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World J Crit Care Med. Jun 9, 2024; 13(2): 91225
Published online Jun 9, 2024. doi: 10.5492/wjccm.v13.i2.91225
Table 1 Comparison of studies of steroids in non-coronavirus disease 2019 acute respiratory distress syndrome
Ref. Country, number of participating sites Number of patients Type of patient population Severity of ARDS Intervention group Control group Primary outcome Remarks Meduri et al [8 ], 1998 United States, 4 24 Adults with ARDS who failed to improve lung injury score by the seventh day of respiratory failure on mechanical ventilation Severe IV Methylprednisolone 2 mg/kg loading dose followed by tapering dosage until day 32 Placebo Improvement in lung function and mortality (both ICU and hospital mortality) Trial stopped early due to huge benefits in corticosteroid group (leading to biases in the treatment effect) Annane et al [9 ], 2006 France, 19 300 Adults with ARDS and septic shock on mechanical ventilation Moderate-to-severe IV Hydrocortisone 50 mg every 6th hourly plus oral 9-α-fludrocortisone for 7 d Placebo Mortality at 28 d in non-responders to short corticotropin test Short corticotropin test with IV tetracosactrin 250 mcg prior to randomization Steinberg et al [10 ], 2006 United States, 25 centres 180 Adults with ARDS of at least 7 d’ duration on mechanical ventilation with P/F ration less than 200 Moderate-to-severe IV Methylprednisolone 2 mg/kg loading dose followed by tapering dosage until day 21 Placebo All-cause mortality at 60 d Long recruitment time, high incidence of neuromyopathy in both groups Meduri et al [11 ], 2007 United States, 5 91 Adults with ARDS on mechanical ventilation Any severity IV Methylprednisolone 1 mg/kg loading dose followed by tapering dosage until day 28 Placebo Reduction in lung injury score by 1-point or successful extubation by day 7 Baseline higher number of patients in placebo group with ‘catecholamine-dependant shock’ may have biased the results Rezk et al [12 ], 2013 Kuwait, 1 27 Adults with ARDS on mechanical ventilation Any severity IV Methylprednisolone 1 mg/kg loading dose followed by tapering dosage until day 28 Placebo Improvement in clinical and laboratory parameters Underpowered, extremely small sample size, ill-defined primary and secondary outcomes Tongyoo et al [13 ], 2016 Thailand, 1 206 Adults with ARDS and severe sepsis Any severity IV Hydrocortisone every 6th hourly for 7 d Placebo All-cause mortality at 28 d Single centre, limited generalizability Villar et al [7 ], 2020 Spain, 17 277 Adults with ARDS Moderate-to-severe IV Dexamethasone 20 mg once daily (day 1 to 5) followed by 10 mg once daily (day 6 to 10) Placebo VFD at 28 d Largest RCT till date, insufficient implementation of prone ventilation in both groups
Table 2 Comparison of studies of steroids in coronavirus disease 2019 acute respiratory distress syndrome
Ref. Acronym/Abbreviation Country, number of participating sites Number of patients Type of patient population Severity of ARDS Intervention group Control group Primary outcome Remarks Tomazini et al [15 ], 2020 CoDEX Brazil, 41 299 Adults with COVID-19 ARDS on mechanical ventilation Moderate-to- severe Standard care plus IV Dexamethasone 20 mg once daily for 5 d followed by 10 mg once daily for 5 d or until ICU discharge, whichever occurred first Standard care VFD at 28 d Open-label trial with no blinding leading to high number of patients in control group receiving corticosteroids
Table 3 Comparison of studies of steroids in coronavirus disease 2019 requiring invasive mechanical ventilation
