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Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)

Identifieur interne : 000403 ( Pmc/Corpus ); précédent : 000402; suivant : 000404

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)

Auteurs : Waleed Alhazzani ; Morten Hylander M Ller ; Yaseen M. Arabi ; Mark Loeb ; Michelle Ng Gong ; Eddy Fan ; Simon Oczkowski ; Mitchell M. Levy ; Lennie Derde ; Amy Dzierba ; Bin Du ; Michael Aboodi ; Hannah Wunsch ; Maurizio Cecconi ; Younsuck Koh ; Daniel S. Chertow ; Kathryn Maitland ; Fayez Alshamsi ; Emilie Belley-Cote ; Massimiliano Greco ; Matthew Laundy ; Jill S. Morgan ; Jozef Kesecioglu ; Allison Mcgeer ; Leonard Mermel ; Manoj J. Mammen ; Paul E. Alexander ; Amy Arrington ; John E. Centofanti ; Giuseppe Citerio ; Bandar Baw ; Ziad A. Memish ; Naomi Hammond ; Frederick G. Hayden ; Laura Evans ; Andrew Rhodes

Source :

RBID : PMC:7101866

Abstract

Background

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed.

Methods

We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations.

Results

The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which 4 are best practice statements, 9 are strong recommendations, and 35 are weak recommendations. No recommendation was provided for 6 questions. The topics were: (1) infection control, (2) laboratory diagnosis and specimens, (3) hemodynamic support, (4) ventilatory support, and (5) COVID-19 therapy.

Conclusion

The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new recommendations in further releases of these guidelines.

Electronic supplementary material

The online version of this article (10.1007/s00134-020-06022-5) contains supplementary material, which is available to authorized users.


