Expert consensus statements for the management of COVID-19-related acute respiratory failure using a Delphi method

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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 ( χ ²) 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 corticosteroids 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 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 decisions for patient management in areas where evidence is either absent or limited.

Trial registration: The study was registered with Clinical trials.gov Identifier: NCT04534569.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13054-021-03491-y.

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Most cited references 72

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Endothelial cell infection and endotheliitis in COVID-19

Zsuzsanna Varga, Andreas J. Flammer, Peter Steiger … (2020)

Cardiovascular complications are rapidly emerging as a key threat in coronavirus disease 2019 (COVID-19) in addition to respiratory disease. The mechanisms underlying the disproportionate effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities, however, remain incompletely understood.1, 2 SARS-CoV-2 infects the host using the angiotensin converting enzyme 2 (ACE2) receptor, which is expressed in several organs, including the lung, heart, kidney, and intestine. ACE2 receptors are also expressed by endothelial cells. 3 Whether vascular derangements in COVID-19 are due to endothelial cell involvement by the virus is currently unknown. Intriguingly, SARS-CoV-2 can directly infect engineered human blood vessel organoids in vitro. 4 Here we demonstrate endothelial cell involvement across vascular beds of different organs in a series of patients with COVID-19 (further case details are provided in the appendix). Patient 1 was a male renal transplant recipient, aged 71 years, with coronary artery disease and arterial hypertension. The patient's condition deteriorated following COVID-19 diagnosis, and he required mechanical ventilation. Multisystem organ failure occurred, and the patient died on day 8. Post-mortem analysis of the transplanted kidney by electron microscopy revealed viral inclusion structures in endothelial cells (figure A, B ). In histological analyses, we found an accumulation of inflammatory cells associated with endothelium, as well as apoptotic bodies, in the heart, the small bowel (figure C) and lung (figure D). An accumulation of mononuclear cells was found in the lung, and most small lung vessels appeared congested. Figure Pathology of endothelial cell dysfunction in COVID-19 (A, B) Electron microscopy of kidney tissue shows viral inclusion bodies in a peritubular space and viral particles in endothelial cells of the glomerular capillary loops. Aggregates of viral particles (arrow) appear with dense circular surface and lucid centre. The asterisk in panel B marks peritubular space consistent with capillary containing viral particles. The inset in panel B shows the glomerular basement membrane with endothelial cell and a viral particle (arrow; about 150 nm in diameter). (C) Small bowel resection specimen of patient 3, stained with haematoxylin and eosin. Arrows point to dominant mononuclear cell infiltrates within the intima along the lumen of many vessels. The inset of panel C shows an immunohistochemical staining of caspase 3 in small bowel specimens from serial section of tissue described in panel D. Staining patterns were consistent with apoptosis of endothelial cells and mononuclear cells observed in the haematoxylin-eosin-stained sections, indicating that apoptosis is induced in a substantial proportion of these cells. (D) Post-mortem lung specimen stained with haematoxylin and eosin showed thickened lung septa, including a large arterial vessel with mononuclear and neutrophilic infiltration (arrow in upper inset). The lower inset shows an immunohistochemical staining of caspase 3 on the same lung specimen; these staining patterns were consistent with apoptosis of endothelial cells and mononuclear cells observed in the haematoxylin-eosin-stained sections. COVID-19=coronavirus disease 2019. Patient 2 was a woman, aged 58 years, with diabetes, arterial hypertension, and obesity. She developed progressive respiratory failure due to COVID-19 and subsequently developed multi-organ failure and needed renal replacement therapy. On day 16, mesenteric ischaemia prompted removal of necrotic small intestine. Circulatory failure occurred in the setting of right heart failure consequent to an ST-segment elevation myocardial infarction, and cardiac arrest resulted in death. Post-mortem histology revealed lymphocytic endotheliitis in lung, heart, kidney, and liver as well as liver cell necrosis. We found histological evidence of myocardial infarction but no sign of lymphocytic myocarditis. Histology of the small intestine showed endotheliitis (endothelialitis) of the submucosal vessels. Patient 3 was a man, aged 69 years, with hypertension who developed respiratory failure as a result of COVID-19 and required mechanical ventilation. Echocardiography showed reduced left ventricular ejection fraction. Circulatory collapse ensued with mesenteric ischaemia, and small intestine resection was performed, but the patient survived. Histology of the small intestine resection revealed prominent endotheliitis of the submucosal vessels and apoptotic bodies (figure C). We found evidence of direct viral infection of the endothelial cell and diffuse endothelial inflammation. Although the virus uses ACE2 receptor expressed by pneumocytes in the epithelial alveolar lining to infect the host, thereby causing lung injury, the ACE2 receptor is also widely expressed on endothelial cells, which traverse multiple organs. 3 Recruitment of immune cells, either by direct viral infection of the endothelium or immune-mediated, can result in widespread endothelial dysfunction associated with apoptosis (figure D). The vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homoeostasis. 5 Endothelial dysfunction is a principal determinant of microvascular dysfunction by shifting the vascular equilibrium towards more vasoconstriction with subsequent organ ischaemia, inflammation with associated tissue oedema, and a pro-coagulant state. 6 Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with presence of viral bodies) and of the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19. COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins.7, 8, 9, 10, 11 This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction, which is associated with male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19.

