BACKGROUND: Dexamethasone 6 mg in patients with severe COVID-19 has been shown to decrease mortality and morbidity. The effects of higher doses of corticosteroid, that would further increase anti-inflammatory effects, are uncertain. The objective of our study was to assess the effect of 20 mg dexamethasone vs. 6 mg dexamethasone intravenously in patients with moderate-to-severe acute respiratory distress syndrome (ARDS) and COVID-19. METHODS: In a multicenter, open-label, randomized trial conducted in nine hospitals in the Czech Republic, we randomized adult patients with ARDS and COVID-19 requiring high-flow oxygen, noninvasive or invasive mechanical ventilation to receive either intravenous high-dose dexamethasone (20 mg/day on days 1-5, 10 mg/day on days 6-10) or standard-dose dexamethasone (6 mg/d, days 1-10). The primary outcome was 28-day ventilator-free days. The five secondary outcomes were 60-day mortality, C-reactive protein dynamics, 14-day WHO (World Health Organization) Clinical Progression Scale score, adverse events and 90-day Barthel index. The long-term outcomes were 180- and 360-day mortality and the Barthel index. The planned sample size was 300, with interim analysis after enrollment of 150 patients. RESULTS: The trial was stopped due to a lack of recruitment, and the follow-up was completed in February 2023. Among 234 randomized patients of 300 planned patients, the primary outcome was available for 224 patients (110 high-dose and 114 standard-dose dexamethasone; median [interquartile range (IQR)] age, 59.0 [48.5-66.0] years; 130 [58.0%] were receiving noninvasive or invasive mechanical ventilation at baseline). The mean number of 28-day ventilator-free days was 8.9 (± 11.5) days for high-dose dexamethasone and 8.0 (± 10.7) days for standard-dose dexamethasone, with an absolute difference of + 0.81 days (95% CI - 2.12-3.73 days). None of the prespecified secondary outcomes, including adverse events, differed between the groups. CONCLUSIONS: Despite not reaching its prespecified enrollment, there was no signal to either benefit or harm high-dose dexamethasone over standard-dose dexamethasone in patients with COVID-19 and moderate-to-severe ARDS. Trial registration Trial registration: ClinicalTrials.gov Identifier: NCT04663555. Registered 10 December 2020, https://clinicaltrials.gov/study/NCT04663555?term=NCT04663555&rank=1 and EudraCT: 2020-005887-70.

2nd Department of Anaesthesiology and Intensive Care Medicine University Hospital Brno Brno Czech Republic

Bloomsbury Institute of Intensive Care Medicine Division of Medicine University College London London UK

Department of Anaesthesia and Intensive Care General University Hospital Prague and the 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Anaesthesia and Intensive Care University Hospital Královské Vinohrady and the 3rd Faculty of Medicine Charles University Šrobárova 1150 10034 Praha Czech Republic

Department of Anaesthesiology and Intensive Care Medicine St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Anaesthesiology and Intensive Care Medicine Tomáš Baťa Regional Hospital Zlín Czech Republic

Department of Anaesthesiology and Intensive Care Medicine University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Anaesthesiology and Intensive Care Medicine University Hospital Olomouc and Faculty of Medicine Palacky University Olomouc Czech Republic

Department of Anaesthesiology and Intensive Care Medicine University Hospital Pilsen and Faculty of Medicine in Pilsen Charles University Plzeň Czech Republic

Department of Anaesthesiology and Intensive Care Military University Hospital Praha and the 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Anesthesiology and Intensive Care Medicine University Hospital Ostrava and Faculty of Medicine University Ostrava Ostrava Poruba Czech Republic

Department of Internal Medicine and Cardiology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Paediatric Anaesthesiology and Intensive Care Medicine University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pharmacology CZECRIN Faculty of Medicine Masaryk University Brno Czech Republic

Department of Simulation Medicine Faculty of Medicine Masaryk University Brno Czech Republic

International Clinical Research Centre at St Anne's University Hospital Brno Czech Republic

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Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384:693–704. PubMed PMC

Webb SA, Higgins AM, McArthur CJ. Glucocorticoid dose in COVID-19: lessons for clinical trials during a pandemic. JAMA. 2021;326:1801–2. PubMed

Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8:267–76. PubMed

Munch MW, Myatra SN, Vijayaraghavan BKT, Saseedharan S, Benfield T, Wahlin RR, et al. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. JAMA. 2021;326:1807–17. PubMed PMC

