPAP as a potential bridge to invasive ventilation and as a ceiling-of-care for patients hospitalized with Covid-19—An observational study

Jonathan Walker ^1,^*, Shaman Dolly ^1,^#, Liji Ng ^1,^#, Melissa Prior-Ong ^1,^#, Kalpana Sabapathy ²

Editor: Andrea Coppadoro³

PMCID: PMC7774971 PMID: 33382796

Abstract

Background

Continuous positive airway pressure (CPAP) ventilation may be used as a potential bridge to invasive mechanical ventilation (IMV), or as a ceiling-of-care for persistent hypoxaemia despite standard oxygen therapy, according to UK guidelines. We examined the association of mode of respiratory support and ceiling-of-care on mortality.

Methods

We conducted a retrospective cohort analysis of routinely collected de-identified data of adults with nasal/throat SARs-CoV-2 swab-positive results, at the Calderdale and Huddersfield NHS Foundation Trust between 10th March-19th April 2020 (outcomes determined on 22nd May).

Findings

Of 347 patients with SARs-CoV-2 swab-positive results, 294 (84.7%) patients admitted for Covid-19 were included in the study. Sixty-nine patients were trialled on CPAP, mostly delivered by face mask, either as an early ceiling of care instituted within 24 hours of admission (N = 19), or as a potential bridge to IMV (N = 44). Patients receiving a ceiling of care more than 24 hours after admission (N = 6) were excluded from the analysis. Two hundred and fifteen patients (73.1%) maximally received air/standard oxygen therapy, and 45 (15.3%) patients maximally received CPAP. Thirty-four patients (11.6%) required IMV, of which 24 had received prior CPAP. There were 138 patients with an early ceiling-of-care plan (pre-admission/within 24h). Overall, 103(35.0%) patients died and 191(65.0%) were alive at study end. Among all patients trialled on CPAP either as a potential bridge to IMV (N = 44) or as a ceiling-of-care (N = 19) mortality was 25% and 84%, respectively. Overall, there was strong evidence for higher mortality among patients who required CPAP or IMV, compared to those who required only air/oxygen (aOR 5.24 95%CI: 1.38, 19.81 and aOR 46.47 95%CI: 7.52, 287.08, respectively; p<0.001), and among patients with early ceiling-of-care compared to those without a ceiling (aOR 41.81 95%CI: 8.28, 211.17; p<0.001). Among patients without a ceiling of care (N = 137), 10 patients required prompt intubation following failed oxygen therapy, but 44 patients received CPAP. CPAP failure, defined as death (N = 1) or intubation (N = 24), occurred in 57% (N = 25) of patients. But in total, 75% (N = 33) of those started on CPAP with no ceiling of care recovered to discharge—19 without the need for IMV, and 14 following IMV.

Conclusion

Our data suggest that among patients with no ceiling-of-care, an initial trial of CPAP as a potential bridge to IMV offers a favourable therapeutic alternative to early intubation. In contrast, among patients with a ceiling-of care, CPAP seems to offer little additional survival benefit beyond oxygen therapy alone. Information on ceilings of respiratory support is vital to interpreting mortality from Covid-19.

Strengths and limitations of this study

Sample size relatively small.
Study sample representative of hospitalised Covid-19 patients in UK.
Previously unreported data on role of ceilings-of-care in hospitalised Covid-19 patients.
Novel data on use of CPAP separated by indication.

Background

SARS-CoV-2 infection which causes Covid-19 was declared a global pandemic by the World Health Organization (WHO) on March 11^th 2020. An estimated seven million people have been infected globally, with approximately 400, 000 recorded deaths as of 11^th June 2020 [1]. In the absence of definitive treatment for SARS-CoV-2, oxygen and respiratory support is the mainstay of management to prevent death. As such, information on the presence of ceilings-of-care which limit escalation of respiratory support is vital to interpreting mortality outcomes [2].

Disease severity from Covid-19 varies widely and invasive mechanical ventilation (IMV) has been used in 8–29% of hospitalised patients [3,4]. In the UK, data suggest that mortality in patients who require IMV is approximately 50% [5]. Current World Health Organization (WHO) guidelines for the management of Covid-19 recommend that a trial of continuous positive airway pressure (CPAP) ventilation may be considered in patients who remain hypoxemic despite standard oxygen therapy (via nasal prongs or Venturi face mask), however this was not initially the case earlier in the pandemic [6,7]. The use of CPAP in Covid-19 has been questioned [8], but in contrast to many other healthcare settings, CPAP is used in the UK in preference to High Flow Nasal Oxygen, largely due to concerns about oxygen supplies. In the UK, CPAP for the management of hypoxemic patients who are admitted to hospital with Covid-19 is indicated as a potential bridge to IMV for patients with no ceilings to their potential care pathways, as a ceiling-of-care and to facilitate extubation [9]. This paper focuses on the first two of these three indications.

A ceiling-of-care is considered in order to avoid unwanted interventions that carry a high risk of failure and unnecessary suffering. All adults admitted to hospital are assessed for frailty and other factors which may make IMV on the Intensive Care Unit (ICU) inappropriate as a treatment modality [10]. When relevant, a treatment escalation and limitation plan is agreed by consensus between clinician, patient and family. This usually involves a “Do not Attempt Cardiopulmonary Resuscitation” order (DNACPR) which almost invariably excludes treatment with IMV. In this case, a trial of CPAP may be considered for patients who require greater respiratory support than standard oxygen therapy alone [10]. For patients unable to tolerate CPAP (for instance some patients find the facial attachment distressing), standard oxygen therapy may have to be used as the ceiling-of-care for respiratory support.

The mode of respiratory support used for patients with persistent hypoxemia despite standard oxygen therapy therefore involves a complex inter-play of disease severity, pre-morbid status, ceiling-of-care decisions, current local guidelines and local resources [9,10]. The aim of our study was to evaluate the outcomes of adult patients admitted to two hospital sites in the UK, who were treated according to national guidelines [9]. We examined factors associated with mortality, including mode of respiratory support and ceiling-of-care. We hope to shed light on the role of CPAP as potential bridge to IMV for patients with no ceilings to their potential care pathways, and as an escalation of respiratory support for patients with a ceiling-of-care.

Methods

Study setting, design and participants

The Calderdale and Huddersfield NHS Foundation Trust (CHFT) operates as a single centre, consisting of two acute hospitals on separate sites with over 800 hospital beds in total, and serving a population of 460,000 across Kirklees and Calderdale in West Yorkshire, England. Prior to the SARS-CoV-2 pandemic, there were approximately four high-dependency (HDU) beds across both hospital sites and ten ICU beds. The latter was increased to 26 ICU beds during the peak of Covid-19 admissions. We conducted a retrospective cohort analysis using routinely collected de-identified data of patients with nasal/throat swab positive results for SARs-CoV-2, admitted during the first six weeks of the Covid-19 epidemic in the region (between 10^th March and 19^th April). Outcome status (death, discharged alive or still an in-patient) was determined on 22^nd May 2020.

Patient and public involvement

Effective management of Covid-19 is a global priority. Patient and public were not involved in the design of the study as it involved a retrospective analysis of routinely collected data from the Electronic Patient Record (EPR). This data was fully anonymised and de-identified prior to being accessed for inclusion in the analysis and the study.

Procedures

Electronic clinical records were examined, and data collection was adapted from the International Severe Acute Respiratory and Emerging Infection Consortium and WHO standardised case record proformas. Data was collated by the medical team within the respiratory department. In addition, we collected information on care home residency and ceiling-of-care planning. We examined all adult patient data with SARs-CoV-2 swab positive results. Clinical management was according to the NHS Specialty specific guidelines [9]. These state that “CPAP is the primary mode of non-invasive respiratory support for hypoxic COVID19 patients. Suggested initial settings are 10 cmH2O + 60% oxygen”.

In this study, patients not maintaining oxygen saturations over 92–94% on 40–60% oxygen via a Venturi mask were commenced on CPAP 10 cm H20 and 10 litres oxygen, adjusted according to physician discretion. CPAP on the ward was delivered by the Breas Medical NIPPY 3+_© ventilator, with oxygen entrained from the wall via piped oxygen attached to a flow meter. Pressure could be adjusted as required, to a maximum of 15 cm H2O and flow could be adjusted to a maximum of 15 litres O2. The default interface used on the ward was a full face mask, but a total face mask was used in a small number of patients who could not tolerate this.

With only one exception, CPAP as a ceiling of care was started on the respiratory wards. CPAP as a bridge to IMV was started on the respiratory wards in most cases. These wards consisted of three bays of four beds, and four side-rooms consisting of one bed. All beds had access to a wall-mounted oxygen supply and could support the use of CPAP. One nurse would typically look after four to eight patients.

Oxygen requirements, which were administered as the minimum required to maintain target oxygen saturations within the range set by national guidelines, were documented as a proxy marker for hypoxemia and hence for severity of disease.

Fourteen patients requiring CPAP were commenced on CPAP Hoods instead of face masks and this was always delivered on ITU, either via the Hamilton-S1^©, or the Hamilton-C3^© Ventilator. With one exception, all of the CPAP Hood patients remained for full escalation.

Exposure and outcome variables and analysis

The primary outcome was mortality and the main exposure of interest was the maximal respiratory support received, defined as ‘air/oxygen’ for patients who were not escalated to either CPAP or IMV; ‘CPAP’ for patients who were not escalated to IMV; ‘IMV’ for patients who were intubated and ventilated (including prior air/oxygen and/or CPAP). A secondary exposure of interest was presence of an early ceiling-of-care plan (defined as pre-existing plans in place prior to admission or within 24h of admission) (S1 Fig).

