Nasa et al. Crit Care (2021) 25:106 https://doi.org/10.1186/s13054-021-03491-y RESEARCH Open Access Expert consensus statements for the management of COVID‑19‑related acute respiratory failure using a Delphi method Prashant Nasa1, Elie Azoulay2, Ashish K. Khanna3, Ravi Jain4, Sachin Gupta5, Yash Javeri6, Deven Juneja7, Pradeep Rangappa8, Krishnaswamy Sundararajan9, Waleed Alhazzani10, Massimo Antonelli11, Yaseen M. Arabi12, Jan Bakker13,14,15, Laurent J. Brochard16, Adam M. Deane17, Bin Du18, Sharon Einav19, Andrés Esteban20, Ognjen Gajic21, Samuel M. Galvagno Jr.22, Claude Guérin23,24, Samir Jaber25,26, Gopi C. Khilnani27, Younsuck Koh28, Jean‑Baptiste Lascarrou29, Flavia R. Machado30, Manu L. N. G. Malbrain31,32, Jordi Mancebo33, Michael T. McCurdy34, Brendan A. McGrath35,36, Sangeeta Mehta37, Armand Mekontso‑Dessap38, Mervyn Mer39, Michael Nurok40, Pauline K. Park41, Paolo Pelosi42,43, John V. Peter44, Jason Phua45, David V. Pilcher46, Lise Piquilloud47, Peter Schellongowski48, Marcus J. Schultz49,50,51, Manu Shankar‑Hari52,53, Suveer Singh54, Massimiliano Sorbello55, Ravindranath Tiruvoipati56, Andrew A. Udy57, Tobias Welte58 and Sheila N. Myatra59* Abstract Background: Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute respiratory failure (C-ARF) has resulted in wide variation in clinical practice. Methods: Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ2) test (p < 0·05 was considered as unstable). Results: Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticos‑ teroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16–24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing *Correspondence: sheila150@hotmail.com 59 Department of Anaesthesia, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Dr. Ernest Borges Road, Parel, Mumbai, India Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​ mmons​.org/publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Nasa et al. Crit Care (2021) 25:106 Page 2 of 17 of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment. Conclusion: Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important deci‑ sions for patient management in areas where evidence is either absent or limited. Trial registration: The study was registered with Clinical trials.gov Identifier: NCT04534569. Keywords: Respiratory distress syndrome adult, COVID-19 ventilatory management, COVID-19 respiratory management, COVID-19 acute respiratory distress syndrome, COVID-19 high flow nasal oxygen, COVID 19 invasive mechanical ventilation Introduction management of C-ARF [13, 14]. The study was registered Infection with the severe acute respiratory syndrome with Clinical trials.gov Identifier: NCT04534569. coronavirus 2 (SARS-CoV-2) has emerged as a pandemic, The steering committee recruited and convened an resulting in unprecedented pressure on healthcare sys- international group of intensivists with expertise in the tems globally. Although most patients present with mild field of acute respiratory failure. E-mail invitations were symptoms including fever and malaise, 8–32% of patients sent to 60 global experts to participate in the Delphi pro- presenting to hospital may require admission to the cess. Upon acceptance, experts were included in the Del- intensive care unit (ICU) [1–3], depending on the admis- phi process to generate agreement. Surveys disseminated sion criteria and available resources, with an ICU mortal- to the experts were prepared using Google Forms. The ity of 34–50% [3, 4]. steering committee members did not participate in the Patients with coronavirus disease 2019 (COVID-19) Delphi process. acute respiratory failure (C-ARF) who are admitted to The overall scope of the project was determined the ICU with hypoxaemia typically require some form through a search and review of available literature on of respiratory support [5]. COVID-19-related acute res- C-ARF, published between ­1st January and ­3rd Septem- piratory distress syndrome (ARDS) may differ from other ber 2020 by the steering committee (Additional file 1). causes of ARDS, since patients may present with pro- A list of interventions for the respiratory management found hypoxaemia accompanied by a wide range of res- of C-ARF was prepared in areas where the committee piratory compliance [6–8]. However, whether ARDS due felt clear evidence was lacking. The list was presented to COVID-19 is clinically similar to other forms of ARDS to experts in the form of a survey questionnaire, which remains a matter of debate [7, 9–11]. Consequently, there included five sections: non-invasive respiratory interven- is no uniform agreement on the optimal management of tions; invasive mechanical ventilation; refractory hypox- respiratory failure, including the most appropriate oxy- aemia; infection control; weaning and tracheostomy. The genation and ventilation strategies that limit or prevent experts subsequently responded to several rounds of sur- additional lung injury or other complications in these vey questionnaires conducted using an iterative approach patients. using the Delphi method, to prioritise topics for inclu- There are few published randomised controlled trials sion, which were repeated until agreement and stability (RCTs) related to the respiratory management of C-ARF. were achieved. Complete details of the Delphi process are As a result, clinical practice variations in the manage- given in Additional file 2. ment of C-ARF exist, making the optimal therapeutic management unclear [12]. Given the dearth of evidence, Agreement and stability we aimed to achieve agreement on the respiratory man- For statements with responses on an ordinal 7–point Lik- agement of C-ARF using a Delphi process, defined by at ert scale, ‘agreement’ was defined as a score of 5–7, ‘neu- least 70% agreement among experts who met pre-speci- tral’ by a score of 4 and ‘disagreement’ by a score of 1–3. fied qualification criteria. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale for a state- Methods ment [13, 14]. Median and interquartile range (IQR) were Delphi process used to describe the central tendency and dispersion of A steering committee of 10 critical care physicians responses. For multiple-choice questions (MCQs), agree- actively involved in the management of patients with ment was defined as achieved if > 80% experts voted for a C-ARF was formed in August 2020. A Delphi pro- particular option. Stability in the responses was assessed cess was used to generate agreement on the respiratory from round three onwards. Stability was assessed Nasa et al. Crit Care (2021) 25:106 Page 3 of 17 between the two concluding rounds for each statement, (13) years and 5 (13%) were female. The majority (92%) using the non-parametric Chi-square (χ2) test. p < 0·05 were affiliated with university hospitals; and their median was considered as a significant variation or unstable. h-index was 33 (11–100). Data from the last stable questionnaire round of the Del- Five survey questionnaire rounds were conducted phi process for each statement were included for prepar- between 4th September and 5th October 2020. Details of ing the final clinical statements. the Delphi rounds are provided in Fig. 2. The results of all 37 survey questionnaire statements used in the Delphi Expert clinical practice statements process are given in Table 1. At the end of the Delphi pro- Expert clinical practice statements were derived by the cess, 27 statements (73%) achieved agreement and stabil- steering committee from the clinical statements that ity from which 20 expert clinical practice statements were generated agreements through the Delphi process. The prepared (Fig. 3). Reports of the first four survey rounds expert clinical practice statements were considered to are provided in the online supplement (Additional file 3: be “strong statements” when a median of ≥ 6 or ≤ 2 on Survey Report 1, Additional file 4: Survey Report 2, Addi- the Likert scale or > 90% votes for any MCQ option were tional file 5: Survey Report 3, and Additional file 6: Sur- achieved [14]. For the expert clinical practice statements, vey Report 4). the term “should” was used for the strong statements and “may” was used for the other statements. Expert clinical practice statements The final results of this survey and the expert clinical Our study rapidly conducted a survey of recognised practice statements were circulated among the experts. international experts using the Delphi process, generat- The manuscript was circulated among the experts ing 27 statements with large agreement on the respira- for editing and approval before it was submitted for tory management of C-ARF. From these statements, 20 publication. expert clinical practice statements were derived, address- ing critical knowledge gaps in clinical management. The Results experts made a number of important and relevant rec- Of the 60 experts invited, 39 (65%) from 20 different ommendations specific to C-ARF covering invasive and countries and six continents participated in the Del- non-invasive respiratory support, pharmacology, airway phi process (Fig. 1); and 37 (95%) completed all rounds management, infrastructure and recovery. of the Delphi process. Median age of the experts was 53 Fig. 1 Geographical distribution