Url:
DOI: 10.1007/s00134-020-06022-5
PubMed: 32222812
PubMed Central: 7101866

Links to Exploration step

PMC:7101866

Le document en format XML

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Hamilton, Canada</nlm:aff>
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Milan, Italy</nlm:aff>
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Monza, Italy</nlm:aff>
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Hamilton, Canada</nlm:aff>
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Riyadh, Saudi Arabia</nlm:aff>
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Riyadh, Kingdom of Saudi Arabia</nlm:aff>
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<institution>The George Institute for Global Health and UNSW,</institution>
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Sydney, Australia</nlm:aff>
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<institution>Royal North Shore Hospital,</institution>
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Sydney, Australia</nlm:aff>
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Charlottesville, VA USA</nlm:aff>
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<institution>University of Washington,</institution>
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Seattle, USA</nlm:aff>
</affiliation>
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London, UK</nlm:aff>
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Hamilton, Canada</nlm:aff>
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Hamilton, Canada</nlm:aff>
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<name sortKey="M Ller, Morten Hylander" sort="M Ller, Morten Hylander" uniqKey="M Ller M" first="Morten Hylander" last="M Ller">Morten Hylander M Ller</name>
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4131 Copenhagen, Denmark</nlm:aff>
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<institution>Intensive Care Department, Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences,</institution>
<institution>King Abdullah International Medical Research Center,</institution>
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Riyadh, Kingdom of Saudi Arabia</nlm:aff>
</affiliation>
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Hamilton, Canada</nlm:aff>
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<institution>McMaster University,</institution>
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Hamilton, Canada</nlm:aff>
</affiliation>
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<author>
<name sortKey="Gong, Michelle Ng" sort="Gong, Michelle Ng" uniqKey="Gong M" first="Michelle Ng" last="Gong">Michelle Ng Gong</name>
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<nlm:aff id="Aff6">
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<institution>Montefiore Healthcare System/Albert Einstein College of Medicine,</institution>
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Bronx, NY USA</nlm:aff>
</affiliation>
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<name sortKey="Fan, Eddy" sort="Fan, Eddy" uniqKey="Fan E" first="Eddy" last="Fan">Eddy Fan</name>
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<nlm:aff id="Aff7">
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<institution>Interdepartmental Division of Critical Care Medicine, Institute of Health Policy, Management and Evaluation,</institution>
<institution>University of Toronto,</institution>
</institution-wrap>
Toronto, Canada</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Oczkowski, Simon" sort="Oczkowski, Simon" uniqKey="Oczkowski S" first="Simon" last="Oczkowski">Simon Oczkowski</name>
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<nlm:aff id="Aff1">
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Hamilton, Canada</nlm:aff>
</affiliation>
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<nlm:aff id="Aff2">
<institution-wrap>
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<institution>Department of Health Research Methods, Evidence, and Impact,</institution>
<institution>McMaster University,</institution>
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Hamilton, Canada</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Levy, Mitchell M" sort="Levy, Mitchell M" uniqKey="Levy M" first="Mitchell M." last="Levy">Mitchell M. Levy</name>
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<nlm:aff id="Aff8">
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<institution>Warren Alpert School of Medicine,</institution>
<institution>Brown University,</institution>
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Providence, RI USA</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="Aff9">
<institution-wrap>
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<institution>Rhode Island Hospital,</institution>
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Providence, RI USA</nlm:aff>
</affiliation>
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<author>
<name sortKey="Derde, Lennie" sort="Derde, Lennie" uniqKey="Derde L" first="Lennie" last="Derde">Lennie Derde</name>
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<nlm:aff id="Aff10">
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<institution-id institution-id-type="ISNI">0000000120346234</institution-id>
<institution>Department of Intensive Care Medicine, University Medical Center Utrecht,</institution>
<institution>Utrecht University,</institution>
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Utrecht, The Netherlands</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="Aff11">
<institution-wrap>
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<institution>Julius Center for Health Sciences and Primary Care,</institution>
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Utrecht, The Netherlands</nlm:aff>
</affiliation>
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<author>
<name sortKey="Dzierba, Amy" sort="Dzierba, Amy" uniqKey="Dzierba A" first="Amy" last="Dzierba">Amy Dzierba</name>
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<nlm:aff id="Aff12">
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<institution>Department of Pharmacy, NewYork-Presbyterian Hospital,</institution>
<institution>Columbia University Irving Medical Center,</institution>
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New York, NY USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Du, Bin" sort="Du, Bin" uniqKey="Du B" first="Bin" last="Du">Bin Du</name>
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<nlm:aff id="Aff13">
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<institution>Peking Union Medical College Hospital,</institution>
</institution-wrap>
1 Shuai Fu Yuan, Beijing, 100730 China</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Aboodi, Michael" sort="Aboodi, Michael" uniqKey="Aboodi M" first="Michael" last="Aboodi">Michael Aboodi</name>
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<nlm:aff id="Aff6">
<institution-wrap>
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<institution-id institution-id-type="ISNI">0000000121791997</institution-id>
<institution>Division of Critical Care Medicine, Division of Pulmonary Medicine, Department of Medicine,</institution>
<institution>Montefiore Healthcare System/Albert Einstein College of Medicine,</institution>
</institution-wrap>
Bronx, NY USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Wunsch, Hannah" sort="Wunsch, Hannah" uniqKey="Wunsch H" first="Hannah" last="Wunsch">Hannah Wunsch</name>
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<nlm:aff id="Aff14">
<institution-wrap>
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<institution-id institution-id-type="ISNI">0000 0000 9743 1587</institution-id>
<institution>Department of Critical Care Medicine,</institution>
<institution>Sunnybrook Health Sciences Centre,</institution>
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Toronto, ON Canada</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="Aff15">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.17063.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id>
<institution>Department of Anesthesia and Interdepartmental Division of Critical Care Medicine,</institution>
<institution>University of Toronto,</institution>
</institution-wrap>
Toronto, ON Canada</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Cecconi, Maurizio" sort="Cecconi, Maurizio" uniqKey="Cecconi M" first="Maurizio" last="Cecconi">Maurizio Cecconi</name>
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<nlm:aff id="Aff16">
<institution-wrap>
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<institution-id institution-id-type="ISNI">0000 0004 1756 8807</institution-id>
<institution>Department of Anesthesia and Intensive Care,</institution>
<institution>Humanitas Clinical and Research Center,</institution>
</institution-wrap>
Rozzano, Milan, Italy</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="Aff17">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.452490.e</institution-id>
<institution>Department of Biomedical Science,</institution>
<institution>Humanitas University,</institution>
</institution-wrap>
Pieve Emanuele, Milan, Italy</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Koh, Younsuck" sort="Koh, Younsuck" uniqKey="Koh Y" first="Younsuck" last="Koh">Younsuck Koh</name>
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<nlm:aff id="Aff18">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.267370.7</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 0533 4667</institution-id>
<institution>Department of Pulmonary and Critical Care Medicine, Asan Medical Center,</institution>
<institution>University of Ulsan College of Medicine,</institution>
</institution-wrap>
Seoul, Korea</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Chertow, Daniel S" sort="Chertow, Daniel S" uniqKey="Chertow D" first="Daniel S." last="Chertow">Daniel S. Chertow</name>
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<nlm:aff id="Aff19">
<institution-wrap>
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<institution-id institution-id-type="ISNI">0000 0001 2164 9667</institution-id>
<institution>Critical Care Medicine Department, National Institutes of Health Clinical Center and Laboratory of Immunoregulation,</institution>
<institution>National Institute of Allergy and Infectious Diseases,</institution>
</institution-wrap>
Baltimore, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Maitland, Kathryn" sort="Maitland, Kathryn" uniqKey="Maitland K" first="Kathryn" last="Maitland">Kathryn Maitland</name>
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<nlm:aff id="Aff20">
<institution-wrap>
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<institution-id institution-id-type="ISNI">0000 0001 2113 8111</institution-id>
<institution>Faculty of Medicine,</institution>
<institution>Imperial College,</institution>
</institution-wrap>
London, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Alshamsi, Fayez" sort="Alshamsi, Fayez" uniqKey="Alshamsi F" first="Fayez" last="Alshamsi">Fayez Alshamsi</name>
<affiliation>
<nlm:aff id="Aff21">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.43519.3a</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 2193 6666</institution-id>
<institution>Department of Internal Medicine, College of Medicine and Health Sciences,</institution>
<institution>United Arab Emirates University,</institution>
</institution-wrap>
PO Box 17666, Al Ain, United Arab Emirates</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Belley Cote, Emilie" sort="Belley Cote, Emilie" uniqKey="Belley Cote E" first="Emilie" last="Belley-Cote">Emilie Belley-Cote</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.25073.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1936 8227</institution-id>
<institution>Department of Medicine,</institution>
<institution>McMaster University,</institution>
</institution-wrap>
Hamilton, Canada</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="Aff22">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.415102.3</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 0545 1978</institution-id>
<institution>Population Health Research Institute,</institution>
</institution-wrap>
Hamilton, Canada</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Greco, Massimiliano" sort="Greco, Massimiliano" uniqKey="Greco M" first="Massimiliano" last="Greco">Massimiliano Greco</name>
<affiliation>
<nlm:aff id="Aff16">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.417728.f</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1756 8807</institution-id>
<institution>Department of Anesthesia and Intensive Care,</institution>
<institution>Humanitas Clinical and Research Center,</institution>
</institution-wrap>
Rozzano, Milan, Italy</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="Aff17">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.452490.e</institution-id>
<institution>Department of Biomedical Science,</institution>
<institution>Humanitas University,</institution>
</institution-wrap>
Pieve Emanuele, Milan, Italy</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Laundy, Matthew" sort="Laundy, Matthew" uniqKey="Laundy M" first="Matthew" last="Laundy">Matthew Laundy</name>
<affiliation>
<nlm:aff id="Aff23">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.451349.e</institution-id>
<institution>Microbiology and Infection Control,</institution>
<institution>St George’s University Hospitals NHS Foundation Trust & St George’s University of London,</institution>
</institution-wrap>
London, UK</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Morgan, Jill S" sort="Morgan, Jill S" uniqKey="Morgan J" first="Jill S." last="Morgan">Jill S. Morgan</name>
<affiliation>
<nlm:aff id="Aff24">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.412162.2</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 0441 5844</institution-id>
<institution>Emory University Hospital,</institution>
</institution-wrap>
Atlanta, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kesecioglu, Jozef" sort="Kesecioglu, Jozef" uniqKey="Kesecioglu J" first="Jozef" last="Kesecioglu">Jozef Kesecioglu</name>
<affiliation>
<nlm:aff id="Aff10">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.5477.1</institution-id>
<institution-id institution-id-type="ISNI">0000000120346234</institution-id>
<institution>Department of Intensive Care Medicine, University Medical Center Utrecht,</institution>
<institution>Utrecht University,</institution>
</institution-wrap>
Utrecht, The Netherlands</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Mcgeer, Allison" sort="Mcgeer, Allison" uniqKey="Mcgeer A" first="Allison" last="Mcgeer">Allison Mcgeer</name>
<affiliation>
<nlm:aff id="Aff25">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.17063.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id>
<institution>Division of Infectious Diseases,</institution>
<institution>University of Toronto,</institution>
</institution-wrap>
Toronto, Canada</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Mermel, Leonard" sort="Mermel, Leonard" uniqKey="Mermel L" first="Leonard" last="Mermel">Leonard Mermel</name>
<affiliation>
<nlm:aff id="Aff8">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.40263.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1936 9094</institution-id>
<institution>Warren Alpert School of Medicine,</institution>
<institution>Brown University,</institution>
</institution-wrap>
Providence, RI USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Mammen, Manoj J" sort="Mammen, Manoj J" uniqKey="Mammen M" first="Manoj J." last="Mammen">Manoj J. Mammen</name>
<affiliation>
<nlm:aff id="Aff26">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.273335.3</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1936 9887</institution-id>
<institution>Department of Medicine, Jacobs School of Medicine and Biomedical Sciences,</institution>
<institution>State University of New York at Buffalo,</institution>
</institution-wrap>
Buffalo, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Alexander, Paul E" sort="Alexander, Paul E" uniqKey="Alexander P" first="Paul E." last="Alexander">Paul E. Alexander</name>
<affiliation>
<nlm:aff id="Aff2">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.25073.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1936 8227</institution-id>
<institution>Department of Health Research Methods, Evidence, and Impact,</institution>
<institution>McMaster University,</institution>
</institution-wrap>
Hamilton, Canada</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="Aff27">GUIDE Research Methods Group, Hamilton, Canada</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Arrington, Amy" sort="Arrington, Amy" uniqKey="Arrington A" first="Amy" last="Arrington">Amy Arrington</name>
<affiliation>
<nlm:aff id="Aff28">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.39382.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 2160 926X</institution-id>
<institution>Houston Children’s Hospital,</institution>
<institution>Baylor College of Medicine,</institution>
</institution-wrap>
Houston, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Centofanti, John E" sort="Centofanti, John E" uniqKey="Centofanti J" first="John E." last="Centofanti">John E. Centofanti</name>
<affiliation>
<nlm:aff id="Aff29">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.25073.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1936 8227</institution-id>
<institution>Department of Anesthesia,</institution>
<institution>McMaster University,</institution>
</institution-wrap>
Hamilton, Canada</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Citerio, Giuseppe" sort="Citerio, Giuseppe" uniqKey="Citerio G" first="Giuseppe" last="Citerio">Giuseppe Citerio</name>
<affiliation>
<nlm:aff id="Aff30">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.7563.7</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 2174 1754</institution-id>
<institution>Department of Medicine and Surgery,</institution>
<institution>Milano-Bicocca University,</institution>
</institution-wrap>
Milan, Italy</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="Aff31">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.415025.7</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1756 8604</institution-id>
<institution>ASST-Monza, Desio and San Gerardo Hospital,</institution>
</institution-wrap>
Monza, Italy</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Baw, Bandar" sort="Baw, Bandar" uniqKey="Baw B" first="Bandar" last="Baw">Bandar Baw</name>
<affiliation>
<nlm:aff id="Aff1">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.25073.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1936 8227</institution-id>
<institution>Department of Medicine,</institution>
<institution>McMaster University,</institution>
</institution-wrap>
Hamilton, Canada</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="Aff32">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.415254.3</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id>
<institution>Department of Emergency Medicine,</institution>
<institution>King Abdulaziz Medical City,</institution>
</institution-wrap>
Riyadh, Saudi Arabia</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Memish, Ziad A" sort="Memish, Ziad A" uniqKey="Memish Z" first="Ziad A." last="Memish">Ziad A. Memish</name>
<affiliation>
<nlm:aff id="Aff33">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.415696.9</institution-id>
<institution>Director, Research and Innovation Centre, King Saud Medical City,</institution>
<institution>Ministry of Health,</institution>
</institution-wrap>
Riyadh, Kingdom of Saudi Arabia</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hammond, Naomi" sort="Hammond, Naomi" uniqKey="Hammond N" first="Naomi" last="Hammond">Naomi Hammond</name>
<affiliation>
<nlm:aff id="Aff34">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.415508.d</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 1964 6010</institution-id>
<institution>Critical Care Division,</institution>
<institution>The George Institute for Global Health and UNSW,</institution>
</institution-wrap>
Sydney, Australia</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="Aff35">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.412703.3</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 0587 9093</institution-id>
<institution>Malcolm Fisher Department of Intensive Care,</institution>
<institution>Royal North Shore Hospital,</institution>
</institution-wrap>
Sydney, Australia</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Hayden, Frederick G" sort="Hayden, Frederick G" uniqKey="Hayden F" first="Frederick G." last="Hayden">Frederick G. Hayden</name>
<affiliation>
<nlm:aff id="Aff36">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.27755.32</institution-id>
<institution-id institution-id-type="ISNI">0000 0000 9136 933X</institution-id>
<institution>Division of Infectious Diseases and International Health, Department of Medicine,</institution>
<institution>University, of Virginia, School of Medicine,</institution>
</institution-wrap>
Charlottesville, VA USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Evans, Laura" sort="Evans, Laura" uniqKey="Evans L" first="Laura" last="Evans">Laura Evans</name>
<affiliation>
<nlm:aff id="Aff37">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.34477.33</institution-id>
<institution-id institution-id-type="ISNI">0000000122986657</institution-id>
<institution>Division of Pulmonary, Critical Care, and Sleep Medicine,</institution>
<institution>University of Washington,</institution>
</institution-wrap>
Seattle, USA</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Rhodes, Andrew" sort="Rhodes, Andrew" uniqKey="Rhodes A" first="Andrew" last="Rhodes">Andrew Rhodes</name>
<affiliation>
<nlm:aff id="Aff38">
<institution-wrap>
<institution-id institution-id-type="GRID">grid.451349.e</institution-id>
<institution>Adult Critical Care,</institution>
<institution>St George’s University Hospitals NHS Foundation Trust & St George’s University of London,</institution>
</institution-wrap>
London, UK</nlm:aff>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Intensive Care Medicine</title>
<idno type="ISSN">0342-4642</idno>
<idno type="eISSN">1432-1238</idno>
<imprint>
<date when="2020">2020</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<sec>
<title>Background</title>
<p id="Par1">The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. </p>
</sec>
<sec>
<title>Methods</title>
<p id="Par2">We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the
<italic>Grading of Recommendations, Assessment, Development and Evaluation</italic>
(GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. </p>
</sec>
<sec>
<title>Results</title>
<p id="Par3">The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which 4 are best practice statements, 9 are strong recommendations, and 35 are weak recommendations. No recommendation was provided for 6 questions. The topics were: (1) infection control, (2) laboratory diagnosis and specimens, (3) hemodynamic support, (4) ventilatory support, and (5) COVID-19 therapy. </p>
</sec>
<sec>
<title>Conclusion</title>
<p id="Par4">The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new recommendations in further releases of these guidelines. </p>
</sec>
<sec>
<title>Electronic supplementary material</title>
<p>The online version of this article (10.1007/s00134-020-06022-5) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
</front>
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<journal-id journal-id-type="nlm-ta">Intensive Care Med</journal-id>
<journal-id journal-id-type="iso-abbrev">Intensive Care Med</journal-id>
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<article-id pub-id-type="pmc">7101866</article-id>
<article-id pub-id-type="publisher-id">6022</article-id>
<article-id pub-id-type="doi">10.1007/s00134-020-06022-5</article-id>
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<surname>Arrington</surname>
<given-names>Amy</given-names>
</name>
<xref ref-type="aff" rid="Aff28">28</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Centofanti</surname>
<given-names>John E.</given-names>
</name>
<xref ref-type="aff" rid="Aff29">29</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Citerio</surname>
<given-names>Giuseppe</given-names>
</name>
<xref ref-type="aff" rid="Aff30">30</xref>
<xref ref-type="aff" rid="Aff31">31</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Baw</surname>
<given-names>Bandar</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff32">32</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Memish</surname>
<given-names>Ziad A.</given-names>
</name>
<xref ref-type="aff" rid="Aff33">33</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hammond</surname>
<given-names>Naomi</given-names>
</name>
<xref ref-type="aff" rid="Aff34">34</xref>
<xref ref-type="aff" rid="Aff35">35</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hayden</surname>
<given-names>Frederick G.</given-names>
</name>
<xref ref-type="aff" rid="Aff36">36</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Evans</surname>
<given-names>Laura</given-names>
</name>
<xref ref-type="aff" rid="Aff37">37</xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Rhodes</surname>
<given-names>Andrew</given-names>
</name>
<address>
<email>andrewrhodes@nhs.net</email>
</address>
<xref ref-type="aff" rid="Aff38">38</xref>
</contrib>
<aff id="Aff1">
<label>1</label>
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<institution-id institution-id-type="ISNI">0000 0004 1936 8227</institution-id>
<institution>Department of Medicine,</institution>
<institution>McMaster University,</institution>
</institution-wrap>
Hamilton, Canada</aff>
<aff id="Aff2">
<label>2</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.25073.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1936 8227</institution-id>
<institution>Department of Health Research Methods, Evidence, and Impact,</institution>
<institution>McMaster University,</institution>
</institution-wrap>
Hamilton, Canada</aff>
<aff id="Aff3">
<label>3</label>
<institution-wrap>
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<institution>Copenhagen University Hospital Rigshospitalet,</institution>
</institution-wrap>
4131 Copenhagen, Denmark</aff>
<aff id="Aff4">
<label>4</label>
Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI), Copenhagen, Denmark</aff>
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<label>5</label>
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<institution>Intensive Care Department, Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences,</institution>
<institution>King Abdullah International Medical Research Center,</institution>
</institution-wrap>
Riyadh, Kingdom of Saudi Arabia</aff>
<aff id="Aff6">
<label>6</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.251993.5</institution-id>
<institution-id institution-id-type="ISNI">0000000121791997</institution-id>
<institution>Division of Critical Care Medicine, Division of Pulmonary Medicine, Department of Medicine,</institution>
<institution>Montefiore Healthcare System/Albert Einstein College of Medicine,</institution>
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Bronx, NY USA</aff>
<aff id="Aff7">
<label>7</label>
<institution-wrap>
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<institution>Interdepartmental Division of Critical Care Medicine, Institute of Health Policy, Management and Evaluation,</institution>
<institution>University of Toronto,</institution>
</institution-wrap>
Toronto, Canada</aff>
<aff id="Aff8">
<label>8</label>
<institution-wrap>
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<institution>Warren Alpert School of Medicine,</institution>
<institution>Brown University,</institution>
</institution-wrap>
Providence, RI USA</aff>
<aff id="Aff9">
<label>9</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.240588.3</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 0557 9478</institution-id>
<institution>Rhode Island Hospital,</institution>
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Providence, RI USA</aff>
<aff id="Aff10">
<label>10</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.5477.1</institution-id>
<institution-id institution-id-type="ISNI">0000000120346234</institution-id>
<institution>Department of Intensive Care Medicine, University Medical Center Utrecht,</institution>
<institution>Utrecht University,</institution>
</institution-wrap>
Utrecht, The Netherlands</aff>
<aff id="Aff11">
<label>11</label>
<institution-wrap>
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<institution-id institution-id-type="ISNI">0000000090126352</institution-id>
<institution>Julius Center for Health Sciences and Primary Care,</institution>
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Utrecht, The Netherlands</aff>
<aff id="Aff12">
<label>12</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.21729.3f</institution-id>
<institution-id institution-id-type="ISNI">0000000419368729</institution-id>
<institution>Department of Pharmacy, NewYork-Presbyterian Hospital,</institution>
<institution>Columbia University Irving Medical Center,</institution>
</institution-wrap>
New York, NY USA</aff>
<aff id="Aff13">
<label>13</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.413106.1</institution-id>
<institution-id institution-id-type="ISNI">0000 0000 9889 6335</institution-id>
<institution>Medical ICU,</institution>
<institution>Peking Union Medical College Hospital,</institution>
</institution-wrap>
1 Shuai Fu Yuan, Beijing, 100730 China</aff>
<aff id="Aff14">
<label>14</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.413104.3</institution-id>
<institution-id institution-id-type="ISNI">0000 0000 9743 1587</institution-id>
<institution>Department of Critical Care Medicine,</institution>
<institution>Sunnybrook Health Sciences Centre,</institution>
</institution-wrap>
Toronto, ON Canada</aff>
<aff id="Aff15">
<label>15</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.17063.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id>
<institution>Department of Anesthesia and Interdepartmental Division of Critical Care Medicine,</institution>
<institution>University of Toronto,</institution>
</institution-wrap>
Toronto, ON Canada</aff>
<aff id="Aff16">