The following baseline exposure variables determined by history and clinical assessment by clinicians, were assessed as potential confounding factors for death: sex, age category, ethnicity, body mass index (BMI), care home residency, pre-existing co-morbidities and clinical features at admission. Age was categorized as younger than 70y, 70-79y, 80-89y and ≥90y to ensure adequate outcome events in each category.

Continuous variables are presented as medians and inter-quartile ranges (IQRs) and categorical variables as counts and percentages. Missing values were excluded. Logistic regression was performed to estimate odds ratios (ORs). Likelihood ratio testing (LRT) was done to assess statistical evidence of association. The multivariable model included sex as a confounding factor a priori. Variables which showed evidence of association (p<0.05) with both mortality and with respiratory support were examined for inclusion in the final multivariable model using a backward stepwise approach. The final multivariable model included age category, sex, respiratory rate at admission, ceiling-of-care plans (pre-admission/within 24h) and maximal respiratory support received. Patients who had a ceiling-of-care instituted more than 24h after admission were omitted as reverse causality was possible, i.e. that a ceiling-of-care was introduced following failure to respond to treatment.

All analyses were performed using Stata^™ version 16.0 for Windows (Stata-Corp, College Station, Texas). Data analysed was departmental, routinely collected and fully anonymized. The Calderdale and Huddersfield NHS Foundation Trust Research and Development office considered this project a service evaluation to establish a standard, and did not require further approval. The database is available on request to the corresponding author.

Results

Patient characteristics in study population overall

During the first six weeks of the Covid-19 epidemic in the Calderdale and Kirklees region of West Yorkshire (between 10^th March and 19^th April), 347 adult patients (≥18y) had SARs-CoV-2 positive nasal/throat swabs (S2 Fig). We excluded patients who were not admitted (N = 18) or were admitted for reasons other than Covid-19, namely those who were swabbed prior to discharge or during hospitalization following admission for another unrelated reason (N = 35). Two-hundred and ninety-four (84.7%) patients were included in the final analysis and 215 (73.1%) of them maximally received air/standard oxygen therapy, 45 (15.3%) received CPAP and 34 (11.6%) received IMV. Twenty-four of the IMV patients had previously failed on CPAP and required further escalation.

Ages ranged from 23-102y (median age 71y (IQR 59,82)) (Table 1). One-hundred and eighty-three (62.2%) patients were male. The majority of patients were White (N = 239, 81.3%), 55 (18.7%) were Asian, 7 (2.3%) Black and 11 (3.7%) patients classified as Other ethnicity. Over one-fifth of patients were care home residents (N = 65, 22.1%).

Table 1. Patient characteristics overall.

Patients overall		N (%)
Socio-demographic characteristics
Sex	Female	111 (37.8)
	Male	183 (62.2)
Age (y)	Median (IQR)	71 (59,82)
	20–49	32 (10.9)
	50–59	46 (15.7)
	60–69	54 (18.4)
	70–79	75 (25.5)
	80–89	66 (22.5)
	≥ 90	21 (7.1)
Ethnicity	White	239 (81.3)
	Asian	55 (12.6)
	Black & other¹	18 (6.1)
BMI (N = 212)	Median (IQR)	27 (23,32)
	15–19.9	14 (6.6)
	20–24.9	63 (29.7)
	25–29.9	59 (27.8)
	≥ 30	76 (35.9)
Care home resident		65 (22.1)
Pre-existing comorbidities²
Hypertension		109 (37.1)
Chronic cardiac disease		90 (30.6)
Diabetes mellitus without complications		56 (19.1)
Diabetes mellitus with complications		26 (8.9)
Dementia		56 (19.1)
Chronic pulmonary disease		49 (16.7)
Chronic neurological disorder		38 (12.9)
Asthma		34 (11.6)
Chronic kidney disease		28 (9.5)
Rheumatological condition		22 (7.5)
Malignant neoplasm		20 (6.8)
Clinical features at admission³
Days since onset of symptoms (N = 253)	Median (IQR)	7 (3,10)
Fever		190 (67.1)
Cough		211 (73.5)
Shortness of breath		181 (62.9)
Temperature (degrees Celsius)	Median (IQR)	36.8 (36.4,37.5)
Respiratory rate (breaths per minute)	Median (IQR)	23 (20,28)
Heart rate (beats per minute)	Median (IQR)	92 (78,106)
CXR at admission	Clear⁴	53 (18.0)
	Unilateral opacities	37 (12.6)
	Bilateral opacities	204 (69.4)
Management
Ceiling-of-care	None	137 (46.6)
	Pre-admission	63 (40.1)
	Within 24 hours	75 (47.8)
	Later during admission	19 (12.1)
Maximal respiratory support	Air/oxygen	215 (73.1)
	CPAP	45 (15.3)
	IMV	34 (11.6)

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¹ Black N = 7 & Other N = 11;

² Co-morbidities with at least 5% prevalence in study population;

³ Three mostly commonly reported symptoms are shown;

⁴ Thirteen patients had non-Covid related changes.

The most common pre-existing co-morbidities were hypertension (N = 109, 37.1%) and chronic cardiac disease (N = 90, 30.6%) (Table 1). Fifty-six (19.0%) patients had dementia. The most commonly self-reported symptoms were fever (N = 190, 64.6%), cough (N = 211, 71.8%) and shortness of breath (N = 181 61.6%) and the median duration since onset of symptoms was 7 days (IQR 3,10). Temperature measured at admission ranged from 27.8–41.4 degrees Celsius (median 36.8, IQR 36.4, 37.5) and 52 (17.7%) had a fever (>37.8 degrees Celsius). One 97y old lady was found on the floor at home and was hypothermic (27.8 degrees Celsius). Respiratory rate at admission ranged from 14–64 breaths/minute (median 23, IQR 20,28) and heart rates ranged from 21–173 beats/minute (median 92, IQR 78,106). The majority of chest radiographs revealed bilateral opacities in 204 (69.4%) and 37 (12.5%) patients had unilateral opacities.

One hundred and fifty-seven of all patients (53.4%) had a ceiling-of-care plan of which 138 (87.9%) were instituted early (63 pre-admission and 75 within 24h of admission). The remaining 19 patients with a ceiling-of-care had it instituted later during admission. The median age of early ceiling-of-care patients (N = 138) was 81y (IQR 74,87) compared to median age of 59y (IQR 52,68) among patients with no ceiling-of-care (N = 137). Among early ceiling-of-care patients, standard oxygen therapy was the ceiling of respiratory support planned for 84 (60.9%) patients, CPAP for 41 (29.7%) patients and it was not pre-specified for 13 patients (9.4%) (the latter all went on to maximally receive air/oxygen). Ninety-five percent (N = 62) of care home residents had a ceiling-of-care, with the majority (64.5% (N = 40)) already having a ceiling plan before admission.

Characteristics of patients by maximal respiratory support received

We examined patient characteristics separately by maximal respiratory support received (Table 2). Age and sex were strongly associated with maximal respiratory support received. Two care home residents received CPAP, but all remaining 63 maximally received air/oxygen therapy. There was statistical evidence of association (X² test) with maximal respiratory support received and the following pre-morbidities chronic cardiac disease (p = 0.008), dementia (p<0.001) and chronic neurological disease (p = 0.03) indicating a greater prevalence in patients maximally treated with air or oxygen, than patients treated with CPAP or IMV. Having diabetes mellitus with complications was also different depending on maximal respiratory support (p = 0.009), with the higher prevalence among CPAP patients, while asthma (p = 0.02) was more common among IMV patients.

Table 2. Patient characteristics by maximal respiratory support received.

		Air/oxygen¹ 215 (%)	CPAP² 45 (%)	IMV³ 34 (%)	X² test p-value⁴
Socio-demographic characteristics
Age (y)	Median (IQR)	76 (63,85)	67 (56,73)	59 (51,67)	<0.001
	20–49	19 (8.9)	5 (11.1)	8 (23.5)	<0.001
	50–59	26 (12.1)	10 (22.2)	10 (29.4)
	60–69	32 (14.9)	11 (24.4)	11 (32.4)
	70–79	54 (25.1)	16 (35.6)	5 (14.7)
	80–89	64 (29.8)	2 (4.4)	0 (0.0)
	≥ 90	20 (9.3)	1 (2.2)	0 (0)
Sex	Female	94 (43.7)	9 (20)	8 (23.5)	0.002
	Male	121 (56.3)	36 (80)	26 (76.5)
Ethnicity	White	179 (83.3)	35 (77.8)	25 (73.5)	0.36
	Asian	22 (10.2)	8 (17.8)	7 (20.6)
	Black, Other	14 (6.5)	2 (4.4)	2 (5.9)
BMI	Median (IQR)	26.4 (22.3,31.1)	29.8 (24.6,33.5)	29.2 (26.8,32.9)	0.02
	15–19.9	13 (8.4)	1 (3.7)	0 (0.0)	0.14
	20–24.9	51 (32.9)	7 (25.93)	5 (16.7)
	25–29.9	41 (26.5)	6 (22.2)	12 (40.0)
	≥ 30	50 (32.3)	13 (48.2)	13 (43.3)
	Missing	60 (27.9)	18 (40.0)	4 (11.8)
Care home resident		63 (29.3)	2 (4.4)	0 (0.0)	<0.001
Pre-existing comorbidities
Hypertension		77 (35.8)	20 (44.4)	12 (35.3)	0.54
Chronic cardiac disease		75 (34.9)	12 (26.7)	3 (8.8)	0.008
Diabetes mellitus without complications		42 (19.5)	8 (17.8)	6 (17.7)	0.94
Diabetes mellitus with complications		13 (6.1)	9 (20.0)	4 (12.1)	0.009
Dementia		54 (25.1)	2 (4.4)	0 (0)	<0.001
Chronic pulmonary disease		36 (16.7)	9 (20.0)	4 (11.8)	0.62
Chronic neurological disease		35 (16.3)	2 (4.4)	1 (2.9)	0.02
Asthma		24 (11.2)	2 (4.4)	8 (23.5)	0.03
Chronic kidney disease		23 (10.7)	4 (8.9)	1 (2.9)	0.35
Rheumatological condition		19 (8.8)	3 (6.7)	0 (0)	0.19
Malignant neoplasm		17 (7.9)	3 (6.8)	0 (0)	0.24
Clinical features at admission
Days since onset of symptoms Median (IQR)		5 (2,9)	7 (4,12)	7 (6,10)	<0.001
*Missing*		38 (17.7)	2 (4.4)	1 (2.9)
Fever		32 (61.4)	30 (66.7)	28 (82.6)	0.03
*Missing*		9 (4.2)	0 (0)	2 (5.9)
Cough		141 (65.6)	39 (86.7)	31 (91.2)	0.002
*Missing*		7 (3.3)	0 (0)	0 (0)
Shortness of breath		123 (57.2)	33 (73.3)	25 (73.5)	0.05
*Missing*		5 (2.3)	0 (0)	1 (2.9)
Temperature	Median (IQR)	36.7 (36.3,37.3)	37.2 (36.7,37.7)	37.4 (36.5,38.2)	<0.001
Respiratory rate	Median (IQR)	22 (19, 26)	26 (20, 29)	28 (24, 32)	<0.001
Heart rate	Median (IQR)	90 (74, 106)	97 (78, 108)	98 (86, 110)	0.04
CXR at admission	Clear⁵	51 (23.7)	2 (4.4)	0 (0.0)	<0.001
Unilateral opacities		35 (16.3)	1 (2.2)	1 (2.9)
Bilateral opacities		129 (60.0)	42 (93.3)	33 (97.1)
Ceiling of care timing	Never	83 (38.6)	20 (44.4)	34 (100)
Pre-admission		62 (28.8)	1 (2.2)	-
Within 24 hours		57 (26.5)	18 (40.0)	-
Later during admission		13 (6.1)	6 (13.3)	-

