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

Abstract

Acute respiratory distress syndrome (ARDS) is a unique entity marked by various etiologies and heterogenous pathophysiologies. There remain concerns regarding the efficacy of particular medications for each severity level apart from respiratory support. Among several pharmacotherapies which have been examined in the treatment of ARDS, corticosteroids, in particular, have demonstrated potential for improving the resolution of ARDS. Nevertheless, it is imperative to consider the potential adverse effects of hyperglycemia, susceptibility to hospital-acquired infections, and the development of intensive care unit acquired weakness when administering corticosteroids. Thus far, a multitude of trials spanning several decades have investigated the role of corticosteroids in ARDS. Further stringent trials are necessary to identify particular subgroups before implementing corticosteroids more widely in the treatment of ARDS. This review article provides a concise overview of the most recent evidence regarding the role and impact of corticosteroids in the management of ARDS.

Key Words: Acute respiratory distress syndrome, Corticosteroids, Septic shock, Community acquired pneumonia, COVID-19, Randomized controlled trials

Core Tip: Acute respiratory distress syndrome (ARDS) was described in 1967. For decades, various pharmacotherapies, including corticosteroids, have been examined for treatment, with corticosteroids showing potential for improving outcomes. However, corticosteroids have potential adverse effects including hospital-acquired infections and intensive care unit acquired weakness. The authors have analysed and reviewed the existing evidence regarding the role of corticosteroids in the management of community acquired pneumonia with respiratory failure, coronavirus disease 2019 pneumonia, septic shock and ARDS.

INTRODUCTION

The diagnosis of acute respiratory distress syndrome (ARDS) dates back to 1967 when Ashbaugh et al[1] first described its existence. The definition of ARDS has undergone several modifications since its initial description. The Berlin definition of ARDS was established in 2012[2]. This definition classifies severity of ARDS into mild, moderate, and severe based on a patient’s PaO₂/FiO₂ (P/F) ratio. There are still uncertainties regarding the efficacy of specific medications for each severity category.Various pharmacotherapies have been tested in ARDS, including corticosteroids, inhaled nitric oxide, GM-CSF, statins, and aspirin.

The 2023 European Society of Intensive Care Medicine recommendations on ARDS broadened the scope of the ARDS definition by discussing the utilisation of high flow nasal oxygen (HFNO) and the suitability of the definition in settings with limited resources[3]. The new global definition of ARDS incorporate criteria that apply to specific ARDS categories[4]. This definition incorporates a new category of non-intubated ARDS for patients on HFNO at ≥ 30 L/min. It also includes a modified definition of ARDS for resource-limited settings.

The pathophysiology of ARDS involves lung injury characterized by diffuse lung inflammation. This is a consequence of the activation of various intricate pathways that encompass injury, inflammation, and coagulation[5]. Epithelial and endothelial damage result in the accumulation of fluid in the alveoli and the development of lung edema. Lung edema eventually leads to ventilation/perfusion mismatching and shunt, ultimately leading to impaired gas exchange. Various pro-inflammatory mediators such as tumor necrosis factor, IL (interleukin)-1β, IL-6, and IL-8 have been identified that perpetuate this vicious cycle of lung inflammation[6]. Leakage of these mediators into the systemic circulation leads to the systemic inflammatory response syndrome.

The degree of systemic involvement and the degree of activation of each of these complex pathways leads to heterogeneity in clinical manifestations of the syndrome as well as in the response to treatment. These differences have prompted further investigation to identify phenotypes, sub-groups, sub-phenotypes, and endotypes in order to more accurately characterise the syndrome in an individual[3].

PHYSIOLOGIC RATIONALE FOR USE OF CORTICOSTEROIDS IN ARDS

The long-standing quest for a panacea in ARDS has remained elusive for several decades. With the exception of protective lung ventilation (low tidal volume) and prone ventilation, there is little evidence to support the effectiveness of any other non-pharmacological respiratory strategy in treating ARDS. Despite persistently high mortality rates of severe ARDS in both high-income and low-and-middle-income nations, no medication has demonstrated unequivocal benefits.

The resolution of ARDS is a synchronised process that entails the suppression of pro-inflammatory pathways and the activation of anti-inflammatory pathways. Corticosteroids in ARDS have shown promise as a pharmacotherapeutic by enhancing the coordinated resolution of ARDS. Research has demonstrated that steroids (most notably dexamethasone) have several effects that go beyond their impact on inflammatory pathways. These include stimulation of fluid absorption, surfactant secretion and reduction in HPV[7]. Investigators have conducted numerous clinical trials utilising steroids in the treatment of ARDS due to the putative advantages associated with them.

