Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial

Marie Warrer Munch; Tine Sylvest Meyhoff; Marie Helleberg; Maj Brit Nørregaard Kjær; Anders Granholm; Carl Johan Steensen Hjortsø; Thomas Steen Jensen; Morten Hylander Møller; Peter Buhl Hjortrup; Mik Wetterslev; Gitte Kingo Vesterlund; Lene Russell; Vibeke Lind Jørgensen; Klaus Tjelle Kristiansen; Thomas Benfield; Charlotte Suppli Ulrik; Anne Sofie Andreasen; Morten Heiberg Bestle; Lone Musaeus Poulsen; Thomas Hildebrandt; Lene Surland Knudsen; Anders Møller; Christoffer Grant Sølling; Anne Craveiro Brøchner; Bodil Steen Rasmussen; Henrik Nielsen; Steffen Christensen; Thomas Strøm; Maria Cronhjort; Rebecka Rubenson Wahlin; Stephan M. Jakob; Luca Cioccari; Balasubramanian Venkatesh; Naomi Hammond; Vivekanand Jha; Sheila Nainan Myatra; Marie Qvist Jensen; Jens Wolfgang Leistner; Vibe Sommer Mikkelsen; Jens S. Svenningsen; Signe Bjørn Laursen; Emma Victoria Hatley; Camilla Meno Kristensen; Ali Al-Alak; Esben Clapp; Trine Bak Jonassen; Caroline Løkke Bjerregaard; Niels Christian Haubjerg Østerby; Mette Mindedahl Jespersen; Dalia Abou-Kassem; Mathilde Languille Lassen; Reem Zaabalawi; Mohammed Mahmoud Daoud; Suhayb Abdi; Nick Meier; Kirstine la Cour; Cecilie Bauer Derby; Birka Ravnholt Damlund; Jens Laigaard; Lene Lund Andersen; Johan Mikkelsen; Jeppe Lundholm Stadarfeld Jensen; Anders Hørby Rasmussen; Emil Arnerlöv; Mathilde Lykke; Mikkel Zacharias Bystrup Holst-Hansen; Boris Wied Tøstesen; Janne Schwab; Emilie Kabel Madsen; Christian Gluud; Theis Lange; Anders Perner

doi:10.1111/aas.13941

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial

Marie Warrer Munch^*, Tine Sylvest Meyhoff, Marie Helleberg, Maj Brit Nørregaard Kjær, Anders Granholm, Carl Johan Steensen Hjortsø, Thomas Steen Jensen, Morten Hylander Møller, Peter Buhl Hjortrup, Mik Wetterslev, Gitte Kingo Vesterlund, Lene Russell, Vibeke Lind Jørgensen, Klaus Tjelle Kristiansen, Thomas Benfield, Charlotte Suppli Ulrik, Anne Sofie Andreasen, Morten Heiberg Bestle, Lone Musaeus Poulsen, Thomas HildebrandtLene Surland Knudsen, Anders Møller, Christoffer Grant Sølling, Anne Craveiro Brøchner, Bodil Steen Rasmussen, Henrik Nielsen, Steffen Christensen, Thomas Strøm, Maria Cronhjort, Rebecka Rubenson Wahlin, Stephan M. Jakob, Luca Cioccari, Balasubramanian Venkatesh, Naomi Hammond, Vivekanand Jha, Sheila Nainan Myatra, Marie Qvist Jensen, Jens Wolfgang Leistner, Vibe Sommer Mikkelsen, Jens S. Svenningsen, Signe Bjørn Laursen, Emma Victoria Hatley, Camilla Meno Kristensen, Ali Al-Alak, Esben Clapp, Trine Bak Jonassen, Caroline Løkke Bjerregaard, Niels Christian Haubjerg Østerby, Mette Mindedahl Jespersen, Dalia Abou-Kassem, Mathilde Languille Lassen, Reem Zaabalawi, Mohammed Mahmoud Daoud, Suhayb Abdi, Nick Meier, Kirstine la Cour, Cecilie Bauer Derby, Birka Ravnholt Damlund, Jens Laigaard, Lene Lund Andersen, Johan Mikkelsen, Jeppe Lundholm Stadarfeld Jensen, Anders Hørby Rasmussen, Emil Arnerlöv, Mathilde Lykke, Mikkel Zacharias Bystrup Holst-Hansen, Boris Wied Tøstesen, Janne Schwab, Emilie Kabel Madsen, Christian Gluud, Theis Lange, Anders Perner

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

Background: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID-19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low-dose hydrocortisone on patient-centred outcomes in adults with COVID-19 and severe hypoxia. Methods: In this multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. Results: The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: −1.1 days, 95% CI −9.5 to 7.3, P =.79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. Conclusions: In this trial of adults with COVID-19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. Trial registration: ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020-001395-15.