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¹Air only (N = 55), oxygen via nasal prongs (N = 72), via face mask (N = 54), via non-rebreather mask (N = 34);

² Seven patients had CPAP with helmet and 38 had CPAP with face mask;

³ Ten patients escalated directly to IMV from air/oxygen while 24 were trialled on CPAP before IMV;

⁴Kruskal-Wallis equality-of-populations rank test was used to compare median values.

Duration since onset of symptoms was strongly associated with maximal respiratory support received (p<0.001). Air/oxygen patients had a shorter median duration of symptoms of 5 days compared with CPAP and IMV patients (both 7 days). There was statistical evidence across clinical characteristics to indicate that patients maximally requiring CPAP or IMV had more severe disease than air/oxygen patients, based on reported symptoms, vital signs and chest radiography.

Among all air/oxygen patients, 28.8% (N = 62) had a ceiling-of-care plan in place prior to admission and a further 26.5% (N = 57) had a plan developed in the first 24h of admission. Nineteen patients (42.2%) maximally received CPAP and had an early ceiling-of-care, and all but one were planned during the first 24h of admission. Overall, ninety-two patients received maximal respiratory support with air/oxygen as planned, while among 76 patients who had a ceiling-of-care plan which allowed for escalation to CPAP, 51 (67.1%) received air/oxygen only. Fourteen patients with ceilings-of-care did not have mode of planned maximal respiratory support recorded.

Patient outcomes

Overall 103 (35.0%) patients died and 187 (63.6%) recovered and were discharged. Four patients (1.4%) remained in hospital at the end of the observation period (median duration– 38 days (IQR 35,40)). The overall number of days of hospitalization ranged from 0 to 42 days (ten patients were discharged and one patient died on the same day of admission), with a median of 7 days (IQR 3,11). The mortality among patients maximally requiring and receiving air/oxygen was 33.0% (N = 71); CPAP was 46.7% (N = 21); IMV was 41.2% (N = 14) (Fig 1). There was no evidence to suggest a difference in median duration of hospitalization between air/oxygen and CPAP patients (6 days (IQR 3,10) and 7 days (IQR 5,11), respectively (X² p = 0.11)) but there was strong evidence for a difference between each of these groups and IMV (24 days (IQR 7,36) (X² p<0.001)).

Mortality by respiratory support received and ceiling-of-care

Patients who were hypoxemic despite standard oxygen therapy, and who required escalation to CPAP, had the highest mortality overall, especially in the sub-group with a ceiling-of-care (Fig 1). However, when patients without a ceiling-of-care are examined separately, mortality is highest among IMV patients (41.2% N = 14), and only one patient in each of the air/oxygen (1.2%) and CPAP (5.0%) sub-groups died.

When all patients who ever received CPAP (including those who went on to require IMV N = 69) are examined, 19 patients had an early ceiling-of-care plan, and 84.2% of these patients died. Among those without any ceiling-of-care (N = 44), 75% recovered and were discharged– 43.1% (N = 19) without requiring IMV and 31.8% (N = 14) after subsequently receiving IMV (Fig 2).

Factors associated with mortality

Older age is strongly associated with a higher risk of death from Covid-19 (Table 3). Sex, BMI and residence in a care home were crudely associated with mortality but after adjusting for age there was no statistical evidence of association. This was also the case for a number of pre-morbidities, namely hypertension, chronic cardiac disease and dementia. Having an early ceiling-of-care pre-admission/within 24 hours of admission was associated with over 40 times the odds of death in the multivariable analysis (aOR 41.81 95% CI 8.28, 211.17; p<0.001), compared to patients with no ceiling-of-care. Maximal respiratory support with CPAP and IMV was not associated with higher mortality compared to air/oxygen in the crude analysis (OR 1.77 95% CI 0.93, 3.40 and OR 1.42 (0.68, 2.97), respectively; p = 0.19). After adjusting for confounding factors there was strong evidence for higher mortality among hypoxemic patients who required escalation to CPAP or IMV (aOR 5.24 95% CI 1.38, 19.81 and aOR 46.47 95% CI 7.52, 287.08, respectively; p<0.001) compared to air/oxygen, although the confidence intervals were overlapping and were wide especially for IMV, due to the small sample.

Table 3. Characteristics of patients who died and predictors of mortality.

Patients overall		Proportion died n/N (%) or median (IQR)	Crude odds ratio (OR)¹ (95% Confidence Interval (CI); Likelihood Ratio Test (LRT) p-value)		Age category adjusted OR² (95% CI; LRT p-value)		Multivariable OR³ (95% CI; LRT p-value)
Socio-demographic characteristics
Age (y)	20–49	2/30 (6.7)	-	0.001			-	<0.001
	50–59	5/41 (12.2)
	60–69	15/54 (27.8)
	70–79	32/75 (42.7)	3.72 (1.95,7.11)				3.33 (1.11,9.86)
	80–89	35/66 (53.0)	5.65 (2.90,10.99)				4.76 (1.44,15.79)
	≥ 90	17/21 (80.1)	21.25 (6.52,69.26)				15.72 (3.15,78.47)
Sex	Female	36/111 (32.4)	-	0.31	-	0.04	-	0.13
	Male	70/183 (38.3)	1.29 (0.79,1.12)	0.31	1.78 (1.02,3.12)	0.04	1.70 (0.85,3.41)	0.13
Ethnicity	White	94/239 (39.3)	-	0.02	-	0.71	-	0.77
	Asian, Black, Other	12/55 (21.8)	0.43 (0.22,0.86)	0.02	0.86 (0.39,1.90)	0.71	0.85 (0.29,2.53)	0.77
BMI⁴		26 (22.4,30)	0.95 (0.90,0.99)	0.03	0.98 (0.94,1.04)	0.56	1.00 (0.94,1.07)	0.87
Care home resident		37/65 (56.9)	3.06 (1.74,5.40)	<0.001	1.63 (0.86,3.07)	0.13	1.51 (0.69,3.33)	0.30
Pre-existing comorbidities
Hypertension		47/109 (43.1)	1.62 (0.99,2.64)	0.05	1.29 (0.75,2.21)	0.36	1.16 (0.58,2.32)	0.67
Chronic cardiac disease		48/90 (53.3)	2.88 (1.72, 4.81)	<0.001	1.43 (0.79,2.59)	0.23	1.18 (0.57,2.43)	0.66
Diabetes mellitus without complications		23/56 (41.1)	1.30 (0.72, 2.36)	0.39	1.30 (0.67,2.49)	0.44	1.15 (0.51,2.66)	0.73
Diabetes mellitus with complications		13/26 (50.0)	1.89 (0.84, 4.25)	0.12	3.10 (1.27,7.55)	0.01	2.73 (0.87,8.52)	0.09
Dementia		32/56 (57.1)	2.95 (1.63,5.36)	<0.001	1.45 (0.74,2.85)	0.28	1.48 (0.68,3.24)	0.32
Chronic pulmonary disease		21/49 (42.9)	1.41 (0.76,2.63)	0.28	1.13 (0.57,2.23)	0.73	0.91 (0.41,2.04)	0.82
Chronic neurological disorder		17/38 (44.78)	1.52 (0.76,3.03)	0.24	1.39 (0.65,2.95)	0.39	1.15 (0.45,2.96)	0.76
Asthma		9/34 (26.5)	0.61 (0.27,1.35)	0.22	0.77 (0.33,1.82)	0.56	0.85 (0.30,2.42)	0.76
Chronic kidney disease		13/28 (46.4)	1.61 (0.74,3.53)	0.23	0.94 (0.40,2.23)	0.89	1.20 (0.43,3.33)	0.73
Rheumatological condition		6/22 (27.3)	0.65 (0.24,1.70)	0.38	0.46 (0.16,1.31)	0.15	0.57 (0.17,1.94)	0.37
Malignant neoplasm		7/20 (35.0)	0.96 (0.37,2.49)	0.94	0.64 (0.23,1.76)	0.39	0.64 (0.18,2.19)	0.47
Clinical features at admission
Temperature (degrees Celsius)		36.7 (36.3,37.5)	0.82 (0.65,1.03)	0.09	1.00 (0.77,1.29)	0.99	0.84 (0.58,1.23)	0.38
Respiratory rate (breaths per minute)		24 (21,30)	1.08 (1.04,1.12)	<0.001	1.12 (1.07,1.18)	<0.001	1.09 (1.03,1.15)	0.003
Heart rate (beats per minute)		92 (81,107)	1.01 (0.99,1.02)	0.38	1.02 (1.00,1.03)	0.02	1.01 (0.99,1.02)	0.47
Management
Ceiling-of-care pre-admission or within 24h⁵		80/138 (58.0)	10.43 (5.60,19.42)	<0.001	6.91 (3.09,15.46)	<0.001	41.81 (8.28,211.17)	<0.001
Maximal respiratory support
Air/oxygen		68/215 (31.6)	-	0.19	-	<0.001		<0.001
CPAP		21/45 (46.7)	1.77 (0.93,3.40)		5.41 (2.32,12.64)		5.24 (1.38,19.81)
IMV		14/34 (41.2)	1.42 (0.68, 2.97)		7.86 (2.93,21.08)		46.47 (7.52, 287.08)