Ref. Acronym/Abbreviation Country, number of participating sites Number of patients Type of patient population Intervention group Control group Primary outcome Comments Angus et al [16 ], 2020 REMAP-CAP Multi-national, 121 403 Adults with presumed or confirmed COVID-19 infection admitted to ICU for respiratory or cardiovascular organ support 2 dosing regimens: Fixed dose – IV Hydrocortisone 50 mg every 6 h for 7 d; Shock-dependant dose - IV Hydrocortisone 50 mg every 6 h while in shock for up to 28 d No hydrocortisone Organ-support free days within 21 d Pragmatic and international design improving the generalizability of results, open-label design with no blinding Horby et al [14 ], 2020 RECOVERY United Kingdom, 175 6425 Adults hospitalized with COVID-19 (later age-limit was removed with inclusion of pregnant or breast-feeding women) IV or oral Dexamethasone 6 mg for 10 d Usual care All-cause mortality within 28 d First trial showing evidence of benefit of corticosteroids in viral pneumonias Jeronimo et al [17 ], 2020 Metcovid Brazil, 1 416 Adults hospitalized with clinical or radiologically suspected COVID-19 IV Methylprednisolone (0.5 mg/kg) twice daily for 5 d Placebo Mortality at 28 d Single centre study with low sample size Dequin et al [18 ], 2020 CAPE COVID France, 9 149 Adults with confirmed of suspected COVID-19 and acute respiratory failure IV hydrocortisone 200 mg/d for 7 d followed by tapering dosage till day 14 Placebo Treatment failure on day 21 Trial stopped early due to release of results of the RECOVERY trial, underpowered Munch et al [19 ], 2021 COVID STEROID Denmark, 12 30 Adults with COVID-19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) IV Hydrocortisone 200 mg/d for 7 d or until hospital discharge Placebo Number of days alive without life support at day 28 Trial terminated early due to external evidence indicating benefit of steroids in COVID-19 Munch et al [20 ], 2021 COVID STEROID 2 Multinational (Europe and India), 26 982 Adults with COVID-19 and severe hypoxaemia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) IV Dexamethasone 12 mg once daily for up to 10 d IV Dexamethasone 6 mg once daily for up to 10 d Number of days alive without life support at day 28 Good generalizability of results since it was conducted in both Europe and India
Table 4 Comparison of major studies of steroids in community-acquired pneumonia
Ref. Country, number of participating sites Number of patients Type of patient population Severity of CAP Intervention group Control group Primary outcome Remarks Confalonieri et al [25 ], 2005 Italy, 6 46 Adults with severe CAP according to 1993 ATS severity criteria Severe IV hydrocortisone 200 mg bolus followed by IV infusion of 10 mg/hr for 7 d Placebo Improvement in P/F ratio and MODS score by study day 8 and reduction in delayed septic shock Small sample size Snijders et al [26 ], 2010 Netherlands, 1 204 Adults hospitalized with CAP Any severity IV or oral Prednisolone 40 mg for 7 d Placebo Clinical cure at day 7 Large number of non-severe CAP patients Meijvis et al [27 ], 2011 Netherlands, 2 302 Adults with CAP without need of intensive care Any severity IV dexamethasone 5 mg daily for 4 d Placebo Length of hospital stay ICU patient excluded Fernandez-Serrano et al [28 ], 2011 Spain, 1 52 Adults up to age 75 with severe CAP according to extent of consolidation and P/F ratio Severe IV methylprednisolone 500 mg bolus followed by tapering infusion over 9 d Placebo Need for mechanical ventilation Small sample size Blum et al [29 ], 2015 Switzerland, 7 785 Adults hospitalized with CAP Any severity Oral prednisolone 50 mg for 7 d Placebo Time to clinical stability Good sample size, primary end-point not clinically relevant Torres et al [30 ], 2015 Spain, 3 120 Adults with severe CAP according to ATS or PSI criteria and CRP > 150 mg/L Severe IV methylprednisolone 0.5 mg/kg twice daily for 5 d Placebo Rate of treatment failure (composite of early and late treatment failure) Inclusion of CRP in inclusion criteria limits generalizability of results Meduri et al [21 ], 2022 United States, 42 584 Adults with severe CAP according to modified ATS/IDSA criteria with admission to intensive or intermediate care Severe IV methylprednisolone 40 mg/d (days 1-7), 20 mg/d (days 8-14), 12 mg/day (days 15-17), 4 mg/d (days 18-20) Placebo All-cause mortality at 60 d Underpowered, delayed initiation of steroids may have masked differences between treatment groups Dequin et al [31 ], 2023 France, 31 800 Adults with severe CAP in ICU Severe IV hydrocortisone 200 mg/d for 8 or 14 d based on improvement in patient’s condition Placebo All-cause mortality at 28 d Largest RCT till date; stopped early (underpowered)