<label>16</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.417728.f</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1756 8807</institution-id>
<institution>Department of Anesthesia and Intensive Care,</institution>
<institution>Humanitas Clinical and Research Center,</institution>
</institution-wrap>
Rozzano, Milan, Italy</aff>
<aff id="Aff17">
<label>17</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.452490.e</institution-id>
<institution>Department of Biomedical Science,</institution>
<institution>Humanitas University,</institution>
</institution-wrap>
Pieve Emanuele, Milan, Italy</aff>
<aff id="Aff18">
<label>18</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.267370.7</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 0533 4667</institution-id>
<institution>Department of Pulmonary and Critical Care Medicine, Asan Medical Center,</institution>
<institution>University of Ulsan College of Medicine,</institution>
</institution-wrap>
Seoul, Korea</aff>
<aff id="Aff19">
<label>19</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.419681.3</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 2164 9667</institution-id>
<institution>Critical Care Medicine Department, National Institutes of Health Clinical Center and Laboratory of Immunoregulation,</institution>
<institution>National Institute of Allergy and Infectious Diseases,</institution>
</institution-wrap>
Baltimore, USA</aff>
<aff id="Aff20">
<label>20</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.7445.2</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 2113 8111</institution-id>
<institution>Faculty of Medicine,</institution>
<institution>Imperial College,</institution>
</institution-wrap>
London, UK</aff>
<aff id="Aff21">
<label>21</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.43519.3a</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 2193 6666</institution-id>
<institution>Department of Internal Medicine, College of Medicine and Health Sciences,</institution>
<institution>United Arab Emirates University,</institution>
</institution-wrap>
PO Box 17666, Al Ain, United Arab Emirates</aff>
<aff id="Aff22">
<label>22</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.415102.3</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 0545 1978</institution-id>
<institution>Population Health Research Institute,</institution>
</institution-wrap>
Hamilton, Canada</aff>
<aff id="Aff23">
<label>23</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.451349.e</institution-id>
<institution>Microbiology and Infection Control,</institution>
<institution>St George’s University Hospitals NHS Foundation Trust & St George’s University of London,</institution>
</institution-wrap>
London, UK</aff>
<aff id="Aff24">
<label>24</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.412162.2</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 0441 5844</institution-id>
<institution>Emory University Hospital,</institution>
</institution-wrap>
Atlanta, USA</aff>
<aff id="Aff25">
<label>25</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.17063.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id>
<institution>Division of Infectious Diseases,</institution>
<institution>University of Toronto,</institution>
</institution-wrap>
Toronto, Canada</aff>
<aff id="Aff26">
<label>26</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.273335.3</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1936 9887</institution-id>
<institution>Department of Medicine, Jacobs School of Medicine and Biomedical Sciences,</institution>
<institution>State University of New York at Buffalo,</institution>
</institution-wrap>
Buffalo, USA</aff>
<aff id="Aff27">
<label>27</label>
GUIDE Research Methods Group, Hamilton, Canada</aff>
<aff id="Aff28">
<label>28</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.39382.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 2160 926X</institution-id>
<institution>Houston Children’s Hospital,</institution>
<institution>Baylor College of Medicine,</institution>
</institution-wrap>
Houston, USA</aff>
<aff id="Aff29">
<label>29</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.25073.33</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1936 8227</institution-id>
<institution>Department of Anesthesia,</institution>
<institution>McMaster University,</institution>
</institution-wrap>
Hamilton, Canada</aff>
<aff id="Aff30">
<label>30</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.7563.7</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 2174 1754</institution-id>
<institution>Department of Medicine and Surgery,</institution>
<institution>Milano-Bicocca University,</institution>
</institution-wrap>
Milan, Italy</aff>
<aff id="Aff31">
<label>31</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.415025.7</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1756 8604</institution-id>
<institution>ASST-Monza, Desio and San Gerardo Hospital,</institution>
</institution-wrap>
Monza, Italy</aff>
<aff id="Aff32">
<label>32</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.415254.3</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1790 7311</institution-id>
<institution>Department of Emergency Medicine,</institution>
<institution>King Abdulaziz Medical City,</institution>
</institution-wrap>
Riyadh, Saudi Arabia</aff>
<aff id="Aff33">
<label>33</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.415696.9</institution-id>
<institution>Director, Research and Innovation Centre, King Saud Medical City,</institution>
<institution>Ministry of Health,</institution>
</institution-wrap>
Riyadh, Kingdom of Saudi Arabia</aff>
<aff id="Aff34">
<label>34</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.415508.d</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 1964 6010</institution-id>
<institution>Critical Care Division,</institution>
<institution>The George Institute for Global Health and UNSW,</institution>
</institution-wrap>
Sydney, Australia</aff>
<aff id="Aff35">
<label>35</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.412703.3</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 0587 9093</institution-id>
<institution>Malcolm Fisher Department of Intensive Care,</institution>
<institution>Royal North Shore Hospital,</institution>
</institution-wrap>
Sydney, Australia</aff>
<aff id="Aff36">
<label>36</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.27755.32</institution-id>
<institution-id institution-id-type="ISNI">0000 0000 9136 933X</institution-id>
<institution>Division of Infectious Diseases and International Health, Department of Medicine,</institution>
<institution>University, of Virginia, School of Medicine,</institution>
</institution-wrap>
Charlottesville, VA USA</aff>
<aff id="Aff37">
<label>37</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.34477.33</institution-id>
<institution-id institution-id-type="ISNI">0000000122986657</institution-id>
<institution>Division of Pulmonary, Critical Care, and Sleep Medicine,</institution>
<institution>University of Washington,</institution>
</institution-wrap>
Seattle, USA</aff>
<aff id="Aff38">
<label>38</label>
<institution-wrap>
<institution-id institution-id-type="GRID">grid.451349.e</institution-id>
<institution>Adult Critical Care,</institution>
<institution>St George’s University Hospitals NHS Foundation Trust & St George’s University of London,</institution>
</institution-wrap>
London, UK</aff>
</contrib-group>
<pub-date pub-type="epub">
<day>28</day>
<month>3</month>
<year>2020</year>
</pub-date>
<fpage>1</fpage>
<lpage>34</lpage>
<history>
<date date-type="received">
<day>15</day>
<month>3</month>
<year>2020</year>
</date>
<date date-type="accepted">
<day>20</day>
<month>3</month>
<year>2020</year>
</date>
</history>
<permissions>
<copyright-statement>© European Society of Intensive Care Medicine and the Society of Critical Care Medicine 2020</copyright-statement>
<license>
<license-p>This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.</license-p>
</license>
</permissions>
<abstract id="Abs1">
<sec>
<title>Background</title>
<p id="Par1">The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. </p>
</sec>
<sec>
<title>Methods</title>
<p id="Par2">We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the
<italic>Grading of Recommendations, Assessment, Development and Evaluation</italic>
(GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. </p>
</sec>
<sec>
<title>Results</title>
<p id="Par3">The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which 4 are best practice statements, 9 are strong recommendations, and 35 are weak recommendations. No recommendation was provided for 6 questions. The topics were: (1) infection control, (2) laboratory diagnosis and specimens, (3) hemodynamic support, (4) ventilatory support, and (5) COVID-19 therapy. </p>
</sec>
<sec>
<title>Conclusion</title>
<p id="Par4">The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new recommendations in further releases of these guidelines. </p>
</sec>
<sec>
<title>Electronic supplementary material</title>
<p>The online version of this article (10.1007/s00134-020-06022-5) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<kwd-group xml:lang="en">
<title>Keywords</title>
<kwd>Coronavirus</kwd>
<kwd>COVID-19</kwd>
<kwd>SARS CoV-2</kwd>
<kwd>Clinical practice guidelines</kwd>
<kwd>Critical illness</kwd>
</kwd-group>
</article-meta>
</front>
<body>
<sec id="Sec1" sec-type="introduction">
<title>Introduction</title>
<p id="Par5">At the end of 2019, a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in an acute respiratory illness epidemic in Wuhan, China [
<xref ref-type="bibr" rid="CR1">1</xref>
]. The World Health Organization (WHO) termed this illness Coronavirus Disease 2019 (COVID-19).</p>
<p id="Par6">By the time this guideline panel was assembled, the COVID-19 had become a pandemic and had affected over 120,000 individuals in more than 80 countries, and resulted in more than 5000 deaths worldwide [
<xref ref-type="bibr" rid="CR2">2</xref>
].</p>
<p id="Par7">The WHO and the United States Center for Disease Control and Prevention (CDC) have issued preliminary guidance on infection control, screening and diagnosis in the general population, but there is limited guidance on the acute management of critically ill patients with severe illness due to COVID-19.</p>
</sec>
<sec id="Sec2">
<title>Guideline scope</title>
<p id="Par8">This guideline provides recommendations to support hospital clinicians managing critically ill adults with COVID-19 in the intensive care unit (ICU). The target users of this guideline are frontline clinicians, allied health professionals, and policymakers involved in the care of patients with COVID-19 in the ICU. The guideline applies to both high and low-middle income settings.</p>
</sec>
<sec id="Sec3">
<title>Guideline Teams and Structure</title>
<p id="Par9">The Surviving Sepsis Campaign (SSC) COVID-19 subcommittee selected panel members in such a way as to obtain a balance of topic expertise, geographic location and, as far as possible, gender. </p>
<p id="Par10">The SSC COVID-19 panel was assembled and worked within very tight timelines in order to issue recommendations in a timely manner. The panel included experts in guideline development, infection control, infectious diseases and microbiology, critical care, emergency medicine, nursing, and public health. The panel was divided into four groups: (1) infection control and testing, (2) hemodynamic support, (3) ventilatory support, and (4) therapy.</p>
<p id="Par11">The
<italic>Guidelines in Intensive Care Development and Evaluation</italic>
(GUIDE) group provided methodological support throughout the guideline development process.</p>
</sec>
<sec id="Sec4">
<title>Management of conflict of interests</title>
<p id="Par12">All panel members completed a conflict of interests (COI) form prior to joining the guideline panel [
<xref ref-type="bibr" rid="CR3">3</xref>
,
<xref ref-type="bibr" rid="CR4">4</xref>
]. We used the GRADEpro guideline development tool (GDT) online software (
<ext-link ext-link-type="uri" xlink:href="http://gdt.guidelinedevelopment.org">http://gdt.guidelinedevelopment.org</ext-link>
) to administer WHO COI disclosure forms to participating panel members. Direct financial and industry-related COIs were not permitted and were considered disqualifying. The development of this guideline did not include any industry input, funding, or financial or non-financial contribution. No member of the guideline panel received honoraria or remuneration for any role in the guideline development process.</p>
</sec>
<sec id="Sec5" sec-type="materials|methods">
<title>Methods</title>
<p id="Par13">The guideline development process is summarized in Fig. 
<xref rid="Fig1" ref-type="fig">1</xref>
. All actionable guideline questions were structured in the Population, Intervention, Control, and Outcome(s) (PICO) format, with explicit definitions, whereas descriptive questions were not.
<fig id="Fig1">
<label>Fig. 1</label>
<caption>
<p>COVID-19 guideline development process</p>
</caption>
<graphic xlink:href="134_2020_6022_Fig1_HTML" id="MO1"></graphic>
</fig>
</p>
<p id="Par14">Content and methods experts in each group participated in developing the guideline questions. The PICO format provided the basis for defining inclusion and exclusion criteria for the literature searches (where performed) and for identification of relevant studies. </p>
<p id="Par15">To facilitate rapid development of recommendations, we did not perform a novel systematic prioritization of outcomes, but used the outcome prioritization informed by the ongoing SSC guideline 2020 work and expert input [
<xref ref-type="bibr" rid="CR5">5</xref>
]. Accordingly, we focused on hospital mortality and serious adverse event outcomes for most questions, and for some included other outcomes deemed critical for decision making.</p>
<sec id="Sec6">
<title>Literature search</title>
<p id="Par16">For some questions, with help of professional medical librarians, we electronically searched major databases, i.e. Cochrane Central and MEDLINE, to identify relevant systematic reviews, randomized controlled trials (RCTs), observational studies, and case series. These electronic searches were performed looking for studies published in English from inception to March 2020. To inform the recommendations on hemodynamic and ventilatory support, we used recently published systematic reviews and asked experts to identify any new relevant studies.</p>
</sec>
<sec id="Sec7">
<title>Selection of studies and data abstraction</title>
<p id="Par17">For selected PICO questions, a pair of reviewers screened titles and abstracts retrieved from the bibliographic databases; for each PICO question, all potentially eligible studies were assessed for eligibility according to pre-specified criteria. Content experts were asked to indicate any additional studies not identified by the search. Subsequently, pairs of reviewers independently abstracted relevant data on the corresponding PICO questions, and items relevant to risk of bias.</p>
<p id="Par18">We obtained intention-to-treat data whenever available; otherwise we used complete case data, i.e. ignoring missing data [
<xref ref-type="bibr" rid="CR6">6</xref>
].</p>
</sec>
<sec id="Sec8">
<title>Quality of evidence</title>
<p id="Par19">We used the
<italic>Grading of Recommendations, Assessment, Development and Evaluation</italic>
(GRADE) approach to assess the quality of evidence [
<xref ref-type="bibr" rid="CR7">7</xref>
], i.e. our confidence in the estimate of the effect to support a recommendation [
<xref ref-type="bibr" rid="CR8">8</xref>
]. The quality of evidence was rated as high, moderate, low, or very low [
<xref ref-type="bibr" rid="CR9">9</xref>
]. We used the GDT online software (
<ext-link ext-link-type="uri" xlink:href="http://gdt.guidelinedevelopment.org">http://gdt.guidelinedevelopment.org</ext-link>
) to generate the evidence profiles (evidence summaries) [
<xref ref-type="bibr" rid="CR10">10</xref>
].</p>
</sec>
<sec id="Sec9">
<title>Using indirect evidence</title>
<p id="Par20">Given the recent emergence of COVID-19, we anticipated that there would be a scarcity of direct evidence, and therefore used a predefined algorithm to decide whether indirect evidence could inform a specific question (Figure S1-2).</p>
<p id="Par21">The SSC COVID-19 panel decided which population to extrapolate evidence from based on the context of the recommendation, and the likelihood of the presence of an effect modifier (Figure S3). Accordingly, we used, as sources of indirect evidence, data on Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome (SARS), and other coronaviruses; in the same way, we considered, as indirect evidence, published data on supportive care in the ICU from studies on influenza and other respiratory viral infections, acute respiratory distress syndrome (ARDS) and sepsis.</p>
</sec>
</sec>
<sec id="Sec10">
<title>Recommendation formulation</title>
<p id="Par22">We used the principles outlined in the evidence to decision framework (EtD) to formulate recommendations, but because of the tight timelines we did not complete the online EtD tables [
<xref ref-type="bibr" rid="CR11">11</xref>
]. The EtD framework covers the following domains: priority setting, magnitude of benefit and harm, certainty of the evidence, patient values, balance between desirable and undesirable effects, resources and cost, equity, acceptability and feasibility.</p>
<p id="Par23">Each of the four subgroups drafted the preliminary recommendations. We use the wording “we recommend” for strong recommendations and “we suggest” for suggestions (i.e. weak recommendations). The implications of the recommendation strength are presented in Table 
<xref rid="Tab1" ref-type="table">1</xref>
. The final list of recommendations was developed by panel discussion and consensus; voting on recommendations was not required. We present the guideline statements and recommendations in Table 
<xref rid="Tab2" ref-type="table">2</xref>
.
<table-wrap id="Tab1">
<label>Table 1</label>
<caption>
<p>Implications of different recommendations to key stakeholders</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left">Recommendation</th>
<th align="left">Meaning</th>
<th align="left">Implications to patients</th>
<th align="left">Implications to clinicians</th>
<th align="left">Implications to policymakers</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left">
<p>Strong recommendation or</p>
<p>Best practice statement</p>
</td>
<td align="left">
<p>Must do or</p>
<p>Must avoid</p>
</td>
<td align="left">Almost all individuals in this situation would want the recommended intervention, and only a small proportion would not want it</td>
<td align="left">Most individuals should receive the recommended course of action</td>
<td align="left">Can be adapted as policy in most situations, including the use as performance indicators</td>
</tr>
<tr>
<td align="left">Weak recommendation</td>
<td align="left">
<p>Consider doing or</p>
<p>Consider avoiding</p>
</td>
<td align="left">The majority of individuals in this situation would want the recommended intervention, but many would not</td>
<td align="left">Different choices are likely to be appropriate for different patients, and the recommendation should be tailored to the individual patient’s circumstances. Such as patients’, family’s, or substitute decision maker’s values and preferences</td>
<td align="left">Policies will likely be variable</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="Tab2">
<label>Table 2</label>
<caption>
<p>Recommendations and statements</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left"></th>
<th align="left">Recommendation</th>
<th align="left">Strength</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" colspan="3">
<bold>INFECTION CONTROL AND TESTING</bold>
</td>
</tr>
<tr>
<td align="left">1</td>
<td align="left">For healthcare workers performing
<bold>aerosol-generating procedures</bold>
<sup>*</sup>
on patients with COVID-19 in the ICU, we
<bold>
<italic>recommend</italic>
</bold>
using
<bold>fitted respirator masks</bold>
(
<bold>N95 respirators, FFP2, or equivalent)</bold>
, as opposed to surgical/medical masks, in addition to other personal protective equipment (i.e. gloves, gown, and eye protection, such as a face shield or safety goggles)</td>
<td align="left">Best practice statement</td>
</tr>
<tr>
<td align="left">2</td>
<td align="left">We
<bold>
<italic>recommend</italic>
</bold>
performing
<bold>aerosol-generating procedures</bold>
on ICU patients with COVID-19 in a negative pressure room</td>
<td align="left">Best practice statement</td>
</tr>
<tr>
<td align="left">3</td>
<td align="left">For healthcare workers providing usual care for non-ventilated COVID-19 patients, we
<bold>
<italic>suggest</italic>
</bold>
using surgical/medical masks, as opposed to respirator masks, in addition to other personal protective equipment (i.e. gloves, gown, and eye protection, such as a face shield or safety goggles)</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">4</td>
<td align="left">For healthcare workers who are performing
<bold>non-aerosol-generating procedures</bold>
on mechanically ventilated (closed circuit) patients with COVID-19, we
<bold>
<italic>suggest</italic>
</bold>
using surgical/medical masks, as opposed to respirator masks, in addition to other personal protective equipment (i.e. gloves, gown, and eye protection, such as a face shield or safety goggles)</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">5</td>
<td align="left">For healthcare workers performing
<bold>endotracheal intubation</bold>
on patients with COVID-19, we
<bold>
<italic>suggest</italic>
</bold>
using video-guided laryngoscopy, over direct laryngoscopy, if available</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">6</td>
<td align="left">For COVID-19 patients requiring
<bold>endotracheal intubation</bold>
, we
<bold>
<italic>recommend</italic>
</bold>
that endotracheal intubation be performed by the healthcare worker who is most experienced with airway management in order to minimize the number of attempts and risk of transmission</td>
<td align="left">Best practice statement</td>
</tr>
<tr>
<td align="left">7.1</td>
<td align="left">For intubated and mechanically ventilated adults with suspicion of COVID-19: For diagnostic testing, we
<bold>
<italic>suggest</italic>
</bold>
obtaining lower respiratory tract samples in preference to upper respiratory tract (nasopharyngeal or oropharyngeal) samples</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">7.2</td>
<td align="left">For intubated and mechanically ventilated adults with suspicion of COVID-19: With regard to lower respiratory samples, we
<bold>
<italic>suggest</italic>
</bold>
obtaining endotracheal aspirates in preference to bronchial wash or bronchoalveolar lavage samples</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left" colspan="3">
<bold>HEMODYNAMICS</bold>
</td>
</tr>
<tr>
<td align="left">8</td>
<td align="left">In adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using dynamic parameters skin temperature, capillary refilling time, and/or serum lactate measurement over static parameters in order to assess fluid responsiveness</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">9</td>
<td align="left">For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using a conservative over a liberal fluid strategy</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">10</td>
<td align="left">For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>recommend</italic>
</bold>
using crystalloids over colloids</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">11</td>
<td align="left">For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using buffered/balanced crystalloids over unbalanced crystalloids</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">12</td>
<td align="left">For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>recommend</italic>
</bold>
<bold>
<italic>against</italic>
</bold>
using hydroxyethyl starches</td>
<td align="left">Strong</td>
</tr>
<tr>
<td align="left">13</td>
<td align="left">For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest against</italic>
</bold>
using gelatins</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">14</td>
<td align="left">For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>suggest against</bold>
using dextrans</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">15</td>
<td align="left">For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest against</italic>
</bold>
the routine use of albumin for initial resuscitation</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">16</td>
<td align="left">For adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using norepinephrine as the first-line vasoactive agent, over other agents</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">17</td>
<td align="left">If norepinephrine is not available, we
<bold>
<italic>suggest</italic>
</bold>
using either vasopressin or epinephrine as the first-line vasoactive agent, over other vasoactive agents, for adults with
<bold>COVID-19 and shock</bold>
</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">18</td>
<td align="left">For adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>recommend against</italic>
</bold>
using dopamine if norepinephrine is available</td>
<td align="left">Strong</td>
</tr>
<tr>
<td align="left">19</td>
<td align="left">For adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
adding vasopressin as a second-line agent, over titrating norepinephrine dose, if target mean arterial pressure (MAP) cannot be achieved by norepinephrine alone</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">20</td>
<td align="left">For adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest titrating</italic>
</bold>
vasoactive agents to target a MAP of 60-65 mmHg, rather than higher MAP targets</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">21</td>
<td align="left">For adults with
<bold>COVID-19 and shock with evidence of cardiac dysfunction and persistent hypoperfusion despite fluid resuscitation and norepinephrine</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
adding dobutamine, over increasing norepinephrine dose</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">22</td>
<td align="left">
<p>For adults with
<bold>COVID-19 and refractory shock</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using low-dose corticosteroid therapy (“shock-reversal”), over no corticosteroid</p>
<p>
<italic>Remark</italic>
: A typical corticosteroid regimen in septic shock is intravenous hydrocortisone 200 mg per day administered either as an infusion or intermittent doses</p>
</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left" colspan="3">
<bold>VENTILATION</bold>
</td>
</tr>
<tr>
<td align="left">23</td>
<td align="left">In adults with COVID-19, we
<bold>
<italic>suggest</italic>
</bold>
starting supplemental oxygen if the peripheral oxygen saturation (SpO
<sub>2</sub>
) is < 92%, and
<bold>
<italic>recommend</italic>
</bold>
starting supplemental oxygen if SpO
<sub>2</sub>
is < 90%</td>
<td align="left">
<p>Weak</p>
<p>Strong</p>
</td>
</tr>
<tr>
<td align="left">24</td>
<td align="left">In adults with COVID-19 and
<bold>acute hypoxemic respiratory failure on oxygen</bold>
, we
<bold>
<italic>recommend</italic>
</bold>
that SpO
<sub>2</sub>
be maintained no higher than 96%</td>
<td align="left">Strong</td>
</tr>
<tr>
<td align="left">25</td>
<td align="left">For adults with COVID-19 and
<bold>acute hypoxemic respiratory failure</bold>
despite conventional oxygen therapy, we
<bold>
<italic>suggest using</italic>
</bold>
HFNC over conventional oxygen therapy</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">26</td>
<td align="left">In adults with COVID-19 and
<bold>acute hypoxemic respiratory failure</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using HFNC over NIPPV</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">27</td>
<td align="left">In adults with COVID-19 and
<bold>acute hypoxemic respiratory failure</bold>
, if HFNC is not available and there is no urgent indication for endotracheal intubation, we
<bold>
<italic>suggest</italic>
</bold>
a trial of NIPPV with close monitoring and short-interval assessment for worsening of respiratory failure</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">28</td>
<td align="left">
<bold>We were not able to make a recommendation</bold>
regarding the use of helmet NIPPV compared with mask NIPPV. It is an option, but we are not certain about its safety or efficacy in COVID-19</td>
<td align="left">No recommendation</td>
</tr>
<tr>
<td align="left">29</td>
<td align="left">In adults with COVID-19 receiving NIPPV or HFNC, we
<bold>
<italic>recommend</italic>
</bold>
close monitoring for worsening of respiratory status, and early intubation in a controlled setting if worsening occurs</td>
<td align="left">Best practice statement</td>
</tr>
<tr>
<td align="left">30</td>
<td align="left">In mechanically ventilated adults with COVID-19 and ARDS, we
<bold>
<italic>recommend</italic>
</bold>
using low tidal volume (Vt) ventilation (Vt 4–8 mL/kg of predicted body weight), over higher tidal volumes (Vt > 8 mL/kg)</td>
<td align="left">Strong</td>
</tr>
<tr>
<td align="left">31</td>
<td align="left">For mechanically ventilated adults with COVID-19 and
<bold>ARDS</bold>
, we
<bold>
<italic>recommend</italic>
</bold>
targeting plateau pressures (Pplat) of < 30 cm H
<sub>2</sub>
O</td>
<td align="left">Strong</td>
</tr>
<tr>
<td align="left">32</td>
<td align="left">
<p>For mechanically ventilated adults with COVID-19 and moderate to severe ARDS, we
<bold>
<italic>suggest</italic>
</bold>
using a higher PEEP strategy, over a lower PEEP strategy.</p>
<p>
<italic>Remarks</italic>
: If using a higher PEEP strategy (i.e. PEEP > 10 cm H
<sub>2</sub>
O), clinicians should monitor patients for barotrauma</p>
</td>
<td align="left">Strong</td>
</tr>
<tr>
<td align="left">33</td>
<td align="left">For mechanically ventilated adults with COVID-19 and ARDS, we
<bold>
<italic>suggest</italic>
</bold>
using a conservative fluid strategy over a liberal fluid strategy</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">34</td>
<td align="left">For mechanically ventilated adults with COVID-19 and
<bold>moderate to severe ARDS</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
prone ventilation for
<bold>12</bold>
<bold>16</bold>
 