Open in a new tab

¹ Logistic regression models were generated whereby for continuous variables the ORs are for each unit increase in value of the given characteristic; for binary variables the reference category was the absence of a given characteristic; for other categorical variables the reference category is indicated in the table; where there were low number of deaths, categories are combined as shown for age and ethnicity;

² Adjusted for age category as in 4 categories: 20-69y, 70-79y, 80-89y, ≥90y;

³ Adjusted for age category, sex, ceiling-of-care pre-admission or within 24h, diabetes mellitus with complications (ie end organ damage) and maximal respiratory support received;

⁴ Missing values for BMI (N = 82) were excluded;

⁵ Patients who had a ceiling-of-care introduced after failure to respond to treatment were excluded (N = 19).

Discussion

In our cohort of 294 hospitalised patients, 69 were trialled on CPAP either as a ceiling-of-care (N = 25), of which only those with an early ceiling-of-care (N = 19) were included in the analysis, or as a potential bridge to IMV (N = 44). Among patients who were trialled on CPAP as a potential bridge to IMV 75% survived—43.2% (N = 19) survived without requiring IMV and a further 31.8% (N = 14) after IMV (Fig 2). Patients who maximally received CPAP also spent significantly less time in hospital compared to IMV patients (median 7 days vs 24 days, X² p<0.001). The implications of our findings are that a trial of CPAP prior to intubation appears to be an effective treatment strategy in selected patients and may have significant benefits both for patient well-being and health system resources, especially in settings where IMV and accompanying intensive care beds are scarce.

In contrast to patients who had CPAP as a potential bridge to IMV, a high mortality was observed among patients on CPAP as a ceiling-of-care (Fig 1), reflecting both severity of disease, as well as frailty, age and co-morbidities in this cohort [11,12].

Overall, in patients with a ceiling of care, mortality was 5 times higher in those requiring CPAP than in patients treated maximally with air/oxygen after adjusting for confounding factors, importantly age. This higher relative mortality is to be expected, given that the indication for CPAP in these patients is hypoxemia not controlled on standard oxygen therapy, due to more severe Covid-19. Mortality among patients with a ceiling-of-care was over 40 times higher than among those without any limits to their potential treatment pathways even after adjusting for age and other confounding factors, likely reflecting treatment limitations, pre-existing frailty and the burden of other co-morbidities in these patients, which we were not able to adjust for.

Existing evidence for CPAP in severe acute respiratory distress is conflicting, and much of it was initially based on non-Covid-19 pathology [13]. A study examining CPAP use in SARS found that CPAP avoided IMV in 70% of patients [14]. Conversely, a study of non-invasive ventilation in critically ill patients with MERS found that over 90% of patients initially treated with non-invasive ventilation required intubation [15]. Studies from Wuhan, China demonstrated a mortality after CPAP of 44–72% with Covid-19 [16,17]. The extent to which the high mortality related to pre-morbid frailty, treatment limitations, severity of disease or a combination is unclear. UK guidelines recommend that when ICU capacity is limited, CPAP (as the preferred form of non-invasive ventilatory support) should be trialed in COVID-19 patients who remain hypoxemic despite standard oxygen therapy [18]. Data from the ISARIC/WHO CCP-UK study on >20,000 Covid-19 patients from 208 acute hospitals across the country indicate that 16% of patients were trialed on CPAP during admission for Covid-19, which is similar to our study [2]. In contrast, data from the US suggest that as little as 1–2% of patients admitted to ICU had a trial of CPAP prior to intubation [3,19].

Alternative modes of non-invasive respiratory support may be superior to CPAP delivered by face mask [20]. In our study, only 14 patients had CPAP with a helmet. A previous randomised trial has demonstrated superiority of CPAP with helmets over CPAP via face masks in avoiding endotracheal intubation (62% vs. 18%) in non-Covid pathology [21]. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure has also been shown to be effective, but the high oxygen consumption associated with this method may present a serious challenge with any surge in demand, hence this was not widely used in the UK [22]. The increased infectious risk posed to healthcare workers from administering non-invasive ventilation modalities such as CPAP also requires further research [14,23]. Randomized controlled trials are underway to identify the most effective form of non-invasive pressure support in Covid-19 in reducing the need for intubation [24,25]. Studies are also emerging globally confirming the usefulness of ward-based CPAP for Covid patients [26,27]. In the meantime, our study provides important insights into the potential utility and limitations of CPAP.

The sample size in this study was relatively small. However, characteristics of our study population were similar to the ISARIC/WHO CCP-UK study data across key features including sex, age, prevalence of co-morbidities and mortality, suggesting that our patients are representative of UK Covid-19 patients [2]. We have not accounted for other treatments our patients received, including as part of the RECOVERY trial which most patients were enrolled in [28]. However, as the trial randomised treatment allocation it is unlikely it would have systematically biased our findings. We have been able to provide novel data on ceilings-of-care and its impact on outcomes from Covid-19. We also had final outcomes on almost all our patients with just 4 still hospitalised in contrast to many other clinical cohorts on Covid-19 [3,17,19,29].

Our data indicate care home residents are not more likely to die after accounting for age in our study. This is re-assuring with regard to the clinical treatment received in hospital by this sub-group of patients against the background of the concerning public health data on the high death toll from Covid-19 among care home residents [30]. Almost a fifth of our patients were of Asian ethnicity, but these patients were on average younger than the majority white population, and it was not associated with increased mortality in our study.

The global scale of the pandemic has the potential to overwhelm many health systems, especially ICU resources. There is an urgent imperative for health systems faced with the prospect of shortage of ventilators to harness the role of ventilator-sparing strategies in the treatment of Covid-19 [31–33]. Our data suggest that among patients with no ceiling-of-care, an initial trial of CPAP in selected patients seems a reasonable therapeutic strategy and may potentially delay or even avert the need for intubation in some patients. In contrast, our findings indicate that the use of CPAP among patients with a ceiling-of care has a high failure rate, and it should be used judiciously in close consultation with patients and their representatives where feasible. Further research on this matter would help future management. Our data highlights the importance of accounting for ceilings of respiratory support when interpreting mortality from Covid-19.

This study has provided novel evidence on the respiratory support of patients with Covid-19 and could have significant implications for patients and health systems faced with the unprecedented impact of the pandemic.

Supporting information

S1 Fig. Conceptual framework of relationship between exposure and confounding variables and mortality.

(DOCX)

Click here for additional data file.^{(70.7KB, docx)}

S2 Fig. Flow diagram of patients included in the study and mortality by mode of respiratory support and ceiling-of-care.

(DOCX)

Click here for additional data file.^{(65.5KB, docx)}

Acknowledgments

We would like to firstly acknowledge the patients and families of patients, for the ordeal they went through and for the many who have been affected by the pandemic. We would also like to thank the institution and staff of Calderdale and Huddersfield NHS Foundation Trust for their continued help and support with this project, in particular the hard work and dedication of colleagues who gave up their valuable free time to acquire data and help with this project: Dr Joshua Storton, Dr Anneka Biswas, Dr Charlotte Spencer, Dr Rehima Aslam, and Dr Mohammad Abdalmohsen.

Data Availability

Data cannot be shared publicly because of risk of re-identification of some patients of the database. Data are available for researchers who meet the criteria for access to confidential data. The data underlying the results presented in this study are available from Tracy Owen (tracy.owen@cht.nhs.uk), Clinical Governance Facilitator, Quality and Safety Team, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield Royal Infirmary, Acre Street, Lindley, Huddersfield HD3 3EA.

Funding Statement

The senior author, Kalpana Sabapathy, received funding from the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement; part of the EDCTP2 programme supported by the European Union. Grant Ref: MR/R010161/1 URL: https://mrc.ukri.org The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0244857.r001

Decision Letter 0

Andrea Coppadoro

Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

2 Sep 2020

PONE-D-20-20968

The role of CPAP as a potential bridge to invasive ventilation and as a ceiling-of-care for patients hospitalised with Covid-19 - an observational study.

PLOS ONE

Dear Dr. Walker,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

As suggested by rev n.3, the results section needs deep improvement. It is very hard to read and understand due to a mix of results regarding patients with treatment limitations and patients with no limitations.

As suggested by rev n.1, the effectiveness of CPAP need to be better discussed in light of the more clear results. Is it effective? Which phenotype of patients may benefit more? is it really futile (too expensive/untolerable/not effective) in patients with treatment limitations?