Bouadma L, Mekontso-Dessap A, Burdet C, Merdji H, Poissy J, Dupuis C, et al. High-dose dexamethasone and oxygen support strategies in intensive care unit patients with severe COVID-19 acute hypoxemic respiratory failure: the COVIDICUS randomized clinical trial. JAMA Intern Med. 2022;182:906–16. PubMed PMC

Maskin LP, Bonelli I, Olarte GL, Palizas F Jr, Velo AE, Lurbet MF, et al. High- versus low-dose dexamethasone for the treatment of COVID-19-related acute respiratory distress syndrome: a multicenter, randomized open-label clinical trial. J Intensive Care Med. 2021;37:491–9. PubMed PMC

Toroghi N, Abbasian L, Nourian A, Davoudi-Monfared E, Khalili H, Hasannezhad M, et al. Comparing efficacy and safety of different doses of dexamethasone in the treatment of COVID-19: a three-arm randomized clinical trial. Pharmacol Rep. 2021;74:229–40. PubMed PMC

Rabascall CX, Lou BX, Dhar S, Hasan Z, Fryman C, Izard S, et al. Randomized open investigation determining steroid dose in severe COVID-19: the ROIDS-dose clinical trial. Cureus. 2022;14:e31086. PubMed PMC

Wu H, Daouk S, Kebbe J, Chaudry F, Harper J, Brown B. Low-dose versus high-dose dexamethasone for hospitalized patients with COVID-19 pneumonia: a randomized clinical trial. PLoS ONE. 2022;17:e0275217. PubMed PMC

Taboada M, Rodríguez N, Varela PM, Rodríguez MT, Abelleira R, González A, et al. Effect of high versus low dose of dexamethasone on clinical worsening in patients hospitalised with moderate or severe COVID-19 pneumonia: an open-label, randomised clinical trial. Eur Respir J. 2022;60:2102518. PubMed PMC

Munch MW, Granholm A, Maláska J, Stašek J, Rodriguez PO, Pitre T, et al. Dexamethasone doses in patients with COVID-19 and hypoxia: a systematic review and meta-analysis. Acta Anaesthesiol Scand. 2023;68:146–66. PubMed

Wagner C, Griesel M, Mikolajewska A, Metzendorf MI, Fischer AL, Stegemann M, et al. Systemic corticosteroids for the treatment of COVID-19: Equity-related analyses and update on evidence. Cochrane Database Syst Rev. 1996;11:CD014963. PubMed PMC

Maláska J, Stašek J, Duška F, Balík M, Máca J, Hruda J, et al. Effect of dexamethasone in patients with ARDS and COVID-19 - prospective, multi-centre, open-label, parallel-group, randomised controlled trial (REMED trial): a structured summary of a study protocol for a randomised controlled trial. Trials. 2021;22:172. PubMed PMC

Maláska J, Stašek J, Duška F, Balík M, Máca J, Hruda J, et al. Effect of dexamethasone in patients with ARDS and COVID-19 (REMED trial)-study protocol for a prospective, multi-centre, open-label, parallel-group, randomized controlled trial. Trials. 2022;23:35. PubMed PMC

Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974;2:81–4. PubMed

Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307:2526–33. PubMed

Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83. PubMed

Yehya N, Harhay MO, Curley MAQ, Schoenfeld DA, Reeder RW. Reappraisal of ventilator-free days in critical care research. Am J Respir Crit Care Med. 2019;200:828–36. PubMed PMC

WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020;20:e192–7. PubMed PMC

Mahoney FI, Barthel DW. Functional evaluation: the Barthel index. Md State Med J. 1965;14:61–5. PubMed

Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020;324:1307–16. PubMed PMC

Grimaldi D, Aissaoui N, Blonz G, Carbutti G, Courcelle R, Gaudry S, et al. Characteristics and outcomes of acute respiratory distress syndrome related to COVID-19 in Belgian and French intensive care units according to antiviral strategies: the COVADIS multicentre observational study. Ann Intensive Care. 2020;10:131. PubMed PMC

Granholm A, Munch MW, Myatra SN, Vijayaraghavan BKT, Cronhjort M, Wahlin RR, et al. Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial. Intensive Care Med. 2022;48:45–55. PubMed PMC

Granholm A, Kjær MN, Munch MW, Myatra SN, Vijayaraghavan BKT, Cronhjort M, et al. Long-term outcomes of dexamethasone 12 mg versus 6 mg in patients with COVID-19 and severe hypoxaemia. Intensive Care Med. 2022;48:580–9. PubMed PMC

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NCT04663555