<bold>h</bold>
, over no prone ventilation</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">35.1</td>
<td align="left">For mechanically ventilated adults with COVID-19 and
<bold>moderate to severe ARDS</bold>
: we
<bold>
<italic>suggest</italic>
</bold>
using, as needed, intermittent boluses of neuromuscular blocking agents (NMBA), over continuous NMBA infusion, to facilitate protective lung ventilation</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">35.2</td>
<td align="left">In the event of persistent ventilator dyssynchrony, the need for ongoing deep sedation, prone ventilation, or persistently high plateau pressures, we
<bold>
<italic>suggest</italic>
</bold>
using a continuous NMBA infusion for up to 48 h</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">36</td>
<td align="left">In mechanically ventilated adults with COVID-19 ARDS, we
<bold>
<italic>recommend against</italic>
</bold>
the routine use of inhaled nitric oxide</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">37</td>
<td align="left">In mechanically ventilated adults with COVID-19, severe ARDS and hypoxemia despite optimizing ventilation and other rescue strategies, we
<bold>
<italic>suggest</italic>
</bold>
a trial of inhaled pulmonary vasodilator as a rescue therapy; if no rapid improvement in oxygenation is observed, the treatment should be tapered off</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">38</td>
<td align="left">For mechanically ventilated adults with COVID-19 and hypoxemia despite optimizing ventilation, we
<bold>
<italic>suggest</italic>
</bold>
using recruitment maneuvers, over not using recruitment maneuvers</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">39</td>
<td align="left">If recruitment maneuvers are used, we
<bold>
<italic>recommend against</italic>
</bold>
using staircase (incremental PEEP) recruitment maneuvers</td>
<td align="left">Strong</td>
</tr>
<tr>
<td align="left">40</td>
<td align="left">
<p>In mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimizing ventilation, use of rescue therapies, and proning, we
<bold>
<italic>suggest</italic>
</bold>
using venovenous (VV) ECMO if available, or referring the patient to an ECMO center</p>
<p>
<italic>Remark</italic>
: Due to the resource-intensive nature of ECMO, and the need for experienced centers and healthcare workers, and infrastructure, ECMO should only be considered in carefully selected patients with COVID-19 and severe ARDS</p>
</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left" colspan="3">
<bold>THERAPY</bold>
</td>
</tr>
<tr>
<td align="left">41</td>
<td align="left">In mechanically ventilated adults with COVID-19 and respiratory failure (
<bold>without ARDS</bold>
), we
<bold>
<italic>suggest against</italic>
</bold>
the routine use of systemic corticosteroids</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">42</td>
<td align="left">
<p>In mechanically ventilated adults with COVID-19
<bold>and ARDS</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using systemic corticosteroids, over not using corticosteroids</p>
<p>
<italic>Remark:</italic>
The majority of our panel support a weak recommendation (i.e. suggestion) to use steroids in the sickest patients with COVID-19 and ARDS. However, because of the very low-quality evidence, some experts on the panel preferred not to issue a recommendation until higher quality direct evidence is available</p>
</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">43</td>
<td align="left">
<p>In mechanically ventilated patients with COVID-19 and respiratory failure, we
<bold>
<italic>suggest</italic>
</bold>
using empiric antimicrobials/antibacterial agents, over no antimicrobials</p>
<p>
<italic>Remark</italic>
: if the treating team initiates empiric antimicrobials, they should assess for de-escalation daily, and re-evaluate the duration of therapy and spectrum of coverage based on the microbiology results and the patient’s clinical status</p>
</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">44</td>
<td align="left">For critically ill adults with COVID-19 who develop fever, we
<bold>
<italic>suggest</italic>
</bold>
using acetaminophen/paracetamol for temperature control, over no treatment</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">45</td>
<td align="left">In critically ill adults with COVID-19, we
<bold>
<italic>suggest against</italic>
</bold>
the routine use of standard intravenous immunoglobulins (IVIG)</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">46</td>
<td align="left">In critically ill adults with COVID-19, we
<bold>
<italic>suggest against</italic>
</bold>
the routine use of convalescent plasma</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">47.1</td>
<td align="left">In critically ill adults with COVID-19: we
<bold>suggest against</bold>
the routine use of lopinavir/ritonavir</td>
<td align="left">Weak</td>
</tr>
<tr>
<td align="left">47.2</td>
<td align="left">
<bold>There is insufficient evidence to issue a recommendation</bold>
on the use of other antiviral agents in critically ill adults with COVID-19</td>
<td align="left">No recommendation</td>
</tr>
<tr>
<td align="left">48</td>
<td align="left">
<bold>There is insufficient evidence to issue a recommendation</bold>
on the use of recombinant rIFNs, alone or in combination with antivirals, in critically ill adults with COVID-19</td>
<td align="left">No recommendation</td>
</tr>
<tr>
<td align="left">49</td>
<td align="left">
<bold>There is insufficient evidence to issue a recommendation</bold>
on the use of chloroquine or hydroxychloroquine in critically ill adults with COVID-19</td>
<td align="left">No recommendation</td>
</tr>
<tr>
<td align="left">50</td>
<td align="left">
<bold>There is insufficient evidence to issue a recommendation</bold>
on the use of tocilizumab in critically ill adults with COVID-19</td>
<td align="left">No recommendation</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
<sec id="Sec11">
<title>Updating the recommendations</title>
<p id="Par24">We will have periodic automated electronic searches sent to assigned panel members every week to identify relevant new evidence as it emerges. Accordingly, we will issue further guideline releases in order to update the recommendations, if needed, or formulate new ones.
<list list-type="simple">
<list-item>
<label>I.</label>
<p id="Par25">
<bold>Infection Control</bold>
</p>
</list-item>
</list>
</p>
</sec>
</sec>
<sec id="Sec12">
<title>Risk of SARS-CoV-2 transmission</title>
<p id="Par26">A recent report from the Chinese Center of Disease Control and Prevention described 72,314 cases of COVID-19 from China, of which 44,672 were laboratory confirmed. Among laboratory-confirmed cases, 1716 (3.8%) were healthcare workers, most of whom, 63% (1080 of 1716), acquired the infection in Wuhan. The report describes that 14.8% (247 of 1668) of infected healthcare workers had severe or critical illness, and that 5 died [
<xref ref-type="bibr" rid="CR12">12</xref>
]. In Italy, as of March 15, 2020, there are 2026 documented COVID-19 cases among healthcare workers [
<xref ref-type="bibr" rid="CR13">13</xref>
]. Although incidence data is not available, these data point to a considerable burden of infection among healthcare workers. The risk of patient-to-patient transmission in the ICU is currently unknown, therefore, adherence to infection control precautions is paramount.</p>
<p id="Par27">Healthcare workers should follow the infection control policies and procedures already in place at their healthcare institutions. We provide the following recommendations and suggestions as considerations rather than a requirement to change institutional infection control policies.
<table-wrap id="Taba">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>1. For healthcare workers performing
<bold>aerosol-generating procedures</bold>
* on patients with COVID-19 in the ICU, we
<bold>
<italic>recommend</italic>
</bold>
using
<bold>fitted respirator masks</bold>
(
<bold>N95 respirators, FFP2, or equivalent)</bold>
, as opposed to surgical/medical masks, in addition to other personal protective equipment (i.e. gloves, gown,and eye protection, such as a face shield or safety goggles)</p>
<p>
<italic>Best practice statement</italic>
.</p>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>*Aerosol-generating procedures in the ICU include: endotracheal intubation, bronchoscopy, open suctioning, administration of nebulized treatment, manual ventilation before intubation, physical proning of the patient, disconnecting the patient from the ventilator, non-invasive positive pressure ventilation, tracheostomy, and cardiopulmonary resuscitation</p>
</table-wrap-foot>
</table-wrap>
</p>
<sec id="Sec13">
<title>Rationale</title>
<p id="Par28">Respirator masks are designed to block 95–99% of aerosol particles. The N95 type conforms to United States Federal Drug Agency standards, and the FFP2 conforms to European standards—European Committee for Standards standards). Staff should be fit tested for each different type. Surgical masks (also known as medical masks) are designed to block large particles, droplets and sprays, but are less effective in blocking small particle aerosols (< 5 μm) [
<xref ref-type="bibr" rid="CR14">14</xref>
].</p>
<p id="Par29">This recommendation is based on a consensus of recommendations from the CDC, WHO, and other public health organizations, along with epidemiologic data demonstrating that aerosol-generating procedures increased risk to healthcare workers during the SARS epidemic. Powered air purifying respirators (PAPRs) can be used by healthcare workers who failed N95 mask fit testing and when N95s are in limited supply.
<table-wrap id="Tabb">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>2. We
<bold>
<italic>recommend</italic>
</bold>
performing
<bold>aerosol-generating procedures</bold>
on ICU patients with COVID-19 in a negative pressure room .</p>
<p>
<italic>Best practice statement</italic>
</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec14">
<title>Rationale</title>
<p id="Par30">Negative pressure rooms are an engineering control intended to prevent the spread of contagious airborne pathogens from room to room (e.g. measles, and tuberculosis). The main goal is to avoid the accidental release of pathogens into a larger space and open facility, thereby protecting healthcare workers and patients in a hospital setting. Negative air pressure is created in the patient’s room to keep the pathogen inside and avoid its diffusion. By adopting this precaution when aerosol-generating procedures like tracheal intubation, bronchoscopies, or non-invasive positive pressure ventilation (NIPPV) are performed within the room, there is a lower risk of cross-contamination among rooms and infection for staff and patients outside the room. Negative pressure is created and maintained by a ventilation system that allows extra air to enter the isolated room by differential pressure, and be exhausted directly to the outside or be filtered through a high-efficiency particulate air (HEPA) filter directly before recirculation. Moreover, the presence of unnecessary staff in the room should be avoided.</p>
<p id="Par31">Negative pressure rooms have proven to be an effective measure that helped to avoid cross-contamination during the SARS epidemic [
<xref ref-type="bibr" rid="CR15">15</xref>
]. Accordingly, for aerosol-generating procedures, the WHO guidance on COVID-19 recommends the use of negative pressure rooms with a minimum of 12 air changes per hour or at least 160 L/second/patient in facilities with natural ventilation [
<xref ref-type="bibr" rid="CR16">16</xref>
]. Bronchoscopies are among the procedures at highest risk of aerosolization, and their use should be minimized. Non-invasive ventilation is also at high risk of aerosolization, and strategies have been described to contain the risk [
<xref ref-type="bibr" rid="CR17">17</xref>
] of virus spread, also according to a previous report on SARS infection [
<xref ref-type="bibr" rid="CR18">18</xref>
].</p>
<p id="Par32">Where this is not feasible, a portable HEPA filter should be used in the room wherever possible. A HEPA filter is a mechanical air filter, used for isolation where maximum reduction or removal of submicron particulate matter from air is required. HEPA filters have been demonstrated to reduce virus transmission in simulated settings [
<xref ref-type="bibr" rid="CR19">19</xref>
].
<table-wrap id="Tabc">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendations</bold>
</td>
</tr>
<tr>
<td align="left">
<p>3. For healthcare workers providing usual care for non-ventilated COVID-19 patients, we
<bold>
<italic>suggest</italic>
</bold>
using surgical/medical masks, as opposed to respirator masks, in addition to other personal protective equipment (i.e. gloves, gown, and eye protection, such as a face shield or safety goggles).</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
<tr>
<td align="left">
<p>4. For healthcare workers who are performing
<bold>non-aerosol-generating procedures</bold>
on mechanically ventilated (closed circuit) patients with COVID-19, we
<bold>suggest</bold>
using surgical/medical masks, as opposed to respirator masks, in addition to other personal protective equipment (i.e. gloves, gown, and eye protection, such as a face shield or safety goggles).</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec15">
<title>Rationale</title>
<p id="Par33">Our recommendations are in line with the WHO guidance, and with the current evidence, which suggests that surgical/medical masks are probably not inferior to N95 respirators for providing protection against laboratory confirmed seasonal respiratory viral infections (e.g. influenza, but not measles). We updated the most recent systematic review and meta-analysis of RCTs [
<xref ref-type="bibr" rid="CR20">20</xref>
], and identified one new RCT [
<xref ref-type="bibr" rid="CR21">21</xref>
]. Overall, 4 RCTs (5549 individuals) randomized healthcare workers to N95 respirators or medical masks [
<xref ref-type="bibr" rid="CR21">21</xref>
<xref ref-type="bibr" rid="CR25">25</xref>
]. The use of medical masks, as opposed to N95 respirators, did not increase laboratory-confirmed respiratory infection (OR 1.06, 95% CI 0.90–1.25). Although the point estimates suggest that use of medical masks was associated with increased risk of influenza-like illness (OR 1.31, 95% CI 0.94, 1.85) and clinical respiratory infection (OR 1.49, 95% CI 0.98–2.28), the differences were not statistically significant. A recent systematic review and meta-analysis reached similar conclusions [
<xref ref-type="bibr" rid="CR26">26</xref>
].</p>
<p id="Par34">Only one RCT reported on coronavirus. On testing for seasonal coronavirus (OC43, HKU1, 229E, NL63) by means of PCR in this non-cluster RCT, 4.3% (9/212) of nurses in the medical mask group had RT-PCR confirmed coronavirus infection as compared with 5.7% (12/210) in the N95 respirator group [
<xref ref-type="bibr" rid="CR22">22</xref>
].</p>
<p id="Par35">When making these recommendations, the panel considered the lack of convincing evidence that N95 respirators improve clinical outcomes, the cost and resources associated with N95 mask use, and the need to preserve the N95 respirator supply for aerosol-generating procedures. Therefore, the panel issued a suggestion to use medical masks in this context. However, SARS-CoV-2 appears to be more easily transmissible and lethal than seasonal influenza. Specifically, an early estimate of the reproductive number (R
<sub>0</sub>
) of SARS-CoV-2, the average number of people an infected person subsequently infects as a function of biological properties of the pathogen in combination with social and environmental factors, is 2.3 [
<xref ref-type="bibr" rid="CR27">27</xref>
]. By comparison, the estimated average R
<sub>0</sub>
for the 1918 influenza pandemic that resulted in an estimated 50 million deaths globally was 1.8, and the estimated average R
<sub>0</sub>
for seasonal influenza is 1.28 [
<xref ref-type="bibr" rid="CR28">28</xref>
]. Therefore, a minimum of a surgical/medical mask is recommended for healthcare workers caring for non-ventilated COVID-19 patients and for healthcare workers who are performing non-aerosol-generating procedures on mechanically ventilated (closed circuit) patients with COVID-19. When scarcity is not an issue, use of a fitted respirator use of a fitted respirator mask is a reasonable option.
<table-wrap id="Tabd">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>5. For healthcare workers performing
<bold>endotracheal intubation</bold>
on patients with COVID-19, we
<bold>
<italic>suggest</italic>
</bold>
using video-guided laryngoscopy, over direct laryngoscopy, if available.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec16">
<title>Rationale</title>
<p id="Par36">There is no direct evidence comparing the use of video-laryngoscopy with direct laryngoscopy for intubation of patients with COVID-19. While SARS-CoV-2 appears to be predominantly spread by large respiratory droplets, intubation is likely a small particle (less than 5 μm) aerosol-generating procedure, which increases the risk of transmission to healthcare workers [
<xref ref-type="bibr" rid="CR29">29</xref>
]. Intubation is particularly risky given the close contact of healthcare workers with the patient’s airway and respiratory secretions. Thus, techniques that can reduce the number of attempts at endotracheal intubation and the duration of the procedure and minimize the proximity between the operator and the patient, should be prioritized, potentially reducing the risk of complications in hypoxic COVID-19 patients. In a systematic review including 64 studies and 7044 patients, video-laryngoscopy reduced the risk of failed intubation (OR 0.35, 95% CI 0.19–0.65), without a significant impact upon the proportion of successful first-pass attempts (OR 0.79, 95% CI 0.48–1.3), hypoxia (OR 0.39, 95% CI 0.1–1.44), or time for tracheal intubation [
<xref ref-type="bibr" rid="CR30">30</xref>
,
<xref ref-type="bibr" rid="CR31">31</xref>
]. In patients with difficult airways, the first-attempt success rate may be improved with video-laryngoscopy [
<xref ref-type="bibr" rid="CR32">32</xref>
].</p>
<p id="Par37">Thus, in settings where video-laryngoscopy is available and staff are skilled in its use, we suggest that it be used, in preference to direct laryngoscopy, to maximize the chances of success. Recognizing that not all centers will have rapid access to video-laryngoscopy or skilled users, this recommendation is conditional.
<table-wrap id="Tabe">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left" colspan="2">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left" colspan="2">
<p>6. For COVID-19 patients requiring
<bold>endotracheal intubation</bold>
, we
<bold>
<italic>recommend</italic>
</bold>
that endotracheal intubation be performed by the healthcare worker who is most experienced with airway management in order to minimize the number of attempts and risk of transmission.</p>
<p>
<italic>Best practice statement</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec17">
<title>Rationale</title>
<p id="Par38">Similar to the reasoning above, factors that maximize the chances of first pass success should be used when intubating patients with suspected or confirmed COVID-19. Thus, we recommend that the healthcare operator with the most experience and skill in airway management should be the first to attempt intubation.
<list list-type="simple">
<list-item>
<label>II.</label>
<p id="Par39">
<bold>Laboratory diagnosis and specimens</bold>
</p>
</list-item>
</list>
</p>
</sec>
</sec>
<sec id="Sec18">
<title>Indications for testing ICU patients for SARS CoV-2</title>
<p id="Par40">The WHO recently declared a COVID-19 pandemic. Accordingly, every critically ill patient arriving with evidence of respiratory infection should be considered potentially infected with SARS-CoV-2. Real-time polymerase chain reaction (RT-PCR) is the gold standard for similar viral infections, including SARS [
<xref ref-type="bibr" rid="CR33">33</xref>
]. Notably, COVID-19 poses several diagnostic challenges due to an extended incubation period (approximately 2 weeks) that includes a prolonged interval (approximately 5 days) of viral shedding prior to the onset of symptoms. Moreover, the duration of asymptomatic shedding is not only variable but may also differ based on the anatomic level (upper versus lower) of the infection in the respiratory system [
<xref ref-type="bibr" rid="CR1">1</xref>
,
<xref ref-type="bibr" rid="CR34">34</xref>
]. Accordingly, the performance of biomolecular assay may vary by site of sampling.
<table-wrap id="Tabf">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendations</bold>
</td>
</tr>
<tr>
<td align="left">7. For intubated and mechanically ventilated adults with suspicion of COVID-19:</td>
</tr>
<tr>
<td align="left">
<p>  7.1 For diagnostic testing, we
<bold>
<italic>suggest</italic>
</bold>
obtaining lower respiratory tract samples in preference to upper respiratory tract (nasopharyngeal or oropharyngeal) samples.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
<tr>
<td align="left">
<p>  7.2 With regard to lower respiratory samples, we
<bold>
<italic>suggest</italic>
</bold>
obtaining endotracheal aspirates in preference to bronchial wash or bronchoalveolar lavage samples.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
<sec id="Sec19">
<title>Rationale</title>
<p id="Par41">COVID-19 diagnosis is based on RT-PCR testing of respiratory samples from nasopharyngeal and oropharyngeal swabs, and of lower respiratory tract samples whenever possible. Bronchoalveolar lavage should be limited and performed only if indicated and with adequate precautions, due to the risk of aerosolization and consequent exposure of healthcare professionals. Similarly, sputum induction should be avoided due to increased risk of aerosolization. Tracheal aspirate specimens appear to carry a lower risk of aerosolization, and can sometimes be obtained without disconnecting the patient from the ventilator.</p>
<p id="Par42">The procedures involved in laboratory RT-PCR testing for SARS-CoV-2 using a number of assays currently in use are well described [
<xref ref-type="bibr" rid="CR35">35</xref>
]. Despite the generally high sensitivity and specificity of RT-PCR-based assays [
<xref ref-type="bibr" rid="CR36">36</xref>
], it may not be enough to rely on oropharyngeal swabs specimens alone for SARS-CoV-2 diagnosis due to their low negative predictive value. In a recent study, only 9 out of 19 (47%) oropharyngeal swabs from COVID-19 patients tested positive by RT-PCR [
<xref ref-type="bibr" rid="CR37">37</xref>
]. Similar data were reported using RT-PCR during the 2002–2003 SARS epidemic [
<xref ref-type="bibr" rid="CR38">38</xref>
]. Using seroconversion as the “gold standard” for SARS diagnosis, RT-PCR assays performed on nasopharyngeal and throat specimens were positive only 65 and 70% of the time, respectively. However, no false positives were observed indicating assay specificity of 100%. Similarly, in a study accounting for CT scan findings among suspected COVID-19 cases, 48% with negative oropharyngeal or nasal swabs were considered highly likely cases, and 33% were considered probable cases [
<xref ref-type="bibr" rid="CR39">39</xref>
]. Consequently, a single negative swab from the upper airway does not rule out SARS-CoV-2 infection and repeated sampling from multiple sites, including the lower airway, will increase diagnostic yield. Similarly, given that coinfection with other viral pathogens has been observed, a positive test for another respiratory virus does not rule out COVID-19, and should not delay testing if there is a high suspicion of COVID-19 [
<xref ref-type="bibr" rid="CR40">40</xref>
]. Given this high specificity, a single positive swab confirms the diagnosis of COVID-19 and is enough to trigger infection control precautions and appropriate treatment of the patient.</p>
<p id="Par43">Lower respiratory tract specimens are considered to give a higher diagnostic yield than upper respiratory specimens in patients with pneumonia, consistent with what was observed for SARS [
<xref ref-type="bibr" rid="CR41">41</xref>
], and should therefore be obtained whenever possible.
<list list-type="simple">
<list-item>
<label>III.</label>
<p id="Par44">
<bold>Supportive care</bold>
</p>
</list-item>
<list-item>
<label>A.</label>
<p id="Par45">
<bold>Hemodynamic support</bold>
</p>
</list-item>
</list>
</p>
</sec>
</sec>
<sec id="Sec20">
<title>Shock and cardiac injury in COVID-19 patients</title>
<p id="Par46">The reported prevalence of shock in adult patients with COVID-19 is highly variable (from 1 to 35%), depending on the patient population studied, the severity of illness, and the definition of shock. In a recent report summarizing the epidemiological characteristics of 44,415 Chinese patients with COVID-19, 2087 (5%) were diagnosed as critical cases, defined as severe hypoxemia and/or the presence of other organ failure, including shock [
<xref ref-type="bibr" rid="CR12">12</xref>
]. In another Chinese study of 1099 patients with COVID-19 with similar severity of illness, only 12 (1.1%) developed shock [
<xref ref-type="bibr" rid="CR1">1</xref>
]. In hospitalized patients, the incidence is likely higher [
<xref ref-type="bibr" rid="CR42">42</xref>
] (Table 
<xref rid="Tab3" ref-type="table">3</xref>
), and may reach 20–35% among patients in the ICU [
<xref ref-type="bibr" rid="CR42">42</xref>
,
<xref ref-type="bibr" rid="CR43">43</xref>
].
<table-wrap id="Tab3">
<label>Table 3</label>
<caption>
<p>Epidemiological characteristics in recent COVID-19 reports</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left">Study</th>
<th align="left">n</th>
<th align="left">ICU admission (%)</th>
<th align="left">Cardiac Injury (%)</th>
<th align="left">Shock (%)</th>
<th align="left">NIPPV (%)</th>
<th align="left">Invasive MV (%)</th>
<th align="left">CFR (%)</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left">Huang et al. [
<xref ref-type="bibr" rid="CR44">44</xref>
]</td>
<td char="." align="char">41</td>
<td align="left">32</td>
<td align="left">12</td>
<td char="." align="char">7</td>
<td char="." align="char">24</td>
<td char="." align="char">5</td>
<td align="left">15</td>
</tr>
<tr>
<td align="left">Chen et al. [
<xref ref-type="bibr" rid="CR65">65</xref>
]</td>
<td char="." align="char">99</td>
<td align="left">23</td>
<td align="left"></td>
<td char="." align="char">4</td>
<td char="." align="char">13</td>
<td char="." align="char">4</td>
<td align="left">11</td>
</tr>
<tr>
<td align="left">Wang et al. [
<xref ref-type="bibr" rid="CR43">43</xref>
]</td>
<td char="." align="char">138</td>
<td align="left">26</td>
<td align="left">7</td>
<td char="." align="char">9</td>
<td char="." align="char">11</td>