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Reviewer #1: In this manuscript, the authors publish their experience with COVID patients, focusing specifically on 2 variables: amount of respiratory support (oxygen alone, CPAP, or invasive mechanical ventilation, or IMV), and outcomes for patients with an existing ceiling of care. While this was a descriptive, observational study, the authors sought to describe both of these presumably because of concern about resource use in the context of COVID, as well as the debate that surrounded early versus late intubation for hypoxemic patients.

The setting is 2 large, linked hospitals in England, under the NHS system. The authors collected a significant amount of demographic and vital sign data and attempted to identify factors associated with outcomes as a function of either ceiling-of-care orders or respiratory level of support.

Overall, while I appreciate that these two issues are interrelated, they are really quite distinct and merging them into a single manuscript complicates interpretation of either problem individually. However, this work clearly demonstrates that the use of CPAP as a bridge to intubation (or as a destination) remains a very reasonable practice, with a very acceptable mortality rate, particularly among those without a prespecified ceiling of care; this is important because it overturns the notion that we should proceed to early intubation of COVID patients (which has largely been abandoned at this time) rather than attempting therapy with NIV or high flow oxygen. I am less confident about their interpretations of ceilings-of-care data, as I will outline below. In addition, the authors overinterpreted or overstated their data in several instances.

Major Issues:

• They argue that, because patients with a ceiling-of-care have an 85% mortality when CPAP is used that the “use of CPAP may be futile.” The determination of futility should account for the amount of resources used and the discomfort to the patient; if CPAP can be delivered without a significant resource drain in a relatively comfortable manner, the potential benefit (that it may save lives) may be worthwhile.

• The authors do not seem to account for the fact that patients with an existing ceiling-of-care likely have multiple medical comorbidities that increase their risk of dying of any insult, COVID or otherwise; thus, the description of mortality among these patients is inherently biased towards higher mortality for those with a ceiling of care, unless some attempt is made to control for the comorbidities that they have. This could be accomplished using accepted comorbidity scales like Elixhauser or Charlson. By extension, it’s hardly surprising that patients with an early ceiling-of-care have higher mortality in multivariable analysis. Similarly, the fact that patients who were trialled on CPAP as a potential bridge to IMV and had 43% survival without requiring IMV likely reflects the fact that those without ceiling-of-care limitations were younger and healthier.

• The authors never provide any data attempting to quantify severity of illness on admission, using accepted scoring systems like SOFA, APACHE, or MEWS. Among other things, controlling for severity of illness in their multivariable model would allow them to quantitatively account for the fact that patients being admitted with ceiling-of-care limitations may well have been sicker, owing to their comorbid illnesses that prompt initiation of such limitations in the first place

• They provide no data about the magnitude of therapy provided with CPAP: were patients titrated up to a certain level? What was the median amount of CPAP support required (which would be directly related to severity of hypoxema)? Did they use Bipap at all? The amount of support provided by 5 of CPAP versus 18/12 of Bipap is quite significant. Was there any variation in determination of “failure” of CPAP and subsequent intubation?

Minor Issues:

• The authors note that the “aim of our study was to evaluate the outcomes of patients… treated according to national guidelines.” Was the standard of care constant over the entire time period? As the authors note, initially, there were recommendations to avoid CPAP and proceed to intubation, and while the NHS recommendations changed in early April, patients were admitted from early March to late April, so the standard of care could conceivably have changed over that time.

• They did not prove that use of CPAP allowed them to avert intubations, and the authors should avoid suggesting this; this analysis could be attempted using a retrospective case-control study, where controls and cases are otherwise matched for severity of illness, demographics, etc and the sole difference is whether or not they were intubated.

Reviewer #2: Overall Impression

This study describes the demographics and outcomes of patients admitted to two acute hospitals and describes characteristics of patients by maximal respiratory support received and characteristics of patients who died.

Outcomes amongst patients that were for full escalation and those that had a ceiling of care (CPAP or oxygen) in place within the first 24 hours of their admission are described.

The numbers of patients that received CPAP treatment are small (19 as ceiling of care, 44 as a potential bridge to IMV.

The majority of the manuscript describes patient characteristics and predictors of mortality. The difference in mortality amongst those who received CPAP as a ceiling of care and those that received CPAP but were deemed eligible for IMV if the treatment did not work are stark (25% v 84%) but the numbers are small.

I think the message is an important one (and fits with our experience). Differences (if present) between the location of care need to be highlighted, as do numbers of patients in each group – For IMV/Full escalation (Number of patients that had air/02, CPAP pre IPPV, IPPV without CPAP, and CPAP) and patients with a ceiling of care (numbers that had air/oxygen and CPAP).

Major points

1) A flow diagram would better illustrate numbers in different groups. The key comparison should be between a) those that were for full escalation that received CPAP and b) those that had a ceiling of care in place that received CPAP. The mortality % in these groups is shown in figure 2 but the numbers (although small) should be made clearer. A flow diagram would be useful.

2) The authors mention that CPAP was largely delivered on general wards. This requires further clarification. Were a greater proportion of those patients that were for IMV treated with CPAP on ITU? If so the location of the treatment/expertise of the staff could be important factors in the differences in mortality.

3) Some clarification regarding the numbers in the different groups would be welcome (eg Line 272-274, 19+44 = 63 rather than 69). This might be facilitated by addressing 1).

Minor points

1) Line 349 – The trials explore the role of NIV/CPAP in reducing the need for (rather than prior to) intubation.

2) Typos in hypertext links (. Missing after www) in several references – eg 12, 28.

Reviewer #3: Overall this is a helpful study that adds to the growing body of evidence of CPAP use in CVOID-19. It is quite wordy for the amount of data it presents but some of that is style preference.

1)Abstract:

Minor: You switch between the use of numbers i.e: 347 in line 48 and words for numbers i.e: Two hundred in line 49.

I would suggest sticking to one format, ideally numbers for everything over 10 and words under 10. This is an issue

throughout the manuscript.

Minor: How many people actually started on CPAP would be helpful to know in abstract. It is nicely worded in line 304 of the discussion. It is slightly confusing for the reader when you state 45 on CPAP and 34 on IMV (but actually some of these 34 started on CPAP they did not straight to IMV)

Minor: Line 54: This line seems to imply that CPAP or IMV were somehow the reason for higher mortality? Is this correct or in fact they are sicker patients compared to those on oxygen. Can I suggest if the later is the case this is reworded, it could imply it is better not to escalate care which I am not sure is your meaning.

2) Introduction.

This is well written. No major problems.

Minor: I am interested you have not mention high flow oxygen anywhere. Why is this? It maybe worth one line in the introduction or methods saying high flow oxygen was not available or not used due to oxygen supply or just not considered etc.

3) Methods

Appears clear and make sense to the reader.

Major: One of the reason that CPAP was considered a risk at the start of COVID was it considered an AGP. There is no mention in your methods other than "largely on wards" of where this took place, what was the nursing ratio?, were extra safety measures used? , did you use negative pressure rooms?, was it only those with ceiling of care that had CPAP on wards, could the place they had CPAP have made a difference to the outcome, Did staff wear full AGP PPE? This document is already wordy heavy you could reduce you introduction or results sections and add a few lines about this in the methods. You may also wish to add a line in the results describing if there were adverse events from the CPAP or suddenly an increase in sickness level among staff that you know about.

Major: There seems to be limited detail on the CPAP give, what pressures where used? Did you have protocol? How much oxygen was used etc.

Minor: Do you have reference number from R&D re: Ethic approval or was it registered as service evaluation?

4) Results: This is the most unclear section of manuscript and need some major revision to make it flow.

If you are going to put key findings at the start of results: Keep them as key finding, Line 183 under key findings describes their characteristics yet this is under key findings. I don't think age and sex of the patients etc is key finding.

Personally I would suggest starting with the numbers in the study then move on to the participant characteristics, key findings can be highlighted in the first section of the discussion. Then have you sub-section of results. I would suggest there is clear section of CPAP as a bridge to IMV (or preventing IMV) and a section on CPAP in those with ceiling care and factors effecting mortality. These are just suggestions but I would like to see the section re worked.

Although it needs stating I would have thought you would expect those with a ceiling care who are on CPAP to have a higher mortality rate as they are logically sicker? The way this results section is written could imply the CPAP contributed to the outcome- if it did this need discussion in the next section, if fact these patient were just sicker this needs some rewording- in discussion you suggest it is due to severity.

It would be helpful to know how much oxygen & what CPAP these patients were on? And how long did it take patients to fail on CPAP and need IMV.

The clinical picture is also not 100% clear, although there are lots of pre-existing condition accounted for, do you have ABG's, is there an P/F ratio you could give us?

5) The discussion is clearer than results.

Major: Line 300. You are not not the first paper to describe CPAP as bridge to IMV. There are several paper from Italy and some from the UK describing similar. You maybe the first describing ceiling care although there are papers from Italy with very similar cohort. Some examples (and there are more): https://erj.ersjournals.com/content/early/2020/07/30/13993003.02130-2020

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3566170

https://bmjopenrespres.bmj.com/content/7/1/e000621.abstract https://bmjopenrespres.bmj.com/content/7/1/e000639.abstract

https://www.medrxiv.org/content/10.1101/2020.06.05.20123307v1

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190517/

Minor: line 319: Again a similar theme, I think you mean CPAP mortality is higher but it is likely to be because of the severity of disease, this need to be clearer throughout the paper if this is how you interpret the results, this is why some markers of severity would have been nice in the results.

Major: line 328 onward, there is existing evidence (albeit limited) in covid-19. I would suggest you try and compare your results to those of Covid-19 studies as well as MERS and SARS papers. There are a few papers/short reports coming from UK hospital coming from UK hospital now, some are listed above, there may well be more.