CURRENT EVIDENCE ON CORTICOSTEROIDS IN ARDS

Steroids in non-covid ARDS

DEXA ARDS trial: The most substantial data supporting the use of steroids in ARDS is derived from the DEXA-ARDS trial conducted by Villar et al[7] in 2020 (Table 1). The trial was conducted in 17 intensive care units (ICUs) in Spain and included patients with P/F ratios less than 200. The intervention group completed a course of dexamethasone, starting with a dosage of 20 mg for 5 d, followed by a dosage of 10 mg for 5 d. Treatment was initiated within 24 h of implementing standardised ventilatory settings. The administration of dexamethasone was maintained for a duration of 10 d, or until the patient was removed from mechanical ventilation if this occurred prior to the 10^th day. All patients in the study were mechanically ventilated. Baseline characteristics of both groups were similar with pneumonia being the primary cause of ARDS. The intervention (dexamethasone) group performed dramatically better with significantly higher number of ventilator-free days (VFD) (12.3 vs 7.9, difference 4.8 d, 95%CI: 2.57–7.03, P < 0.0001). Most secondary outcomes including all-cause mortality at day 60 were significantly better in dexamethasone group with no significant difference in adverse events and complications. The authors concluded that early administration of dexamethasone could reduce duration of mechanical ventilation in patients with established moderate-to-severe ARDS. The DEXA-ARDS trial has faced criticism however, mostly due to insufficient implementation of prone ventilation in both groups and the premature termination of the trial due to inadequate recruitment. Comparison of studies of steroids in non-coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome is shown in Table 1[8-13].

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.

Steroids in Covid ARDS

RECOVERY trial: The largest body of evidence in use of steroids for COVID-19 comes from the RECOVERY Trial by the RECOVERY Collaborative group in 2020 conducted in 175 National Health Services hospitals in the United Kingdom (Tables 2 and 3). This trial included 6425 patients with 2104 in dexamethasone group and 4321 in the usual care group[14]. The trial examined multiple different treatment options in hospitalized patients with COVID-19 using an adaptive design. The intervention (dexamethasone) group received dexamethasone 6 mg daily (intravenous (IV) or oral) for 10 d. There was a significant reduction in 28-d age-adjusted mortality in the dexamethasone group (21.6% vs 24.6%, rate ratio 0.83, 95%CI: 0.74–0.92, P < 0.001). Notably, secondary subgroup analysis showed that 28-d age-adjusted mortality rate was significantly lower in patients receiving mechanical ventilation and in patients requiring oxygen therapy. The subgroup not receiving any oxygen showed no significant difference in age-adjusted mortality. Also, dexamethasone reduced 28-d mortality in patients who had symptom duration of > 7 d but not among those with symptom duration of < 7 d. The results from the RECOVERY Trial demonstrated that outcome was improved in COVID-19 when dexamethasone was administered at a moderate dose of 6 mg per day for a duration of 10 d. The RECOVERY trial was the first instance of steroids showing benefit in viral pneumonias. An inherent limitation of the study was that the investigators solely examined 28-d mortality. Therefore, the assessment did not include infectious complications caused by steroids after 28-d. The authors also did not classify individuals as either having ARDS or not. Comparison of studies of steroids in COVID-19 acute respiratory distress syndrome is shown in Table 2[15]. Comparison of studies of steroids in COVID-19 requiring invasive mechanical ventilation is mentioned in Table 3[16-20].

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.

Steroids in community acquired pneumonia

ESCAPe trial: The ESCAPe trial conducted by Meduri et al[21] in 2022 in the United States demonstrated equipoise. A total of 586 patients with severe community-acquired pneumonia (CAP) (defined as fulfilling 1 major and 3 minor of the modified ATS/IDSA criteria) within 72-96 h of hospital admission were randomized to receive either IV Methylprednisolone 40 mg/d through day 7 (then tapered until day 20) or placebo (Table 4). There was no significant difference in all-cause mortality at 60 d (16% vs 18%, OR: 0.9, 95%CI: 0.57–1.4). However, this study was underpowered to detect any differences between the two groups.

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.