of countries represented by the experts. KSA: Kingdom of Saudi Arabia; UK: United Kingdom; USA: United States of America. Different shades of green represent the number of experts Nasa et al. Crit Care (2021) 25:106 Page 4 of 17 Fig. 2 Flow diagram of the steps of the Delphi process. N: number of experts; MCQ: multiple choice question; PICO: Patient problem, Intervention: Comparison and Outcome The Delphi methodology is a well-recognized process haemorrhage with capillary damage are also noted in to generate guidance based on consensus using collective patients with non-COVID-19-related ARDS [18, 19]. In intelligence [13, 14]. The expert clinical practice state- a cohort of 31 patients with COVID-19, higher lung com- ments address important bedside decisions for patient pliance and volumes were found compared to patients management in areas where the current evidence is with non-COVID-19 ARDS for a given PaO2/FiO2 [6, 8, either absent or limited. These expert statements along 20]. This created the controversy that the pathophysiol- with a discussion of the available literature are detailed ogy of COVID-19-related ARDS is different from con- below. ventional ARDS [6, 7, 9–11]. Though there may be some differences in the pathophysiology of COVID-19 and Is COVID‑19‑related ARDS similar to other forms of ARDS? non-COVID-19 ARDS, the clinical presentation is similar Expert statement [16–18]. The respiratory mechanics of ventilated patients COVID-19-related ARDS is clinically similar to other with C-ARF were noted to be similar to classical ARDS in forms of ARDS. larger observational multicentre studies [21–23]. Further studies incorporating lung imaging and perfusion analy- Discussion sis will better address this important pathophysiological The pathophysiology of COVID-19 involves SARS- and clinical issue in future. CoV-2 invasion of host cells using angiotensin convert- ing enzyme 2 (ACE2) receptor present in lungs and Corticosteroids other organs. The viral invasion is followed by replica- Expert statement tion in type II alveolar pneumocytes that induces a dys- Systemic corticosteroids should be used in patients with regulated host immune response which in turn causes critical COVID-19. alveolar damage and ARDS [15]. Lung autopsy studies Dexamethasone is the preferred choice of systemic cor- in patients who died from COVID-19 demonstrate dif- ticosteroids in patients of C-ARF. fuse alveolar damage along with significant endotheliitis The daily dose of dexamethasone should be 6 mg. and microthrombi in the pulmonary microvascula- The preferred duration of systemic corticosteroids is ture [16–18]. Diffuse alveolar damage and alveolar 5–10 days. Nasa et al. Crit Care (2021) 25:106 Page 5 of 17 Table 1 Consensus and stability analysis of the clinical statements on the respiratory management of C-ARF Agree. (%) Neutral (%) Disagree. (%) Median (IQR) χ2 p-value Section-1: Non-invasive respiratory interventions 1. The pathophysiology of C-ARF is similar to that of ARDS 86.5 0 13.5 5 (0) 0.05 2. Based on your experience, awake self-proning may improve oxygenation in 91.9 8.1 0 5 (1) 1.0 patients with C-ARF 3. Based on your experience, awake self-proning may prevent the need for 54.0 35.1 10.9 5 (1) 0.71 invasive mechanical ventilation in patients with C-ARF* 4. In which of the following clinical scenarios should awake self-proning be NA 0.21 initiated in patients with C-ARF? Supplemental oxygen required to maintain ­SpO2 > 90% 97.8 Moderate-to-severe COVID-19 73 Increased work of breathing (observed subjectively) 45.9 Tachypnea (respiratory rate ≥ 30/min) 37.8 Never 0 5. HFNO can be considered as an alternative strategy for oxygen support 97.3 2.7 0 6 (0) 0.09 before invasive mechanical ventilation 6. When do you initiate HFNO in patients with C-ARF? NA 0.28 Unable to maintain ­SpO2 > 90% using high flow oxygen delivery device 97.3 through a mask Increasing oxygen requirement 81.1 Moderate-to-severe COVID-19 73 Tachypnea (respiratory rate ≥ 30/min) 56.8 Increased work of breathing (observed subjectively) 54.1 Never 0 7. Based on your experience, HFNO may avoid the need for tracheal intubation 81.1 18.9 0 5 (0) 0.35 and invasive mechanical ventilation in patients with C-ARF 8. NIV can be considered as an alternative strategy for oxygen support before 64.8 18·9 16.3 5 (2) 0.88 invasive mechanical ventilation* 9. NIV may be considered in the following clinical scenarios in patients with NA 0.44 C-ARF? Mixed Respiratory failure (hypercapnia and hypoxemia) 94.6 Increased work of breathing (observed subjectively) 81.1 Unable to maintain ­SpO2 more than 90% with high flow oxygen delivery 67.6 through a mask Moderate-to-severe COVID-19 59.5 Tachypnea (respiratory rate ≥ 30/min) 51.4 Unable to maintain Spo2 more than 90% with HFNO 45.9 10. Based on your experience, NIV may avoid the need for tracheal intubation 64.8 21.6 13.5 5 (1) 0.06 and invasive mechanical ventilation in patients with C-ARF* 11. The use of systemic corticosteroids could potentially avoid the need for 86.5 10.8 0.27 tracheal intubation and invasive mechanical ventilation in C-ARF 12. In which clinical context would you choose to initiate corticosteroids in NA 0.35 C-ARF? Critical COVID-19 91.9 Oxygen requirement to maintain ­SpO2 more than 92% 73 Moderate-to-severe COVID-19 75.7 All patients with C-ARF 37.8 Taking into consideration of inflammatory markers (CRP etc.) 24.3 Never 0 13. Which corticosteroid is your preferred choice in patients with C-ARF? NA 0.30 Dexamethasone 86.5 Methylprednisolone 16.2 Type of steroid is immaterial 16.2 Nasa et al. Crit Care (2021) 25:106 Page 6 of 17 Table 1 (continued) Agree. (%) Neutral (%) Disagree. (%) Median (IQR) χ2 p-value Hydrocortisone 5.4 14. What daily dose of corticosteroid (equivalent dose of dexamethasone) you NA 0.22 prescribe for C-ARF? 6 mg (equal to 8 mg of dexamethasone phosphate) 91.9 7 mg–20 mg 10.8 > 20 mg 2.7 Other 0 15. What duration of corticosteroid use would you prefer for patients with NA 0.81 C-ARF? 5–10 days 86.5 Extended duration for more than 10 days depending on the clinical response 13.5 11–14 days 2.7 More than 14 days 2.7 Section-2: Invasive mechanical ventilation 1. Which of the following options may be considered as an appropriate trigger NA 0.05 for tracheal intubation in C-ARF? Altered mental status 91.9 Hemodynamic instability 81.1 Failure to maintain ­SpO2 > 90% with other non-invasive respiratory interven‑ 81.1 tions Persistent respiratory distress 78.4 PaO2/FiO2 less than 100 67.6 Increased work of breathing (observed subjectively) 62.2 PaO2/FiO2 less than 200 18.9 Tachypnea (respiratory rate ≥ 30/min) 3.8 2. “Lung protective ventilation” should be used for patients with C-ARF on IMV 100 0 0 6 (1) 1.0 3. A low PEEP strategy (≤ 10 cm of H2O) is usually considered during IMV of 29.7 51.4 18.9 4 (1) 0.003 C-ARF* 4. How would you select PEEP in a patient of C-ARF on invasive mechanical NA NA ventilation with thorax CT scan showing bilateral pulmonary infiltrates, ­PaO2/FiO2 ratio less than 100 mm Hg, plateau pressure 27 cm of ­H2O and PEEP of 6 cm of ­H2O?* Obtaining the best static compliance or lowest driving pressure 54.1 Recruitment manoeuvre followed by PEEP set to either optimal ­SpO2 or static 40.5 lung compliance Incremental PEEP to target plateau pressure less than 30 cm ­H2O 40.5 Using ARDS-net protocol PEEP tables 37.8 Based on pressure–volume curve 29.7 Using esophageal balloon 16.2 Other 8.1 5. NMBA may be considered during early phase of the invasive mechanical 89.1 8.2 2.7 6 (1) 0·74 ventilation of C-ARF to avoid patient-ventilator dyssynchrony 6. The invasive mechanical ventilation strategy in C-ARF should be targeted to NA 0.94 the following? Tidal volume 4–6 ml/kg of predicted body weight 89.2 Plateau pressure ≤ 30 cm of ­H2O 89.2 Driving pressure ≤ 15 cm of ­H2O 78.4 Oxygenation ­(PaO2/FiO2 ratio) 29.4 Tidal volume 7–8 ml/kg of predicted body weight 10.8 Other 0 Section-3: Refractory hypoxemia Nasa et al. Crit Care (2021) 25:106 Page 7 of 17 Table 1 (continued) Agree. (%) Neutral (%) Disagree. (%) Median (IQR) χ2 p-value 1. The use of RM in patients with refractory hypoxemia in the setting of C-ARF 89.2 5.4 5.4 5 (1) 0.26 needs to be personalized to the individual patient in view of its potential deleterious effects 2. Prone position during invasive mechanical ventilation of C-ARF improves 97.3 2.7 0 6 (1) 0.09 oxygenation 3. Prone position during invasive mechanical ventilation of C-ARF is effective NA 0.25 when done for (duration per session)? 16–24 h 94.6 12–15 h 16.2 > 24 h 5.4 12–16 h 0 4. Advanced invasive mechanical ventilation (APRV, PRVC, etc.) modes may be 16.3 43.2 40.5 4(2) 0.03 beneficial in refractory hypoxemia with C-ARF* 5. The following adjuvant therapies are effective in refractory hypoxemia with NA 0.1 C-ARF?