Overall once the key message is made clearer and ideally a little more data regarding the severity of patients is added this is a helpful paper that adds to the body of evidence regarding oxygen/CPAP and IMV in COVID. I would suggested this is more of a very helpful case series than novel new research and it maybe better presenting it than way.

**********

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Reviewer #1: Yes: Philip Verhoef

Reviewer #2: Yes: Hassan Burhan

Reviewer #3: No

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PLoS One. 2020 Dec 31;15(12):e0244857. doi: 10.1371/journal.pone.0244857.r002

Author response to Decision Letter 0

5 Nov 2020

Response:

Thank you for raising this. On application for approval, our local R&D Department noted that this project is examining recognised treatment protocols and procedures using internal data, which would be de-identified for the purposes of data analysis outside the institution. As such they considered this project a service evaluation to establish a standard, and as such did not require further approval A clarification about this has been added to the Methods section, in lines 105- 107 where it states “Data analysed was departmental, routinely collected and fully anonymized, and as such The Calderdale and Huddersfield NHS Foundation Trust Research and Development office considered this project a service evaluation to establish a standard, and did not require further approval. “

The study is registered with the Calderdale and Huddersfield NHS Foundation Trust Clinical Governance Department.

We have also stated in line 126-127 of Methods that “This data was fully anonymised and de-identified prior to inclusion in the analysis and the study.”

Response:

Thank you; we have highlighted this in the text. Please see response to point 2 above. We can confirm that all data was fully anonymised and de-identified prior to inclusion in the analysis and the study. We have changed the wording to read “This data was fully anonymised and de-identified prior to being accessed for inclusion in the analysis and the study” in lines 126- 127. This is now highlighted in the ethics statement of the online submission form. The Trust Caldicott guardian has approved the use of data for this purpose.

Response:

Thank you for the guidance. We have now removed any reference to data which is not reproducible from our dataset.

Response:

Thank you for the helpful link. We have ensured our final draft complies with the above guidelines.

Major Issues:

Response:

We thank the reviewers for raising this point, and we have clarified the wording in line 64 of the Abstract to read “CPAP seems to offer little additional survival benefit beyond oxygen therapy alone” in this group. Intolerance to CPAP is well described in the literature and is also re-enforced in local UK guidelines where it states that “hoods and masks can be distressing for patients” and that “CPAP should not be used in those with agitation and confusion.” (Ref 9 in the manuscript).

The reviewer is correct that a trial of CPAP may be worthwhile if it can be delivered in a relatively comfortable manner, but survival rate in those with a DNACPR is comparable to those treated without CPAP, and especially in the setting of confusion and agitation CPAP can result in significant distress. For this reason, its use in this population group should be carefully considered.

Response:

This is correct, and we have highlighted this very point in line 357- 352 of the Discussion where we state “a high mortality was observed among patients on CPAP as a ceiling-of-care (Figure-1), reflecting both severity of disease, as well as frailty, age and co-morbidities in this cohort.”

Similarly, in line 367- 374 we state that a “higher relative mortality is to be expected given that the indication for escalation of respiratory support to CPAP was due to greater severity of Covid-19. Mortality among patients with a ceiling-of-care was over 40 times higher than among those without any limits to their potential treatment pathways even after adjusting for age and other confounding factors, reflecting the limited treatment received, residual effects of pre-existing frailty and burden of other pre-morbidities in patients with an early ceiling-of-care which we were not able to adjust for.”

The relationship between co-morbidities and outcomes in Covid has been described in many other studies, such as Docherty (Ref 2) as well as the ICNARC data (Ref 5), and although co-morbidities individually and collectively are associated with increased mortality, it is clear from these and other studies that, at the time of this study, age was by far the single most influential determinant of outcome, and this finding was also reflected in our data. Since then, however, other studies have identified frailty as an even better prognostic indicator than age:

National UK Guidelines (NICE) specified from the start of the pandemic that “on admission to hospital” doctors should “assess all adults for frailty” (Ref 10)

This approach is limited but pragmatic and was adopted at our Trust from the beginning. The outcome of adhering to UK guidelines is that all patients admitted with Covid were naturally separated into two distinct cohorts of patients: those deemed by the treating doctors to be too frail for invasive ventilation, and those who were deemed less frail.

Ceiling of Care decision were thus made in accordance with UK guidelines mainly on the basis of frailty, rather than comorbidities. NICE Guidelines state that medics should “Sensitively discuss a possible 'do not attempt cardiopulmonary resuscitation' decision with all adults with capacity and an assessment suggestive of increased frailty (for example, a CFS score of 5 or more).”

This study examined the quantitative differences in outcome between these two different cohorts, independent of comorbidity scales such as Elixhauser or Charlsson, which currently and at the time of the pandemic played no formal role in escalation decisions within the UK.

The higher mortality seen in patients who were assessed as being frail was certainly expected, but at the time of this study their outcomes and response to treatment relative to non-frail patients had not been quantified.

Response:

Thank you. The reviewers are correct in pointing out that quantifying severity of illness would enrich the data. However, the SOFA and APACHE scoring systems require arterial blood gasses which were not indicated in the majority of our cohort. Indeed, in the UK, national guidelines specify that “ unless there are reasons to suspect CO2 retention, arterial lines/blood gases are not needed, and patients can be monitored using continuous peripheral arterial oxygen saturation (SpO2) with an appropriate level of nursing support” (Ref 9 in the manuscript).

On our EPR, oxygen saturations prior to oxygen administration were not reliably captured in the majority of cases.

Oxygen saturations were usually recorded once the target saturations had been achieved, meaning this data was homogenous (with nearly all oxygen saturations documented as being over 92%), with oxygen requirements as the only variable parameter. Thus we had to rely on oxygen requirements as a proxy measure for hypoxia. Other observations, such as heart rate and blood pressure, were used in the study and these have been documented in Table 3.

Response:

Thank you. We have now clarified this in the Procedures section of Methods, line 135-137. We have written:

“Clinical management was according to the NHS Specialty specific guidelines (Ref 9). These state that “CPAP is the primary mode of non-invasive respiratory support for hypoxic COVID19 patients. Suggested initial settings are 10 cmH2O + 60% oxygen.”

In this study, patients not maintaining oxygen saturations over either 92% or 94% on 40 - 60% oxygen via a venturi were commenced on CPAP 10 cm H20 and 10 litres oxygen, according to physician discretion.

This could be adjusted as required, to a maximum of 15 cm H2O and 15 litres O2.”

The text clearly states that the patients included in the study were on CPAP only, and not BiPAP. As an interesting aside – and not included in this study - BiPAP was used on only three patients: in two patients BiPAP was administered on the ward and titrated to oxygen saturations of 88-92%, as a ceiling of care. One survived. Another had BiPAP as a bridge on ITU, and was subsequently intubated, but did not survive.

Minor Issues:

Thank you, that is a good point. Internationally, guidelines certainly changed considerably over this time, but the standard of care pertinent to CPAP use within our hospitals was constant over this time period. UK Specialty guides on the use of non-invasive respiratory support in adult patients with coronavirus Version 2 was published on 26th March 2020. This outlined the treatment strategy: If RR ≥ 20bpm with SpO2≤94% on FiO2 >40%, start NRB oxygen and senior review to consider starting a “trial CPAP 10cm H2O with FiO2 0.6”

Our local guidelines had used the same protocol prior to Version 2, with the exception that our CPAP devices used entrained oxygen of 10 litres on initiation, rather than an FiO2 of 0.6, and in practice CPAP was often not started until O2 saturations were 92% or less on 40% O2 via a venturi.

Version 3 published on the 3rd April did not alter this.

With regards to clinical decisions on ceilings of care, the National Institute for Clinical Excellence (NICE) sets many of the clinical guidelines within the UK.

NICE COVID-19 rapid guideline: critical care in adults was published on 20th March 2020. This recommended that healthcare professionals “sensitively discuss a possible 'do not attempt cardiopulmonary resuscitation' decision with all adults with capacity and an assessment suggestive of increased frailty (for example, a CFS score of 5 or more).”

Again, assessment of frailty had been used in our Trust, and many other Trusts, prior to formal nationalisation of the guidelines by NICE, and the standard of care did not change substantially over the course of this study.

Response:

Thank you, we have changed the wording to reflect this point in line 62 – 64 of the introduction, where it now states: “Our data suggest that among patients with no ceiling-of-care, an initial trial of CPAP as a potential bridge to IMV offers a favourable therapeutic alternative to early intubation. In contrast, among patients with a ceiling-of care, CPAP seems to offer little additional survival benefit beyond oxygen therapy alone.”

It is correct that we did not prove that use of CPAP allowed us to avert intubations. However, at the time this study was undertaken, high flow nasal oxygen was not routinely used in our hospitals or in the UK generally, and so patients who were not able to maintain their oxygen saturations on standard concentrated oxygen therapy alone, essentially had two escalation options: CPAP or intubation, and it is likely that the majority of patients for full escalation on CPAP would have required intubation had CPAP not been available. Within our data, 43% of patients who were trialled on CPAP survived without intubation

Reviewer #2: Overall Impression

Outcomes amongst patients that were for full escalation and those that had a ceiling of care (CPAP or oxygen) in place within the first 24 hours of their admission are described.

The numbers of patients that received CPAP treatment are small (19 as ceiling of care, 44 as a potential bridge to IMV.

Major points

Response:

We agree with the reviewer that a flow diagram is helpful and in fact had already included exactly this figure in the Supplementary material (Supplementary Figure 2). If the editorial team think it is feasible, we would be happy to include this in the main manuscript.

Response:

Thank you, that is an important point. Patients who were not for intubation in the event of deterioration were almost exclusively treated on the wards. Only one was treated on ITU.