<td char="." align="char">12</td>
<td align="left"></td>
</tr>
<tr>
<td align="left">Guan et al. [
<xref ref-type="bibr" rid="CR1">1</xref>
]</td>
<td char="." align="char">1099</td>
<td align="left"></td>
<td align="left"></td>
<td char="." align="char">1</td>
<td char="." align="char">5.1</td>
<td char="." align="char">2.3</td>
<td align="left">1</td>
</tr>
<tr>
<td align="left">Yang et al. [
<xref ref-type="bibr" rid="CR42">42</xref>
]</td>
<td char="." align="char">52</td>
<td align="left">100</td>
<td align="left">23</td>
<td char="." align="char">35</td>
<td char="." align="char">55.8</td>
<td char="." align="char">42.3</td>
<td align="left">62</td>
</tr>
<tr>
<td align="left">Zhou et al. [
<xref ref-type="bibr" rid="CR45">45</xref>
]</td>
<td char="." align="char">191</td>
<td align="left">26</td>
<td align="left">17</td>
<td char="." align="char">20</td>
<td char="." align="char">14</td>
<td char="." align="char">17</td>
<td align="left">28</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>
<italic>CFR</italic>
case fatality rate,
<italic>ICU</italic>
intensive care unit,
<italic>NIPPV</italic>
non-invasive positive pressure ventilation</p>
</table-wrap-foot>
</table-wrap>
</p>
<p id="Par47">Cardiac injury (elevation of cardiac injury biomarkers above the 99th percentile upper reference limit) has been reported in 7–23% of patients with COVID-19 in Wuhan, China [
<xref ref-type="bibr" rid="CR42">42</xref>
<xref ref-type="bibr" rid="CR45">45</xref>
]. While the prevalence of cardiac injury may correlate with the prevalence of shock, a lack of systematic screening for cardiac dysfunction in hemodynamically stable patients means that this association cannot be taken as certain (Table 
<xref rid="Tab3" ref-type="table">3</xref>
).</p>
<p id="Par48">The prognosis of patients with COVID-19 and shock has not been systematically reported. In a study of 150 patients from 2 hospitals in Wuhan, China, shock was a major reason for death in 40%, and may, at least in part, be due to fulminant myocarditis [
<xref ref-type="bibr" rid="CR46">46</xref>
].</p>
<p id="Par49">Studies on risk factors associated with shock in patients with COVID-19 are lacking. The majority of those that are available report unadjusted estimates [
<xref ref-type="bibr" rid="CR12">12</xref>
,
<xref ref-type="bibr" rid="CR42">42</xref>
,
<xref ref-type="bibr" rid="CR46">46</xref>
]. Despite methodological limitations, these studies suggest that older age, comorbidities (especially diabetes and cardiovascular disease including hypertension), lower lymphocyte count, higher D-dimer level, and possibly cardiac injury are risk factors to consider.</p>
<sec id="Sec21">
<title>Fluid therapy</title>
<p>
<table-wrap id="Tabg">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>8. In adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using dynamic parameters skin temperature, capillary refilling time, and/or serum lactate measurement over static parameters in order to assess fluid responsiveness.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec22">
<title>Rationale</title>
<p id="Par50">There is no direct evidence addressing the optimal resuscitation strategy in patients with COVID-19 and shock, therefore the panel based this recommendation on indirect evidence drawn from critically ill patients in general.</p>
<p id="Par51">In a systematic review and meta-analysis of 13 RCTs (n = 1652) examining the effect of dynamic assessment of fluid therapy on important patient outcomes in adult ICU patients requiring fluid resuscitation [
<xref ref-type="bibr" rid="CR47">47</xref>
], the use of dynamic assessment to guide fluid therapy was found to reduce mortality (RR 0.59, 95% CI 0.42–0.83), ICU length of stay (MD − 1.16 days, 95% CI − 1.97 to − 0.36) and duration of mechanical ventilation (− 2.98 h, 95% CI − 5.08 to − 0.89). Of note, only one trial focused on patients with septic shock. Dynamic parameters used in these trials included stroke volume variation (SVV), pulse pressure variation (PPV), and stroke volume change with passive leg raising or fluid challenge. Among the examined dynamic parameters, passive leg raising followed by PPV and SVV appears to predict fluid responsiveness with highest accuracy [
<xref ref-type="bibr" rid="CR48">48</xref>
]. The static parameters included components of early goal-directed therapy, e.g. central venous pressure (CVP) and mean arterial pressure (MAP).</p>
<p id="Par52">The use of serum lactate levels to guide resuscitation of patients with shock has been summarized in a systematic review and meta-analysis of 7 RCTs (n = 1301) [
<xref ref-type="bibr" rid="CR49">49</xref>
]. Compared with central venous oxygen saturation (ScVO2) guided therapy, early lactate clearance-directed therapy was associated with a reduction in mortality (RR 0.68, 95% CI 0.56–0.82), shorter ICU length of stay (MD 1.64 days, 95% CI − 3.23 to − 0.05), and shorter duration of mechanical ventilation (MD − 10.22  h, 95% CI − 15.94 to − 4.50). However, a high lactate level does not always indicate hypovolemia; it may also be caused by mitochondrial dysfunction, liver failure, beta-agonists, mesenteric ischemia, or epinephrine.</p>
<p id="Par53">In the ANDROMEDA-SHOCK trial, capillary refill testing (CRT) every 30 min was associated with a non-significant reduction in mortality (HR 0.75, 95% CI 0.55–1.02) compared with serum lactate measurement every 2 h [
<xref ref-type="bibr" rid="CR50">50</xref>
]. CRT is a simple and easy test that can be used in almost any setting. Given the possible improvements in mortality, length of stay, and duration of mechanical ventilation that they may produce, as well as their availability, we suggest using dynamic parameters skin temperature, capillary refilling time, and/or lactate measurement over static parameters to assess fluid responsiveness in patients with COVID-19 and shock.
<table-wrap id="Tabh">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>9. For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using a conservative over a liberal fluid strategy.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec23">
<title>Rationale</title>
<p id="Par54">No direct evidence exists on patients with COVID-19 and shock, therefore the panel used indirect evidence from critically ill patients with sepsis and ARDS to inform this recommendation.</p>
<p id="Par55">A recent systematic review of 9 RCTs (n = 637 patients) comparing restricted versus liberal fluid volumes in the initial resuscitation of patients with sepsis found no statistically significant difference in mortality (RR 0.87, 95% CI 0.69–1.10) and serious adverse events (RR 0.91, 95% CI 0.78–1.05) [
<xref ref-type="bibr" rid="CR51">51</xref>
]. However, all assessed outcomes favored conservative fluid therapy (lower volumes). Importantly, the quantity and quality of evidence were both judged to be very low, suggesting that more research is needed.</p>
<p id="Par56">Correspondingly, in a 2017 meta-analysis of 11 RCTs (n = 2051 patients), adults and children with ARDS or sepsis managed according to a conservative fluid strategy in the post-resuscitation phase of critical illness had more ventilator-free days and shorter ICU stays than patients managed according to a liberal fluid strategy [
<xref ref-type="bibr" rid="CR52">52</xref>
] (see section on respiratory support for more details). In 2011, a large RCT of 3141 febrile African children (FEAST) found that children randomized to fluid boluses with saline or albumin had increased mortality compared with children not receiving fluid boluses [
<xref ref-type="bibr" rid="CR53">53</xref>
].</p>
<p id="Par57">In the absence of data demonstrating a benefit of the use of liberal fluid strategies in critically ill patients with sepsis or ARDS, and considering that the majority of COVID-19 patients in the ICU develop ARDS, we suggest an initial conservative approach to fluid resuscitation in patients with COVID-19 and shock.
<table-wrap id="Tabi">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>10. For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>recommend</italic>
</bold>
using crystalloids over colloids.</p>
<p>
<italic>Strong recommendation, moderate quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec24">
<title>Rationale</title>
<p id="Par58">Since there exists no direct evidence on shock in patients with COVID-19, the panel based this recommendation on indirect evidence from critically ill patients in general.</p>
<p id="Par59">In a systematic review of 69 RCTs (n = 30,020 patients) that compared the use of crystalloids versus colloids in critically ill patients [
<xref ref-type="bibr" rid="CR54">54</xref>
], no outcomes favored the use of colloids. Considering that some colloids are harmful (see below), all colloids are more costly than crystalloids, and availability of colloids is limited in some settings (e.g. some low- and middle-income countries), we recommend using crystalloids for fluid resuscitation in patients with COVID-19 and shock.
<table-wrap id="Tabj">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>11. For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using buffered/balanced crystalloids over unbalanced crystalloids.</p>
<p>
<italic>Weak recommendation, moderate quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec25">
<title>Rationale</title>
<p id="Par60">No direct evidence addresses this question in patients with COVID-19 and shock; the panel therefore based this recommendation on indirect evidence from critically ill patients in general.</p>
<p id="Par61">A systematic review and meta-analysis of 21 RCTs (n = 20,213 patients) comparing intravenous buffered (balanced) crystalloid solutions versus 0.9% saline for resuscitation of critically ill adults and children [
<xref ref-type="bibr" rid="CR55">55</xref>
] reported no significant differences in hospital mortality (OR 0.91, 95% CI 0.83–1.01) or acute kidney injury (OR 0.92, 95% CI 0.84–1.00) between the treatments. However, the point estimates for both outcomes suggest a potential for benefit from buffered crystalloid solutions. In the absence of apparent harm, and considering the roughly equivalent costs, we suggest using buffered crystalloid solutions over unbalanced crystalloid solutions for resuscitation of patients with COVID-19 and shock. In settings with limited availability of buffered solutions, 0.9% saline remains a reasonable alternative.
<table-wrap id="Tabk">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>12. For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>recommend</italic>
</bold>
against using hydroxyethyl starches.</p>
<p>
<italic> Strong recommendation, moderate quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec26">
<title>Rationale</title>
<p id="Par62">Given the absence of direct evidence on patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general.</p>
<p id="Par63">A systematic review of 69 RCTs (n = 30,020 patients) compared the use of crystalloids versus colloids in critically ill patients; 24 of these RCTs (n = 11,177 patients) compared the use of crystalloids with the use of starches [
<xref ref-type="bibr" rid="CR54">54</xref>
]. When the data were pooled, no statistically significant difference in mortality was observed at the end of follow-up (RR 0.97, 95% CI 0.86–1.09), within 90 days (RR 1.01, 95% CI 0.90–1.14), or within 30 days (RR 0.99, 95% CI 0.90–1.09). The authors, however, reported an increased risk of blood transfusion (RR 1.19, 95% CI 1.02–1.39) and renal replacement therapy (RRT) with starches (RR 1.30, 95% CI 1.14–1.48). Given the risk of clinically significant harm and of the apparent absence of benefits from the use of hydroxyethyl starches, we recommend against their use for resuscitation of patients with COVID-19 and shock.
<table-wrap id="Tabl">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>13. For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest against</italic>
</bold>
using gelatins.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec27">
<title>Rationale</title>
<p id="Par64">Since no study has evaluated this question in patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general.</p>
<p id="Par65">In a systematic review of 69 RCTs (n = 30,020 patients) comparing crystalloid versus colloid use in critically ill patients, crystalloids were compared with gelatins in 6 RCTs (n = 1698) [
<xref ref-type="bibr" rid="CR54">54</xref>
]. No statistically significant difference in all-cause mortality was observed at the end of the follow-up (RR 0.89, 95% CI 0.74–1.08), within 90 days (RR 0.89, 95% CI 0.73–1.09), or within 30 days (RR 0.92, 95% CI 0.74–1.16), although point estimates favored the use of crystalloids. Considering the absence of any benefit of gelatins, and their higher costs, we suggest against using gelatins for resuscitation of patients with COVID-19 and shock.
<table-wrap id="Tabm">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>14. For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest against</italic>
</bold>
using dextrans.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec28">
<title>Rationale</title>
<p id="Par66">Given the absence of direct evidence on patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general.</p>
<p id="Par67">A systematic review and meta-analysis on crystalloid versus colloid use in critically ill patients identified 19 trials comparing crystalloids with dextrans (n = 4736) [
<xref ref-type="bibr" rid="CR54">54</xref>
]. It reported similar mortality rates at the end of follow-up (RR 0.99, 95% CI 0.88–1.11) and within 90 days (RR 0.99, 95% CI 0.87–1.12), but a possibly increased risk of blood transfusion in the dextran arm (RR 0.92, 95% CI 0.77–1.10).</p>
<p id="Par68">In view of a possible increased risk of blood transfusion (bleeding) and higher costs associated with dextrans, we suggest against their use for resuscitation of patients with COVID-19 and shock.
<table-wrap id="Tabn">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>15. For the
<bold>acute resuscitation</bold>
of adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest against</italic>
</bold>
the routine use of albumin for initial resuscitation.</p>
<p>
<italic>Weak recommendation, moderate quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec29">
<title>Rationale</title>
<p id="Par69">Since there is no direct evidence on patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general.</p>
<p id="Par70">A systematic review and meta-analysis identified 20 RCTs (n = 13,047) comparing albumin with crystalloid use [
<xref ref-type="bibr" rid="CR54">54</xref>
]. It demonstrated no significant difference in all-cause mortality at the end of the follow-up (RR 0.98, 95% CI 0.92–1.06), within 90 days (RR 0.98, 95% CI 0.92–1.04), or within 30-days (RR 0.99, 95% CI 0.93–1.06). The risks of blood transfusion (RR 1.31, 95% CI 0.95–1.80) and RRT (RR 1.11, 95% CI 0.96–1.27) were also similar.</p>
<p id="Par71">In the absence of a benefit of albumin, and considering its cost and limited availability, we suggest against its routine use for the initial resuscitation of patients with COVID-19 and shock.</p>
</sec>
<sec id="Sec30">
<title>Vasoactive agents</title>
<p>
<table-wrap id="Tabo">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>16. For adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using norepinephrine as the first-line vasoactive agent, over other agents.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec31">
<title>Rationale</title>
<p id="Par72">There is no direct evidence on patients with COVID-19 and shock, therefore the panel based this recommendation on indirect evidence from critically ill patients in general.</p>
<p id="Par73">A systematic review of 28 RCTs (n = 3497 patients) and a clinical practice guideline from 2016 summarized the available body of evidence on the best first-line vasopressor for patients with shock [
<xref ref-type="bibr" rid="CR56">56</xref>
,
<xref ref-type="bibr" rid="CR57">57</xref>
].</p>
<p id="Par74">As norepinephrine is the most widely studied vasoactive agent with a low a priori risk of undesirable effects, we suggest using norepinephrine as the first-line vasoactive agent in patients with COVID-19 and shock.
<table-wrap id="Tabp">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>17. If norepinephrine is not available, we
<bold>
<italic>suggest</italic>
</bold>
using either vasopressin or epinephrine as the first-line vasoactive agent, over other vasoactive agents, for adults with
<bold>COVID-19 and shock</bold>
.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec32">
<title>Rationale</title>
<p id="Par75">In the absence of direct evidence on patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general. In a systematic review of 28 RCTs (n = 3497 patients) norepinephrine was compared with both vasopressin and epinephrine, but no trials directly compared the two options [
<xref ref-type="bibr" rid="CR57">57</xref>
]. If norepinephrine is not available, we suggest using either vasopressin or epinephrine, as both agents have been assessed in RCTs without showing clear evidence of harm. Factors determining the choice between vasopressin and epinephrine may include availability and contraindications to the two agents. With vasopressin, digital ischemia may be a concern; with epinephrine, tachycardia and excess lactate production may be considerations.
<table-wrap id="Tabq">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>18. For adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>recommend against</italic>
</bold>
using dopamine if norepinephrine is available.</p>
<p>
<italic> Strong recommendation, high quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec33">
<title>Rationale</title>
<p id="Par76">Because no direct evidence addresses this question in patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients.</p>
<p id="Par77">A 2016 Cochrane systematic review found 6 RCTs (n = 1400) comparing norepinephrine and dopamine in patients with shock [
<xref ref-type="bibr" rid="CR57">57</xref>
]. When pooled, the results showed no significant difference in all-cause mortality, but the point estimate favored norepinephrine (RR 1.07, 95% CI 0.99–1.16), and an increased risk of arrhythmias (RR 2.34, 95% CI 1.46–3.78) was found in the dopamine arm.</p>
<p id="Par78">On the basis of an increased risk of harm, including a possible increased risk of mortality in patients treated with dopamine, we recommend against using dopamine in patients with COVID-19 and shock where norepinephrine or alternatives are available (see recommendation 17).
<table-wrap id="Tabr">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>19. For adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
adding vasopressin as a second-line agent, over titrating norepinephrine dose, if target mean arterial pressure (MAP) cannot be achieved by norepinephrine alone.</p>
<p>
<italic>Weak recommendation, moderate quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec34">
<title>Rationale</title>
<p id="Par79">In the absence of data on patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general.</p>
<p id="Par80">In a recent clinical practice guideline, the use of vasopressin and vasopressin analogs in critically ill adults with distributive shock was assessed [
<xref ref-type="bibr" rid="CR58">58</xref>
]. Analyzing 25 RCTS (n = 3737 patients), the authors found low certainty of a reduction in mortality (RR 0.91, 95% CI 0.85–0.99), high certainty of a reduction in atrial fibrillation (RR 0.77, 95% CI 0.67–0.88), and moderate certainty of an increased risk of digital ischemia (RR 2.56, 95% CI 1.24–5.25) with the addition of vasopressin or its analogs to catecholamines. Another recent systematic review reached similar conclusion [
<xref ref-type="bibr" rid="CR59">59</xref>
]. In view of these findings, we suggest adding vasopressin as a second-line agent, over titrating norepinephrine dose, if target MAP cannot be achieved by norepinephrine alone in patients with COVID-19 and shock.
<table-wrap id="Tabs">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>20. For adults with
<bold>COVID-19 and shock</bold>
, we
<bold>
<italic>suggest titrating</italic>
</bold>
vasoactive agents to target a MAP of 60–65 mmHg, rather than higher MAP targets.</p>
<p>
<italic>Weak recommendation, moderate quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec35">
<title>Rationale</title>
<p id="Par81">No direct evidence informs this recommendation; it is based on indirect evidence from critically ill patients.</p>
<p id="Par82">A recent individual patient-data meta-analysis of 2 RCTs (n = 894 patients) comparing higher versus lower blood pressure targets for vasopressor therapy in adult patients with shock reported no significant difference in 28-day mortality (OR 1.15, 95% CI 0.87–1.52), 90-day mortality (OR 1.08, 95% CI 0.84–1.44), myocardial injury (OR 1.47, 95% CI 0.64–3.56), or limb ischemia (OR 0.92, 95% CI 0.36–2.10) [
<xref ref-type="bibr" rid="CR60">60</xref>
]. The risk of arrhythmias was increased in patients allocated to the higher target group (OR 2.50, 95% CI 1.35–4.77). Correspondingly, the recently published 65 trial reports an absolute risk difference in mortality of 3% (RR 0.93, 95% CI 0.85–1.03) in favor of a MAP target of 60–65 mmHg (lower target), as compared to a standard of care MAP target (higher target) [
<xref ref-type="bibr" rid="CR61">61</xref>
].</p>
<p id="Par83">With an indication of improved outcome with lower MAP targets (and no firm indication of harm), we suggest titrating vasoactive agents to a target of 60–65 mmHg.
<table-wrap id="Tabt">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>21. For adults with
<bold>COVID-19 and shock with evidence of cardiac dysfunction and persistent hypoperfusion despite fluid resuscitation and norepinephrine</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
adding dobutamine, over increasing norepinephrine dose.</p>
<p>
<italic> Weak recommendation, very low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec36">
<title>Rationale</title>
<p id="Par84">In the absence of direct evidence in patients with COVID-19 and shock, the panel used indirect evidence from critically ill patients to inform this recommendation. In a clinical practice guideline from 2018 assessing the optimal inotropic agent in patients with acute circulatory failure (shock), no RCTs comparing dobutamine vs. placebo or no treatment were identified [
<xref ref-type="bibr" rid="CR62">62</xref>
]. Based on a physiological rationale, we suggest adding dobutamine, over no treatment, in patients with COVID-19 and shock with evidence of cardiac dysfunction and persistent hypoperfusion despite fluid resuscitation and high doses of norepinephrine. The use of dobutamine in shock, including in COVID-19 patients with shock, is a research priority.
<table-wrap id="Tabu">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>22. For adults with
<bold>COVID-19 and refractory shock</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using low-dose corticosteroid therapy (“shock-reversal”), over no corticosteroid therapy.</p>
<p>
<italic> Weak recommendation, very low-quality evidence</italic>
.</p>
</td>
</tr>
<tr>
<td align="left">
<bold>Remark:</bold>
A typical corticosteroid regimen in septic shock is intravenous hydrocortisone 200 mg per day administered either as an infusion or intermittent doses.</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec37">
<title>Rationale</title>
<p id="Par85">Since no data exist on the use of steroids in patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general. Both a 2018 systematic review of 22 RCTs (n = 7297 patients) comparing low-dose corticosteroid therapy versus no corticosteroid therapy in adult patients with septic shock [
<xref ref-type="bibr" rid="CR63">63</xref>
] and a clinical practice guideline [
<xref ref-type="bibr" rid="CR64">64</xref>
] report no significant difference in short-term mortality (RR 0.96, 95% CI 0.91–1.02), long-term mortality (RR 0.96, 95% CI 0.90–1.02), or serious adverse events (RR 0.98, 95% CI 0.90–1.08). However, time to resolution of shock and length of stay in ICU and in hospital were shorter with corticosteroid therapy.</p>
<p id="Par86">As time to resolution of shock and length of stay (especially in ICU) are important cost considerations, we suggest using low-dose corticosteroid therapy in patients with COVID-19 and refractory shock. Below, we provide further guidance on patients with COVID-19 and respiratory failure in the absence of refractory shock.
<list list-type="simple">
<list-item>
<label>B.</label>
<p id="Par87">Ventilatory support</p>
</list-item>
</list>
</p>
<p id="Par88">The prevalence of hypoxic respiratory failure in patients with COVID-19 is 19% [
<xref ref-type="bibr" rid="CR12">12</xref>
]. Recent reports from China showed that 4–13% of COVID-19 patients in these studies received non-invasive positive pressure ventilation (NIPPV), and that 2.3–12% required invasive mechanical ventilation (Table 
<xref rid="Tab3" ref-type="table">3</xref>
) [
<xref ref-type="bibr" rid="CR1">1</xref>
,
<xref ref-type="bibr" rid="CR12">12</xref>
,
<xref ref-type="bibr" rid="CR42">42</xref>
,
<xref ref-type="bibr" rid="CR43">43</xref>
,
<xref ref-type="bibr" rid="CR65">65</xref>
]. Although the true incidence of hypoxic respiratory failure in patients with COVID-19 is not clear, it appears that about 14% will develop severe disease requiring oxygen therapy, and 5% will require ICU admission and mechanical ventilation [
<xref ref-type="bibr" rid="CR12">12</xref>
]. Another study reported on 52 critically ill COVID-19 patients; 67% of these patients had ARDS, 33 (63.5%) received high-flow nasal cannula (HFNC), 56% invasive mechanical ventilation, and 42% NIPPV [
<xref ref-type="bibr" rid="CR42">42</xref>
].</p>
</sec>
<sec id="Sec38">
<title>Risk factors for respiratory failure</title>
<p id="Par89">Risk factors associated with respiratory failure requiring mechanical ventilation are not clearly described in published reports, although from the limited available data, risk factors associated with a critical illness/ICU admission included older age (> 60 years), male gender, and the presence of underlying comorbidities such as diabetes, malignancy, and immunocompromised state [
<xref ref-type="bibr" rid="CR1">1</xref>
,
<xref ref-type="bibr" rid="CR12">12</xref>
,
<xref ref-type="bibr" rid="CR42">42</xref>
,
<xref ref-type="bibr" rid="CR43">43</xref>
]. The CDC reported an overall case-fatality rate (CFR) of 2.3%, with a CFR of 14.8% in patients aged 80 years or older. In critically ill patients, the CFR was 49.0%, and it was higher than 50% in those who received invasive mechanical ventilation. The presence of pre-existing comorbid conditions such as cardiovascular disease, diabetes, chronic respiratory disease, hypertension, and cancer were associated with higher risk of death [