* None 54.1 Inhaled nitric oxide 45.9 Other 5.4 Nebulized prostacyclin 8.1 6. V-V ECMO may be considered in C-ARF patients on invasive mechanical NA 0.48 ventilation? Only in patients with refractory hypoxemia, who do not respond to other 83.8 adjuvant therapies Depending on the national/institutional policy and judicious resource alloca‑ 62.2 tion decision Only in patients who have failed or have a contraindication to prone position‑ 45.9 ing Early in patients with C-ARF without a trial of prone positioning 2.7 Cannot comment 0 Never 0 Section-4: Infection control 1. The following are considered as aerosol-generating procedures (AGPs)? NA 0.54 Tracheal intubation 100 Tracheostomy 100 Bronchoscopy 100 Tracheal extubation 97.3 Bag and mask ventilation 97.3 Non-invasive ventilation 97.3 Open suctioning (oral or tracheal) 97.3 Nebulization 94.6 High-flow nasal oxygen therapy 81.1 Chest physiotherapy 64.9 Invasive mechanical ventilation 10 2. HFNO produces less aerosols as compared to NIV with face mask* 37.8 54.1 8.1 4 (1) 0.002 3. The following measures may be considered in the ICU to prevent cross- NA 0.66 transmission of SARS-CoV-2? Closed suction system 100 Airborne infection isolation room 89.2 Video laryngoscopy over conventional laryngoscopy for intubation 86.5 Heat and moisture exchange filters 62.2 Ventilatory circuit modification for NIV /invasive mechanical ventilation 54.1 Increasing outdoor air ventilation rates (opening windows of ICU) 51.4 Nasa et al. Crit Care (2021) 25:106 Page 8 of 17 Table 1 (continued) Agree. (%) Neutral (%) Disagree. (%) Median (IQR) χ2 p-value NIV with helmet 48.6 Subglottic secretion drainage endotracheal tube 32.4 Intubation boxes 35.1 Delaying tracheal extubation up to ten days 2.7 Which personal protective equipment is acceptable for use during an AGP in NA 0.08 ICU?* Coverall, goggles or face shield, surgical gloves and N95 (FFP 2) mask 64.9 Coverall, surgical gloves, N95 (FFP 2) mask, goggles and face shield 59.5 Coverall, goggles or face shield, surgical gloves and FFP 3 mask 45.9 Coverall, surgical gloves and powered air-purifying respirator (PAPR) 40.5 PAPR and surgical gloves 8.1 Coverall, goggles or face shield, surgical gloves and surgical mask 2.7 N95 and surgical gloves 0 Section-5: Weaning and tracheostomy 1. Which weaning strategy would you prefer for liberation from invasive NA 0.33 mechanical ventilation in patients with C-ARF? Pressure support ventilation trial for 30 min to 2 h 89.2 Protocolized weaning 27 T-piece trial for 30 min to 2 h 13.5 Automated weaning protocol on mechanical ventilation 8.1 2. Chest physiotherapy could be beneficial in patients with C-ARF* 62.2 32.4 5.4 5 (1) 0.20 3. Early mobilization of patients is beneficial in patients on respiratory support 94.6 5.4 0 5 (1) 0.16 for C-ARF 4. Delay in liberation from invasive mechanical ventilation has lower risk of 2.7 24.3 73 2 (2) 0.38 reintubation in patients with C-ARF 5. When should tracheostomy be considered to facilitate weaning from inva‑ NA 0.80 sive mechanical ventilation? Same timing as in a non-COVID-19 patient 91.9 Failed tracheal extubation 13.5 Later than you would perform in a non-COVID-19 patient 10.8 Earlier than you would perform in a non-COVID-19 patient 0 Which of the following technique of performing tracheostomy is preferred in NA 0.42 patients with C-ARF? Percutaneous tracheostomy with or without guidance (ultrasound or bron‑ 89.2 choscopic) Surgical tracheostomy in the operation theatre 24.9 Surgical tracheostomy at the bed side 16.2 Other 2.7 Likert scale responses are presented as a percentage of agreement, neutral and disagreement Options of the multiple-choice type statements are presented in descending order of consensus Consensus was achieved when there was > 70% agreement/disagreement for the Likert scale and > 80% for multiple-choice type statements *Clinical statements that did not reach consensus Median and interquartile range (IQR) were used to describe the central tendency of responses and dispersion along the central value p value was calculated using χ2: Chi-square. p value was a measure of stability in responses between the two concluding rounds for each statement. p < 0·05 was considered as a significant variation or unstable Critical COVID-19 is used for ARDS (as per the Berlin definition), sepsis and septic shock (WHO severity definition for COVID-19)24 Agree: agreement; Disagree: disagreement; IQR: interquartile range; C-ARF: COVID-19-related acute respiratory failure; ARDS: acute respiratory distress syndrome; HFNO: high-flow nasal oxygen; NIV: non-invasive ventilation; COVID-19: coronavirus disease 2019; PEEP: positive end expiratory pressure; CT: computed tomography; NMBA: neuromuscular blocking agent; APRV: airway pressure release ventilation; PRVC: pressure-regulated volume control; V–V ECMO: veno–venous extracorporeal membrane oxygenation; AGP: aerosol-generating procedure; ICU: intensive care unit; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; FFP: filtering face piece; PAPR: powered air-purifying respirator. Nasa et al. Crit Care (2021) 25:106 Page 9 of 17 Fig. 3 Expert clinical practice statements for the respiratory management of COVID-19-related acute respiratory failure. *Strong statement (a median of ≥ 6 or ≤ 2 on the Likert scale or > 90% votes for any MCQ option were achieved). HFNO: high flow nasal oxygen; NIV: non-invasive ventilation; NMBA: neuromuscular blocking agent; PEEP: positive end-expiratory pressure; VV-ECMO: veno-venous extracorporeal membrane oxygenation; PSV: pressure support ventilation; COVID-19: coronavirus disease 2019; ICU: intensive care unit; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; C-ARF: COVID-19-related acute respiratory failure Discussion However, some questions remain unanswered, such as There is a strong suggestion for the use of systemic corti- the type, duration of corticosteroid therapy, timing of ini- costeroids in critical COVID-19 [World Health Organisa- tiation and role of a higher dose [28]. The results of ongo- tion (WHO) definition for COVID-19-ARDS, sepsis and ing trials (ClinicalTrials.gov Identifier NCT04395105 and septic shock] to reduce the need for invasive mechanical NCT04509973) will provide further information. ventilation [24]. Experts preferred the use of dexametha- sone at a dose of 6 mg daily for a duration of 5–10 days, Awake self‑proning as used in the RECOVERY trial over other corticoster- Expert statement oids, higher dose and longer duration [25]. The RECOV- Awake self-proning may improve oxygenation when used ERY trial and subsequent trials on corticosteroids in in patients with C-ARF requiring supplemental oxygen to COVID-19 found a mortality benefit with its use [25–27]. maintain oxygen saturation ­(SpO2) > 90%. Nasa et al. Crit Care (2021) 25:106 Page 10 of 17 Discussion Non‑invasive ventilation and continuous positive airway Use of early prone position in patients with severe ARDS pressure (CPAP) on invasive mechanical ventilation has been shown to sig- Expert statement nificantly reduce mortality [28]. Though small observa- NIV should be considered in patients with mixed res- tional studies in non-COVID-19 [29] and COVID-19 [30, piratory failure (hypercapnia and hypoxemia) and may be 31] patients have reported improvements in oxygenation used in patients with increased work of breathing which with awake self-proning, its impact on reducing tracheal is observed subjectively. intubation or mortality is unknown. Studies have shown either conflicting results or are difficult to interpret, as Discussion awake self-proning was used in combination with other NIV failure and higher ICU mortality were observed in non-invasive respiratory support [29–31]. In addition, patients with moderate-to-severe ARDS in a sub-analysis there is a concern about delaying intubation in patients of the LUNG SAFE study including 2813 non-COVID in whom awake self-proning is used [32]. Ongoing RCTs patients receiving NIV [40]. There are inconclusive on awake self-proning in C-ARF (ClinicalTrials.gov Iden- data regarding the role of NIV in reducing the need for tifier NCT04395144, NCT04347941, NCT04350723) may invasive mechanical ventilation or mortality in C-ARF provide further guidance. patients, from small retrospective studies [41, 42]. CPAP was used in small retrospective studies with some ben- High Flow Nasal Oxygen (HFNO) efit in reducing tracheal intubation in mild-to-moderate Expert statement COVID-19-related ARDS [43, 44]. Helmet CPAP is also HFNO therapy should be considered as an alternative used for management of C-ARF and recommended strategy for oxygen support. over HFNO to limit the exposure of healthcare work- HFNO should be used in patients who are unable to ers (HCW) to aerosols [45]. However, the evidence on maintain SpO2 > 90% using oxygen delivery through a effectiveness of helmet CPAP in C-ARF in reducing the venturi mask or may be used in patients with increasing need of tracheal intubation is conflicting [46, 47]. In addi- oxygen requirement. tion, the helmet interface may not be universally avail- HFNO may avoid the need for tracheal intubation and able. Future trials comparing HFNO with helmet CPAP invasive mechanical ventilation in patients with C-ARF. may settle this debate. (ClinicalTrials.gov Identifier NCT04395807). Discussion HFNO and non-invasive ventilation (NIV) [full-face mask Tracheal intubation or nasal mask delivering pressure support plus positive Expert statement end-expiratory pressure (PEEP)] were initially avoided The appropriate triggers for tracheal intubation include in patients with C-ARF due to the concern around infec- altered mental status, hemodynamic