About three quarters of Patients treated with CPAP as a bridge to IMV were treated on the wards. Interestingly, mortality was higher if CPAP was delivered on ITU and we think this is because more unstable patients were selected to be treated on ITU. Hence, we thought data relating to location of CPAP delivery is likely to only demonstrate bias and was not included. We do have this data available, and would be happy to include it if the editors advise so, but unfortunately it is not in our original raw data set.

We have, however, adjusted the wording in lines 141- 142 of the Methods section to read “With only one exception, CPAP as a ceiling of care was started on the respiratory wards in all cases. CPAP as a bridge to IMV was started on the respiratory wards in most cases.”

Factors that might be expected to contribute to an excess mortality - staffing ratios and skill mixes on the wards, for instance - demonstrated wide variability throughout the day and throughout the week. Furthermore, the extent to which a patient could be closely monitored depended on where they were in a ward – for instance, whether they were isolated in a side room or in a highly visible open bay.

We would not be able to account for these variables in a study of this size, so the location of CPAP was not examined further.

3) Some clarification regarding the numbers in the different groups would be welcome (eg Line 272-274, 19+44 = 63 rather than 69). This might be facilitated by addressing 1).

Response:

We thank the reviewer for highlighting this; as is described in Response 1 to Reviewer #2 above, the flow diagram in the Supplementary material (Supplementary Figure 2) does help to clarify the numbers and we would be glad to include it in the main manuscript. The six patients unaccounted for in the above were patients who had a ceiling of care introduced later during the admission. As described in lines 174- 176 of the Statistical analysis “Patients who had a ceiling-of-care instituted more than 24h after admission were omitted as reverse causality was possible, i.e. that a ceiling-of-care was introduced following failure to respond to treatment.”

Minor points

1) Line 349 – The trials explore the role of NIV/CPAP in reducing the need for (rather than prior to) intubation.

Response:

Thank you for pointing this out. This has now been corrected, and line 396 - 400 now reads: Randomized controlled trials are underway to identify the most effective form of non-invasive pressure support in Covid-19 in reducing the need for intubation. Studies are emerging globally confirming the usefulness of ward-based CPAP for Covid patients. In the meantime, our study provides important insights into the potential utility and limitations of CPAP.”

2) Typos in hypertext links (. Missing after www) in several references – eg 12, 28.

Response: We thank the reviewers for highlighting these errors and have rectified them.

1)Abstract:

Minor: You switch between the use of numbers i.e: 347 in line 48 and words for numbers i.e: Two hundred in line 49.

I would suggest sticking to one format, ideally numbers for everything over 10 and words under 10. This is an issue

throughout the manuscript.

Response:

Thank you. We have adhered to widely accepted convention to use words to cite numbers at the beginning of sentences and numerals thereafter. For numbers up to ten, we also adhere with convention and use words.

Response:

Thank you. We have added this to the abstract as suggested. Lines 51 – 53 now state “Two hundred and fifteen patients (73.1%) maximally received air/standard oxygen therapy, and 45 (15.3%) patients maximally received CPAP. Thirty-four patients (11.6%) required IMV, of which 24 had received prior CPAP.”

Response:

Thank you. We have adjusted the wording in this section to make this more explicit. Lines 56 – 59 now reads: “Overall, there was strong evidence for higher mortality among patients who required CPAP or IMV, compared to those who required only air/oxygen (aOR 5.24 95%CI: 1.38,19.81 and aOR 46.47 95%CI: 7.52,287.08, respectively; p<0.001), and among patients with early ceiling-of-care compared to those without a ceiling (aOR 41.81 95%CI: 8.28,211.17; p<0.001).”

We have emphasized in the Discussion (current version) and illustrated through Supplementary Figure 1 that higher mortality seen in CPAP and ITU patients, as compared to patients requiring only oxygen, is thought to reflect greater severity of disease necessitating higher levels of therapy.

2) Introduction.

This is well written. No major problems.

Response

Thank you. We have clarified this in the introduction by stating in lines 86-89 that “The use of CPAP in Covid-19 has been questioned,8 but in contrast to many other healthcare settings, CPAP is used in the UK in preference to High Flow Nasal Oxygen, largely due to concerns about oxygen supplies.”

3) Methods

Appears clear and make sense to the reader.

Response:

Thank you. Like most UK hospitals we had very limited negative pressure rooms (as a matter of fact we had 2) and these were quickly overwhelmed with the Covid pandemic. The location of CPAP, and why this was not explored in greater detail, has been previously explained in response 2 to reviewer #2 above. A fuller description of the respiratory wards has been added to the Procedures of the Method section.

For Covid cases requiring AGPs such as CPAP within our hospital sites, the priority was to fill negative pressure rooms initially, then once these were full to decant into open bays of proven Covid cases, then full wards.

Full PPE was worn in the presence of any AGPs, although the exact definition of “full PPE” did vary throughout the study, according to guidelines and availability of resources. It was considered beyond the scope of this study to investigate adverse effects of CPAP (other than failure and death), or the effect of PPE on healthcare workers in the presence of AGPs.

Major: There seems to be limited detail on the CPAP give, what pressures where used? Did you have protocol? How much oxygen was used etc.

Response:

We thank the reviewer for highlight this and it has now been explained more fully in the Procedures section of Methods, and explained above in the response to Reviewer #1.

NHS Guidelines were followed. These state that “CPAP is the primary mode of non-invasive respiratory support for hypoxaemic COVID19 patients. Suggested initial settings are 10 cmH2O + 60% oxygen.”

In this study, local guidelines were followed which closely reflected NHS Guidelines: patients not maintaining oxygen saturations over either 92% or 94% on 40 - 60% oxygen via a venturi were commenced on CPAP 10 cm H20 and 10 litres oxygen, according to physician discretion.

This could be adjusted, as required, to a maximum of 15 cm H2O and 15 litres O2. Pressure was adjusted in preference to oxygen.

In total, BiPAP was used on only three patients: in two patients BiPAP was administered on the ward and titrated to oxygen saturations of 88-92%, as a ceiling of care. One survived. Another had BiPAP as a bridge on ITU, and was subsequently intubated, but did not survive.

Minor: Do you have reference number from R&D re: Ethic approval or was it registered as service evaluation?

Response:

Thank you for raising this. On application for approval, our local R&D Department noted that this project is examining a recognised treatment using internal data, which would be de-identified for the purposes of data analysis outside the institution. As such they considered this project a service evaluation to establish a standard, and as such did not require further approval. A clarification about this has been added to the Methods section, as mentioned in the response above.

4) Results: This is the most unclear section of manuscript and need some major revision to make it flow.

Response:

We thank the reviewers for the helpful feedback and have re-arranged the Results as indicated in track changes.

Response:

Thank you. This same point was also raised by reviewer #1, and we have hopefully addressed this in our response above.

It would be helpful to know how much oxygen & what CPAP these patients were on? And how long did it take patients to fail on CPAP and need IMV.

The clinical picture is also not 100% clear, although there are lots of pre-existing condition accounted for, do you have ABG's, is there an P/F ratio you could give us?

Response:

Thank you.

UK national guidelines relating to CPAP in Covid patients specify that “ Unless there are reasons to suspect CO2 retention, arterial lines/blood gases are not needed, and patients can be monitored using continuous peripheral arterial oxygen saturation (SpO2) with an appropriate level of nursing support” (Ref 9 in the manuscript).

On our EPR, oxygen saturations prior to oxygen administration were not reliably captured in the majority of cases.

Oxygen saturations were usually recorded once the target saturations had been achieved, meaning there was a great deal of homogeneity in this data, which contributed little to the clinical picture. Oxygen requirements were thus the variable parameter which we had to rely on as a proxy measure for hypoxia.

Similarly, accurate and reliable documentation of when CPAP was initiated and stopped, when breaks were given, when pressures and oxygen were adjusted, and how much proning was effected, was scarce. Although a very interesting question, it was decided we did not have enough reliable data to pursue this line of enquiry.

5) The discussion is clearer than results.

Major: Line 300. You are not not the first paper to describe CPAP as bridge to IMV. There are several paper from Italy and some from the UK describing similar. You may be the first describing ceiling care although there are papers from Italy with very similar cohort. Some examples (and there are more):

https://erj.ersjournals.com/content/early/2020/07/30/13993003.02130-2020

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3566170

https://bmjopenrespres.bmj.com/content/7/1/e000639.abstract

https://www.medrxiv.org/content/10.1101/2020.06.05.20123307v1

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190517/

Response.

We would like to thank the reviewers for these helpful links. Our manuscript was first submitted to PLOS One on June 27th, and we have changed the wording to more accurately reflect the large body of literature that has since been published. We have also referenced a selection of these articles in lines 396- 400 in the manuscript as an update. Here we have stated “Randomized controlled trials are underway to identify the most effective form of non-invasive pressure support in Covid-19 in reducing the need for intubation.( Referenced to 24, 25) Studies are also emerging globally confirming the usefulness of ward-based CPAP for Covid patients.” (Referenced to 26, 27)

Response:

Thank you. This is a point previously raised, and we hope we have fully addressed it in our first response to reviewer #1.

Response: We thank the reviewers for bringing these articles to our attention. Please see response above. This has now been referred to in the manuscript in line 396- 400 where it states “Randomized controlled trials are underway to identify the most effective form of non-invasive pressure support in Covid-19 in reducing the need for intubation. Studies are also emerging globally confirming the usefulness of ward-based CPAP for Covid patients.”

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PLoS One. doi: 10.1371/journal.pone.0244857.r003

Decision Letter 1

Andrea Coppadoro

27 Nov 2020

PONE-D-20-20968R1

The role of CPAP as a potential bridge to invasive ventilation and as a ceiling-of-care for patients hospitalised with Covid-19 - an observational study.

PLOS ONE

Dear Dr. Walker,

The reviewers positively commented the new version of the manuscript; however, few more changes are requested for the manuscript to be accepted for publication.

