Steroids in acute respiratory distress syndrome: A panacea or still a puzzle?

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

ARDS: Acute respiratory distress syndrome; VFD: Ventilator-free days; RCT: Randomised controlled trial; ICU: Intensive care unit.

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

ARDS: Acute respiratory distress syndrome; COVID-19: Coronavirus disease 2019; VFD: Ventilator-free days; ICU: Intensive care unit.

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

ARDS: Acute respiratory distress syndrome; COVID-19: Coronavirus disease 2019; CAP: Community-acquired pneumonia; ICU: Intensive care unit.

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)

ATS: American thoracic society; PSI: Pneumonia severity index; CRP: C-reactive protein; IDSA: Infectious Diseases Society of America; CAP: Community-acquired pneumonia; ICU: Intensive care unit; RCT: Randomised controlled trial.

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

ICU: Intensive care unit.

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

COVID-19: Coronavirus disease 2019; RT-PCR: Reverse transcription polymerase chain reaction; ARDS: Acute respiratory distress syndrome.

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

COVID-19: Coronavirus disease 2019; ARDS: Acute respiratory distress syndrome; CAP: Community-acquired pneumonia; ICU: Intensive care unit.