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Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

Maximilian Ackermann, Stijn Verleden, Mark Kuehnel … (2020)

Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19.

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Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study

Annemarie Docherty, Ewen Harrison, Christopher A Green … (2020)

Abstract Objective To characterise the clinical features of patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United Kingdom during the growth phase of the first wave of this outbreak who were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study, and to explore risk factors associated with mortality in hospital. Design Prospective observational cohort study with rapid data gathering and near real time analysis. Setting 208 acute care hospitals in England, Wales, and Scotland between 6 February and 19 April 2020. A case report form developed by ISARIC and WHO was used to collect clinical data. A minimal follow-up time of two weeks (to 3 May 2020) allowed most patients to complete their hospital admission. Participants 20 133 hospital inpatients with covid-19. Main outcome measures Admission to critical care (high dependency unit or intensive care unit) and mortality in hospital. Results The median age of patients admitted to hospital with covid-19, or with a diagnosis of covid-19 made in hospital, was 73 years (interquartile range 58-82, range 0-104). More men were admitted than women (men 60%, n=12 068; women 40%, n=8065). The median duration of symptoms before admission was 4 days (interquartile range 1-8). The commonest comorbidities were chronic cardiac disease (31%, 5469/17 702), uncomplicated diabetes (21%, 3650/17 599), non-asthmatic chronic pulmonary disease (18%, 3128/17 634), and chronic kidney disease (16%, 2830/17 506); 23% (4161/18 525) had no reported major comorbidity. Overall, 41% (8199/20 133) of patients were discharged alive, 26% (5165/20 133) died, and 34% (6769/20 133) continued to receive care at the reporting date. 17% (3001/18 183) required admission to high dependency or intensive care units; of these, 28% (826/3001) were discharged alive, 32% (958/3001) died, and 41% (1217/3001) continued to receive care at the reporting date. Of those receiving mechanical ventilation, 17% (276/1658) were discharged alive, 37% (618/1658) died, and 46% (764/1658) remained in hospital. Increasing age, male sex, and comorbidities including chronic cardiac disease, non-asthmatic chronic pulmonary disease, chronic kidney disease, liver disease and obesity were associated with higher mortality in hospital. Conclusions ISARIC WHO CCP-UK is a large prospective cohort study of patients in hospital with covid-19. The study continues to enrol at the time of this report. In study participants, mortality was high, independent risk factors were increasing age, male sex, and chronic comorbidity, including obesity. This study has shown the importance of pandemic preparedness and the need to maintain readiness to launch research studies in response to outbreaks. Study registration ISRCTN66726260.

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Author and article information

Contributors

Sheila N. Myatra:

ORCID: http://orcid.org/0000-0001-6761-163X

sheila150@hotmail.com

Journal

Journal ID (nlm-ta): Crit Care

Title: Critical Care

Publisher: BioMed Central (London )

ISSN (Print): 1364-8535

ISSN (Electronic): 1466-609X

Publication date (Electronic): 16 March 2021

Publication date PMC-release: 16 March 2021

Publication date Collection: 2021

Volume: 25

Electronic Location Identifier: 106

Affiliations

[1 ]Critical Care Medicine, NMC Speciality Hospital, Dubai, United Arab Emirates

[2 ]GRID grid.508487.6, ISNI 0000 0004 7885 7602, Saint-Louis teaching hospital – APHP – and University of Paris, ; Paris, France