CAPE-COD trial: The results of the CAPE-COD trial of 2023 conducted in France are in stark contrast to the ESCAPe trial[22]. A total of 800 patients diagnosed with severe CAP with a pneumonia severity index score greater than 130, caused by any aetiology except influenza, and without septic shock, were randomly assigned to receive IV hydrocortisone 200 mg/d for a duration of 8 d (which could be extended to 14 d if there was no improvement by day 4), or placebo (Table 4). All-cause mortality between the two groups was significantly different (6.2% vs 11.9%, P = 0.006). The trial demonstrated a 48% relative risk reduction in mortality, with a number needed to treat of 18. This convincing data supports the administration of IV hydrocortisone in patients with severe CAP. Furthermore, a total of 50% of patients involved in this randomised controlled trial were receiving mechanical ventilation. The trial was limited by its premature termination caused by the COVID pandemic, resulting in insufficient statistical power. Nevertheless, given the substantial reduction in mortality, it is unlikely that the trial outcomes would have varied had the trial achieved its complete recruitment. A second limitation was with the trial's restricted external validity, given the epidemiology of severe CAP infections in developed nations compared to LMIC nations. The potential for reactivation of latent illnesses, such as tuberculosis in LMIC patient populations cannot be underestimated.

The differences between the CAPE-COD trial and ESCAPe trial results can potentially be ascribed to two main factors. Hydrocortisone was administered within 24 h of hospital presentation (if meeting severity criteria) in the former, but in the latter, it was given considerably later, up to 96 h after hospital presentation (if meeting severity criteria). Secondly, influenza patients were excluded in the former whereas almost 10% patients tested positive for influenza in the ESCAPe trial. Several prior meta-analyses have provided evidence indicating that the administration of steroids in patients with influenza pneumonia may cause harm[23]. The 2019 IDSA/ATS guidelines, which were created well before these studies were published, suggest not to routinely use steroids in patients with severe CAP[24]. Comparison of major studies of steroids in community-acquired pneumonia is shown in Table 4[25-30].

Steroids in ARDS with septic shock

ADRENAL trial: The largest body of evidence examining steroids in septic shock is derived from the ADRENAL trial, which involved the random allocation of 3658 patients in 69 medical-surgical ICUs to receive either IV hydrocortisone (intervention) or placebo (control) (Table 5)[31]. In order to be enrolled in the study, patients were required to receive vasopressors and/or inotropes for a minimum duration of 4 h and to be on mechanical ventilation (including non-invasive ventilation). There was no significant difference in the primary outcome of 90-d mortality between the two groups. However, multiple secondary outcomes were improved in the hydrocortisone group including median days to resolution of shock, median time to cessation of initial mechanical ventilation and median time to discharge from the ICU. Notably, hyperglycemia was significantly higher in the hydrocortisone group. The primary site of infection in all patients in the ADRENAL trial was pulmonary (33.8% in the hydrocortisone group vs 36.5% in the placebo group). However, there was a lack of subgroup data addressing the specific number of patients with ARDS at the time of randomization. Comparative analysis of major studies of steroids in septic shock is shown in Table 5[32-35].

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.

Recent systematic reviews and metanalysis on steroids in ARDS

In a systematic review and meta-analysis in 2020 which included the RECOVERY trial, van Paassen et al[36] reported significantly reduced mortality in the corticosteroid group with a reduction in the need for and duration of mechanical ventilation (Table 6). A trend towards more infections and antibiotic usage was however, present in patients randomized to receive steroids.

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.

A systematic review and metanalysis by Chaudhuri et al[37] in 2021 which included 18 randomised controlled trials (RCTs) enrolling 2826 patients demonstrated that corticosteroids reduced mortality in ARDS of any aetiology (RR: 0.82, 95%CI: 0.72–0.95, ARR: 8%, 95%CI: 2.2%–12.5%). Of note, patients with COVID-19 -- including data from the RECOVERY trial -- was included in this meta-analysis.

Lin et al[38] in 2021 performed a meta-analysis on 9 RCTs with 1371 participants, demonstrating that corticosteroid use was associated with reduced mortality (RR: 0.83, 95%CI: 0.74–0.93, P < 0.01). Further, no increased risk of new infections or hyperglycemia was identified.

In 2022, a systematic review and metanalysis by Chang et al[39] included 14 RCTs enrolling 1607 patients and showed that corticosteroids reduced the risk of mortality in patients with ARDS (RR: 0.78, 95%CI: 0.70–0.87, P < 0.01). Interestingly, no significant adverse events were observed compared to placebo or standard support therapy. Despite the inclusion of COVID-19 patients, data from the RECOVERY trial was not incorporated into this meta-analysis.

Yoshihiro et al[40] in 2022 conducted a network meta-analysis specially looking at differences in efficacy among different doses and types of steroids. The comparators included high-dose methylprednisolone, low-dose methylprednisolone, hydrocortisone, dexamethasone and no steroids. There were no significant differences between the groups with respect to mortality. However, the number of VFD was greater when using low-dose methylprednisolone than when not using any steroids. The authors concluded that further studies are needed to justify the optimal type and dose of steroid.