instability and fail- tious aerosol generation. However, limited availability of ure to maintain SpO2 > 90% with non-invasive respira- invasive ventilators and ICU beds, favourable experience tory interventions. in small studies and increasing availability of personal protective equipment (PPE) have led to increased use of Discussion non-invasive therapies [33–35]. Patients on non-invasive The decision for tracheal intubation in patients receiving respiratory support need continuous monitoring to avoid non-invasive respiratory support is challenging, requir- any delays in tracheal intubation. A recent clinical prac- ing a fine balance between early intubation and risks tice guideline gave a strong recommendation for the use of invasive mechanical ventilation versus the adverse of HFNO over conventional oxygen therapy in patients effects of delaying intubation. The impact of early versus with acute hypoxemic respiratory failure (AHRF) to delayed tracheal intubation has not been compared in prevent tracheal intubation [36]. Though there has been patients with C-ARF. The decision for tracheal intuba- conflicting evidence regarding the use of HFNO to pre- tion in COVID-19 patients may be best determined using vent invasive mechanical ventilation in C-ARF, experts a combination of factors that include clinical acumen, recommended its use [37–39]. However, robust studies oxygen saturation, dyspnoea and respiratory rate [48, regarding the risk of aerosol dispersion, optimal settings, 49]. Experts recommended the use of clinical criteria to comparison with other non-invasive respiratory supports be preferred over the use of arterial blood gas or imaging and outcomes are lacking in C-ARF patients. findings to determine the need for tracheal intubation. Nasa et al. Crit Care (2021) 25:106 Page 11 of 17 Lung protective ventilation this lack of certainty and may be supported by the rela- Expert statement tive safety demonstrated so far. Clinical experience from Lung protective ventilation (LPV) should be used for around the world over the last year has demonstrated patients with C-ARF on IMV. that it can be difficult to ventilate these patients in the The targets for LPV in C-ARF include tidal volume very acute phase without NMBA, thus the apparent dis- of 4–6 ml/kg of predicted body weight, plateau pres- cordance between the recommendation of the experts sure ≤ 30 cm of H­ 2O and driving pressure ≤ 15 cm of and the literature in non-COVID-19 patients. How- H2O. ever, recent guidelines recommend the use of an NMBA infusion for 48 h in patients with refractory hypoxemia Discussion despite deep sedation to facilitate lung protective ventila- Experts agreed that the COVID-19-related ARDS is clini- tion strategy or prone positioning and/or when there is cally similar to other forms of ARDS; hence, there was a high respiratory drive despite optimal sedation [54, 55]. full agreement for the use of lung protective ventilatory There are no published trials evaluating the use of NMBA strategies (tidal volume 4–6 mL/kg of predicted body on outcomes of ventilated patients with C-ARF. weight and plateau pressure ≤ 30 cm of ­ H2O). Severe hypoxaemia with near normal respiratory system compli- Prone ventilation ance, a combination rarely seen in ARDS, had been noted Expert statement in small studies [6, 7]. However, in large observational Prone position in patients with C-ARF on invasive multicentre studies, the respiratory mechanics of venti- mechanical ventilation should be used for a duration of lated patients with COVID-19-related ARDS were noted 16–24 h per session to improve oxygenation. to be similar to non-COVID-19 ARDS [20–22]. Discussion Recruitment manoeuvres Prone position for ventilated patients with C-ARF was Expert statement strongly suggested by experts, for a duration of 16–24 h Recruitment manoeuvres may be considered only in per session, similar to the indication in non-COVID- selected patients with C-ARF on invasive mechanical 19-related ARDS [28, 53, 56]. ventilation, in view of their potential deleterious effects. Discussion Veno‑Venous extracorporeal membrane oxygenation (V‑V Diffuse alveolar damage, endotheliitis and microthrombi ECMO) in pulmonary microvasculature have been reported in Expert statement small autopsy studies of COVID-19 patients [16–18]. V-V ECMO may be considered in patients with refrac- Microthrombi causing hypoxaemia will not respond to tory hypoxemia on invasive mechanical ventilation, who PEEP or a recruitment manoeuvre. The experts suggested do not respond to other adjuvant therapies. that recruitment manoeuvres, if ever used should be individualised, in view of the potential harmful effects as Discussion seen in non-COVID-19-related ARDS [50, 51]. These recommendations are in agreement with the WHO and extracorporeal life support organisation Neuromuscular blocking agents (NMBA) (ELSO) guidelines for the management of COVID-19 [24, Expert statement 57]. Though higher mortality was reported during initial NMBA may be considered during the early phase of inva- days of the pandemic, there is increasing experience and sive mechanical ventilation in case of patient-ventilator evolving evidence showing favourable outcomes with dyssynchrony. ECMO in COVID-19 patients [58–60]. In a recent meta- analysis, the 90-day mortality was lower in non-COVID- Discussion 19-related ARDS patients on ECMO as compared to Recent meta-analyses have not demonstrated unambigu- conventional ventilation [61]. In the EOLIA trial, the ous benefits on important patient outcomes with the use greatest benefit of V-V ECMO was seen in patients with of NMBA in non-COVID ARDS [52, 53]. It is possible moderate-to-severe ARDS or severe respiratory acido- that the impact of NMBA infusion on mortality depends sis after optimisation of ventilator settings [62]. Experts on the strategy used in the control arm. The strong sug- recommend V-V ECMO for patients with refractory gestion in favour of the use of NMBA by our experts, in hypoxemia when lung protective ventilation and prone case of patient-ventilator dyssynchrony contrasts with ventilation have failed or the latter is contraindicated. Nasa et al. Crit Care (2021) 25:106 Page 12 of 17 Infection control Early mobilisation Expert statement Expert statement Bag mask ventilation, HFNO, NIV, tracheal intubation, Early mobilization may be beneficial in patients on res- open suctioning, bronchoscopy, tracheal extubation and piratory support for C-ARF. tracheostomy may be considered as aerosol-generating procedures in and outside the ICU. Discussion Airborne infection isolation rooms and video laryn- Experts suggested that early mobilisation may be benefi- goscopes may be considered during tracheal intubation; cial in patients with C-ARF receiving respiratory support; a closed suction system should be considered to reduce given the evidence that early mobilisation of ICU patients cross-transmission of SARS-CoV-2 in the ICU. has significant benefits [72]. Discussion Tracheostomy There is limited evidence regarding aerosol-generating Expert statement procedures, or the use of airborne infection isolation The timing of tracheostomy to facilitate weaning from rooms, use of video laryngoscopes during tracheal intu- mechanical ventilation should be the same as in non- bation and closed suction systems to mitigate aerosol COVID-19 patients. generation in COVID-19 patients [35, 63, 64]. Simulation Percutaneous dilatational tracheostomy (PDT) with or studies on aerosol production during tracheal intuba- without guidance (using ultrasound or bronchoscopic) tion and extubation have provided divergent results [65, may be preferred over other techniques. 66]. There is conflicting evidence on aerosol generation with NIV or HFNO [35, 67, 68]. The experts have taken Discussion a conservative approach, labelling procedures as aero- The timing and technique of tracheostomy, due to pos- sol generating, until robust evidence is generated to the sible aerosol generation or dispersion, have generated contrary. intense debate among clinicians [73]. The safe period for performing a tracheostomy in COVID-19 patients is rec- ommended to be 10–21 days after tracheal intubation to Weaning from invasive mechanical ventilation reduce infectious risk. [73]. However, no increased risk of Expert statement infection to healthcare workers was observed, when clini- Weaning should not be delayed, for the threat of the risk cal judgment-based instead of fixed timing tracheostomy of reintubation. was performed with appropriate PPE use [72]. Modifica- A pressure support ventilation trial for 30 min to 2 h tions to tracheostomy techniques are recommended in may be preferred over other weaning strategies. COVID-19 patients to reduce aerosolisation risk [75]. Although surgical tracheostomy was recommended over Discussion PDT, based on experiences from the SARS epidemic, the Weaning and extubation (in particular the strategy use of PDT in COVID-19 patients has not shown any of delaying weaning) are very relevant to COVID-19 increased risk to healthcare workers till date [74]. patients, due to concerns of the increased risk of aero- sol exposure to the healthcare worker, if there is failure Dissensus among the