key: cord-256790-odlcfhcr authors: Alviset, S.; Riller, Q.; Aboab, J.; Dilworth, K.; Billy, P. A.; Lombardi, Y.; Azzi, M.; Ferreira Vargas, L.; Laine, L.; Lermuzeaux, M.; Memain, N.; Silva, D.; Tchoubou, T.; Ushmurova, D.; Dabbagh, H.; Escoda, S.; Lefrancois, R.; Nardi, A.; Ngima, A.; IOOS, V. title: Continuous positive airway pressure face-mask ventilation to manage massive influx of patients requiring respiratory support during the SARS-CoV-2 outbreak date: 2020-06-03 journal: nan DOI: 10.1101/2020.06.01.20118018 sha: doc_id: 256790 cord_uid: odlcfhcr Background: Since December 2019, a global outbreak of coronavirus disease (COVID-19) is responsible for massive influx of patients with acute respiratory failure in hospitals. We describe the characteristics, clinical course, and outcomes of COVID-19 patients treated with continuous positive airway pressure (CPAP) in a large public hospital in France. Method: It is a single centre retrospective observational cohort. From 27th March to 23rd April, consecutive patients receiving 10 to 15 l/min of oxygen with a non-rebreather mask, who had signs of respiratory failure or were unable to maintain an SpO2 > 90%, were treated by CPAP with a face-mask unless the ICU physician judged that immediate intubation was indicated. The main outcome under study was reasons for CPAP discontinuation. Results: A total of 585 patients were admitted in Delafontaine hospital for COVID-19. ICU was quickly overwhelmed. Fifty-nine out of 159 (37%) patients requiring ICU care had to be referred to other hospitals. CPAP therapy was initiated in 49 patients and performed out of ICU in 41 (84%). Reasons for discontinuation of CPAP were intubation for invasive ventilation in 25 (51%) patients, improvement in 16 (33%), poor tolerance in 6 (12%) and death in 2 (4%). A decision not to intubate had been taken for the 2 patients who died while on CPAP. Conclusions: Treatment with CPAP is feasible and safe in a non-ICU environment in the context of a massive influx of patients. One third of these patients with high oxygen requirements did not eventually need invasive ventilation. The outbreak of the novel coronavirus disease 2019 (COVID-19) began in Wuhan, China in December 2019. Since then, it has rapidly spread around the world. As of May 19th, 2020, the WHO reported a total of 4 731 458 COVID-19 cases globally, with 6.67% mortality. In a large UK cohort, death from COVID-19 was strongly associated with being male, older age, deprivation, uncontrolled diabetes and severe asthma 1 . The nature of the pulmonary lesions triggered by SARS-CoV-2 is still a matter of debate. Some histopathological studies suggest that diffuse alveolar damage is not the single pattern 2, 3 . Disorders of the pulmonary circulation (thrombosis, endothelial injury) and organizing pneumonia may also be present. Many intensivists have observed that the classical clinical features of ARDS after intubation such as low pulmonary compliance are not found in all patients. A classification of mechanicallyventilated patients according to the driving pressure level after intubation has been proposed (L and H phenotypes) 4, 5 . In terms of clinical management, initial recommendations suggested early intubation and ARDS-type ventilator settings 6 . Although some studies suggest a role for noninvasive ventilation in mild ARDS 7-10 , invasive mechanical ventilation remains the standard of care, especially for severe cases. During the Chinese and European COVID-19 outbreaks, a number of critical care teams proposed using high flow nasal cannula or non-invasive ventilation at least for initial management [11] [12] [13] [14] . Optimal respiratory support for COVID-19 patients presenting with acute hypoxemic respiratory failure, however, remains unknown. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. . https://doi.org/10.1101/2020.06.01.20118018 doi: medRxiv preprint The district of Seine Saint Denis has been the worst affected area during the 2020 SARS-CoV-2 outbreak in Parisian region 15 . It is densely populated and has a highdeprivation index. From mid-March until end-April 2020, the Delafontaine Hospital, a large public hospital in Saint Denis, experienced a massive influx of patients requiring mechanical ventilation for acute respiratory failure due to COVID-19. During this period, the hospital in-patient bed capacity for non-ICU COVID-19 patients expanded to 210 beds. A total of 585 patients with SARS-CoV-2 infection were hospitalised. Despite increasing the number of intensive care beds from 18 to 32, the ICU was quickly overwhelmed. Fifty-nine (37%) out of 159 patients requiring ICU care had to be referred to other hospitals ( Figure 1 ). To manage the flow of patients presenting from 27th march onwards, continuous positive airway pressure (CPAP) via face mask interface was considered in all patients with signs of respiratory failure despite 10 to 15 l/min of oxygen delivered by