[3 ]GRID grid.241167.7, ISNI 0000 0001 2185 3318, Wake Forest University School of Medicine, Winston-Salem, NC and Outcomes Research Consortium , ; Cleveland, USA

[4 ]Mahatma Gandhi Medical College and Hospital, Jaipur, India

[5 ]Narayana Super Speciality Hospital, Gurugram, India

[6 ]Regency Super Speciality Hospital, Lucknow, India

[7 ]GRID grid.459746.d, ISNI 0000 0004 1805 869X, Max Super Speciality Hospital, ; New Delhi, India

[8 ]GRID grid.492708.0, Columbia Asia Referral Hospital, ; Bengaluru, India

[9 ]GRID grid.416075.1, ISNI 0000 0004 0367 1221, Royal Adelaide Hospital and The University of Adelaide, ; Adelaide, Australia

[10 ]GRID grid.25073.33, ISNI 0000 0004 1936 8227, McMaster University, ; Hamilton, Canada

[11 ]GRID grid.414603.4, Fondazione Policlinico Universitario A. Gemelli IRCCS, ; Rome, Italy

[12 ]GRID grid.412149.b, ISNI 0000 0004 0608 0662, King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Centre, ; Riyadh, Saudi Arabia

[13 ]GRID grid.137628.9, ISNI 0000 0004 1936 8753, New York University School of Medicine and Columbia University College of Physicians & Surgeons, ; New York, USA

[14 ]GRID grid.5645.2, ISNI 000000040459992X, Erasmus MC University Medical Center, ; Rotterdam, The Netherlands

[15 ]GRID grid.7870.8, ISNI 0000 0001 2157 0406, Pontificia Universidad Catolica de Chile, ; Santiago, Chile

[16 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael’s Hospital, Unity Health Toronto, and University of Toronto, ; Toronto, Canada

[17 ]GRID grid.416153.4, ISNI 0000 0004 0624 1200, Royal Melbourne Hospital and The University of Melbourne, ; Melbourne, Australia

[18 ]GRID grid.413106.1, ISNI 0000 0000 9889 6335, Peking Union Medical College Hospital, ; Peking, China

[19 ]The Shaare Zedek Medical Center, Jerusalem, Israel

[20 ]GRID grid.413448.e, ISNI 0000 0000 9314 1427, Hospital Universitario de Getafe, CIBER de Enfermedades Respiratorias, ; Madrid, Spain

[21 ]Mayo Clinic, Maryland, USA

[22 ]GRID grid.410443.6, ISNI 0000 0004 0370 3414, University of Maryland, ; Maryland, USA

[23 ]GRID grid.25697.3f, ISNI 0000 0001 2172 4233, University de Lyon, ; Lyon, France

[24 ]Institut Mondor de Recherches Biomédicales, Medecine Intensive Réanimation Hôpital Edouard Herriot Lyon, and Medecine Intensive Réanimation Hôpital Edouard Herriot Lyon, Créteil, France

[25 ]GRID grid.157868.5, ISNI 0000 0000 9961 060X, Montpellier University Hospital, ; Montpellier, France

[26 ]GRID grid.121334.6, ISNI 0000 0001 2097 0141, Hôpital Saint-Éloi, CHU de Montpellier, Phy Med Exp, , Université de Montpellier, ; Montpellier, France

[27 ]GRID grid.418817.3, ISNI 0000 0004 1800 339X, PSRI Hospital, ; New Delhi, India

[28 ]GRID grid.267370.7, ISNI 0000 0004 0533 4667, Asan Medical Center, , University of Ulsan College of Medicine, ; Seoul, South Korea

[29 ]GRID grid.277151.7, ISNI 0000 0004 0472 0371, Nantes University Hospital, ; Nantes, France

[30 ]GRID grid.411249.b, ISNI 0000 0001 0514 7202, Federal University of São Paulo, ; São Paulo, Brazil

[31 ]International Fluid Academy, Lovenjoel, Belgium

[32 ]GRID grid.8767.e, ISNI 0000 0001 2290 8069, Faculty of Engineering, Department of Electronics and Informatics, Vrije Universiteit Brussel (VUB), ; Brussels, Belgium