Table 5 Comparison of major studies of steroids in septic shock
Ref. Acronym/Abbreviation Country, number of participating sites Number of patients Type of patient population Intervention group Control group Primary outcome Remarks Annane et al [33 ], 2002 --- France, 19 300 Adults with septic shock IV hydrocortisone 50 mg bolus every 6th hourly and oral Fludrocortisone 50 mcg every 24 h for 7 d Placebo Mortality at 28 d Trial has subdivided patients into ACTH stimulation responders and non-responders Sprung et al [34 ], 2008 CORTICUS Multi-national, 52 499 Adults with septic shock IV hydrocortisone 50 mg every 6th hourly for 5 d, then 50 mg every 12th hourly for 3 d, then 50 mg once daily for 3 d Placebo Mortality at 28 d Study found a non-statistically significant increased risk of superinfection with steroid group Keh et al [35 ], 2016 HYPRESS Germany, 34 380 Adults with severe sepsis IV hydrocortisone bolus 50 mg followed by a continuous infusion of 200 mg daily for 3 d Placebo Underpowered study Annane et al [36 ], 2018 APROCCHSS France, 34 1241 Adults with septic shock IV hydrocortisone 50 mg bolus every 6th hourly and oral fludrocortisone 50 mcg every 24 h for 7 d Placebo Mortality at 90 d Showed benefit in 90-d mortality contrasting to no benefit in ADRENAL trial Venkatesh et al [32 ], 2018 ADRENAL Multi-national, 69 3800 Adults with septic shock IV hydrocortisone 200 mg every day for a maximum of 7 d or until ICU discharge or death Placebo Mortality at 90 d Largest trial till date on steroids in septic shock
Table 6 List of recent systematic reviews and metanalysis on steroids in acute respiratory distress syndrome
Ref. Number and type of studies included Number of patients Type of patient population Primary outcome Remarks Ni et al [23 ], 2019 10, observational studies 6548 Adults with influenza pneumonia Mortality Mortality higher in patients receiving corticosteroids van Passen et al [37 ], 2020 44, observational studies and RCTs 20,197 Adults with COVID-19 diagnosed by RT-PCR Short-term mortality and viral clearance (based on RT-PCR in respiratory specimens) Reduced short-term mortality. However, signal for delayed viral clearance Lin et al [39 ], 2021 9, RCTs 1371 Adults with ARDS Hospital mortality Heterogeneity in the studies included Chaudhuri et al [38 ], 2021 18, RCTs 2826 Adults with ARDS (including patients with COVID-19) Mortality Largest metanalysis examining corticosteroids in ARDS of any cause Chang et al [40 ], 2022 14, RCTs 1607 Any age with ARDS of any cause 28-d mortality Included children in the participants of metanalysis, found mortality benefit with corticosteroids Yoshihito et al [41 ], 2022 9, RCTs 1212 Adults with ARDS Hospital mortality No significant difference found
Table 7 Suggested steroids in acute respiratory distress syndrome based on evidence until now
Category of ARDS Steroid details COVID-19 ARDS Dexamethasone, 6 mg IV, start after 1 wk of symptom onset, duration for 10 d or until hospital discharge (if sooner) Non-COVID-19 ARDS No high-quality evidence available; hydrocortisone, 200 mg per day, start within 24 h of onset of severe CAP, duration for 8 d or 14 d (based on level of improvement at day 4) ARDS with septic shock Hydrocortisone, 200 mg per day, start if need of vasopressors or inotropes for a minimum of 4 h, duration for a maximum of 7 d or until ICU discharge or death