experts on the respiratory of tracheal extubation and need for a reintubation. In management of C‑ARF addition, there are concerns of aerosol generation with The following clinical statements did not achieve the the use of the open T-piece as compared to pressure sup- desired agreement and stability despite several iterative port ventilation. Nevertheless, the experts were strongly Delphi rounds. This reflects existing areas of uncertainty. against delaying extubation in order to potentially reduce There was no agreement among the experts that awake risks of later reintubation, suggesting the use of similar self-proning may prevent the need for invasive mechani- criteria as in non-COVID-19 patients [69]. The recom- cal ventilation. Experts did not recommend the use of mendation regarding the weaning strategy is consistent NIV in all patients with C-ARF as an alternative strat- with recent evidence supporting pressure support ven- egy for oxygen support or to avoid the need for invasive tilation for 30 min over T-piece for two hours, although mechanical ventilation, unlike with HFNO. In addition, this is not universally accepted [70, 71]. the experts did not agree that HFNO produces fewer aer- osols as compared to NIV with face mask. There was disagreement for the use of non-conven- tional modes of mechanical ventilation including airway Nasa et al. Crit Care (2021) 25:106 Page 13 of 17 Table 2 Research priorities in COVID-19-related acute respiratory failure Pathophysiology Exploration of “personalised” respiratory interventions based on phenotypes (using clinical, physiological, biological or radiological criteria) Awake self-proning Optimal technique (such as complete prone or side to side), timing and duration Impact on escalation of respiratory support, tracheal intubation and mortality Effect of combination with HFNO or NIV on outcome measures HFNO Risk of aerosolisation, optimal setting, monitoring and prediction of failure Comparison with NIV/CPAP and weaning strategies Use in moderate-to-severe hypoxemia ­(PaO2/FiO2 less than 200 mm Hg) Impact on outcomes (ICU/hospital length of stay and mortality) NIV (including CPAP) Risk of aerosolisation, monitoring, helmet versus other interfaces Multimodal strategies with HFNO Impact on escalation of respiratory support, outcomes (ICU/hospital length of stay and mortality) Impact of NIV in subset of patients with mixed respiratory failure, cardiogenic pulmonary oedema and COVID-19-re‑ lated ARDS Corticosteroids Effect of timing of initiation, different types, dose, optimal duration, tapering schedule Impact of laboratory biomarkers on timing, dose and duration of corticosteroid Interaction of corticosteroids with other COVID-19 therapeutics such as Remdesivir, Baricitinib, etc Invasive mechanical ventilation Initiation of invasive mechanical ventilation: Optimal timing, triggers and technique with respect to patient and HCW safety Impact of non-conventional ventilation strategies based on respiratory mechanics on outcomes (ICU/hospital length of stay and mortality) Sedation and NMBA: Optimal sedation strategy and monitoring techniques. Timing, duration, technique (continuous versus bolus) and monitoring of NMBA PEEP: Strategy for personalisation and method of selection Fluid management: Restrictive versus liberal. Impact on ARDS phenotypes Assessing fluid responsiveness Weaning and liberation: Optimal timing and strategy. Impact of HFNO or NIV post-extubation. Predictive measures for failure ECMO: Optimal timing and patient selection. Resource planning in the constraints of a pandemic Tracheostomy Optimal timing, strategy for HCWs safety and post-procedure care. Direct effect of SARS-CoV-2 virus on larynx and trachea Infection control Strategy for HCWs safety during aerosol generating procedures in resource limited settings Role of different types of PPE and strategies to optimize their use De-escalation of isolation precautions: time and/or testing based Impact of different interventional strategies on the reduction in aerosolisation Efficacy and safety of tele-ICU or remote monitoring to limit exposure HFNO: high-flow nasal oxygen; NIV: non-invasive ventilation; CPAP: continuous positive airway pressure; ICU: intensive care unit; COVID-19: coronavirus disease 2019; ARDS: acute respiratory distress syndrome; HCW: healthcare worker; NMBA: neuromuscular blocking agent; PEEP: positive end-expiratory pressure; ECMO: extracorporeal membrane oxygenation; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; PPE: personal protective equipment pressure release ventilation and pressure-regulated vol- related to specific chest physiotherapy interventions were ume control. There was no agreement for higher versus not asked, which may be a limitation. A personalised lower PEEP strategy, nor the method of PEEP selection in approach may be required with some of these interven- these patients. Lung hyperinflation has been reported in tions, depending on the patient, phase of illness and the small case series of patients with C-ARF with the use of respiratory mechanics. The benefits of chest physiother- high PEEP [76, 77]. There was disagreement for the effec- apy in ventilated patients with C-ARF are unclear, with tiveness of adjuvant therapies for refractory hypoxaemia limited evidence on the risks of aerosol dispersion of the (inhaled nitric oxide, nebulized prostacyclin, etc.). This virus with some of the therapeutic manoeuvres [79]. likely reflects the lack of any demonstrable benefits with any of the salvage therapies, other than prone ventilation Strengths and limitations [56]. Our work has several strengths. Firstly, our panel There was no agreement on any combination of PPE included a large number of global experts in the field over the other. A Cochrane meta-analysis (24 studies of respiratory failure, with experience in the manage- with 2278 participants) on the role of PPE in prevent- ment of C-ARF and with diverse geographical repre- ing infections among healthcare workers concluded that sentation. Secondly, anonymity of experts and their there was no difference between various types of PPE individual responses were preserved until completion, [78]. There was no agreement on the beneficial effect of to avoid inherent bias during the Delphi process due to chest physiotherapy in patients with C-ARF. Questions Nasa et al. Crit Care (2021) 25:106 Page 14 of 17 dominance and group pressure. Thirdly, we were able Acknowledgements None. to successfully complete the process over five survey rounds, maintaining a tight timeline (one month) despite Authors’ contributions experts being busy during a pandemic, which was essen- The steering committee included PN, SNM, RJ EA, AKK, SG, YJ, DJ, PR and KS. SNM served as moderator of the working group. PN, SNM and RJ contributed tial considering the rapidly evolving evidence. Fourthly, to conception and design of the work, data acquisition, data interpretation we were able to achieve agreement in 73% of our clinical and drafting of the manuscript. EA, AKK, SG, YJ, DJ, PR and KS contributed to statements. design of the work, data acquisition, data interpretation and drafting of the manuscript. PN and RJ did the literature search and data analysis, PN and Our work has limitations. It is difficult to answer ’yes’ SNM prepared the figures. The members of the steering committee did not or ’no’ to some questions, as a personalised approach respond to the survey questionnaires. The experts included were WA, MA, may be required for some clinical interventions. It is also YMA, JB, LJB, AMD, BD, SE, AE, OG, SMG, CG, SJ, GCK, YK, JBL, FRM, MLNGM, JM, AM, MTM, BAM, SM, AM, MM, MN, PKP, PP, JVP, JP, DVP, LP, PS, MJS, MSH, SS, possible that the responses from the experts could have MS, RT, AAU and TW. The experts completed the survey questionnaire in the been influenced by the way they interpreted the state- various rounds of the Delphi process; the result of which was used to draft the ments. The feedback from the experts (allowed in all the expert clinical practice statements. All authors read and approved the final manuscript. rounds) and the stability of the responses should have ensured fidelity of the responses and minimised the risk Funding of responder bias. Secondly, factors such as non-availa- No funding was received for this study. bility of or inadequate experience with some treatment Availability of data and materials modalities and variation in regional guidelines may have Supporting data are available with the corresponding author. influenced the opinions of experts and affected the gen- Ethical approval and consent to participate eration of statements. Thirdly, some aspects of respira- Ethical approval is not applicable for this study. Consent to participate in the tory management, such as extubation to NIV or HFNO study was taken from all experts. to prevent re-intubation, were not included. Consent for publication These expert clinical practice statements will provide Consent for publication was taken from all co-authors. guidance to the clinician at the bedside. However, sev- eral questions regarding the respiratory management of Competing interests EA reports having taken professional fees for lectures from