[33 ]GRID grid.413396.a, ISNI 0000 0004 1768 8905, Hospital Universitari Sant Pau, ; Barcelona, Spain

[34 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, University of Maryland School of Medicine, ; Maryland, USA

[35 ]GRID grid.498924.a, Manchester University NHS Foundation Trust, ; Manchester, UK

[36 ]GRID grid.5379.8, ISNI 0000000121662407, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, , University of Manchester, Academic Health Sciences Centre, ; Manchester, UK

[37 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Sinai Health and the University of Toronto, ; Toronto, Canada

[38 ]GRID grid.412116.1, ISNI 0000 0001 2292 1474, Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Henri-Mondor, Service de Medicine Intensive Réanimation, and Univ Paris Est Créteil, CARMAS, ; Créteil, France

[39 ]GRID grid.11951.3d, ISNI 0000 0004 1937 1135, Charlotte Maxeke Johannesburg Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand, ; Johannesburg, South Africa

[40 ]GRID grid.50956.3f, ISNI 0000 0001 2152 9905, Cedars-Sinai Medical Center, , Smidt Heart Institute, ; Los Angeles, USA

[41 ]GRID grid.214458.e, ISNI 0000000086837370, University of Michigan, ; Ann Arbor, USA

[42 ]San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences , Genoa, Italy

[43 ]GRID grid.5606.5, ISNI 0000 0001 2151 3065, Department of Surgical Sciences and Integrated Sciences, , University of Genoa , ; Genoa, Italy

[44 ]GRID grid.11586.3b, ISNI 0000 0004 1767 8969, Christian Medical College, ; Vellore, India

[45 ]GRID grid.412106.0, ISNI 0000 0004 0621 9599, Alexandra Hospital and National University Hospital, ; Singapore, Singapore

[46 ]GRID grid.1002.3, ISNI 0000 0004 1936 7857, Alfred Health, and Monash University, ; Melbourne, Australia

[47 ]GRID grid.8515.9, ISNI 0000 0001 0423 4662, Lausanne University Hospital and Lausanne University, ; Lausanne, Switzerland

[48 ]GRID grid.22937.3d, ISNI 0000 0000 9259 8492, Medical University of Vienna, ; Vienna, Austria

[49 ]Amsterdam University Medical Center, Amsterdam, The Netherlands

[50 ]GRID grid.10223.32, ISNI 0000 0004 1937 0490, Mahidol University, ; Bangkok, Thailand

[51 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, University of Oxford, ; Oxford, UK

[52 ]GRID grid.420545.2, Guy’s and St Thomas’ NHS Foundation Trust, ; London, UK

[53 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, King’s College London, ; London, UK

[54 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Royal Brompton Hospital and Chelsea and Westminster Hospital, Imperial College, ; London, UK

[55 ]Anesthesia and Intensive Care , AOU Policlinico - San Marco, Catania, Italy

[56 ]Peninsula Health and Monash University, Melbourne, Australia

[57 ]GRID grid.1002.3, ISNI 0000 0004 1936 7857, Monash University, ; Melbourne, Australia

[58 ]Department of Respiratory Medicine, German Centre of Lung Research, Hannover, Germany

[59 ]GRID grid.410871.b, ISNI 0000 0004 1769 5793, Department of Anaesthesia, Critical Care and Pain, , Tata Memorial Hospital, Homi Bhabha National Institute, ; Dr. Ernest Borges Road, Parel, Mumbai India

Author information

Sheila N. Myatra http://orcid.org/0000-0001-6761-163X

Article

Publisher ID: 3491

DOI: 10.1186/s13054-021-03491-y

PMC ID: 7962430

PubMed ID: 33726819

SO-VID: e8d99033-dee4-4341-a4b0-df473f1249d1

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Open AccessThis 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://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 29 January 2021

Date accepted : 4 February 2021

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ScienceOpen disciplines: Emergency medicine & Trauma

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

Data availability:

ScienceOpen disciplines: Emergency medicine & Trauma

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

Expert consensus statements for the management of COVID-19-related acute respiratory failure using a Delphi method

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Novel Coronavirus Disease COVID-19

Most cited references 72

Endothelial cell infection and endotheliitis in COVID-19

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study

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