Original language	English
Journal	Acta Anaesthesiologica Scandinavica
Volume	65
Issue number	10
Pages (from-to)	1421-1430
Number of pages	10
ISSN	0001-5172
DOIs	https://doi.org/10.1111/aas.13941
Publication status	Published - Nov 2021

Bibliographical note

Keywords

corticosteroids
COVID-19
hydrocortisone
placebo-controlled trial
randomised clinical trial
SARS-CoV-2

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Munch, M. W., Meyhoff, T. S., Helleberg, M., Kjær, M. B. N., Granholm, A., Hjortsø, C. J. S., Jensen, T. S., Møller, M. H., Hjortrup, P. B., Wetterslev, M., Vesterlund, G. K., Russell, L., Jørgensen, V. L., Kristiansen, K. T., Benfield, T., Ulrik, C. S., Andreasen, A. S., Bestle, M. H., Poulsen, L. M., ... Perner, A. (2021). Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial. Acta Anaesthesiologica Scandinavica, 65(10), 1421-1430. Advance online publication. https://doi.org/10.1111/aas.13941

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title = "Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial",

abstract = "Background: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID-19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low-dose hydrocortisone on patient-centred outcomes in adults with COVID-19 and severe hypoxia. Methods: In this multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. Results: The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: −1.1 days, 95% CI −9.5 to 7.3, P =.79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. Conclusions: In this trial of adults with COVID-19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. Trial registration: ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020-001395-15.",

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author = "Munch, {Marie Warrer} and Meyhoff, {Tine Sylvest} and Marie Helleberg and Kj{\ae}r, {Maj Brit N{\o}rregaard} and Anders Granholm and Hjorts{\o}, {Carl Johan Steensen} and Jensen, {Thomas Steen} and M{\o}ller, {Morten Hylander} and Hjortrup, {Peter Buhl} and Mik Wetterslev and Vesterlund, {Gitte Kingo} and Lene Russell and J{\o}rgensen, {Vibeke Lind} and Kristiansen, {Klaus Tjelle} and Thomas Benfield and Ulrik, {Charlotte Suppli} and Andreasen, {Anne Sofie} and Bestle, {Morten Heiberg} and Poulsen, {Lone Musaeus} and Thomas Hildebrandt and Knudsen, {Lene Surland} and Anders M{\o}ller and S{\o}lling, {Christoffer Grant} and Br{\o}chner, {Anne Craveiro} and Rasmussen, {Bodil Steen} and Henrik Nielsen and Steffen Christensen and Thomas Str{\o}m and Maria Cronhjort and Wahlin, {Rebecka Rubenson} and Jakob, {Stephan M.} and Luca Cioccari and Balasubramanian Venkatesh and Naomi Hammond and Vivekanand Jha and Myatra, {Sheila Nainan} and Jensen, {Marie Qvist} and Leistner, {Jens Wolfgang} and Mikkelsen, {Vibe Sommer} and Svenningsen, {Jens S.} and Laursen, {Signe Bj{\o}rn} and Hatley, {Emma Victoria} and Kristensen, {Camilla Meno} and Ali Al-Alak and Esben Clapp and Jonassen, {Trine Bak} and Bjerregaard, {Caroline L{\o}kke} and {\O}sterby, {Niels Christian Haubjerg} and Jespersen, {Mette Mindedahl} and Dalia Abou-Kassem and Lassen, {Mathilde Languille} and Reem Zaabalawi and Daoud, {Mohammed Mahmoud} and Suhayb Abdi and Nick Meier and {la Cour}, Kirstine and Derby, {Cecilie Bauer} and Damlund, {Birka Ravnholt} and Jens Laigaard and Andersen, {Lene Lund} and Johan Mikkelsen and Jensen, {Jeppe Lundholm Stadarfeld} and Rasmussen, {Anders H{\o}rby} and Emil Arnerl{\"o}v and Mathilde Lykke and Holst-Hansen, {Mikkel Zacharias Bystrup} and T{\o}stesen, {Boris Wied} and Janne Schwab and Madsen, {Emilie Kabel} and Christian Gluud and Theis Lange and Anders Perner",

note = "{\textcopyright} 2021 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.",

year = "2021",

month = nov,

doi = "10.1111/aas.13941",

language = "English",

volume = "65",

pages = "1421--1430",

journal = "Acta Anaesthesiologica Scandinavica",

issn = "0001-5172",

publisher = "Wiley-Blackwell",

number = "10",

}

Munch, MW, Meyhoff, TS, Helleberg, M, Kjær, MBN, Granholm, A, Hjortsø, CJS, Jensen, TS, Møller, MH, Hjortrup, PB, Wetterslev, M, Vesterlund, GK, Russell, L, Jørgensen, VL, Kristiansen, KT, Benfield, T, Ulrik, CS, Andreasen, AS, Bestle, MH, Poulsen, LM, Hildebrandt, T, Knudsen, LS, Møller, A, Sølling, CG, Brøchner, AC, Rasmussen, BS , Nielsen, H, Christensen, S, Strøm, T, Cronhjort, M, Wahlin, RR, Jakob, SM, Cioccari, L, Venkatesh, B, Hammond, N, Jha, V, Myatra, SN, Jensen, MQ, Leistner, JW, Mikkelsen, VS, Svenningsen, JS, Laursen, SB, Hatley, EV, Kristensen, CM, Al-Alak, A, Clapp, E, Jonassen, TB, Bjerregaard, CL, Østerby, NCH, Jespersen, MM, Abou-Kassem, D, Lassen, ML, Zaabalawi, R, Daoud, MM, Abdi, S, Meier, N, la Cour, K, Derby, CB, Damlund, BR, Laigaard, J, Andersen, LL, Mikkelsen, J, Jensen, JLS, Rasmussen, AH, Arnerlöv, E, Lykke, M, Holst-Hansen, MZB, Tøstesen, BW, Schwab, J, Madsen, EK, Gluud, C, Lange, T & Perner, A 2021, 'Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial', Acta Anaesthesiologica Scandinavica, vol. 65, no. 10, pp. 1421-1430. https://doi.org/10.1111/aas.13941