Gilead, Pfizer, C-ARF remain unanswered and new evidence is being Baxter and Alexion. His research group has been supported by Ablynx, Fisher generated at a rapid rate. We have summarized these as & Paykel, Jazz Pharma and MSD, all outside the scope of submitted work. AKK future research priorities in Table 2. reports institutional funding for 2 trials, a randomized Clinical Trial of CLR2.0 Hemofiltration Treatment (C2Rx) in Severe or Critically Ill Adults With COVID- 19 Infection (ClinicalTrials.gov Identifier: NCT04537975) and Blood Volume Assessment in COVID-19 ICU Patients—BVAC19 (ClinicalTrials.gov Identifier: Conclusions NCT04517695). He is site PI for SCCM Discovery Network Viral Infection and Using a Delphi method, an agreement among experts Respiratory Illness Universal Study [VIRUS]: COVID-19 Registry (ClinicalTri‑ als.gov Identifier: NCT04323787) and is a member of American Society of was reached for 27 statements on the respiratory man- Anesthesiologists (ASA) COVID-19 task force. AKK is a key opinion leader and agement of C-ARF, addressing important decisions for consults for Medtronic, Edwards Lifesciences, Philips North America and Zoll patient management in areas where evidence is either Medical, is on the advisory board for Potrero Medical and Retia Medical and receives compensation for his position for the chair of the trial steering com‑ absent or limited. Strong evidence from high-quality clin- mittee for the SILtuximab in Viral ARds (SILVAR) Study (SILVAR) (ClinicalTrials. ical trials is needed to clarify the remaining uncertainties. gov Identifier: NCT04616586) all outside the scope of the submitted work. He While these expert clinical practice statements provide is also funded with a Clinical and Translational Science Institute (CTSI) NIH/ NCTAS KL2 TR001421 award for a trial on continuous postoperative hemody‑ clinical direction with C-ARF, some of these general namic and saturation monitoring. AKK is a founding member of BrainX LLC, a principles may help with the management of other viral collaborative platform for research and development of artificial intelligence pneumonias or future variants of the SARS-CoV-2 strain. technology in critical care and perioperative medicine. YJ is a member of CII Medical Task Force, India and a member of the steering committee for a Phase 3, Prospective, Randomized, Open Label, Comparative, Clinical Study To Evalu‑ Supplementary Information ate Efficacy And Safety Of Ulinastatin Plus Standard-Of-Care Compared To The online version contains supplementary material available at https​://doi. Standard-Of-Care In Treatment Of Acute Respiratory Distress Syndrome (ARDS) org/10.1186/s1305​4-021-03491​-y. In Hospitalized COVID-19 Infection Patients. WAH is a co-chair of COVID-19 surviving sepsis campaign guidelines. MA is a panel member of Surviving Sep‑ sis Campaign. YMA is a co-investigator on COVI-PRONE trial (ClinicalTrials.gov Additional file 1. Search Strategy and Selection Criteria. Identifier: NCT04350723) and is a panel member of Surviving Sepsis Campaign Additional file 2. Details and Results of the Delphi process. CPG. LJB reports grants from Medtronic Covidien, grants and non-financial support from Fisher Paykel, non-financial support from Air Liquide, Sentec, Additional file 3. Survey Report 1. Philips and General Electric (patent), all outside the scope of submitted work. Additional file 4. Survey Report 2. SJ reports receiving consulting fees from Drager, Medtronic, Baxter, Frese‑ nius and Fisher & Paykel, all outside the scope of submitted work. JBL received Additional file 5. Survey Report 3. lectures fees from BD and Zoll (outside the scope: cooling devices), all outside Additional file 6. Survey Report 4. the scope of submitted work. MLNGM is a co-founder, past-President and current Treasurer of WSACS (The Abdominal Compartment Society, http:// www.wsacs​.org). MLNGM is member of the medical advisory Board of Pulsion Nasa et al. Crit Care (2021) 25:106 Page 15 of 17 Medical Systems (part of Getinge group) and Serenno Medical, consults for Academic Health Sciences Centre, Manchester, UK. 37 Sinai Health and the Uni‑ Baxter, BD, BBraun, ConvaTec, Acelity, Spiegelberg and Holtech Medical and versity of Toronto, Toronto, Canada. 38 Assistance Publique - Hôpitaux de Paris, is co-founder of the International Fluid Academy (IFA) which is integrated Hôpitaux Universitaires Henri-Mondor, Service de Medicine Intensive Réani‑ within the not-for-profit charitable organization iMERiT (International Medical mation, and Univ Paris Est Créteil, CARMAS, Créteil, France. 39 Charlotte Maxeke Education and Research Initiative) under the Belgian law, all outside the scope Johannesburg Academic Hospital and Faculty of Health Sciences, University of submitted work. JM reports personal fees (last three years) from Faron, of the Witwatersrand, Johannesburg, South Africa. 40 Cedars‑Sinai Medical Medtronic and Janssen, all outside the scope of submitted work. AM reports Center, Smidt Heart Institute, Los Angeles, USA. 41 University of Michigan, Ann grants from Fischer Paykel, Baxter and Ferring, and personal fees from Air Liq‑ Arbor, USA. 42 San Martino Policlinico Hospital, IRCCS for Oncology and Neu‑ uide, Amomed and Addmedica, all outside the scope of submitted work. MN rosciences, Genoa, Italy. 43 Department of Surgical Sciences and Integrated is an advisor with Avant-Grande Health Inc and receive stock option for this Sciences, University of Genoa, Genoa, Italy. 44 Christian Medical College, Vel‑ role, all outside the submitted work. PKP reports grant funding from NIH for lore, India. 45 Alexandra Hospital and National University Hospital, Singapore, Operation Warp Speed COVID clinical trials and from DoD, Eli Lilly, Bristol Myers Singapore. 46 Alfred Health, and Monash University, Melbourne, Australia. 47 Squibb, ATOX Bio, Marcus Foundation, all outside the scope of submitted Lausanne University Hospital and Lausanne University, Lausanne, Switzer‑ work. She is a council member of Society of Critical Care Medicine. LP reports land. 48 Medical University of Vienna, Vienna, Austria. 49 Amsterdam University lectures fees from Hamilton and Getinge and consultant fees from Löwen‑ Medical Center, Amsterdam, The Netherlands. 50 Mahidol University, Bangkok, stein, all outside the scope of submitted work. MSH reports funding and Thailand. 51 University of Oxford, Oxford, UK. 52 Guy’s and St Thomas’ NHS support by the National Institute for Health Research Clinician Scientist Award Foundation Trust, London, UK. 53 King’s College London, London, UK. 54 Royal (CS-2016–16-011). Also, the views expressed in this publication are those of Brompton Hospital and Chelsea and Westminster Hospital, Imperial College, the author and not necessarily those of the NHS, the National Institute for London, UK. 55 Anesthesia and Intensive Care, AOU Policlinico - San Marco, Health Research or the Department of Health and Social Care. MS reports Catania, Italy. 56 Peninsula Health and Monash University, Melbourne, Australia. 57 paid consultancy, lecture grants: Teleflex Medical (Athlone, Ireland); Verathon Monash University, Melbourne, Australia. 58 Department of Respiratory Medical (Bothell, USA); travel grants, lecture grants: MSD Italy, MSD USA; Medicine, German Centre of Lung Research, Hannover, Germany. 59 Depart‑ Baxter Italy, all outside the scope of submitted work. AAU reports member‑ ment of Anaesthesia, Critical Care and Pain, Tata Memorial Hospital, Homi ship of Management Committee, SPRINT-SARI Australia. TW reports research Bhabha National Institute, Dr. Ernest Borges Road, Parel, Mumbai, India. Grants from DFG, BMBF, EU, WHO, fees for lectures from AstraZeneca, Basilea, Biotest, Bayer, Boehringer, GSK, MSD, Novartis, Pfizer, Roche, Sanofi Aventis, all Received: 29 January 2021 Accepted: 4 February 2021 outside the scope of submitted work. He is a member on advisory Board of AstraZeneca, Basilea, Biotest, Bayer, Boehringer, GSK, Janssens, Novartis, Pfizer, Roche, Sanofi Aventis. SNM reports membership of COVID-19 Surviving Sepsis Campaign (SSC) guidelines committee and being on the steering committee of the COVID Steroid 2 Trial (ClinicalTrials.gov Identifier: NCT04509973) and the References HydrOxychloroquine Prophylaxis Evaluation (HOPE) Trial (CTRI registration No. 1. Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, et al. CTRI/2020/05/025067). All other authors declare no competing interest. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort Author details study. BMJ. 2020;369:m1985. 1 Critical Care Medicine, NMC Speciality Hospital, Dubai, United Arab Emirates. 2. Kim L, Garg S, O’Halloran A, Whitaker M, Pham H, Anderson EJ, et al. 2 Saint-Louis teaching hospital – APHP – and University of Paris, Paris, France. Risk Factors for Intensive Care Unit Admission and In-hospital Mortality 3 Wake Forest University School of Medicine, Winston-Salem, NC and Out‑ among Hospitalized Adults Identified through the U.S. Coronavirus Dis‑ comes Research Consortium, Cleveland, USA. 4 Mahatma Gandhi Medical ease 2019 (COVID-19)-Associated Hospitalization Surveillance Network College and Hospital, Jaipur, India. 5 Narayana Super Speciality Hospital, (COVID-NET). Clin Infect Dis. 2020: ciaa1012. Gurugram, India. 