EVALUATION OF ARDS SUB-GROUPS

Pulmonary versus extrapulmonary ARDS

Depending on the type of insult leading to ARDS, Gattinoni etal identified the phenotype as being pulmonary (ARDSp) or extrapulmonary (ARDSexp)[41]. ARDSp mostly impacts the alveolar epithelium, while ARDSexp primarily affects the capillary endothelium. Significant differences between the categories have been identified in terms of respiratory mechanics and response to PEEP, with ARDSp demonstrating more compliance and lesser response to PEEP compared to ARDSexp. In a meta-analysis by Agarwal et al[42], no significant differences in mortality were observed between the two groups. Currently, no specific study has examined the precise effects of corticosteroids in ARDSp compared to ARDSexp.

Trauma-related ARDS

Several risk factors associated with the development of trauma-related ARDS include advanced age, male gender, greater injury severity score, numerous rib fractures, trauma-induced lung contusion, and flail chest. Tignanelli et al[43] in a nation-wide cohort study of United States found that almost one third of patients with trauma-related ARDS has mild to moderate injury with injury severity score ≤ 15, indicating that even lesser degrees of trauma can lead to trauma-related ARDS. Large-scale studies have not yet investigated the role of corticosteroids in this particular group of patients with trauma-induced ARDS.

TYPE, DOSE AND TIMING OF CORTICOSTEROIDS IN ARDS

In light of the heterogeneity of clinical trials in the type, dose, timing of initiation and duration of therapy for corticosteroids in ARDS, future clinical trials should look at specific subgroups of patients divided as per the below-mentioned sub-groups (Table 7).

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.

INHALED STEROIDS IN ARDS

Inhaled corticosteroids have been investigated for their effectiveness in preventing ARDS in patients at risk, but no positive outcomes have been observed in early studies[44,45]. Inhaled steroids have been shown to be beneficial in diffuse alveolar haemorrhage leading to ARDS[46]. In a recent RCT, Festic et al[47] investigated the use of inhaled corticosteroids and beta agonists for early treatment of ARDS in order to mitigate the advancement of the condition. A total of 61 adult patients who were at risk of developing ARDS were administered aerosolized budesonide/formoterol in the intervention group, whereas the control group received a placebo. The intervention group showed a significant improvement in the primary outcome of oxygenation. However, this study was solely conducted as a phase IIa study to establish the safety, feasibility, and possible effectiveness of using inhaled corticosteroids and beta agonists at an early stage. To improve local bioavailability and minimize systemic adverse effects, various alternative inhalation treatments have been tested in patients with ARDS, resulting in different levels of positive and negative outcomes[48].

ONGOING RESEARCH AND POTENTIAL FUTURE RESEARCH AREAS

The RECOVERY trial demonstrated significant advantages of use of steroids in patients with COVID-19 pneumonia requiring oxygen therapy and ventilation[14]. Conducting a targeted assessment of the particular causes of ARDS will aid in identifying any indication of favourable or unfavourable outcomes, as opposed to examining the several factors that contribute to ARDS, as was done in previous RCTs prior to the RECOVERY study.

Furthermore, adopting a more inclusive definition of ARDS and conducting clinical trials to evaluate the efficacy of steroids within this inclusive definition should be performed[49,50]. Previous RCTs have utilised different definitions due to changing ARDS classifications, resulting in a diverse population of patients (which may obscure any indication of benefit or harm).

In addition, mortality is an important measure, but it is affected by many other factors, so it is often hard to replicate in critically ill patients. Future trials should additionally focus on other endpoints such as ventilator free days or ICU length of stay, rather than solely considering mortality. The DEXA-ARDS trial aimed to examine significant, patient-focused outcomes[7].

The failure of studies in ARDS has been linked to several factors, including heterogenous trial patient populations, diverse mechanisms of action of pharmacological treatments, and low patient enrolment rates. Machine learning can be employed to enhance the design of clinical trials in ARDS[51].

CONCLUSION

Numerous trials and analyses over decades have attempted to examine the role of steroids in ARDS. The evidence varies due to a wide spectrum of aetiologies and heterogeneous nature of the disease process in ARDS. Currently available evidence supports the use of corticosteroids for managing severe cases of CAP, septic shock, and acute respiratory failure associated with COVID-19. However, the use of corticosteroids for ARDS cannot be endorsed in the same manner. Additional rigorous trials are required with identification of specific subgroups, prior to the broader implementation of corticosteroids in the management of ARDS.