non-rebreather mask. In this single centre retrospective observational cohort study, we aim to describe the outcomes, in terms of clinical improvement without progression to intubation, need for intubation and mortality of patients supported with CPAP in our hospital during the SARS-CoV-2 outbreak. We reviewed the characteristics, clinical course and outcomes of all consecutive adults with proven COVID-19 treated with CPAP in ICU or in wards between 27th March and 23 April. During this 4 week-period, patients receiving 10-15 l/min oxygen through a non-rebreather mask who had clinical signs of respiratory failure or were All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. . https://doi.org/10.1101/2020.06.01.20118018 doi: medRxiv preprint unable to maintain an SpO2 > 90% were assessed for treatment with CPAP via facemask unless the ICU physician judged that immediate intubation was indicated. Every patient included in the study had a thoracic CT scan compatible with COVID-19 pneumonia and/or a positive SARS-CoV-2 PCR on naso-pharyngeal swab or broncho-alveolar lavage. The following baseline patient characteristics were retrieved from patient electronic medical record : sex, age, comorbidities, body mass index (BMI), withholding / withdrawal of life-sustaining therapies, associated COVID-19 therapies (antivirals, steroids, immuno-modulating therapies, prone positioning), oxygen flow rate and SpO2 before and after starting CPAP treatment, duration of CPAP treatment, medical unit where CPAP treatment was performed, reasons for discontinuation of CPAP, duration of invasive mechanical ventilation, SAPS2 score for patients admitted in ICU, driving pressure and P/F ratio on first day of mechanical ventilation. The clinical outcomes (i.e. discharges from hospital, mortality) were recorded until the final day of follow-up on May 13 th . CPAP of 5 to 10 cm H2O was delivered via a face mask dedicated to non-invasive ventilation (Performa Track®) with one of 2 types of CPAP valve (Boussignac™ or CPAP-O-two™) or alternatively, an ICU ventilator (Servo I® or Evita Infinity V500®). Treatment was undertaken in a medical ward, the emergency department (ED) shortstay unit or the ICU. An electrostatic heat and moisture exchanger filter (DAR™) was placed between the mask and the CPAP valve to prevent aerosolization of virus through expired gases. All patients were admitted to a single room with All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. . https://doi.org/10.1101/2020.06.01.20118018 doi: medRxiv preprint implementation of contact and airborne precautions; however some rooms were without a window. Medical and nursing staff in wards unfamiliar with non-invasive ventilation were trained by the intensivist who initiating the CPAP treatment. Patients received an initial prolonged session lasting at least 4 hours before being reassessed of their need of invasive mechanical ventilation. If the patient could be temporarily taken off CPAP without an immediate fall of SpO2 below 90% (on O2 15l/min via non-rebreather mask) or recurrence of clinical signs of acute respiratory failure, CPAP treatment was resumed for 2 hours every 4 hours. Progressive weaning of CPAP was performed according to clinical signs, pulse oximetry and arterial blood gases. If possible, patients were managed in the ICU (nurse/patient ratio 1:2). If no ICU bed was available (as in over 80% cases), patients with CPAP were shifted to the ED short-stay unit (8 beds) adjacent to the ICU (nurse/patient ratio 1:4) which allowed frequent re-evaluation of the patient's state by the intensivist on call. In the eventuality of no bed availability in the ED short stay unit, CPAP treatment was instituted and managed in the medical ward were the patient had been admitted (nurse/patient ratio 1:7 during the outbreak). Ward patients on CPAP (and those with high O2 requirements) were systematically reviewed overnight by the duty resident responsible for the COVID-19 medical wards. Non-invasive ventilation (NIV) with bi-level pressure modes was not used for three reasons: Firstly the number of ventilators available could not ensure surge capacity in the context of massive patient influx. Secondly, the increase in positive pressure during inspiration carries a greater risk of aerosolization of virus particles. The final reason was to keep pressure support ventilation as an option for pre-oxygenation before intubation in case it was indicated. Using bi-level pressure modes would have also required more intensive training of ward staff unfamiliar with NIV techniques. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. . https://doi.org/10.1101/2020.06.01.20118018 doi: medRxiv preprint No a priori statistical sample size calculation was performed. Sample size was equal to the number of patients treated during the study period. Quantitative values are expressed as the median (interquartile range, IQR), and qualitative values are presented as numbers (percentages). Univariate analysis was performed using Fisher exact test or Wilcoxon test, as appropriate. All tests were two-sided and a p value <0.05 was considered statistically significant. Because of alpha inflation due to multiple comparisons, findings should be interpreted as exploratory. A Cox hazard proportional model was fit for time to intubation, controlling for potential confounders in the cohort of 39 patients analysed. All variables available at baseline and associated with intubation in univariate analysis with a p-value <0.10 were selected. Variables selected are: CT-scan severity (<50% vs. Missing data for SpO 2 (n=3) at CPAP initiation were imputed based on the maximal bias assumption (i.e., low SpO 2 in non-intubated patients and high SpO 2 in intubated patients). Variables with more than 10 % missing values were not implemented in the multivariate analysis. The analyses were carried out using R version 3.6.2 (The R Project For Statistical Computing, Vienna, Austria; http://www.R-project.org). The study was approved by the national ethics review board (CNRIPH -Commission Nationale des Recherches Impliquant la Personne Humaine) under the number All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. . Forty-nine consecutive patients were treated with CPAP between 27 th March and 23 rd April ( Figure 2 ). Initiation of CPAP occurred throughout the entire study period and followed the epidemic curve ( Figure 1 ). SARS-CoV-2 pneumonia was confirmed by PCR from upper or lower respiratory tract in 39 (79%) patients and by thoracic CT scan in the remaining patients. Twenty-six (53%) patients were eventually intubated and a total of 17 (34%) died. Patients' characteristics are presented in table 1. The median age was 65 years (IQR=54-71) and 36 (73%) were men. Forty-one (84%) patients had at least one comorbidity. The most frequent were hypertension (31 patients, 63%), obesity (13 patients, 34%) and diabetes (16 patients, 33%). The median duration of symptoms before hospital admission was 6 days (IQR = 5-9). Thoracic CT-scan at admission showed mild (10 to 25%), moderate (25 to 50%) or severe (>50%) lung involvement in 13 (27%), 23 (46%) and 13 (27%) patients respectively. Modalities of CPAP therapy and associated interventions are described in table 2. CPAP was performed out of ICU in 41 (84%) cases. Median duration of CPAP therapy was 3 days (IQR=1-5). Reasons for discontinuation of CPAP were intubation for invasive ventilation in 25 (51%) patients, improvement in 16 (33%), poor tolerance in 6 (12%) and death in 2 (4%). A decision not to intubate had been taken with the patient and their family for the 2 patients who died while on CPAP. All patients All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. . Patients who improved with CPAP were compared to the group who ultimately progressed to needing intubation. Characteristics regarding age, sex, comorbidities and disease presentation were similar in both groups. Patient who improved on CPAP were treated later in their hospital stay, had higher oxygen saturation before CPAP initiation, longer duration of CPAP and received more often concomitant double dose prophylactic anticoagulation. A cox proportional hazard model was made to assess for confounding factors, variables associated with the risk of intubation in univariate analysis (p value < 0.10) were selected. Thoracic CT-scan All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. This single center retrospective observational study describes the largest cohort to date of COVID-19 adult patients treated with CPAP via face mask. The main purpose of using CPAP was to facilitate management of the patient flow of those potentially requiring invasive ventilation during this SARS-CoV-2 outbreak. CPAP via face mask does not require a ventilator, and could thus be instituted and run on non-ICU wards. This proved critical in this particular instance. Fifteen (31%) patients improved with CPAP treatment, and eventually did not go on to require invasive ventilation though they were very hypoxemic (11 (73%) of them required 15L/min oxygen). Other than 2 patients with a do-not-intubate order, no death occurred during CPAP therapy. Mortality was 42.3% in the patient group requiring intubation. This was related to the severity of illness (median SAPS2 score of 57) but may be also due to difficulties in maintaining the quality of ICU care during a crisis All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. . https://doi.org/10.1101/2020.06.01.20118018 doi: medRxiv preprint situation. Mortality data for COVID-19 patients on invasive ventilation is still scarce, but early reports from China and the US showed mortality rate ranging between 76 and 97% [16] [17] [18] [19] . In Bergamo (Italy), an overall mortality of 61.2% was reported among 99 patients necessitating ventilator support by Helmet CPAP (84%), non-invasive (8%) or invasive (8%) ventilation in the setting of the SARS-CoV-2 outbreak 20 . In a larger study in Lombardy, of 1591 ICU patients admitted with COVID-19, 72% were mechanically ventilated while 9% were treated with non-invasive ventilation. Mortality rate was 26% at the end of the study period with 920 (58%) patients were still in ICU 21 . In Vancouver (Canada), the mortality rate among 117 patients (of which 62.3% were on mechanical ventilation) admitted in 6 ICUs was 15.3%, while 10.3% remained in the ICU 22 . Use of CPAP has already been reported in outbreaks of acute severe respiratory infection such as the 2003 SARS epidemic. However it was used in patients with less profound hypoxemia than in our cohort (5 to 6 l/m), and a lower percentage (10 to 30%) of patients required intubation 23, 24 . This study has several limitations. Firstly, due to its retrospective design, we were unable to collect additional data that could have contributed to a better understanding of the role of CPAP in managing hypoxemic respiratory failure in COVID-19. Data on actual pressure levels delivered to each patient and the number of hours per day of CPAP therapy could not be retrieved. In addition, it was not possible to ascertain in all patients whether vital signs (SpO2, respiratory rate) and arterial blood gases were taken while on CPAP or while on non-rebreather mask. Finally, the absence of a control group does not allow us to make any firm conclusion on the role of CPAP in avoiding intubation. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. Choosing the appropriate interface is critical to decrease leaks and minimize aerosolization and there may be some advantages to select full face masks. Helmet is another option but is more difficult to handle in a non-ICU setting. Patients with profound hypoxemia and high respiratory rate who are treated with CPAP may be exposed to self-induced lung injury. We attempted to collect the values for driving pressures immediately after intubation, but these data was unfortunately only available in a few cases. This should be investigated in further studies. On one hand, CPAP treatment may have in fact triaged a group of patients who were less severe. This selection effect is suggested by the higher levels of SpO2 at initiation of CPAP in the group of patients who improved compared with the group of All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. . patients who progressed to intubation. CPAP therapy could have potentially worsened the condition of patients whose intubation was then effectively delayed. The high SAPS2 scores of the intubated patients in the study provide some evidence to this effect. On the other hand, there may be some advantages of using CPAP even for patients who are subsequently intubated. CPAP prior to intubation may reduce the duration of However, the likely increased risk of contamination of heath care workers, notably if personal protective equipment is inadequate, must be taken in account. CPAP could also be considered as a first-line respiratory support strategy in less hypoxemic patients without significant respiratory failure in association with other strategies to improve oxygenation, such as prone positioning 27,28 . In conclusion, we found treatment with face mask CPAP to be feasible and safe in a non-ICU environment and in the context of a massive influx of patient. It was useful to post-pone intubation and to manage the flow of patient requiring invasive ventilation. We also found, that among patients who have low SpO2 and /or signs of respiratory failure while on 15l/min O2 via non rebreather mask about one third eventually did not need invasive ventilation. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. . https://doi.org/10.1101/2020.06.01.20118018 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. Hazard ratio of intubation adjusted for CT-scan severity (more or less of 50 % of lung involved by SARS-CoV2 induced lesions), low saturation (SpO2, < 92 % or > 92 %), delay in days between hospitalisation and CPAP initiation (two groups based on the median value of CPAP delay), use of anticoagulant treatment grouped by dosage: simple dose prophylaxis (1), double dose prophylaxis (2) or curative treatment (3) . P values are indicated as the result of likelihood-ratio test. The validity of the proportional hazards assumption was tested using cox.zph() function in R (P values > 0.05) and by visualisation of Schoenfeld residuals. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 3, 2020. . https://doi.org/10.1101/2020.06.01.20118018 doi: medRxiv preprint OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients. medRxiv Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation Time to consider histologic pattern of lung injury to treat critically ill patients with COVID-19 infection COVID-19 pneumonia: different respiratory treatments for different phenotypes? 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