6 Regency Super Speciality Hospital, Lucknow, India. 7 Max 3. European Centre for Disease Prevention and Control (ECDC). COVID-19 Super Speciality Hospital, New Delhi, India. 8 Columbia Asia Referral Hospital, Surveillance Report (Week 44, 2020). https​://covid​19-surve​illan​ce-repor​ Bengaluru, India. 9 Royal Adelaide Hospital and The University of Adelaide, t.ecdc.europ​a.eu Accessed 11 November 2020. Adelaide, Australia. 10 McMaster University, Hamilton, Canada. 11 Fondazi‑ 4. Armstrong RA, Kane AD, Cook TM. Outcomes from intensive care in one Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 12 King Saud Bin patients with COVID-19: a systematic review and meta-analysis of obser‑ Abdulaziz University for Health Sciences and King Abdullah International vational studies. Anaesthesia. 2020;75:1340–9. Medical Research Centre, Riyadh, Saudi Arabia. 13 New York University School 5. Grasselli G, Pesenti A, Cecconi M. Critical care utilization for the COVID-19 of Medicine and Columbia University College of Physicians & Surgeons, New outbreak in Lombardy, Italy: early experience and forecast during an York, USA. 14 Erasmus MC University Medical Center, Rotterdam, The Nether‑ emergency response. JAMA. 2020;323:1545–6. lands. 15 Pontificia Universidad Catolica de Chile, Santiago, Chile. 16 Keenan 6. Gattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L, et al. Research Centre, Li Ka Shing Knowledge Institute, St Michael’s Hospital, COVID-19 pneumonia: different respiratory treatments for different Unity Health Toronto, and University of Toronto, Toronto, Canada. 17 Royal phenotypes? Intensive Care Med. 2020;46:1099–102. Melbourne Hospital and The University of Melbourne, Melbourne, Australia. 7. Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. 18 Peking Union Medical College Hospital, Peking, China. 19 The Shaare Zedek COVID-19 does not lead to a “typical” acute respiratory distress syndrome. Medical Center, Jerusalem, Israel. 20 Hospital Universitario de Getafe, CIBER Am J Respir Crit Care Med. 2020;201:1299–300. de Enfermedades Respiratorias, Madrid, Spain. 21 Mayo Clinic, Maryland, USA. 8. Gattinoni L, Meissner K, Marini JJ. The baby lung and the COVID-19 era. 22 University of Maryland, Maryland, USA. 23 University de Lyon, Lyon, France. Intensive Care Med. 2020;46:1438–40. 24 Institut Mondor de Recherches Biomédicales, Medecine Intensive Réanima‑ 9. Tobin MJ, Laghi F, Jubran A. P-SILI is not justification for intubation of tion Hôpital Edouard Herriot Lyon, and Medecine Intensive Réanimation COVID-19 patients. Ann Intensive Care. 2020;10:105. Hôpital Edouard Herriot Lyon, Créteil, France. 25 Montpellier University Hos‑ 10. Tobin MJ, Laghi F, Jubran A. Caution about early intubation and mechani‑ pital, Montpellier, France. 26 Hôpital Saint‑Éloi, CHU de Montpellier, Phy Med cal ventilation in COVID-19. Ann Intensive Care. 2020;10:78. Exp, Université de Montpellier, Montpellier, France. 27 PSRI Hospital, New Delhi, 11. Fan E, Beitler JR, Brochard L, Calfee CS, Ferguson ND, Slutsky AS, et al. India. 28 Asan Medical Center, University of Ulsan College of Medicine, Seoul, COVID-19-associated acute respiratory distress syndrome: is a different South Korea. 29 Nantes University Hospital, Nantes, France. 30 Federal University approach to management warranted? Lancet Respir Med. 2020;8:816–21. of São Paulo, São Paulo, Brazil. 31 International Fluid Academy, Lovenjoel, 12. Azoulay E, de Waele J, Ferrer R, Staudinger T, Borkowska M, Povoa P, et al. Belgium. 32 Faculty of Engineering, Department of Electronics and Informatics, International variation in the management of severe COVID-19 patients. Vrije Universiteit Brussel (VUB), Brussels, Belgium. 33 Hospital Universitari Sant Crit Care. 2020;24:486. Pau, Barcelona, Spain. 34 University of Maryland School of Medicine, Maryland, 13. Diamond IR, Grant RC, Feldman BM, Pencharz PB, Ling SC, Moore AM, USA. 35 Manchester University NHS Foundation Trust, Manchester, UK. 36 Divi‑ et al. Defining consensus: a systematic review recommends meth‑ sion of Infection, Immunity and Respiratory Medicine, School of Biological odologic criteria for reporting of Delphi studies. J Clin Epidemiol. Sciences, Faculty of Biology Medicine and Health, University of Manchester, 2014;67:401–9. Nasa et al. Crit Care (2021) 25:106 Page 16 of 17 14. Taylor E. We Agree, Don’t We? The Delphi Method for Health Environ‑ 35. Agarwal A, Basmaji J, Muttalib F, Granton D, Chaudhuri D, Chetan D, ments Research. HERD. 2020;13:11–23. et al. High-flow nasal cannula for acute hypoxemic respiratory failure 15. Mason RJ. Pathogenesis of COVID-19 from a cell biology perspective. Eur in patients with COVID-19: systematic reviews of effectiveness and its Respir J. 2020;55:2000607. risks of aerosolization, dispersion, and infection transmission. Can J 16. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel Anaesth. 2020;67:1217–48. AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 36. Rochwerg B, Einav S, Chaudhuri D, Mancebo J, Mauri T, Helviz Y, 2020;395:1417–8. et al. The role for high flow nasal cannula as a respiratory support 17. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, strategy in adults: a clinical practice guideline. Intensive Care Med. et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in 2020;46:2226–37. Covid-19. N Engl J Med. 2020;383:120–8. 37. Vianello A, Arcaro G, Molena B, Turato C, Sukthi A, Guarnieri G, et al. 18. Barton LM, Duval EJ, Stroberg E, Ghosh S, Mukhopadhyay S. COVID-19 High-flow nasal cannula oxygen therapy to treat patients with hypox‑ autopsies, Oklahoma, USA. Am J Clin Pathol. 2020;153:725–33. emic acute respiratory failure consequent to SARS-CoV-2 infection. 19. Kumar R, Lee MH, Mickael C, Kassa B, Pasha Q, Tuder R, et al. Pathophysiol‑ Thorax. 2020;75:998–1000. ogy and potential future therapeutic targets using preclinical models of 38. Xia J, Zhang Y, Ni L, Chen L, Zhou C, Gao C, et al. High-flow nasal COVID-19. ERJ Open Res. 2020;6:00405–2020. oxygen in coronavirus disease 2019 patients with acute hypoxemic 20. Chiumello D, Busana M, Coppola S, Romitti F, Formenti P, Bonifazi M, respiratory failure: a multicenter. Retrospective Cohort Study Crit Care et al. Physiological and quantitative CT-scan characterization of COVID- Med. 2020;48:e1079–86. 19 and typical ARDS: a matched cohort study. Intensive Care Med. 39. Patel M, Gangemi A, Marron R, Chowdhury J, Yousef I, Zheng M, et al. 2020;46:2187–96. Retrospective analysis of high flow nasal therapy in COVID-19-related 21. Grasselli G, Tonetti T, Protti A, Langer T, Girardis M, Bellani G, et al. Patho‑ moderate-to-severe hypoxaemic respiratory failure. BMJ Open Respir physiology of COVID-19-associated acute respiratory distress syndrome: Res. 2020;7:e000650. a multicentre prospective observational study. Lancet Respir Med. 40. Bellani G, Laffey JG, Pham T, Madotto F, Fan E, Brochard L, et al. Nonin‑ 2020;8:1201–8. vasive ventilation of patients with acute respiratory distress syndrome 22. Ferrando C, Suarez-Sipmann F, Mellado-Artigas R, Hernández M, Gea A, insights from the LUNG SAFE study. Am J Respir Crit Care Med. Arruti E, et al. Clinical features, ventilatory management, and outcome of 2017;195:67–77. ARDS caused by COVID-19 are similar to other causes of ARDS. Intensive 41. Belenguer-Muncharaz A, Hernández-Garcés H. Failure of non- Care Med. 2020;46:2200–11. invasive ventilation after use of high-flow oxygen therapy in 23. Grieco DL, Bongiovanni F, Chen L, Menga LS, Cutuli SL, Pintaudi G, et al. patients with SARS-Coronavirus-2 pneumonia. Med Intensiva. Respiratory physiology of COVID-19-induced respiratory failure com‑ 2020;S0210–5691(20):30220–5. pared to ARDS of other etiologies. Crit Care. 2020;24:529. 42. Mukhtar A, Lotfy A, Hasanin A, El-Hefnawy I, El Adawy A. Outcome of 24. WHO COVID-19 clinical management: living guidance COVID-19. Living non-invasive ventilation in COVID-19 critically ill patients: a Retrospective guidance. Updated 25 January 2021. https​://apps.who.int/iris/handl​ observational Study. Anaesth Crit Care Pain Med. 2020;39:579–80. e/10665​/33888​2 Accessed 27 January 2021. 43. Vitacca M, Nava S, Santus P, Harari S. Early consensus management for 25. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham non-ICU acute respiratory failure SARS-CoV-2 emergency in Italy: from M, Bell JL, Linsell L, et al. Dexamethasone in hospitalized patients with ward to trenches. Eur Respir J. 2020;55:2000632. Covid-19—preliminary report. N Engl J Med Jul. 2020: NEJMoa2021436. 44. Pagano A, Porta G, Bosso G, Allegorico E, Serra C, Dello Vicario F, et al. 26. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Non-invasive CPAP in mild and moderate ARDS secondary to SARS- Group, Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, Angus DC, et al. CoV-2. Respir Physiol Neurobiol. 