TY - JOUR

T1 - Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia

T2 - The COVID STEROID randomised, placebo-controlled trial

AU - Munch, Marie Warrer

AU - Meyhoff, Tine Sylvest

AU - Helleberg, Marie

AU - Kjær, Maj Brit Nørregaard

AU - Granholm, Anders

AU - Hjortsø, Carl Johan Steensen

AU - Jensen, Thomas Steen

AU - Møller, Morten Hylander

AU - Hjortrup, Peter Buhl

AU - Wetterslev, Mik

AU - Vesterlund, Gitte Kingo

AU - Russell, Lene

AU - Jørgensen, Vibeke Lind

AU - Kristiansen, Klaus Tjelle

AU - Benfield, Thomas

AU - Ulrik, Charlotte Suppli

AU - Andreasen, Anne Sofie

AU - Bestle, Morten Heiberg

AU - Poulsen, Lone Musaeus

AU - Hildebrandt, Thomas

AU - Knudsen, Lene Surland

AU - Møller, Anders

AU - Sølling, Christoffer Grant

AU - Brøchner, Anne Craveiro

AU - Rasmussen, Bodil Steen

AU - Nielsen, Henrik

AU - Christensen, Steffen

AU - Strøm, Thomas

AU - Cronhjort, Maria

AU - Wahlin, Rebecka Rubenson

AU - Jakob, Stephan M.

AU - Cioccari, Luca

AU - Venkatesh, Balasubramanian

AU - Hammond, Naomi

AU - Jha, Vivekanand

AU - Myatra, Sheila Nainan

AU - Jensen, Marie Qvist

AU - Leistner, Jens Wolfgang

AU - Mikkelsen, Vibe Sommer

AU - Svenningsen, Jens S.

AU - Laursen, Signe Bjørn

AU - Hatley, Emma Victoria

AU - Kristensen, Camilla Meno

AU - Al-Alak, Ali

AU - Clapp, Esben

AU - Jonassen, Trine Bak

AU - Bjerregaard, Caroline Løkke

AU - Østerby, Niels Christian Haubjerg

AU - Jespersen, Mette Mindedahl

AU - Abou-Kassem, Dalia

AU - Lassen, Mathilde Languille

AU - Zaabalawi, Reem

AU - Daoud, Mohammed Mahmoud

AU - Abdi, Suhayb

AU - Meier, Nick

AU - la Cour, Kirstine

AU - Derby, Cecilie Bauer

AU - Damlund, Birka Ravnholt

AU - Laigaard, Jens

AU - Andersen, Lene Lund

AU - Mikkelsen, Johan

AU - Jensen, Jeppe Lundholm Stadarfeld

AU - Rasmussen, Anders Hørby

AU - Arnerlöv, Emil

AU - Lykke, Mathilde

AU - Holst-Hansen, Mikkel Zacharias Bystrup

AU - Tøstesen, Boris Wied

AU - Schwab, Janne

AU - Madsen, Emilie Kabel

AU - Gluud, Christian

AU - Lange, Theis

AU - Perner, Anders

PY - 2021/11

Y1 - 2021/11

N2 - Background: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID-19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low-dose hydrocortisone on patient-centred outcomes in adults with COVID-19 and severe hypoxia. Methods: In this multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. Results: The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: −1.1 days, 95% CI −9.5 to 7.3, P =.79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. Conclusions: In this trial of adults with COVID-19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. Trial registration: ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020-001395-15.

AB - Background: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID-19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low-dose hydrocortisone on patient-centred outcomes in adults with COVID-19 and severe hypoxia. Methods: In this multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. Results: The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID-19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: −1.1 days, 95% CI −9.5 to 7.3, P =.79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. Conclusions: In this trial of adults with COVID-19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. Trial registration: ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020-001395-15.

KW - corticosteroids

KW - COVID-19

KW - hydrocortisone

KW - placebo-controlled trial

KW - randomised clinical trial

KW - SARS-CoV-2

UR - http://www.scopus.com/inward/record.url?scp=85115113342&partnerID=8YFLogxK

U2 - 10.1111/aas.13941

DO - 10.1111/aas.13941

M3 - Journal article

C2 - 34138478

AN - SCOPUS:85115113342

SN - 0001-5172

VL - 65

SP - 1421

EP - 1430

JO - Acta Anaesthesiologica Scandinavica

JF - Acta Anaesthesiologica Scandinavica

IS - 10

ER -

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial

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