<xref ref-type="bibr" rid="CR12">12</xref>
].
<table-wrap id="Tabv">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendations</bold>
</td>
</tr>
<tr>
<td align="left">
<p>23. In adults with COVID-19, we
<bold>
<italic>suggest</italic>
</bold>
starting supplemental oxygen if the peripheral oxygen saturation (SpO
<sub>2</sub>
) is < 92% (weak recommendation, low-quality evidence), and
<bold>
<italic>recommend</italic>
</bold>
starting supplemental oxygen if SpO
<sub>2</sub>
is < 90%.</p>
<p>
<italic>Strong recommendation, moderate quality evidence</italic>
.</p>
</td>
</tr>
<tr>
<td align="left">
<p>24. In adults with COVID-19 and
<bold>acute hypoxemic respiratory failure on oxygen</bold>
, we
<bold>
<italic>recommend</italic>
</bold>
that SpO
<sub>2</sub>
be maintained no higher than 96%.</p>
<p>
<italic>Strong recommendation, moderate quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec39">
<title>Rationale</title>
<p id="Par90">A recent study described the disease course of 1009 patients with COVID-19 in China and showed that 41% of all hospitalized patients and over 70% of those with severe disease required supplemental oxygen [
<xref ref-type="bibr" rid="CR1">1</xref>
]. In critically ill patients, hypoxia can be detrimental and is associated with poor outcomes [
<xref ref-type="bibr" rid="CR66">66</xref>
]. There are no randomized or non-randomized studies on the use of oxygen in adults with COVID-19. However, the panel used indirect evidence from the acutely ill population to inform the recommendations.</p>
<p id="Par91">A systematic review and meta-analysis of 25 RCTs (16,037 patients) showed that a liberal oxygen strategy is associated with increased risk of hospital mortality (RR1.21, 95% CI 1.03–1.43) in acutely ill patients [
<xref ref-type="bibr" rid="CR67">67</xref>
]. Furthermore, a meta-regression showed a linear association between risk of death and higher SpO
<sub>2</sub>
targets [
<xref ref-type="bibr" rid="CR67">67</xref>
]. The median SpO
<sub>2</sub>
in the liberal oxygen group was 96% (IQR 96–98) across all trials. A recent clinical practice guideline recommended that SpO
<sub>2</sub>
be maintained no higher than 96% [
<xref ref-type="bibr" rid="CR68">68</xref>
].</p>
<p id="Par92">Subsequent trials provided further guidance on oxygenation targets. The ICU-ROX trial randomized 1000 critically ill patients to receive either conservative oxygen (based on a protocol to dial down oxygen) or usual care. This trial showed no difference in 180-day mortality between the two groups (OR 1.05, 95% CI 0.81–1.37) [
<xref ref-type="bibr" rid="CR69">69</xref>
]. The ICU-ROX trial did not compare hyperoxia with a conservative oxygen strategy; instead it compared usual care with a conservative oxygen strategy.</p>
<p id="Par93">The recent LOCO2 trial randomized patients with ARDS to a conservative oxygen arm (target SpO
<sub>2</sub>
88% to 92%) or a liberal oxygen arm (target SpO
<sub>2</sub>
 ≥ 96%). The trial was stopped early for futility and possible harm after 61 deaths had occurred in 205 included patients for 28-day mortality [risk difference (RD) 7.8%, 95% CI; −4.8–20.6] [
<xref ref-type="bibr" rid="CR70">70</xref>
]. At 90 days, the conservative oxygen arm had a higher risk of death (RD 14.0%, 95% CI, 0.7–27.2).</p>
<p id="Par94">Considering the associated patient harm at the extremes of SpO
<sub>2</sub>
targets and the increased cost of liberal oxygen use, as well as the potential to reduce equity if oxygen resources are depleted, the panel issued a strong recommendation against using oxygen to target SpO
<sub>2</sub>
 > 96%, and a strong recommendation to avoid lower values (SpO
<sub>2</sub>
 < 90%). Therefore, a reasonable SpO
<sub>2</sub>
range for patients receiving oxygen is 92–96%.
<table-wrap id="Tabw">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>25. For adults with COVID-19 and
<bold>acute hypoxemic respiratory failure</bold>
despite conventional oxygen therapy, we
<bold>
<italic>suggest using</italic>
</bold>
HFNC over conventional oxygen therapy.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec40">
<title>Rationale</title>
<p id="Par95">As there is no direct evidence on patients with COVID-19, the panel used indirect evidence from the critically ill population to inform this recommendation. In an RCT comparing HFNC with conventional oxygen therapy in patients with acute hypoxic respiratory failure, HFNC resulted in reduced 90-day mortality (OR 0.42, 95% CI 0.21–0.85), but did not reduce the risk of intubation [
<xref ref-type="bibr" rid="CR71">71</xref>
]. A systematic review and meta-analysis of 9 RCTs (2093 patients) showed that HFNC reduces intubation compared with conventional oxygen (RR 0.85, 95% CI 0.74–0.99), but does not affect the risk of death or ICU length of stay [
<xref ref-type="bibr" rid="CR72">72</xref>
<xref ref-type="bibr" rid="CR74">74</xref>
]. Even though the evidence on mortality and length of stay was not as strong, the reduction in the need for intubation is an important finding, particularly from the perspective of pandemics such as COVID-19, where resources such as critical care beds and ventilators may become limited. In addition, in SARS, there are reports of increased transmission of disease to healthcare workers, especially nurses, during endotracheal intubation (OR 6.6, 95% Cl 2.3–18.9) [
<xref ref-type="bibr" rid="CR29">29</xref>
,
<xref ref-type="bibr" rid="CR75">75</xref>
,
<xref ref-type="bibr" rid="CR76">76</xref>
]. Although this is a finding based mostly on retrospective observational studies, HFNC does not seem to confer an increased risk of transmission of disease. In studies evaluating bacterial environmental contamination, HFNC presented a contamination risk similar to that of conventional oxygen [
<xref ref-type="bibr" rid="CR77">77</xref>
]. In SARS, healthcare workers exposed to HFNC were not at increased risk of developing disease [
<xref ref-type="bibr" rid="CR75">75</xref>
]. Finally, patients may find HFNC more comfortable than, or at least as comfortable as, conventional oxygen therapy [
<xref ref-type="bibr" rid="CR71">71</xref>
,
<xref ref-type="bibr" rid="CR74">74</xref>
]. Although some authors advised avoiding the use of HFNC in patients with COVID-19 due to the fear of disease transmission, studies supporting this advice are lacking [
<xref ref-type="bibr" rid="CR78">78</xref>
]. Although some have proposed that patients wear face masks while on HFNC therapy, we are uncertain about the efficacy and safety of this approach. This question could be addressed in future studies.
<table-wrap id="Tabx">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>26. In adults with COVID-19 and
<bold>acute hypoxemic respiratory failure</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
using HFNC over NIPPV.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec41">
<title>Rationale</title>
<p id="Par96">In adults with COVID-19 and acute respiratory failure, we suggest the use of HFNC over NIPPV. In an RCT comparing HFNC with NIPPV in patients with acute hypoxic respiratory failure, HFNC resulted in reduced mortality at 90 days (HR 2.50, 95% CI 1.31–4.78), but did not significantly affect the need for intubation (50% failure rate in NIPPV vs 47% in conventional oxygen and 40% in HFNC groups;
<italic>p</italic>
 = 0.18) [
<xref ref-type="bibr" rid="CR71">71</xref>
]. Another meta-analysis comparing HFNC with NIPPV showed HFNC to decrease the need for intubation of patients, yet without significantly reducing mortality or ICU length of stay [
<xref ref-type="bibr" rid="CR72">72</xref>
]. Additionally, patients may find HFNC more comfortable than NIPPV [
<xref ref-type="bibr" rid="CR71">71</xref>
]. Given the evidence for a decreased risk of intubation with HFNC compared with NIPPV in acute hypoxemic respiratory failure, and studies suggesting that NIPPV may carry a greater risk of nosocomial infection of healthcare providers, we suggest HFNC over NIPPV. However, any patients receiving HFNC or NIPPV should be monitored closely and cared for in a setting where intubation can be facilitated in the event of decompensation, as the failure rate may be high and emergency intubation in an uncontrolled setting may increase the risk of nosocomial infection of healthcare providers [
<xref ref-type="bibr" rid="CR79">79</xref>
,
<xref ref-type="bibr" rid="CR80">80</xref>
].
<table-wrap id="Taby">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>27. In adults with COVID-19 and
<bold>acute hypoxemic respiratory failure</bold>
, if HFNC is not available and there is no urgent indication for endotracheal intubation, we
<bold>suggest</bold>
a trial of NIPPV with close monitoring and short-interval assessment for worsening of respiratory failure.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
<tr>
<td align="left">28.
<bold>We were not able to make a recommendation</bold>
regarding the use of helmet NIPPV compared with mask NIPPV. It is an option, but we are not certain about its safety or efficacy in COVID-19.</td>
</tr>
<tr>
<td align="left">
<p>29. In adults with COVID-19 receiving NIPPV or HFNC, we
<bold>
<italic>recommend</italic>
</bold>
close monitoring for worsening of respiratory status, and early intubation in a controlled setting if worsening occurs.</p>
<p>
<italic> Best practice statement</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec42">
<title>Rationale</title>
<p id="Par97">In adults presenting with hypoxic respiratory failure from COVID-19, there is no direct evidence to support the use of NIPPV; furthermore, some prior studies suggested that it may be associated with an increased risk of infection transmission to healthcare workers. Meta-analyses of RCTs showed reductions in both intubation and mortality risks with NIPPV in hypoxic respiratory failure. However, these meta-analyses included studies focused on immunocompromised, acute cardiogenic pulmonary edema, or post-operative patients; their findings may therefore be less applicable to COVID-19 patients, in whom acute hypoxemic respiratory failure and ARDS are more common presentations. [
<xref ref-type="bibr" rid="CR43">43</xref>
,
<xref ref-type="bibr" rid="CR81">81</xref>
<xref ref-type="bibr" rid="CR83">83</xref>
] In acute hypoxemic respiratory failure with an etiology other than cardiogenic pulmonary edema, NIPPV has a high failure rate. In one RCT, failure was reported in 49% of patients with hypoxic respiratory failure ventilated with NIPPV; these patients therefore required intubation [
<xref ref-type="bibr" rid="CR71">71</xref>
]. In addition, patients with hypoxic respiratory failure randomized to NIPPV had higher mortality (28%, 95% CI 21–37%) than those treated with conventional oxygen therapy (23%, 95% CI 16–33%) or HFNC (13%, 95% CI 7–20%) (
<italic>p</italic>
 = 0.02).</p>
<p id="Par98">In a cohort of Middle East Respiratory Syndrome (MERS) patients, NIPPV was not associated with improved mortality or length of stay, compared with patients who were intubated without trying NIPPV [
<xref ref-type="bibr" rid="CR79">79</xref>
]. However, NIPPV was associated with a high failure rate (92.4%), leading to intubation. Patients who received NIPPV prior to intubation had increased inhaled nitric oxide requirements and increased mortality [
<xref ref-type="bibr" rid="CR79">79</xref>
]. Failure rates in other pandemics, such as influenza, H1N1 and SARS, range from 10 to 70%, while demonstrations of efficacy mainly come from case series and observational studies rather than RCTs, leading to practice variation. In China, the use of NIPPV for pandemic respiratory infection is common, whereas guidelines from Europe, Hong Kong, and the US advise against NIPPV as a first-line therapy in H1N1 [
<xref ref-type="bibr" rid="CR84">84</xref>
]. There are additional concerns over the use of NIPPV in respiratory pandemics like COVID-19: NIPPV may aggravate severe forms of lung injury as a result of injurious transpulmonary pressures and large tidal volumes [
<xref ref-type="bibr" rid="CR85">85</xref>
,
<xref ref-type="bibr" rid="CR86">86</xref>
], and may delay initiation of invasive mechanical ventilation, leading to emergency or more unstable intubations that can increase the risk of transmission to the healthcare team [
<xref ref-type="bibr" rid="CR85">85</xref>
]. In addition, NIPPV is an aerosol-generating procedure that can increase the risk of transmission of disease to healthcare workers [
<xref ref-type="bibr" rid="CR29">29</xref>
]. Several other studies and meta-analyses of SARS have also highlighted the risk of nosocomial spread of the disease with NIPPV [
<xref ref-type="bibr" rid="CR76">76</xref>
,
<xref ref-type="bibr" rid="CR87">87</xref>
].</p>
<p id="Par99">The balance between benefit and harm when using NIPPV in adults with COVID-19 is unclear. If, in certain COVID-19 patients, other forms of respiratory failure, such as acute hypercapnic respiratory failure or acute cardiogenic pulmonary edema, are known to be the cause of respiratory failure, NIPPV may be beneficial [
<xref ref-type="bibr" rid="CR88">88</xref>
,
<xref ref-type="bibr" rid="CR89">89</xref>
]. However, because limited experience with NIPPV in pandemics suggests a high failure rate, we recommend that any patient receiving NIPPV be monitored closely and cared for in a setting where intubation can be facilitated in the event of decompensation [
<xref ref-type="bibr" rid="CR79">79</xref>
,
<xref ref-type="bibr" rid="CR80">80</xref>
]. However, when resources become stretched, there may be insufficient ability to provide invasive ventilation, and even a moderate chance of success with NIPPV may justify its use.</p>
<p id="Par100">If NIPPV is used, helmet NIPPV is an attractive option, if available. A single-center RCT showed decreased intubation and improved mortality from NIPPV delivered by helmet in ARDS patients [
<xref ref-type="bibr" rid="CR90">90</xref>
]. Of particular importance in the setting of a pandemic such as COVID-19, NIPPV by helmet has also been shown to reduce exhaled air dispersion, whereas face masks were insufficient [
<xref ref-type="bibr" rid="CR91">91</xref>
]. However, helmet NIPPV is more expensive, and without direct evidence of benefit in COVID-19 patients, resources should not be utilized to acquire this equipment if is not already available. Figure 
<xref rid="Fig2" ref-type="fig">2</xref>
summarizes the recommendations on HFNC and NIPPV in patients with COVID-19.
<fig id="Fig2">
<label>Fig. 2</label>
<caption>
<p>Summary of recommendations on the initial management of hypoxic COVID-19 patients</p>
</caption>
<graphic xlink:href="134_2020_6022_Fig2_HTML" id="MO2"></graphic>
</fig>
</p>
</sec>
</sec>
<sec id="Sec43">
<title>Invasive Mechanical Ventilation</title>
<p>
<table-wrap id="Tabz">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>30. In mechanically ventilated adults with COVID-19 and ARDS, we
<bold>
<italic>recommend</italic>
</bold>
using low tidal volume (Vt) ventilation (Vt 4–8 mL/kg of predicted body weight), over higher tidal volumes (Vt > 8 mL/kg).</p>
<p>
<italic>Strong recommendation, moderate quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
<sec id="Sec44">
<title>Rationale</title>
<p id="Par101">Currently there are no studies addressing mechanical ventilation strategies in COVID-19 patients. However, the panel of experts believes that mechanically ventilated patients with COVID-19 should be managed similarly to other patients with acute respiratory failure in the ICU.</p>
<p id="Par102">While mechanical ventilation is a potentially life-saving intervention, it can worsen lung injury and, through ventilator-induced lung injury (VILI), contribute to multiorgan failure in patients with ARDS [
<xref ref-type="bibr" rid="CR86">86</xref>
]. One of the main ventilator strategies to minimize VILI is low Vt ventilation.</p>
<p id="Par103">A systematic review and meta-analysis of RCTs found an inverse association between larger Vt gradient and mortality [
<xref ref-type="bibr" rid="CR92">92</xref>
]. In addition, authors found that using a protocolized low Vt strategy with high PEEP (9 RCTs and 1629 patients) reduced the risk of death (RR, 0.80, 95% CI, 0.66–0.98) [
<xref ref-type="bibr" rid="CR92">92</xref>
]. Our analysis of 5 RCTs (1181 patients) showed a reduction in hospital mortality with low Vt ventilation (RR 0.73, 95% CI 0.63–0.85) [
<xref ref-type="bibr" rid="CR93">93</xref>
<xref ref-type="bibr" rid="CR98">98</xref>
]. On the basis of the available body of evidence, several guidelines recommended using low Vt (4–8 mL/kg of predicted body weight) in patients with ARDS [
<xref ref-type="bibr" rid="CR99">99</xref>
,
<xref ref-type="bibr" rid="CR100">100</xref>
].</p>
<p id="Par104">The panel judged the magnitude of benefit to be moderate, the cost to be low, and the intervention to be acceptable and feasible to implement, and they therefore issued a strong recommendation to use low Vt (4–8 mL/kg predicted body weight) when ventilating patients with ARDS (Fig. 
<xref rid="Fig3" ref-type="fig">3</xref>
).
<fig id="Fig3">
<label>Fig. 3</label>
<caption>
<p>Summary of recommendations on the management of patients with COVID-19 and ARDS</p>
</caption>
<graphic xlink:href="134_2020_6022_Fig3_HTML" id="MO3"></graphic>
</fig>
</p>
</sec>
<sec id="Sec45">
<title>Practical considerations</title>
<p id="Par105">The ARDSNet study protocol set the initial Vt at 6 mL/kg which can be increased to 8 mL/kg if the patient is double triggering or if inspiratory airway pressure decreases below PEEP [
<xref ref-type="bibr" rid="CR95">95</xref>
].</p>
<p id="Par106">Strict adherence to target Vt in spontaneously breathing patients with ARDS is a challenge; patient-ventilator dyssynchrony is not uncommon [
<xref ref-type="bibr" rid="CR101">101</xref>
].
<table-wrap id="Tabaa">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>31. For mechanically ventilated adults with COVID-19 and
<bold>ARDS</bold>
, we
<bold>
<italic>recommend</italic>
</bold>
targeting plateau pressures (Pplat) of < 30 cm H
<sub>2</sub>
O</p>
<p>
<italic> Strong recommendation, moderate quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec46">
<title>Rationale</title>
<p id="Par107">There are no clinical trials examining the effect of plateau pressure (Pplat) limitation on COVID-19 induced ARDS. However, there is a large body of indirect evidence in patients with ARDS. Along with low Vt ventilation, Pplat limitation is a lung protective strategy to limit VILI. A systematic review and meta-analysis of RCTs found that using a lung protective strategy including protocolized low Vt and Pplat < 30 cmH
<sub>2</sub>
O (9 RCTs and 1629 patients) reduced the risk of death (RR, 0.80, 95% CI 0.66–0.98)[
<xref ref-type="bibr" rid="CR92">92</xref>
]. A subsequent meta-analysis of RCTs comparing ventilatory strategies with low and high Pplat in patients with ARDS (15 studies) found that short-term mortality was higher in patients with Pplat > 32 cmH
<sub>2</sub>
O during the first week in the ICU (Day 1: RR 0.77, 95% CI 0.66–0.89; Day 3: RR 0.76, 95% CI 0.64–0.90; Day 7: RR 0.78, 95% CI 0.65–0.93)[
<xref ref-type="bibr" rid="CR102">102</xref>
].</p>
<p id="Par108">On the basis of the available body of evidence, several guidelines recommended keeping Pplat < 30 cm H
<sub>2</sub>
O in patients with ARDS [
<xref ref-type="bibr" rid="CR99">99</xref>
,
<xref ref-type="bibr" rid="CR100">100</xref>
].</p>
<p id="Par109">The panel judged the magnitude of benefit to be moderate, the cost to be low, the patients’ values to be consistent, and the intervention to be acceptable and feasible to implement, and therefore, issued a strong recommendation to keep Pplat < 30 cmH
<sub>2</sub>
O when ventilating patients with ARDS.</p>
</sec>
<sec id="Sec47">
<title>Practical considerations</title>
<p id="Par110">The ARDSNet study protocol set the initial Vt at 6 mL/kg, and then measured Pplat (after a 0.5 s inspiratory pause) [
<xref ref-type="bibr" rid="CR95">95</xref>
]. If the Pplat > 30 cmH
<sub>2</sub>
O, Vt could be reduced in 1 mL/kg (to 4 mL/kg) steps until Pplat was within range.
<table-wrap id="Tabab">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>32. For mechanically ventilated adults with COVID-19 and moderate to severe ARDS, we
<bold>
<italic>suggest</italic>
</bold>
using a higher PEEP strategy, over a lower PEEP strategy.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
<tr>
<td align="left">
<bold>Remarks</bold>
: If using a higher PEEP strategy (i.e. PEEP > 10 cm H
<sub>2</sub>
O), clinicians should monitor patients for barotrauma.</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec48">
<title>Rationale</title>
<p id="Par111">In ARDS, extrinsic PEEP is used to prevent repeated opening and closing of alveoli (i.e. atelectotrauma), and therefore to reduce VILI. In addition, PEEP increases and sustains alveolar recruitment, which improves oxygenation and reduces oxygen requirement.</p>
<p id="Par112">There are no clinical trials examining the effect of PEEP on coronavirus-induced ARDS. However, there is a large body of indirect evidence in patients with ARDS. An individual patient data meta-analysis (IPDMA) of the 3 largest trials (2299 patients) of high PEEP [
<xref ref-type="bibr" rid="CR103">103</xref>
<xref ref-type="bibr" rid="CR105">105</xref>
] found no difference in in-hospital mortality in all patients (RR 0.94, 95% CI 0.86–1.04) [
<xref ref-type="bibr" rid="CR106">106</xref>
]. However, in patients with ARDS, a higher PEEP strategy resulted in lower ICU mortality (RR 0.85, 95% CI 0.76–0.95), lower in-hospital mortality (RR 0.90, 95% CI 0.81–1.0), and a reduction in the use of rescue therapies (RR 0.63, 95% CI 0.53–0.75), at the expense of a possible increase in the risk of pneumothorax [
<xref ref-type="bibr" rid="CR106">106</xref>
].</p>
<p id="Par113">A recent systematic review and meta-analysis of 9 RCTs (3612 patients) examined the effect of a higher PEEP strategy on patient-important outcomes [
<xref ref-type="bibr" rid="CR107">107</xref>
]. Overall, a higher PEEP strategy did not reduce hospital mortality (RR 0.92, 95% CI, 0.79–1.07). However, in a subgroup of trials that enrolled patients with oxygenation response to PEEP (6 RCTS, 1888 patients), the use of high PEEP significantly reduced in-hospital mortality, compared with a lower PEEP strategy (RR 0.83, 95% CI 0.69–0.98). Although the body of evidence suggests a beneficial effect of higher PEEP in selected patients, the results are likely to be confounded by the fact that low Vt ventilation was not used in the control arm of these trials [
<xref ref-type="bibr" rid="CR108">108</xref>
].</p>
<p id="Par114">There is no clear and agreed upon definition of higher PEEP; moreover, the optimal PEEP level in ARDS patients is unknown, and is likely to vary based on the extent of disease, lung compliance, and other factors. In the aforementioned IPDMA, the median PEEP level in the high PEEP arm was 15.3 and 13.3 cm H
<sub>2</sub>
O on days 1 and 3, respectively, compared with median values of 9 and 8.2 cm H
<sub>2</sub>
O on days 1 and 3 in the low PEEP arm [
<xref ref-type="bibr" rid="CR106">106</xref>
]. Although arbitrary, clinicians could consider PEEP levels > 10 cm H
<sub>2</sub>
O to constitute a higher PEEP strategy, and PEEP levels < 10 cm H
<sub>2</sub>
O as a lower PEEP strategy.</p>
</sec>
<sec id="Sec49">
<title>Practical considerations</title>
<p id="Par115">Because the IPDMA combined different strategies to set higher PEEP, a reasonable starting point would be to implement a strategy used in the large RCTs that were included (i.e. ALVEOLI, LOV, and ExPRESS) [
<xref ref-type="bibr" rid="CR103">103</xref>
<xref ref-type="bibr" rid="CR105">105</xref>
]. After increasing the PEEP level, clinicians should monitor their patients for evidence of barotrauma. Importantly, higher PEEP may result in higher Pplat, which is associated with its own risks and benefits when Pplat > 30 cmH
<sub>2</sub>
O. Clinicians can use the ARDS Network protocol strategies to determine the optimal PEEP level. Other available strategies include decremental PEEP strategy, the esophageal balloon technique, and electrical impedance tomography. However, the effect of using these techniques on clinical outcomes is unknown.
<table-wrap id="Tabac">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>33. For mechanically ventilated adults with COVID-19 and ARDS, we
<bold>
<italic>suggest</italic>
</bold>
using a conservative fluid strategy over a liberal fluid strategy.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec50">
<title>Rationale</title>
<p id="Par116">The optimal fluid strategy in COVID-19 is not known, however, it is plausible that these patients will respond to fluid similarly to other ARDS patients. The limited data available on COVID-19 show that cardiac failure, alone or in combination with respiratory failure, was the cause of 40% of COVID-19 deaths [
<xref ref-type="bibr" rid="CR46">46</xref>
]. Another study showed that 44% of COVID-19 patients had arrhythmia [
<xref ref-type="bibr" rid="CR43">43</xref>
]. The data suggest the presence of myocardial injury in some patients with COVID-19. Few RCTs have been published that compare conservative or deresuscitative with liberal fluid strategies in ARDS. A recent systematic review included 5 RCTs enrolling 1206 patients with ARDS. The risk of death was similar in both groups: 28% in the conservative fluid strategy group and 31.1% in the liberal strategy group (RR 0.91, 95% CI 0.77–1.07) [
<xref ref-type="bibr" rid="CR52">52</xref>
]. This study included RCTs in critically ill patients with or without ARDS, and the authors found that a conservative fluid strategy increased ventilator-free days (MD 1.82 days; 95% CI 0.53–3.10 days) and reduced ICU length of stay (MD − 1.88 days, 95% CI − 0.12 to − 3.64 days), compared with a liberal fluid strategy. There was no difference in harm, including renal failure between the two groups. The landmark trial in ARDS patients (FACTT) found a significant reduction in the duration of mechanical ventilation with a conservative fluid strategy [
<xref ref-type="bibr" rid="CR109">109</xref>
]. Furthermore, the majority of patients with COVID-19 in the ICU are elderly, and may develop myocardial dysfunction that could limit their ability to handle large fluid volumes [
<xref ref-type="bibr" rid="CR46">46</xref>
]. In view of the moderate benefit observed in other ARDS populations, the possible reduced cost of administering less fluids, and the feasibility of the intervention, the panel issued a weak recommendation favoring conservative fluid strategy in patients with COVID-19 and ARDS
<table-wrap id="Tabad">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>34. For mechanically ventilated adults with COVID-19 and
<bold>moderate to severe ARDS</bold>
, we
<bold>
<italic>suggest</italic>
</bold>
prone ventilation for
<bold>12</bold>
<bold>16</bold>
 
<bold>h</bold>
, over no prone ventilation.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec51">
<title>Rationale</title>
<p id="Par117">In a series of 81 patients with COVID-19, radiographic features progressed over the first 1–2 weeks after symptom onset from predominant ground glass opacities to a mixed pattern of predominant basilar consolidation. This latter pattern may suggest a role for prone ventilation [
<xref ref-type="bibr" rid="CR110">110</xref>
].</p>
<p id="Par118">Prone positioning theoretically makes ventilation more homogeneous by decreasing ventral alveolar distention and dorsal alveolar collapse [
<xref ref-type="bibr" rid="CR111">111</xref>
]. This may reduce the difference between the dorsal and ventral transpulmonary pressures, in addition to reducing lung compression [
<xref ref-type="bibr" rid="CR112">112</xref>
] and improving perfusion [
<xref ref-type="bibr" rid="CR113">113</xref>
].</p>
<p id="Par119">A recent study that described the clinical course of COVID-19 in the ICU showed that prone ventilation was used in 11.5% of patients (6 out of 52) [
<xref ref-type="bibr" rid="CR42">42</xref>
]. However, there are no studies available that describe the clinical course of patients with COVID-19 who were ventilated in the prone position.</p>
<p id="Par120">A recent systematic review and meta-analysis of 9 RCTs (2129 patients) showed that prone ventilation for at least 12 h in patients with moderate to severe ARDS reduced mortality (5 RCTs; RR 0.74, 95% CI 0.56–0.99), but had no effect on mortality in studies that used prone ventilation for < 12 h (3 RCTs; RR 1.03, 95% CI 0.88–1.20). On the other hand, prone ventilation increased the risks of pressure sores (RR 1.22, 95% CI 1.06–1.41) and endotracheal tube obstruction (RR 1.76, 95% CI 1.24–2.50) [
<xref ref-type="bibr" rid="CR114">114</xref>
]. Other systematic reviews reached similar conclusions [
<xref ref-type="bibr" rid="CR115">115</xref>
<xref ref-type="bibr" rid="CR117">117</xref>
].</p>
<p id="Par121">We have moderate certainty that prone ventilation for more than 12 h in patients with moderate to severe ARDS reduces mortality, but may increase the risk of pressure sores and endotracheal tube obstruction. Healthcare workers proning patients with COVID-19 should be trained in the proper technique for proning and take infection control precautions in the event of accidental endotracheal tube disconnection from the ventilator. Proning itself is not associated with significant cost, and we believe that it may provide significant benefit. Further, proning can be implemented in low- and middle-income settings, and efforts should be made to provide the necessary training and education of healthcare workers to facilitate the practice (
<ext-link ext-link-type="uri" xlink:href="https://www.youtube.com/watch%3fv%3dE_6jT9R7WJs">https://www.youtube.com/watch?v=E_6jT9R7WJs</ext-link>
).</p>
</sec>
<sec id="Sec52">
<title>Practical considerations</title>
<p id="Par122">A protocol for proning should be used at all institutions, based on the available resources and level of training. If prone ventilation is used, healthcare workers should be aware of complications such as pressure sores, vascular line and endotracheal tube displacement, facial edema, transient hemodynamic instability, corneal abrasions, brachial plexus injury, and hemodialysis vascular access flow issues.</p>
<p id="Par123">In addition, clinicians should be familiar with the absolute contraindications for prone ventilation, such as unstable spine, open abdomen or open chest (i.e. surgery or trauma). Enteral nutrition via nasogastric or nasoduodenal tube can be continued during proning [
<xref ref-type="bibr" rid="CR118">118</xref>
,
<xref ref-type="bibr" rid="CR119">119</xref>
].
<table-wrap id="Tabae">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">35. For mechanically ventilated adults with COVID-19 and
<bold>moderate to severe ARDS</bold>
:</td>
</tr>
<tr>
<td align="left">
<p>  35.1. (NMBA), over continuous NMBA infusion, to facilitate protective lung ventilation.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
<tr>
<td align="left">
<p>  35.2. In the event of persistent ventilator dyssynchrony, the need for ongoing deep sedation, prone ventilation, or persistently high plateau pressures, we
<bold>
<italic>suggest</italic>
</bold>
using a continuous NMBA infusion for up to 48 h.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec53">
<title>Rationale</title>
<p id="Par124">Several professional societies have issued recommendations on the use of NMBAs in ARDS [
<xref ref-type="bibr" rid="CR100">100</xref>
,
<xref ref-type="bibr" rid="CR120">120</xref>
<xref ref-type="bibr" rid="CR123">123</xref>
]. Most issued recommendations favoring the use of an NMBA infusion in patients with moderate to severe ARDS. These recommendations were mostly based on the pooled estimates from 3 RCTs (431 patients) showing a reduction in 90-day mortality with an NMBA infusion as compared with no NMBA infusion [
<xref ref-type="bibr" rid="CR124">124</xref>
]. However, the results of the Re-evaluation of Systemic Early Neuromuscular Blockade (ROSE) trial challenged those of previous trials. The ROSE trial investigators randomized 1006 patients with moderate or severe ARDS to receive either an infusion of NMBA for 48 h or intermittent NMBA boluses on an as needed basis [
<xref ref-type="bibr" rid="CR125">125</xref>
]. The ROSE trial showed that a continuous infusion of cisatracurium did not improve any patient important outcomes.</p>
<p id="Par125">Due to differences in design between the ROSE trial and the earlier trials, we did not perform a meta-analysis for mortality outcome, although the pooled estimate for barotrauma favored continuous NMBA infusion (RR 0.55, 95% CI 0.35–0.85). The panel suggests that a continuous NMBA infusion should be reserved for patients who have an indication for ongoing paralysis in which intermittent dosing may not suffice, such as patients with persistent ventilator dyssynchrony, and patients needing ongoing deep sedation prone ventilation, or persistently high plateau pressures. The effect of NMBAs on long-term outcomes is unclear.
<table-wrap id="Tabaf">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendations</bold>
</td>
</tr>
<tr>
<td align="left">
<p>36. In mechanically ventilated adults with COVID-19 ARDS, we
<bold>
<italic>recommend against</italic>
</bold>
the routine use of inhaled nitric oxide.</p>
<p>
<italic>Strong recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
<tr>
<td align="left">
<p>37. In mechanically ventilated adults with COVID-19, severe ARDS and hypoxemia despite optimizing ventilation and other rescue strategies, we
<bold>suggest</bold>
a trial of inhaled pulmonary vasodilator as a rescuetherapy; if no rapid improvement in oxygenation is observed, the treatment should be tapered off.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec54">
<title>Rationale</title>
<p id="Par126">There are no studies that describe the use of pulmonary vasodilators in COVID-19 patients. A Cochrane review identified 13 RCTs (1243 patients) on inhaled nitric oxide in ARDS; this treatment showed no significant effect on mortality (RR 1.04, 95% CI 0.9–1.19), and was associated with an increased risk of acute kidney injury (RR 1.59, 95% CI 1.17–2.16). Inhaled nitric oxide results in a transient improvement in oxygenation. The subgroup of studies reporting PaO
<sub>2</sub>
/FiO
<sub>2</sub>
(mm Hg) values up to 24 h after the intervention showed a statistically significant difference in favor of inhaled nitric oxide, which was not present beyond 24 h. No study assessed the use of inhaled nitric oxide as a “rescue” therapy [
<xref ref-type="bibr" rid="CR126">126</xref>
]. Because of the possible harm from inhaled nitric oxide and the absence of a clear mortality benefit, the panel issued a strong recommendation against its routine use in patients with ARDS. However, in view of the finding of improved oxygenation, a trial of inhaled nitric oxide as a “rescue” therapy, after trying other options, is reasonable if available. If inhaled nitric oxide is used without a good response in terms of oxygenation, it should be tapered off to avoid rebound the pulmonary vasoconstriction that can occur with prolonged use and abrupt discontinuation.</p>
<p id="Par127">No adequately powered RCTs have evaluated inhaled prostacyclins such as ilioprost, therefore, we could not recommend against or for their use in severe ARDS.
<table-wrap id="Tabag">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendations</bold>
</td>
</tr>
<tr>
<td align="left">
<p>38. For mechanically ventilated adults with COVID-19 and hypoxemia despite optimizing ventilation, we
<bold>
<italic>suggest</italic>
</bold>
using recruitment maneuvers, over not using recruitment maneuvers.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
<tr>
<td align="left">
<p>39. If recruitment maneuvers are used, we
<bold>
<italic>recommend against</italic>
</bold>
using staircase (incremental PEEP) recruitment maneuvers.</p>
<p>
<italic>Strong recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec55">
<title>Rationale</title>
<p id="Par128">No studies have assessed the role of recruitment maneuvers (RMs) in patients with ARDS secondary to COVID-19. RMs aim to improve oxygenation by increasing transpulmonary pressure to open atelectatic alveoli [
<xref ref-type="bibr" rid="CR127">127</xref>
]. However, exposure to high levels of positive pressure may lead to barotrauma, as well as cause transient hypotension in already critically ill and unstable patients.</p>
<p id="Par129">We assessed 8 indirect RCTs assessing RMs in ARDS patients, including patients with sepsis due to bacterial or viral pneumonia. Varying strategies were used to help recruit atelectatic lungs, however two strategies, in particular, were common in the 8 RCTs included in this meta-analysis. Traditional RMs are described as prolonged inspiratory holds for a set duration of time on higher levels of CPAP, most commonly 35–40 cm H
<sub>2</sub>
O for 40 s [
<xref ref-type="bibr" rid="CR93">93</xref>
,
<xref ref-type="bibr" rid="CR104">104</xref>
,
<xref ref-type="bibr" rid="CR128">128</xref>
,
<xref ref-type="bibr" rid="CR129">129</xref>
]. Incremental PEEP titration RMs are described as incremental increases in PEEP from 25 to 35 to 45 cm H
<sub>2</sub>
0 for 1–2 min each [
<xref ref-type="bibr" rid="CR130">130</xref>
<xref ref-type="bibr" rid="CR133">133</xref>
].</p>
<p id="Par130">In a systematic review and meta-analysis of 6 RCTs (1423 patients), RMs reduced mortality and the use of rescue interventions, and improved oxygenation at 24 h without increasing the risk of barotrauma [
<xref ref-type="bibr" rid="CR134">134</xref>
]. Similarly, we identified 8 RCTs (2544 patients) that reported on in-hospital mortality. In these studies, RMs were not associated with reduced mortality (RR 0.90, 95% CI 0.78–1.04). However, subgroup analyses suggested that traditional RMs significantly reduced mortality (RR 0.85, 95% CI 0.75–0.97), whereas incremental PEEP titration RMs increased mortality (RR 1.06, 95% CI 0.97–1.17). While the effects of RMs on oxygenation may be transient, the studies showed a significant improvement in oxygenation after 24 h. Trials used different PEEP strategies in intervention and control arms; RMs are best combined with a higher PEEP strategy.</p>
<p id="Par131">Patients with severe ARDS and hypoxemia may benefit from traditional recruitment maneuvers along with higher levels of PEEP, but evidence specific to COVID-19 is needed. Patients receiving RMs should be monitored closely for severe desaturation, hypotension or barotrauma. RMS should be stopped if they lead to patient deterioration.
<table-wrap id="Tabah">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>40. In mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimizing ventilation, use of rescue therapies, and proning, we
<bold>
<italic>suggest</italic>
</bold>
using venovenous (VV) ECMO if available, or referring the patient to an ECMO center.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
<p>
<bold>Remark</bold>
: Due to the resource-intensive nature of ECMO, and the need for experienced centers and healthcare workers, and infrastructure, ECMO should only be considered in carefully selected patients with COVID-19 and severe ARDS.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec56">
<title>Rationale</title>
<p id="Par133">There are no clinical trials of ECMO in COVID-19 patients. A recent report from China suggested that 11.5% of COVID-19 cases in the ICU received ECMO [
<xref ref-type="bibr" rid="CR42">42</xref>
], but the clinical courses and the outcomes of these patients have not been reported yet.</p>
<p id="Par134">The Ministry of Health in Saudi Arabia established an ECMO program during the MERS-CoV epidemic. In a retrospective cohort study of 35 patients with MERS-CoV and refractory hypoxemia, the group of patients who received VV ECMO had lower in-hospital mortality (65 vs. 100%,
<italic>p</italic>
 = 0.02) [
<xref ref-type="bibr" rid="CR135">135</xref>
]. However, this cohort study is at high risk of selection bias given its retrospective design.</p>
<p id="Par135">Only two RCTs have evaluated ECMO vs. conventional mechanical ventilation in severe ARDS. Guidelines published in 2017 were unable to provide specific guidance on the use of ECMO, and further research was recommended [
<xref ref-type="bibr" rid="CR99">99</xref>
]. Although the most recent RCT (EOLIA) was stopped early for futility [
<xref ref-type="bibr" rid="CR136">136</xref>
], a re-analysis of this trial using a Bayesian approach provided a more favorable interpretation, suggesting lower mortality with ECMO in severe ARDS [
<xref ref-type="bibr" rid="CR137">137</xref>
]. A recent systematic review including two RCTs (429 patients) found a reduction in 60-day mortality with ECMO (RR 0.73, 95% CI 0.58–0.92), but the risk of major bleeding was higher with ECMO [
<xref ref-type="bibr" rid="CR138">138</xref>
].</p>
<p id="Par136">ECMO is a resource-intensive technique restricted to specialized centers, and it remains an extremely limited resource. Therefore, its use as a rescue therapy should be reserved for carefully selected patients [
<xref ref-type="bibr" rid="CR139">139</xref>
]. Future studies describing the outcomes of COVID-19 patients on ECMO and the mechanisms of death will advance our understanding and guide practice.
<list list-type="simple">
<list-item>
<label>IV.</label>
<p id="Par137">
<bold>COVID-19 therapy</bold>
</p>
</list-item>
</list>
</p>
<p id="Par138">In this section we will discuss possible treatment options for SARS CoV-2 and its complications, including antiviral agents, immunosuppressive agents, immunomodulators and other therapies.</p>
</sec>
</sec>
<sec id="Sec57">
<title>Cytokine storm syndrome</title>
<p id="Par139">Cytokine storm syndrome is a hyperinflammatory state that is characterized by fulminant multi-organ failure and elevation of cytokine levels. A recent study from China showed that COVID-19 is associated with a cytokine elevation profile that is reminiscent of secondary hemophagocytic lymphohistiocytosis (HLH) [
<xref ref-type="bibr" rid="CR44">44</xref>
]. Some authors even suggest that we screen critically ill COVID-19 patients for secondary HLH using the Hscore [
<xref ref-type="bibr" rid="CR140">140</xref>
], and that corticosteroids and other immunosuppressive agents can be used in patients with a high likelihood of HLH [
<xref ref-type="bibr" rid="CR141">141</xref>
]. More evidence is needed before we can make recommendations on the treatment options for cytokine storm.
<table-wrap id="Tabai">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendations</bold>
</td>
</tr>
<tr>
<td align="left">
<p>41. In mechanically ventilated adults with COVID-19 and respiratory failure (
<bold>without ARDS</bold>
), we
<bold>
<italic>suggest against</italic>
</bold>
the routine use of systemic corticosteroids.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
<tr>
<td align="left">
<p>42. In mechanically ventilated adults with COVID-19
<bold>and ARDS</bold>
, we suggest using systemic corticosteroids, over not using corticosteroids.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
<p>
<bold>Remark:</bold>
The majority of our panel support a weak recommendation (i.e. suggestion) to use steroids in the sickest patients with COVID-19 and ARDS. However, because of the very low-quality evidence, some experts on the panel preferred not to issue a recommendation until higher quality direct evidence is available.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
<sec id="Sec58">
<title>Rationale</title>
<p id="Par141">There are no controlled clinical trials on the use of corticosteroids in COVID-19 patients or other coronaviruses. A published, but not peer-reviewed, report of 26 patients with severe COVID-19 reports that the use of methylprednisolone at 1–2 mg/kg/day for 5–7 days was associated with shorter duration of supplemental oxygen use (8.2 days vs. 13.5 days;
<italic>p</italic>
 < 0.001) and improved radiographic findings [
<xref ref-type="bibr" rid="CR142">142</xref>
]. Although interesting, we judged these preliminary reports to be an insufficient basis for formulating recommendations, due to the risk of confounding. Therefore, we used indirect evidence from community acquired pneumonia, ARDS, and other viral infections to inform our recommendation.</p>
<p id="Par142">There are several RCTs on the use of systemic corticosteroids in hospitalized patients with community-acquired pneumonia, mostly non-ICU patients, some with sepsis or septic shock. A systematic review and meta-analysis of RCTs showed that using corticosteroids may reduce the need for mechanical ventilation (5 RCTs; 1060 patients; RR 0.45, 95% CI 0.26–0.79), ARDS (4 RCTs; 945 patients; RR 0.24, 95% CI 0.10–0.56) and the duration of hospitalization (6 RCTs; 1499 patients; MD − 1.00 day, 95% CI, − 1.79 to − 0.21), but increase the risk of hyperglycemia requiring treatment [
<xref ref-type="bibr" rid="CR143">143</xref>
]. However, these trials included different populations, the effect on mortality outcome was unclear, and they used different drugs and dosing regimens. In addition, there are some concerns about corticosteroid use in viral pneumonias. Therefore, the results may not be generalizable to the COVID-19 population.</p>
<p id="Par143">There are many published observational studies on the use of steroids in viral pneumonias (i.e. influenza virus, coronaviruses, and others), but they are prone to confounding, as sicker patients usually receive corticosteroids. We updated a recent Cochrane review on the use of corticosteroids in influenza [
<xref ref-type="bibr" rid="CR144">144</xref>
] and searched for studies on other coronaviruses. We included a total of 15 cohort studies on influenza and 10 on coronaviruses. Our meta-analysis of adjusted ORs showed an association between corticosteroid use and increased mortality (OR 2.76, 95% CI 2.06–3.69), but the effect in the patients with other coronaviruses was unclear (OR 0.83, 95% CI 0.32–2.17). Also, these studies are limited by significant heterogeneity. We found significant homogeneity between observational studies on the use of corticosteroids in ARDS caused by coronaviruses and in general viral ARDS (I
<sup>2</sup>
 = 82% and 77% respectively). Furthermore, in both cases, the summary statistic tended toward harm with the use of steroids.</p>
<p id="Par144">We updated a recent Cochrane review [
<xref ref-type="bibr" rid="CR145">145</xref>
] and identified an additional RCT [
<xref ref-type="bibr" rid="CR146">146</xref>
] dealing with ARDS. Overall, we included 7 RCTs enrolling 851 patients with ARDS. The use of corticosteroids reduced mortality (RR 0.75, 95% CI 0.59–0.95) and duration of mechanical ventilation (MD − 4.93 days, 95% CI − 7.81 to − 2.06). However, these trials were not focused on viral ARDS, which limits the generalizability of their results to COVID-19 patients. In addition, we reviewed observational studies on corticosteroid use in viral ARDS, and identified 4 cohort studies. Although the point estimate showed increased mortality, the CI included substantial harm and benefit (OR 1.40, 95% CI 0.76–2.57). In a recent RCT (INTEREST trial), the use of recombinant interferon β1b (rIFN β1ba) did not reduce mortality in ARDS patients, but in the subgroup of patients receiving corticosteroids, rIFN β1ba use was associated with increased mortality (OR, 2.53, 95% CI 1.12–5.72) [
<xref ref-type="bibr" rid="CR147">147</xref>
]. The only direct evidence comes from a retrospective cohort study of 201 patients with COVID-19 pneumonia. This study showed an association between corticosteroid use and lower mortality in patients with COVID-19 and ARDS (HR 0.38, 95% CI 0.20–0.72). However, the estimate was not adjusted for confounding factors [
<xref ref-type="bibr" rid="CR148">148</xref>
].</p>
<p id="Par145">The effect of corticosteroids in COVID-19 patients with sepsis or septic shock may be different. Recent systematic reviews and meta-analyses of RCTs in sepsis showed small improvements in mortality and faster resolution of shock with corticosteroid use, compared with not using corticosteroids [
<xref ref-type="bibr" rid="CR63">63</xref>
,
<xref ref-type="bibr" rid="CR149">149</xref>
,
<xref ref-type="bibr" rid="CR150">150</xref>
] (see the previous section on hemodynamic support).</p>
<p id="Par146">It is widely recognized that corticosteroids have a range of adverse effects. In viral pneumonia in the ICU, several studies showed increase in viral shedding with corticosteroid use [
<xref ref-type="bibr" rid="CR151">151</xref>
<xref ref-type="bibr" rid="CR153">153</xref>
], potentially indicating viral replication, but the clinical implication of increased viral shedding is uncertain.</p>
<p id="Par147">Considering the above, the panel issued a suggestion against the routine use of systemic corticosteroids for respiratory failure in COVID-19, and a suggestion to use corticosteroids in the sicker population of COVID-19 with ARDS. If clinicians use corticosteroids in ARDS, they should use lower dosing and shorter treatment courses.
<table-wrap id="Tabaj">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>43. In mechanically ventilated patients with COVID-19 and respiratory failure, we
<bold>
<italic>suggest</italic>
</bold>
using empiric antimicrobials/antibacterial agents, over no antimicrobials.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
<tr>
<td align="left">
<bold>Remark</bold>
: if the treating team initiates empiric antimicrobials, they should assess for de-escalation daily, and re-evaluate the duration of therapy and spectrum of coverage based on the microbiology results and the patient’s clinical status.</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec59">
<title>Rationale</title>
<p id="Par148">There are no controlled clinical trials evaluating the use of empiric antimicrobials in COVID-19 patients or other coronaviruses. This recommendation is therefore based upon extrapolation of data from other viral pneumonias, particularly influenza [
<xref ref-type="bibr" rid="CR154">154</xref>
]. Identifying bacterial co-infection or superinfection in patients with COVID-19 is challenging, as the symptoms may be similar to those of the underlying viral infection. The diagnostic difficulty is reflected in high rates of intravenous antibiotics administered in Wuhan: 53% with non-severe disease and > 90% of patients admitted to hospital or the ICU [
<xref ref-type="bibr" rid="CR1">1</xref>
,
<xref ref-type="bibr" rid="CR42">42</xref>
,
<xref ref-type="bibr" rid="CR43">43</xref>
]. Data on the prevalence of bacterial superinfection in patients with COVID-19 are limited, as in larger case studies clinicians were often too overwhelmed to systematically obtain high-quality samples [
<xref ref-type="bibr" rid="CR1">1</xref>
].</p>
<p id="Par149">In critically ill patients with MERS, 18% had bacterial and 5% viral co-infections [
<xref ref-type="bibr" rid="CR155">155</xref>
]. Co-infection with
<italic>Staphylococcus aureus</italic>
is common with influenza pneumonia and can be especially virulent [
<xref ref-type="bibr" rid="CR154">154</xref>
]. Recent clinical practice guidelines recommend initiating empiric antibacterial therapy in adults with community-acquired pneumonia who test positive for influenza [
<xref ref-type="bibr" rid="CR154">154</xref>
]. Data from critically ill patients demonstrate secondary infection in about 11% of cases, although the numbers are small. Isolated organisms included gram-negative organisms such as
<italic>K. pneumoniae, P. aeruganosa,</italic>
and
<italic>S. marcescens.</italic>
On the basis of these limited data it is difficult to determine patterns of superinfection, including the risk of
<italic>S. aureus</italic>
infection, commonly seen in influenza.</p>
<p id="Par150">In patients with COVID-19 and hypoxic respiratory failure requiring mechanical ventilation, the panel suggest empiric antimicrobial treatment, on the basis that superinfection is reasonably common in this population and may to lead to a substantial increase in mortality, as in pandemic influenza [
<xref ref-type="bibr" rid="CR156">156</xref>
<xref ref-type="bibr" rid="CR158">158</xref>
]. Therefore, critically ill patients with suspected or confirmed COVID-19 should be treated with empiric antimicrobial therapy in accordance with the clinical syndrome (e.g. community-acquired or hospital-acquired pneumonia). Secondary infections occur in patients with COVID-19, but the incidence is unknown given the very limited data [
<xref ref-type="bibr" rid="CR159">159</xref>
]. These infections should be treated according to clinical and microbiological data.
<table-wrap id="Tabak">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>44. For critically ill adults with COVID-19 who develop fever, we
<bold>
<italic>suggest</italic>
</bold>
using acetaminophen/paracetamol for temperature control, over no treatment.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec60">
<title>Rationale</title>
<p id="Par151">The majority of patients with COVID-19 develop fever during hospitalization (92% of those with severe disease). In the largest report from China, the median temperature across 1099 patients was 38.3 °C (IQR 37.8–38.9) [
<xref ref-type="bibr" rid="CR1">1</xref>
]. Data from critically ill patients in general are available. We reviewed the literature and identified 12 RCTs (1785 patients) that examined the effect of fever control in the critically ill population, excluding neurological indication for temperature control [
<xref ref-type="bibr" rid="CR160">160</xref>
<xref ref-type="bibr" rid="CR171">171</xref>
]; active temperature management (pharmacologic or non-pharmacologic) did not reduce the risk of death (RR 1.03, 95% CI 0.81–1.31), ICU length of stay (MD − 0.07 days, 95% CI − 0.70–0.56), but it was effective in reducing body temperature (MD − 0.36 °C, 95% CI − 0.42 lower to − 0.29). Given the safety of acetaminophen and lack of harm in the body of evidence, increasing patient comfort through fever management maybe important. Therefore, we issued a suggestion for clinicians to consider using pharmacologic agents for controlling fever in COIVD-19 patients.</p>
<p id="Par152">The use of non-steroidal anti-inflammatory drugs to treat fever in patients with COVID-19 continues to be debated. Until more evidence is available, we suggest using acetaminophen/paracetamol to treat fever.
<table-wrap id="Tabal">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>45. In critically ill adults with COVID-19, we
<bold>suggest against</bold>
the routine use of standard intravenous immunoglobulins (IVIG).</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec61">
<title>Rationale</title>
<p id="Par153">The use of intravenous immunoglobulin (IVIG) has been reported in several series of COVID-19 patients, but no efficacy data are available [
<xref ref-type="bibr" rid="CR172">172</xref>
]. In the absence of adequate titers of neutralizing antibodies, standard intravenous immunoglobulin is unlikely to have a biologic effect in COVID-19. While IVIG may have immunomodulatory actions, its use can, rarely, also be associated with an increased risk of serious adverse events including anaphylactic reactions, aseptic meningitis, renal failure, thromboembolism, hemolytic reactions, transfusion-related lung injury, and other late reactions [
<xref ref-type="bibr" rid="CR173">173</xref>
]. Preparations of anti-SARS-CoV-2 polyclonal or monoclonal antibodies are being developed. However, data from recent trials on the use of antibody-based therapies (immune plasma, hyperimmune globulin, monoclonal antibody to hemagglutinin stalk)[
<xref ref-type="bibr" rid="CR173">173</xref>
] in hospitalized seasonal influenza patients did not demonstrate improvement in outcomes [
<xref ref-type="bibr" rid="CR174">174</xref>
<xref ref-type="bibr" rid="CR176">176</xref>
].
<table-wrap id="Tabam">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">
<p>46. In critically ill adults with COVID-19, we
<bold>suggest against</bold>
the routine use of convalescent plasma.</p>
<p>
<italic>Weak recommendation, low-quality evidence</italic>
.</p>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec62">
<title>Rationale</title>
<p id="Par154">Convalescent plasma obtained from patients who have recovered from COVID-19 has been suggested as a potential therapy that may provide passive immunity from SARS-CoV2-specific antibodies [
<xref ref-type="bibr" rid="CR177">177</xref>
]. Convalescent plasma has been used to treat several other viral infections, including those caused by SARS coronavirus, avian influenza A (H5N1) virus, and influenza A (H1N1) pdm09 virus [
<xref ref-type="bibr" rid="CR178">178</xref>
<xref ref-type="bibr" rid="CR182">182</xref>
]. A recent meta-analysis of observational studies using passive immunotherapy for the treatment of severe acute respiratory infections of viral etiology suggests that convalescent plasma therapy was associated with reduction in mortality (OR 0.25, 95% CI 0.14–0.45) [
<xref ref-type="bibr" rid="CR183">183</xref>
]. During the current outbreak in China, convalescent plasma was used in some patients with COVID-19 [
<xref ref-type="bibr" rid="CR184">184</xref>
]. However, data on the efficacy and safety of convalescent plasma are limited, and the target for sufficient levels of neutralizing antibody titers against SARS-CoV-2 is unknown. A study on MERS concluded that use of convalescent plasma might be feasible but was challenging due to a small pool of potential donors with sufficiently high antibody titers [
<xref ref-type="bibr" rid="CR185">185</xref>
]. An RCT in patients with confirmed Ebola virus disease showed that convalescent plasma, with unknown levels of neutralizing antibodies, was not associated with improvement in survival [
<xref ref-type="bibr" rid="CR186">186</xref>
]. Another RCT in patients with seasonal influenza treated with high-titer versus low-titer anti-influenza immune plasma was terminated for futility because of the lack of effect on the primary outcome measured by a 6-point ordinal scale of clinical status on Day 7 [
<xref ref-type="bibr" rid="CR187">187</xref>
]. Given the lack of convincing evidence from RCTs and the uncertainty surrounding the optimal preparation of convalescent plasma and its safety, we suggest that it should not be routinely used in treating patients with COVID-19 until more evidence is available.
<table-wrap id="Taban">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">47. In critically ill adults with COVID-19:</td>
</tr>
<tr>
<td align="left">  47.1. We
<bold>
<italic>suggest against</italic>
</bold>
the routine use of lopinavir/ritonavir (weak recommendation, low-quality evidence).</td>
</tr>
<tr>
<td align="left">  47.2.
<bold>There is insufficient evidence to issue a recommendation</bold>
on the use of other antiviral agents in critically ill adults with COVID-19.</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec63">
<title>Rationale</title>
<p id="Par155">The prolonged detection of SARS-CoV-2 RNA in the respiratory tract and sometimes other sites of seriously ill COVID-19 patients provides the rationale for administration of antiviral agents to reduce replication in efforts to improve clinical outcomes [
<xref ref-type="bibr" rid="CR45">45</xref>
]. At present, no direct-acting antivirals have been proven to inhibit replication or provide clinical benefit in COVID-19 or MERS patients.</p>
<p id="Par156">A considerable number of agents approved for other indications have been proposed for use, but the comments below address the most promising ones. Several others are undergoing testing (e.g. arbidol [umifenovir], favipiravir, ribavirin, traditional Chinese medicines, inhaled interferons), alone or in combinations, and in one or more countries.</p>
<p id="Par157">Lopinavir is an antiretroviral protease inhibitor used in combination with ritonavir to ensure adequate lopinavir exposure for the treatment of human immunodeficiency virus (HIV) infection [
<xref ref-type="bibr" rid="CR188">188</xref>
]. Because it was found to show in vitro activity against SARS-CoV, lopinavir/ritonavir was administered, in combination with high-dose oral ribavirin and a tapering course of systemic corticosteroids, in a cohort of 41 patients with SARS, and was found to be associated with significantly fewer adverse clinical outcomes (ARDS or death) compared with ribavirin alone used in 111 historical controls that received ribavirin and corticosteroids [
<xref ref-type="bibr" rid="CR189">189</xref>
]. In a high-throughput screening for antiviral compounds, lopinavir inhibited replication of MERS-CoV in vitro [
<xref ref-type="bibr" rid="CR190">190</xref>
]. In an animal model of MERS-CoV infection, treatment with lopinavir/ritonavir or IFN-β1b was associated with virologic, histologic and clinical improvement versus placebo [
<xref ref-type="bibr" rid="CR191">191</xref>
]. Lopinavir/ritonavir in combination with interferon beta 1-b is being tested in an RCT in MERS-CoV patients [
<xref ref-type="bibr" rid="CR192">192</xref>
]. This combination was considered the second candidate in a WHO research prioritization list of therapeutic agents [
<xref ref-type="bibr" rid="CR193">193</xref>
]. The drug has a generally good safety profile, but may have interactions with many drugs commonly used in critically ill patients (
<ext-link ext-link-type="uri" xlink:href="http://www.covid19-druginteractions.org/">http://www.covid19-druginteractions.org/</ext-link>
).</p>
<p id="Par158">A recent RCT compared the use of lopinavir/ritonavir to usual care in 199 hospitalized patients with COVID-19 in China [
<xref ref-type="bibr" rid="CR194">194</xref>
]. In this trial, lopinavir/ritonavir did not significantly reduce 28-day mortality (RD − 5.8%; 95% CI − 17.3 to 5.7) or time to clinical improvement (MD 1.31 days, 95% CI 0.95–1.80). In addition, lopinavir/ritonavir was associated with more adverse events [
<xref ref-type="bibr" rid="CR194">194</xref>
]. This trial is the only available direct evidence on the use of lopinavir/ritonavir in patients with COVID-19, however, it has several limitations. The trial was unblinded and it enrolled a small number of patients (n = 199) with a small number of events (44 deaths in total), which limits our confidence in its results. Nevertheless, the routine use of lopinavir/ritonavir in critically ill patients is probably not warranted, and a weak recommendation against the routine use of lopinavir/ritonavir in critically ill COVID-19 patients is reasonable.</p>
<p id="Par159">Lopinavir/ritonavir is one of the arms in a planned WHO core treatment protocol for hospitalized patients with COVID-19, and in the REMAP-CAP (Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia) trial (NCT02735707) The results of ongoing trials will help increase the precision of estimates and the certainty in the evidence.</p>
<p id="Par160">Remdesivir is the prodrug of an adenosine analog, which incorporates into nascent viral RNA chains and results in premature termination. It was considered the most promising drug in an informal consultation on research prioritization of candidate therapeutic agents by WHO [
<xref ref-type="bibr" rid="CR195">195</xref>
]. Currently, there are published case reports but no published trials on the use of remdesivir in COVID-19. Remdesivir demonstrated effective inhibition of SARS-CoV-2, MERS-CoV, and SARS-CoV in in vitro studies [
<xref ref-type="bibr" rid="CR196">196</xref>
]. Furthermore, studies in animal models of MERS-CoV showed that it was more effective than control and superior to lopinavir/ritonavir combined with systemic IFN-β [
<xref ref-type="bibr" rid="CR197">197</xref>
,
<xref ref-type="bibr" rid="CR198">198</xref>
]. Although intravenous remdesivir appears to adequately tolerated, a recent RCT showed that it was less effective than several antibody therapies in Ebola virus disease [
<xref ref-type="bibr" rid="CR199">199</xref>
]. There are several ongoing RCTs that aim to examine the efficacy and safety of intravenous remdesivir for severe COVID-19 (clinicaltrials.gov NCT04257656) and for mild and moderate COVID-19 (clinicaltrials.gov NCT04252664). Another trial sponsored by the National Institute of Allergy and Infectious Diseases is recruiting patients in USA (clinicaltrials.gov NCT04280705). We will update our guidelines as new evidence emerges.
<table-wrap id="Tabao">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">48.
<bold>There is insufficient evidence to issue a recommendation</bold>
on the use of recombinant rIFNs, alone or in combination with antivirals, in critically ill adults with COVID-19.</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec64">
<title>Rationale</title>
<p id="Par161">Recombinant interferon, often combined with ribavirin therapy, has been used in patients with MERS and SARS [
<xref ref-type="bibr" rid="CR179">179</xref>
,
<xref ref-type="bibr" rid="CR200">200</xref>
<xref ref-type="bibr" rid="CR202">202</xref>
]. Different preparations of recombinant rIFNs (rIFN-α2a, rIFN-α2b, rIFN-β1a and rIFN-β1b) have shown activity against MERS-CoV in Vero and LLC-MK2 cells, and in a rhesus macaque model of MERS-CoV infection [
<xref ref-type="bibr" rid="CR200">200</xref>
,
<xref ref-type="bibr" rid="CR201">201</xref>
,
<xref ref-type="bibr" rid="CR203">203</xref>
]. The largest cohort of critically ill patients with MERS showed that rIFN-α2a, rIFN-α2b, rIFN-β1a and ribavirin were not associated with lower mortality (OR 1.03, 95% CI .73–1.44) or reduced viral clearance when adjusted for time-varying covariables [
<xref ref-type="bibr" rid="CR204">204</xref>
]. The relative effectiveness of different interferons against SARS-CoV-2 is unknown at this point.</p>
<p id="Par162">In vitro data showed that rIFN-β displayed the strongest MERS-CoV inhibition among different rIFN preparations (rIFN-α2b, rIFN-γ, rIFN-universal, and rIFN-α2a, rIFN-β), at 41 times lower than the previously reported 50% inhibitory concentration (IC50) of rIFN-α2b [
<xref ref-type="bibr" rid="CR203">203</xref>
,
<xref ref-type="bibr" rid="CR205">205</xref>
]. An RCT to examine the effect of a combination of lopinavir/ritonavir and rIFN-β-1b on mortality of hospitalized patients with MERS is currently recruiting patients [
<xref ref-type="bibr" rid="CR206">206</xref>
]. Unpublished data indicate that IFN-β inhibits SARS-C0V-2 in cell culture, and IFNs have been prioritized for study in COVID-19 by the WHO.
<table-wrap id="Tabap">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">49.
<bold> There is insufficient evidence to issue a recommendation</bold>
on the use of chloroquine or hydroxychloroquine in critically ill adults with COVID-19.</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec65">
<title>Rationale</title>
<p id="Par163">Chloroquine and its metabolite, hydroxychloroquine, are antimalarial agents that have demonstrated antiviral effects on SARS-CoV and SARS-CoV-2 in vitro [
<xref ref-type="bibr" rid="CR196">196</xref>
,
<xref ref-type="bibr" rid="CR207">207</xref>
,
<xref ref-type="bibr" rid="CR208">208</xref>
]. Prior studies found inhibitory effects of chloroquine for multiple RNA viruses in vitro, but RCTs in treatment of dengue and chikungunya virus infections and of influenza prophylaxis failed to demonstrate antiviral or clinical benefits [
<xref ref-type="bibr" rid="CR209">209</xref>
]. In one non-human primate model of chikungunya infection, it was shown that chloroquine’s immunomodulatory effects were associated with delayed immune responses, higher levels of viral replication, and worse illness [
<xref ref-type="bibr" rid="CR210">210</xref>
]. A news briefing suggested that its use in more than 100 patients showed “that it was superior to the control in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus negative conversion, and shortening the disease course”, but the data have not been published yet [
<xref ref-type="bibr" rid="CR211">211</xref>
]. A recent consensus document recommended chloroquine phosphate 500 mg twice daily for minimum of 5 days, with dose modifications if severe gastrointestinal side effects occur [
<xref ref-type="bibr" rid="CR212">212</xref>
]. Since chloroquine is not available in some countries, hydroxychloroquine is an alternative. A recent study in China explored various dosing regimens of chloroquine and hydroxychloroquine using physiologically-based pharmacokinetic models [
<xref ref-type="bibr" rid="CR208">208</xref>
]. The study found hydroxychloroquine to be more potent than chloroquine in inhibiting SARS-CoV-2 in vitro. Based on these models, a hydroxychloroquine loading dose of 400 mg twice daily followed by 200 mg twice daily for 4 days was recommended [
<xref ref-type="bibr" rid="CR208">208</xref>
]. A recent systematic review found no published studies in COVID-19 patients [
<xref ref-type="bibr" rid="CR213">213</xref>
]. Pending the results of ongoing trials, we were unable to issue a recommendation for or against chloroquine.
<table-wrap id="Tabaq">
<table frame="hsides" rules="groups">
<tbody>
<tr>
<td align="left">
<bold>Recommendation</bold>
</td>
</tr>
<tr>
<td align="left">50.
<bold>There is insufficient evidence to issue a recommendation</bold>
on the use of tocilizumab in critically ill adults with COVID-19.</td>
</tr>
</tbody>
</table>
</table-wrap>
</p>
</sec>
<sec id="Sec66">
<title>Rationale</title>
<p id="Par164">Tocilizumab is a humanized immunoglobulin that functions in the immune response and blocks IL-6 receptor binding to IL-6. It has been approved for CRS and other inflammatory conditions related to IL-6 related inflammation, such as rheumatoid arthritis and juvenile idiopathic arthritis [
<xref ref-type="bibr" rid="CR214">214</xref>
<xref ref-type="bibr" rid="CR217">217</xref>
]. Severely ill patients with COVID-19 may have an extreme immune response leading to severe respiratory failure. In such cases, inhibition of IL-6 may help attenuate the cytokine release syndrome by reducing cytokine concentrations and acute phase reactant production [
<xref ref-type="bibr" rid="CR218">218</xref>
]. Ongoing trials of tocilizumab will help address the safety and efficacy of this therapy in COVID-19.</p>
<p id="Par165">From the rheumatoid arthritis literature, a systematic review and meta-analysis of 6 RCTs (3 with 8/mg dose and 3 with 4 mg/kg dose) showed an increased risk of adverse events compared with control treatment (OR 1.53, 95% CI 1.26–1.86), and an increased risk of infections (OR 1.30, 95% CI 1.07–1.58) [
<xref ref-type="bibr" rid="CR219">219</xref>
]. Another systematic review and meta-analysis of RCTs on tocilizumab in rheumatoid arthritis found an increased risk of infectious respiratory adverse events (RR 1.53, 95% CI 1.04–2.25) [
<xref ref-type="bibr" rid="CR220">220</xref>
]. Since we have no data on the safety or efficacy of tocilizumab in COVID-19, we were unable to issue a recommendation.</p>
</sec>
</sec>
<sec id="Sec67">
<title>Other agents</title>
<p id="Par166">Nafamostat is a synthetic serine protease inhibitor and a potent inhibitor of MERS CoV. Nitazoxanide is an antiprotozoal agent with antiviral potential against several respiratory viruses including influenza, parainfluenza, respiratory syncytial virus, and rhinovirus. An in vitro study showed that both nafamostat and nitazoxanide inhibited SARS-CoV-2 [
<xref ref-type="bibr" rid="CR196">196</xref>
]. An RCT in patients with acute uncomplicated influenza demonstrated that the use of nitazoxanide reduced the duration of symptoms [
<xref ref-type="bibr" rid="CR221">221</xref>
]. However, in hospitalized patients with severe acute respiratory infection in Mexico, nitazoxanide was not found to be superior to placebo [
<xref ref-type="bibr" rid="CR222">222</xref>
].</p>
</sec>
<sec sec-type="supplementary-material">
<title>Electronic supplementary material</title>
<sec id="Sec68">
<p>Below is the link to the electronic supplementary material.
<supplementary-material content-type="local-data" id="MOESM1">
<media xlink:href="134_2020_6022_MOESM1_ESM.docx">
<caption>
<p>Supplementary material 1 (DOCX 3742 kb)</p>
</caption>
</media>
</supplementary-material>
</p>
</sec>
</sec>
</body>
<back>
<fn-group>
<fn>
<p>This article is co-published in the journals Intensive Care Medicine (DOI:10.1007/s00134-020-06022-5) and Critical Care medicine (DOI:10.1097/CCM.0000000000004363).</p>
</fn>
<fn>
<p>
<bold>Publisher's Note</bold>
</p>
<p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p>
</fn>
</fn-group>
<ack>
<title>Acknowledgements</title>
<p>We would like to acknowledge Drs. Zainab Al duhailib, Kimberly Lewis, Malik Farooqi, and Jessica Bartoszko for their support with conducting systematic reviews and meta-analyses for some of the guideline questions.</p>
</ack>
<notes notes-type="funding-information">
<title>Funding</title>
<p>There was no dedicated funding for this guideline.</p>
</notes>
<notes notes-type="ethics">
<title>Compliance with ethical standards</title>
<notes notes-type="COI-statement">
<title>Conflicts of interest</title>
<p id="Par167">Dr. Yaseen Arabi is the principal investigator on a clinical trial for lopinavir/ritonavir and interferon in Middle East respiratory syndrome (MERS) and he was a nonpaid consultant on antiviral active for MERS-coronavirus (CoV) for Gilead Sciences and SAB Biotherapeutics. He is an investigator on REMAP-CAP trial and is a Board Members of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). Dr. Eddy Fan declared receiving consultancy fees from ALung Technologies and MC3 Cardiopulmonary. Dr. Maurizio Cecconi declared consultancy work with Edwards Lifesciences, Directed Systems, and Cheetah Medical. Dr. Lennie Derde is the NVIC (Dutch National ICU society) chair of Taskforce Infectious Diseases (standing committee), member of ESICM Coronavirus Taskforce (started with this outbreak), chair ESICM Clinical Training Committee, all are unpaid positions. Dr. Frederick Hyden is non-compensated consultant to Gilead Sciences (antivirals for RVIS including remdesivir), Regeneraon (monoclonals for RVIs including MERS), and SAB Biotherapeutics (polyclonal antibodies for RVIs including MERS). Other authors declared no conflict of interest.</p>
</notes>
</notes>
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