- The delivery of CPAP in your study needs to be clarified under many aspects. 1) Which interface was used? In the discussion, you state that 14 patients used helmet, while (I assume) the large part used a tight face mask. Report the exact numbers in the methods section and, if the sentence is correct, reword in the abstract “Sixty-nine patients were trialled on CPAP, mostly delivered by face mask, …”. 2) Which type of system was used to provide flow? Is it a free-flow Venturi, (I guess that’s not the case, since you state “CPAP is used in the UK in preference to High Flow Nasal Oxygen, largely due to concerns about oxygen supplies” and you refer to 10-15 l/min of oxygen consumption) a Bussignac valve system, a ventilator/turbine system? I guess that you used different systems for helmets and masks. Please add all the requested information in the methods section.

- abstract: there are conflicting information: “Sixty-nine patients were trialled on CPAP either as a ceiling of care (N=25) or as a potential bridge to IMV (N=44).” but later you state “Among all patients trialled on CPAP either as a potential bridge to IMV (N=44) or as a ceiling-of-care (N=19) mortality...”. please report only one of the two sentences to avoid confusion (is it 25+44 or 19+44?) and check consistency with figure 2 of the supplements

- abstract: please report some data about use of CPAP in patients without ceiling of care. Add a sentence like “Among patients without ceiling of care (n=AA), a CPAP trial was started in BB, while CC needed prompt intubation; CPAP failure leading to intubation occurred in DD, while EE patients successfully recovered without intubation maximally receiving CPAP”

If I desumed the numbers correctly, it should be: AA=156; BB=44; CC=10; DD about 26; EE=18

- Figure 1: add the raw number of patients for each column

- Figure 2 supplements: add the number of excluded patients (apparently numbers are missing)

Please submit your revised manuscript by Jan 11 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Andrea Coppadoro

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: Many thanks for addressing the issues raised on initial review. I think supplemental figure 2 would be better if included in the body of the manuscript. That aside, no other recommendations.

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Reviewer #1: Yes: Philip A. Verhoef, MD, PhD

Reviewer #2: No

PLoS One. 2020 Dec 31;15(12):e0244857. doi: 10.1371/journal.pone.0244857.r004

Author response to Decision Letter 1

14 Dec 2020

Dear PLOS ONE Academic Editor and Team

Thank you for your carefully considered review, detailing your helpful suggestions. I will address each point individually below, in red.

1. The delivery of CPAP in your study needs to be clarified under many aspects. 1) Which interface was used? In the discussion, you state that 14 patients used helmet, while (I assume) the large part used a tight face mask. Report the exact numbers in the methods section and, if the sentence is correct, reword in the abstract “Sixty-nine patients were trialled on CPAP, mostly delivered by face mask, …”. 2) Which type of system was used to provide flow? Is it a free-flow Venturi, (I guess that’s not the case, since you state “CPAP is used in the UK in preference to High Flow Nasal Oxygen, largely due to concerns about oxygen supplies” and you refer to 10-15 l/min of oxygen consumption) a Bussignac valve system, a ventilator/turbine system? I guess that you used different systems for helmets and masks. Please add all the requested information in the methods section.

Thank you. The Procedures section of Methods has been amended to address the above points, and now reads as follows:

“In this study, patients not maintaining oxygen saturations over 92- 94% on 40 - 60% oxygen via a Venturi mask were commenced on CPAP 10 cm H20 and 10 litres oxygen, adjusted according to physician discretion. CPAP on the ward was delivered by the Breas Medical NIPPY 3+© ventilator, with oxygen entrained from the wall via piped oxygen attached to a flow meter. Pressure could be adjusted as required, to a maximum of 15 cm H2O and flow could be adjusted to a maximum of 15 litres O2. The default interface used on the ward was a full face mask, but a total face mask was used in a small number of patients who could not tolerate this.

With only one exception, CPAP as a ceiling of care was started on the respiratory wards in all cases. CPAP as a bridge to IMV was started on the respiratory wards in most cases. These wards consisted of three bays of four beds, and four side-rooms consisting of one bed. All beds had access to a wall-mounted oxygen supply and could support the use of CPAP. One nurse would typically look after four to eight patients.

Fourteen patients requiring CPAP were commenced on CPAP Hoods instead of face masks and this was always delivered on ITU, either via the Hamilton-S1©, or the Hamilton-C3© Ventilator. With one exception, all the CPAP Hood patients remained for full escalation. “

Thank you.

We have now updated the findings section of the abstract to read “Sixty-nine patients were trialed on CPAP, mostly delivered by face mask, either as an early ceiling of care instituted within 24 hours of admission (N=19), or as a potential bridge to IMV (N=44). Patients receiving a ceiling of care more than 24 hours after admission (N=6) were excluded from the analysis.”

The results section reads:

“When all patients who ever received CPAP (including those who went on to require IMV N=69) are examined, 19 patients had an early ceiling-of-care plan…”

In the Discussion section, we have amended the opening sentence to read:

“In our cohort of 294 hospitalized patients, 69 were trialed on CPAP either as a ceiling-of-care (N=25), of which only those with an early ceiling-of-care (N=19) were included in the analysis, or as a potential bridge to IMV (N=44).”

We hope this clarifies this point, and achieves better consistency for readers. The six patients unaccounted for in the above were patients who had a ceiling of care introduced later during the admission. As described in lines 174- 176 of the Statistical analysis “Patients who had a ceiling-of-care instituted more than 24h after admission were omitted as reverse causality was possible, i.e. that a ceiling-of-care was introduced following failure to respond to treatment.”

If I desumed the numbers correctly, it should be: AA=156; BB=44; CC=10; DD about 26; EE=18

Thank you.

I think AA=156 includes the 19 patients whose ceiling of care permitted CPAP but not IMV. The corrected number, for patients without a ceiling of care, is therefore 137 (see Table 1). The final numbers should therefore be:

AA = 137; BB=44; CC=10; DD= 25, EE= 19

I have added the following text to the abstract:

“Among patients without a ceiling of care (N= 137), 10 patients required prompt intubation following failed oxygen therapy, but 44 patients received CPAP. CPAP failure, defined as death (N=1) or intubation (N=24), occurred in 57% (N= 25) of patients. But in total, 75% (N=33) of those started on CPAP with no ceiling of care recovered to discharge - 19 without the need for IMV, and 14 following IMV.”

This corresponds to the Mortality by respiratory support received and ceiling-of-care subsection of the Results section, where is states that “Among those without any ceiling-of-care (N=44), 75% recovered and were discharged – 43.1% (N=19) without requiring IMV and 31.8% (N=14) after subsequently receiving IMV (Figure-2). “

- Figure 1: add the raw number of patients for each column

This has now been done. For consistency, I have also added another version of Figure 2, depicting the raw numbers, but left the original one as well, in the hope that the editorial board may decide which version they prefer. The authors’ preference would be with the second version depicting the raw numbers.

- Figure 2 supplements: add the number of excluded patients (apparently numbers are missing)

This has now been done.

Once again, thank you very much for your thorough review of the manuscript, which we have all found very helpful and instructive.

We look forward to hearing from you.

Kind regards,

Jonathan Walker

PLoS One. doi: 10.1371/journal.pone.0244857.r005

Decision Letter 2

Andrea Coppadoro

18 Dec 2020

The role of CPAP as a potential bridge to invasive ventilation and as a ceiling-of-care for patients hospitalised with Covid-19 - an observational study.

PONE-D-20-20968R2

Dear Dr. Walker,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Andrea Coppadoro

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

In your final submission you can include the revised version of figure 2 (the numbered version); please change the font color on the blue bars (black doesn't read).

PLoS One. doi: 10.1371/journal.pone.0244857.r006

Acceptance letter

Andrea Coppadoro

22 Dec 2020

PONE-D-20-20968R2

The role of CPAP as a potential bridge to invasive ventilation and as a ceiling-of-care for patients hospitalized with Covid-19 - an observational study.

Dear Dr. Walker:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Andrea Coppadoro

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Conceptual framework of relationship between exposure and confounding variables and mortality.

(DOCX)

Click here for additional data file.^{(70.7KB, docx)}

S2 Fig. Flow diagram of patients included in the study and mortality by mode of respiratory support and ceiling-of-care.

(DOCX)

Click here for additional data file.^{(65.5KB, docx)}

Attachment

Submitted filename: PLOS Final Response.docx

Click here for additional data file.^{(33KB, docx)}

Data Availability Statement

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PERMALINK

The role of CPAP as a potential bridge to invasive ventilation and as a ceiling-of-care for patients hospitalized with Covid-19—An observational study

Jonathan Walker

Shaman Dolly

Liji Ng

Melissa Prior-Ong

Kalpana Sabapathy

Roles

Abstract

Background

Methods

Findings

Conclusion

Strengths and limitations of this study

Background

Methods

Study setting, design and participants

Patient and public involvement

Procedures

Exposure and outcome variables and analysis

Results

Patient characteristics in study population overall

Table 1. Patient characteristics overall.

Characteristics of patients by maximal respiratory support received

Table 2. Patient characteristics by maximal respiratory support received.

Patient outcomes

Fig 1. Mortality of patients by maximal respiratory support received, overall and stratified by ceiling-of-care.

Mortality by respiratory support received and ceiling-of-care

Fig 2. Outcomes among all patients who ever received CPAP, by ceiling-of-care status (numbered version).

Factors associated with mortality

Table 3. Characteristics of patients who died and predictors of mortality.

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Andrea Coppadoro

Roles

Transfer Alert

Author response to Decision Letter 0

Decision Letter 1

Andrea Coppadoro

Roles

Author response to Decision Letter 1

Decision Letter 2

Andrea Coppadoro

Roles

Acceptance letter

Andrea Coppadoro

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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