2020;280:103489. Association between administration of systemic corticosteroids and mor‑ 45. Ashish A, Unsworth A, Martindale J, Sundar R, Kavuri K, Sedda L, et al. tality among critically ill patients with COVID-19: a meta-analysis. JAMA. CPAP management of COVID-19 respiratory failure: a first quantitative 2020;324:1–13. analysis from an inpatient service evaluation. BMJ Open Respir Res. 27. Siemieniuk R, Rochwerg B, Agoritsas T, Lamontagne F, Leo YS, Mac‑ 2020;7(1):e000692. donald H, et al. A living WHO guideline on drugs for covid-19. BMJ. 46. Aliberti S, Radovanovic D, Billi F, Sotgiu G, Costanzo M, Pilocane T, Saderi 2020;370:m3379. L, et al. Helmet CPAP treatment in patients with COVID-19 pneumonia: a 28. Guérin C, Reignier J, Richard J-C, Beuret P, Gacouin A, Boulain T, et al. multicentre cohort study. Eur Respir J. 2020;56:2001935. Prone positioning in severe acute respiratory distress syndrome. N Engl J 47. Ashish A, Unsworth A, Martindale J, Sundar R, Kavuri K, Sedda L, et al. Med. 2013;368:2159–68. CPAP management of COVID-19 respiratory failure: a first quantitative 29. Ding L, Wang L, Ma W, He H. Efficacy and safety of early prone positioning analysis from an inpatient service evaluation. BMJ Open Respir Res. combined with HFNC or NIV in moderate to severe ARDS: a multi-center 2020;7:e000692. prospective cohort study. Crit Care. 2020;24:28. 48. Wei H, Jiang B, Behringer EC, Hofmeyr R, Myatra SN, Wong DT, et al. 30. Coppo A, Bellani G, Winterton D, Di Pierro M, Soria A, Faverio P, et al. Fea‑ Controversies in airway management of COVID-19 patients: updated sibility and physiological effects of prone positioning in non-intubated information and international expert consensus recommendations. Br J patients with acute respiratory failure due to COVID-19 (PRON-COVID): a Anaesth. 2021;126:361–6. prospective cohort study. Lancet Respir Med. 2020;8:765–74. 49. Tobin MJ. Basing respiratory management of COVID-19 on physiological 31. Ferrando C, Mellado-Artigas R, Gea A, Arruti E, Aldecoa C, Adalia R, et al. principles. Am J Respir Crit Care Med. 2020;201:1319–20. Awake prone positioning does not reduce the risk of intubation in 50. Pensier J, de Jong A, Hajjej Z, Molinari N, Carr J, Belafia F, et al. Effect of COVID-19 treated with high-flow nasal oxygen therapy: a multicenter, lung recruitment maneuver on oxygenation, physiological parameters adjusted cohort study. Crit Care. 2020;24:597. and mortality in acute respiratory distress syndrome patients: a system‑ 32. Padrão EMH, Valente FS, Besen BAMP, Rahhal H, Mesquita PS, de Alencar atic review and meta-analysis. Intensive Care Med. 2019;45:1691–702. JCG, et al. Awake prone positioning in COVID-19 hypoxemic respiratory 51. Papazian L, Aubron C, Brochard L, Chiche JD, Combes A, Dreyfuss D, et al. failure: exploratory findings in a single-center retrospective cohort study. Formal guidelines: management of acute respiratory distress syndrome. Acad Emerg Med. 2020;27:1249–59. Ann Intensive Care. 2019;9:69. 33. NHS England. Guidance for the role and use of non-invasive respiratory 52. Ho ATN, Patolia S, Guervilly C. Neuromuscular blockade in acute support in adult patients with COVID19 (confirmed or suspected) 6 April respiratory distress syndrome: a systematic review and meta-analysis of 2020, Version 3. https​://www.engla​nd.nhs.uk/coron​aviru​s/wp-conte​nt/ randomized controlled trials. J Intensive Care. 2020;8:12. uploa​ds/sites​/52/2020/03/speci​alty-guide​-NIV-respi​rator​y-suppo​rt-and- 53. Tarazan N, Alshehri M, Sharif S, Al Duhailib Z, Møller MH, Belley-Cote coron​aviru​s-v3.pdf. Accessed 7 October 2020. E, et al. Neuromuscular blocking agents in acute respiratory distress 34. Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviv‑ syndrome: updated systematic review and meta-analysis of randomized ing Sepsis Campaign: guidelines on the management of critically ill trials. Intensive Care Med Exp. 2020;8:61. adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 54. Hraiech S, Yoshida T, Annane D, Duggal A, Fanelli V, Gacouin A, et al. 2020;46:854–87. Myorelaxants in ARDS patients. Intensive Care Med. 2020;46:2357–72. Nasa et al. Crit Care (2021) 25:106 Page 17 of 17 55. Alhazzani W, Belley-Cote E, Møller MH, Angus DC, Papazian L, Arabi YM, 69. Fan E, Zakhary B, Amaral A, McCannon J, Girard TD, Morris PE, et al. Libera‑ et al. Neuromuscular blockade in patients with ARDS: a rapid practice tion from mechanical ventilation in critically ill adults. An official ATS/ guideline. Intensive Care Med. 2020;46:1977–86. ACCP clinical practice guideline. Ann Am Thorac Soc. 2017;14:441–3. 56. Cherian SV, Kumar A, Akasapu K, Ashton RW, Aparnath M, Malhotra 70. Subirà C, Hernández G, Vázquez A, Rodríguez-García R, González-Castro A, A. Salvage therapies for refractory hypoxemia in ARDS. Respir Med. García C, et al. Effect of pressure support vs T-piece ventilation strategies 2018;141:150–8. during spontaneous breathing trials on successful extubation among 57. ELSO. COVID-19 registry dashboard. https​://www.elso.org/Regis​try/FullC​ patients receiving mechanical ventilation: a randomized clinical trial. OVID1​9Regi​stryD​ashbo​ard.aspx. Accessed 9 October 2020. JAMA. 2019;321:2175–82. 58. Lorusso R, Combes A, Coco VL, De Piero ME, Belohlavek J. ECMO for 71. Goligher EC, Detsky ME, Sklar MC, Campbell VT, Greco P, Amaral ACKB, COVID-19 patients in Europe and Israel. Intensive Care Med. 2021. https​:// et al. Rethinking inspiratory pressure augmentation in spontaneous doi.org/10.1007/s0013​4-020-06272​-3. breathing trials. Chest. 2017;151:1399–400. 59. Barbaro RP, MacLaren G, Boonstra PS, Iwashyna TJ, Slutsky AS, Fan E, et al. 72. Tipping CJ, Harrold M, Holland A, Romero L, Nisbet T, Hodgson CL. The Extracorporeal membrane oxygenation support in COVID-19: an inter‑ effects of active mobilisation and rehabilitation in ICU on mortality and national cohort study of the Extracorporeal Life Support Organization function: a systematic review. Intensive Care Med. 2017;43:171–83. registry. Lancet. 2020;396:1071–8. 73. McGrath BA, Brenner MJ, Warrillow SJ, Pandian V, Arora A, Cameron TS, 60. Schmidt M, Hajage D, Lebreton G, Monsel A, Voiriot G, Levy D, et al. Extra‑ et al. Tracheostomy in the COVID-19 era: global and multidisciplinary corporeal membrane oxygenation for severe acute respiratory distress guidance. Lancet Respir Med. 2020;8:717–25. syndrome associated with COVID-19: a retrospective cohort study. Lancet 74. McGrath BA, Brenner MJ, Warrillow SJ. Tracheostomy for COVID-19: busi‑ Respir Med. 2020;8:1121–31. ness as usual? Br J Anaesth. 2020;125:867–71. 61. Combes A, Peek GJ, Hajage D, Hardy P, Abrams D, Schmidt M, et al. ECMO 75. Avilés-Jurado FX, Prieto-Alhambra D, González-Sánchez N, de Ossó J, for severe ARDS: systematic review and individual patient data meta- Arancibia C, Rojas-Lechuga MJ, Ruiz-Sevilla L, et al. Timing, complications, analysis. Intensive Care Med. 2020;46:2048–57. and safety of tracheotomy in critically ill patients with COVID-19. JAMA 62. Combes A, Hajage D, Capellier G, Demoule A, Lavoué S, Guervilly C, et al. Otolaryngol Head Neck Surg. 2020;147:1–8. Extracorporeal membrane oxygenation for severe acute respiratory 76. Roesthuis L, van den Berg M, van der Hoeven H. Advanced respiratory distress syndrome. N Engl J Med. 2018;378:1965–75. monitoring in COVID-19 patients: use less PEEP! Crit Care. 2020;24:230. 63. De Jong A, Pardo E, Rolle A, Bodin-Lario S, Pouzeratte Y, Jaber S. Airway 77. Schultz MJ. High versus low PEEP in non-recruitable collapsed lung tis‑ management for COVID-19: a move towards universal videolaryngo‑ sue: possible implications for patients with COVID-19. Lancet Respir Med. scope? Lancet Respir Med. 2020;8:555. 2020;8:e44. 64. Ahn JY, An S, Sohn Y, Cho Y, Hyun JH, Baek YJ, et al. Environmental con‑ 78. Verbeek JH, Rajamaki B, Ijaz S, Tikka C, Ruotsalainen JH, Edmond MB, tamination in the isolation rooms of COVID-19 patients with severe pneu‑ et al. Personal protective equipment for preventing highly infectious monia requiring mechanical ventilation or high-flow oxygen therapy. J diseases due to exposure to contaminated body fluids in healthcare staff. Hosp Infect. 2020;106:570–6. Cochrane Database Syst Rev. 2019;7:CD011621. 65. Brown J, Gregson FKA, Shrimpton A, Cook TM, Bzdek BR, Reid JP, et al. A 79. Lazzeri M, Lanza A, Bellini R, Bellofiore A, Cecchetto S, Colombo A, et al. quantitative evaluation of aerosol generation during tracheal intubation Respiratory physiotherapy in patients with COVID-19 infection in acute and extubation. Anaesthesia. 2021;76:174–81. setting: a Position Paper of the Italian Association of Respiratory Physi‑ 66. Ward JD, Phan TD, Nguyen LV, Wynne DD, Scott DA, Clinical Aerosolisation otherapists (ARIR). Monaldi Arch Chest Dis. 2020. https​://doi.org/10.4081/ Study Group. Aerosolisation during tracheal intubation and extubation in monal​di.2020.1285. an operating theatre setting. Anaesthesia. 2021;76:182–8. 67. Haymet A, Bassi GL, Fraser JF. Airborne spread of SARS-CoV-2 while using high-flow nasal cannula oxygen therapy: myth or reality? Intensive Care Publisher’s Note Med. 2020;46:2248–51. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 68. Hui DS, Chow BK, Lo T, Sang OTY, Ko FW, Ng SS, et al. Exhaled air disper‑ lished maps and institutional affiliations. sion during high-flow nasal cannula therapy versus CPAP via different masks. Eur Respir J. 2019;53:1802339. Ready to submit your research ? Choose BMC and benefit from: • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations • maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions