
==== Front
J Intensive Med
J Intensive Med
Journal of Intensive Medicine
2097-0250
2667-100X
Elsevier

S2667-100X(24)00033-1
10.1016/j.jointm.2024.02.002
Review
Glucocorticoid therapy for acute respiratory distress syndrome: Current concepts
Zhao Yuanrui
Yao Zhun
Xu Song
Yao Lan
Yu Zhui yuzhui@whu.edu.cn
⁎
Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
⁎ Corresponding author: Zhui Yu, Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China. yuzhui@whu.edu.cn
01 4 2024
10 2024
01 4 2024
4 4 417432
23 10 2023
30 1 2024
7 2 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Acute respiratory distress syndrome (ARDS), a fatal critical disease, is induced by various insults. ARDS represents a major global public health burden, and the management of ARDS continues to challenge healthcare systems globally, especially during the pandemic of the coronavirus disease 2019 (COVID-19). There remains no confirmed specific pharmacotherapy for ARDS, despite advances in understanding its pathophysiology. Debate continues about the potential role of glucocorticoids (GCs) as a promising ARDS clinical therapy. Questions regarding GC agent, dose, and duration in patients with ARDS need to be answered, because of substantial variations in GC administration regimens across studies. ARDS heterogeneity likely affects the therapeutic actions of exogenous GCs. This review includes progress in determining the GC mechanisms of action and clinical applications in ARDS, especially during the COVID-19 pandemic.

Keywords

Acute respiratory distress syndrome
Glucocorticoids
Steroids
COVID-19
Clinical trials
Heterogeneity
Managing Editor: Jingling Bao/Zhiyu Wang
==== Body
pmcIntroduction

Acute respiratory distress syndrome (ARDS), a common clinical syndrome of acute respiratory failure, is characterized by refractory hypoxemia with bilateral infiltrates on chest imaging, which cannot be explained by acute cardiac failure or fluid overload.[1,2] Supportive treatments including lung-protective ventilation, prone position ventilation, and restrictive fluid infusion improve the outcomes of ARDS. However, no specific drug has been found effective in its treatment.[3] Because of their obvious anti-inflammatory role, glucocorticoids (GCs) have been used to treat ARDS for decades, especially during the Coronavirus disease 2019 (COVID-19) pandemic, though their pharmacologic mechanisms of action on ARDS remain unclear. Herein, we first review the ARDS definition, etiology, epidemiology, and pathophysiology. We then discuss the effects and mechanisms by which GCs affect ARDS, and how ARDS heterogeneity affects GC actions. Finally, we address the side effects of GCs.

ARDS Definition, Epidemiology, Etiology, and Pathophysiology

Definition

The definition of ARDS has undergone four versions since it was first published in 1967. Because the COVID-19 pandemic emphasized the importance of expanding its definition, the global definition published in 2023 expanded the Berlin definition, to provide a more feasible diagnosis, especially in resource-limited areas.[4]

An important modification in the newest definition is the inclusion of treatment with high flow nasal oxygen >30 L/min without required partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2), positive end-expiratory pressure. Many patients with mild hypoxemia or rapidly improving ARDS are thus now eligible for inclusion in clinical trials, substantially changing epidemiological estimates of ARDS incidence and misclassification of ARDS severity and diagnosis.[5] Another major change is the criteria for hypoxemia, with the recommendation to use peripheral oxygen saturation (SpO2)/FiO2 to diagnose ARDS when SpO2 ≤97 % and blood gas is unavailable, instead of PaO2/FiO2. The advantage of this is that SpO2/FiO2 can be measured continuously, non-invasively, and with high sensitivity. However, the validity of SpO2/FiO2 as an alternative to PaO2/FiO2 remains controversial, especially considering evidence of racial bias and high-dose vasopressor use.[6,7] The new definition also recommends lung ultrasound (LUS) as an alternative for detecting bilateral (non-cardiogenic) filtration, especially when chest radiography/computed tomography (CT) is unavailable. However, the lack of clear rules for using LUS in ARDS diagnosis is a major flaw of the current definition, and it may lead to ARDS misclassification.

ARDS is a clinical syndrome, rather than a disease. The global definition is not “new,” but rather an expansion of the Berlin definition to meet the current situation. Indeed, there may not be a “best” ARDS definition. Rather, we must assess the definition's reliability and validity across settings and patient groups to provide “better” diagnostic criteria.[8]

Epidemiology

Despite significant progress in understanding its pathogenesis and the use of supportive therapies, the incidence of ARDS remains high, especially in resource-restrained regions. It occurs in approximately 10% of patients in the intensive care unit (ICU) and 23% of those who are ventilated[9] with morbidity increases from 30% to 52% during the COVID-19 pandemic.[10] There is a significant increase in mortality with each increase in ARDS severity category, with 34.9% for mild, 40.3% for moderate, and 46.1% for severe ARDS.[9,11]

Etiology

ARDS can be caused by various factors including, but not restricted, to pneumonia, sepsis, pancreatitis, aspiration of gastric contents, severe trauma and burns, and smoke inhalation.[2] E-cigarette and vaping product use-associated lung injury[12] and COVID-19[13] have also emerged as new causes of ARDS. In recent studies, sepsis, pneumonia, and aspiration of gastric contents together accounted for >85 % of ARDS cases.[9,[14], [15], [16], [17]] (The known causes of ARDS are shown in Table 1.)Table 1 Causes of acute respiratory distress syndrome.

Table 1:Pulmonary (direct)	Non-/extra-pulmonary (indirect)	
Pneumonia• Bacterial

• Viral

• Fungal

• Opportunistic

	Non-pulmonary sepsis• Abdominal

• Urinary

• Bloodstream

• Others

	
Near drowning	Pancreatitis	
Aspiration of gastric contents	Severe traumatic injury	
Ventilation-associated injury	Severe burn injury	
Inhalation injury	Drug toxicity	
	Neurogenic	
	Transfusion of blood products	
	Radiation pneumonitis	
	Cardiopulmonary bypass	
	Ischemia-reperfusion injury after transplantation	

Pathophysiology

ARDS is an acute inflammatory syndrome of the alveoli and capillaries, characterized by alveolar epithelium and capillary endothelial injury with subsequent inflammatory exudation from alveolar capillaries.[18] Direct and indirect insults damage the alveolar structure and microvasculature (Figure 1A). Damage to the endothelial–epithelial barrier is essential in the development of ARDS, which leads to intra-alveolar and interstitial edema due to increased capillary permeability.Figure 1 GC mechanisms in the exudative phase of ARDS. A: Direct and indirect insults damage the alveolar structure and microvasculature. B: During the exudative phase, alveolar resident macrophages are activated into M1-like macrophages, leading to the production of chemokines and proinflammatory cytokines that promote the accumulation of neutrophils and monocytes in the alveolus. To minimize the damage, activated neutrophils produce proinflammatory mediators such as ROS, NETs, COX-2, iNOS, MPO, and elastase. M1-like macrophages help T cells differentiate into Th1, Th2, Treg, and Th17 subgroups. AEC I and AEC II are injured, and surfactant production decreases. Platelet aggregation and microthrombus formation cause intra-microvascular and intra-alveolar thrombosis, all of which injure barrier functions, leading to intra-alveolar and interstitial edema and respiratory failure. GCs suppress the NF-κB pathway to inhibit downstream proinflammatory mediator release, enhance antigen uptake in DCs and NKCs, and contribute to anti-inflammation effects by elevating proportions of Th2, Treg, and Th17 subgroups, and reducing the Th1 subgroup. Despite repressing the expression of adhesion molecules to prevent adhesion and extravasation of neutrophils, GCs also induce expression and secretion of Anx-1 to further induce apoptosis of neutrophils in the inflammatory site. Created by Biorender.

AEC: Alveolar epithelial cell; Anx-1: Annexin-1; AQPs: Aquaporins; ARDS: Acute respiratory distress syndrome; COX-2: Cyclooxygenase-2; CXCL: C-X-C motif chemokine ligand; DAMP: Damage-associated molecular pattern; DCs: Dendritic cells; ENaC: Epithelial sodium channels; E-sel: E-selectin; GC: Glucocorticoid; IL: Interleukin; iNOS: Inducible nitric oxide synthase; l-sel: l-selelctin; LTB4: Leukotriene B4; MHC: Major histocompatibility complex; MMPs: Matrix metalloproteinases; MPO: Myeloperoxidase; NETs: Neutrophil extracellular traps; NF-κB: Nuclear factor kappa-B; NKC: Natural killer cell; PAMP: Pathogen-associated molecular patterns; ROS: Reactive oxygen species; TCR: T cell receptor; Th cell: T helper cell; TNF: Tumor necrosis factor.

Fig. 1:

Exudative phase

In the exudative phase, the activated alveolar resident macrophages release proinflammatory mediators, leading to the accumulation of neutrophils, monocytes, and effector T cells.[19] Recruitment of neutrophils to the lung is a key step in the pathogenesis of ARDS.[20] Proinflammatory mediators, mostly interleukin-8 (IL-8), released from either alveolar resident macrophage or activated intravascular immune cells, cause neutrophils to be primed, adhered, and then crossover the capillary wall into the interstitium and alveoli, releasing reactive oxygen species (ROS), antimicrobial peptides, proinflammatory lipid-derived mediators, and neutrophil extracellular traps (NETs) to kill pathogens and limit inflammatory diffusion.[21] This robust host defense response also damages the surrounding tissue. Activation of the platelet and complementary system aggravated by tumor necrosis factor (TNF)-mediated expression of tissue factors (TFs) leads to microvascular thrombus formation, together with dysfunction of tight junctions and ion channels (e.g., epithelial sodium channels [ENaC] and sodium-potassium pump [Na+/K+-ATPase]), cell necrosis and apoptosis, hyaline membrane formation, and mechanical stretch. All of these further contribute to endothelial–epithelial barrier dysfunction, resulting in protein-rich fluid exudation from the capillary into interstitium and then the alveoli[[22], [23], [24], [25]] (Figure 1B).

Proliferative phase

In the proliferative phase, alveolar resident macrophages shift to the anti-inflammatory phenotype (i.e., M2), clearing neutrophils and excessive NETs through the efferocytosis process.[26,27] Alveolar epithelial cells (AECs) II begin to differentiate into AEC I, and tight junctions, along with adhere junctions, begin reconstructing and reestablishing the integrity of the endothelial–epithelial barrier.[28] The protein-rich edema fluid and hyaline membrane begin to be reabsorbed by re-expression of ion channels and aquaporins (AQPs).[29] However, prolonged lifespan and delayed apoptosis of neutrophils exaggerate NETs release that, along with decreased phagocytosis function of macrophages to apoptotic neutrophils and NETs, sustain inflammation in ARDS[30,31] (Figure 2A).Figure 2 GC mechanisms in the proliferative and fibrotic phase of ARDS. A: The proliferative phase aims to resolve inflammation and reconstruct damaged structures. GCs induce phenotypic changes in macrophages from proinflammatory M1 to anti-inflammatory M2, activate macrophages to remove apoptotic cells, and improve the proportion of Treg cells, which release TGF-β, contributing to inflammation resolution. GCs can augment NETs production for inflammation clearance, but excessive NETs production leads to persistent inflammation and aggressive injuries. Following GC therapy, ion channel (ENaC, Na+/K+-ATPase, Ca2+/Cl−/K+ pump, and AQPs) activity and quantity increase to hasten edema clearance. Surfactant production is increased with enhanced proliferation of AEC II. B: During the fibrotic phase, despite promoting re-epithelialization, GCs prevent the collagen deposition process and help to maintain the coagulation–fibrinolysis balance. Created by Biorender.

AEC: Alveolar epithelial cell; AQPs: Aquaporins; ARDS: Acute respiratory distress syndrome; ENaC: Epithelial sodium channels; GC: Glucocorticoid; IGF: Insulin-like growth factor; IL: Interleukin; NETs: Neutrophil extracellular traps; PAI: Plasminogen activator inhibitor; PDGF: Platelet derived growth factor; TGF: Transforming growth factor; vWF: von Willebrand factor.

Fig. 2:

Fibrosis phase

During the fibrosis phase, M2-like macrophages and activated AEC II release factors, including transforming growth factor (TGF)-β, platelet-derived growth factor, and insulin-like growth factor-1 (IGF-1), induce extensive deposition of extracellular matrix. However, extensive basement membrane damage and lack of surfactant production can cause atelectasis and persistent interstitial and intra-alveolar inflammatory exudation[18,32] (Figure 2B).

Mechanisms of GCs in ARDS

GCs are considered a promising treatment of ARDS based on their anti-inflammatory, anti-oxidant, anti-fibrosis, and immunoregulation effects. However, the clinical effects remain controversial due to different ARDS phenotypes and variance in illness severity. Other influencing factors include GC type, initial time, dosage, and duration.[33] (The known mechanisms of GC actions are shown in Supplementary Box 1.)

Nuclear factor kappa-B (NF-κB) and activator protein-1, among other proinflammatory TFs, are primarily targeted by glucocorticoid receptor (GR)-mediated gene suppression to limit the inflammatory response.[34] Glucocorticoid-induced leucine zipper (GILZ), a key regulator of GC effects, downregulates toll-like receptor-2 (TLR-2) expression and NF-κB, activator protein-1, and mitogen-activated protein kinase pathway activities, thus inhibiting downstream proinflammatory gene expressions.[35,36] GCs can inhibit the NF-κB signal pathway by inducing inhibitor kappa B-alpha expression.[19] They can also upregulate mitogen-activated protein kinase phosphatase-1 expression, then attenuate extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and Jun N-terminal kinase signaling by either directly by binding to mitogen-activated protein kinase phosphatase-1 promoter or indirectly upregulating GILZ.[37,38] Annexin-1 (Anx-1), the first GC-induced annexin superfamily member to be characterized, inhibits the expression or activity of proinflammatory eicosanoids, cyclooxygenase (COX), and inducible nitric oxide (NO) synthase (iNOS) by repression of phospholipase A2.[39,40] Anx-1 can also prevent neutrophil adhesion to endothelial layers, and interfere with excessive inflammatory cell transmigration.[41] GCs can further induce vasorelaxation by activating phosphoinositide 3-kinase (PI3K) in a concentration-dependent manner, with lower dosages of GCs causing an increase in NO production and higher doses of GCs causing a decrease in NO production.[42] Moreover, GCs can block several inflammatory pathways by promoting expressions of specific proteins. Increased IL-10 expression inhibits NF-κB, activates PI3K, downregulates TLR-4, and induces macrophage apoptosis, all of which help to resolve inflammation.[43] In macrophages and endothelial cells, GCs protect endothelial barrier function by upregulating the sphingosine kinase 1 gene, which leads to elevated plasma sphingosine 1-phosphate.[44] Moreover, GCs stimulate the expression of cluster of differentiation163 (CD163), a scavenger receptor that marks alternatively activated macrophages and monocytes, prompting them to phagocytose apoptotic cells and attenuate inflammation.[45] GCs also reduce blood flow to inflammatory areas by several mechanisms, consisting of upregulating endothelin and angiotensin-converting enzyme expression, sensitizing endothelial cells to vasoconstrictors, and suppressing the generation of vasodilators.[46]

Nearly all nucleated cells express GR, but GCs exert different actions on different cell types. The antigen uptake of dendritic cells (DCs) can be enhanced by GCs, which further down-regulate the expression of major histocompatibility complex-II molecules, co-stimulatory molecules, and proinflammatory cytokines (e.g., IL-1, IL-6, and IL-12).[47] GCs can extend the lifespan of natural killer cells (NKCs) stimulated by IL-2 and IL-12, protect NKCs from cytokine-induced death, and increase expression of interferon (IFN)-γ and IL-6, which further exert anti-inflammatory effects.[48] GCs can suppress T cell expression of co-stimulatory molecules (CD2/CD8), cytokines (IL-1/IL-2/IL-5/IL-8/IL-13, IFN-α/IFN-β/IFN-γ), and chemokines, resulting in potent T cell suppression.[49,50] Simultaneously, by inhibiting macrophages and DCs from producing IL-12 and IFN-γ, GCs can reduce Th1 cell activation and promote Th17 cell differentiation, leading to increased expression of the anti-inflammatory mediator TGF-β and introducing a shift from Th1 to Th2 immunity.[[51], [52], [53]] By boosting the number of Treg cells and enhancing their capacity to generate IL-10, Treg cells become resistant to GC-induced apoptosis.[54,55]

Innate immune cells, primarily neutrophils and macrophages, play an essential role during the inflammatory response. GCs stimulate the expression of TLR-2 and Nod-like receptor-3, increase circulating bone marrow-derived neutrophils, and enhance the innate immune system's ability to react instantly to inflammation.[56,57] Tissue infiltration of neutrophils can be targeted by GCs via (1) down-regulated expressions of L, P, and E-selection to reduce capture and rolling[58] and (2) reduce the adhesion molecules on both the endothelium[59] and leukocytes[60] to prevent adhesion and detachment. GCs also reduce expressions of ROS, COX-2, and iNOS[61,62] and inhibit chemotaxis and phagocytosis of neutrophils.[63] GCs inhibit the synthesis of proinflammatory mediators by enhancing IL-1 receptor-associated kinase-M expression in both macrophages and epithelial cells.[64,65] Furthermore, GCs can promote an anti-inflammatory phenotype in monocytes by preventing oxidative stress-induced apoptosis, permitting them to migrate rapidly into inflammatory sites.[66]

A hallmark of ARDS, the inflammatory pulmonary edema caused by the damaged endothelial–epithelial barrier is also the key target of exogenous GCs. Inflammatory cytokines can prevent fluid transport by inactivation of ENaC and Na+/K+-ATPase.[29] GCs can activate the PI3K/phosphatidylinositol-3,4,5-trisphosphate (PIP3) pathway or increase SGK1 synthesis to inhibit iNOS, then activate ion channels.[24] GCs control Na+ transport by inducing steroid-induced proteins that alter ENaC trafficking, assembly, and degradation.[24] GCs also down-regulate channel permeability by inhibiting AQPs.[67] It has also been suggested that GCs rapidly decrease basal intracellular Ca2+ levels by interfering with Ca2+ cycling from intracellular stores into the cytoplasm, reducing ATP consumption and ROS production, thus affecting cellular energy metabolism.[68]

During the rehabilitation and fibrotic phase of ARDS, GCs prevent collagen deposition and re-epithelialization, to restore tissue integrity and function.[69,70] After administering GCs, levels of plasminogen activator inhibitor (PAI)-1 increase, while von Willebrand factor and fibrinogen levels decline, potentially maintaining the proper coagulation–fibrinolysis balance.[71] Moreover, GILZ acts as a negative regulator of Ras- and Raf-induced proliferation and a critical mediator of GCs antiproliferative activity.[72]

Heterogeneity of ARDS

A main reason why observational and randomized trials fail is that ARDS is, by nature, heterogeneous.[73] Negative results may indicate a treatment that is truly ineffective or a masking signal from harm in a subset of patients with a similar phenotype.[74] Identifying a patient's ARDS endotype and subphenotype facilitates assigning them to various treatment groups and assessing results more precisely. Both prognostic enrichment (identifying subgroups who are more likely to have a particular endpoint) and predictive enrichment (identifying subgroups who are more likely to respond to a given intervention due to the mechanism of benefit) help to improve clinical trial efficacy.[75,76] See Figure 3 for a schematic representation of ARDS heterogeneity.Figure 3 ARDS heterogeneity and future perspectives. The ARDS is heterogeneous by nature and markedly impacts treatment efficacy. The center of the donut graph represents four main ARDS heterogeneity factors: clinical, physiological, radiographical, and biological. Circles within each section show identified subphenotypes. Omics approaches (left) and AI-assisted conceptual models (right) may help to identify specific subphenotypes and promote precision medicine. Created by Biorender.

AI: Artificial intelligence; AKI: Acute kidney injury; ARDS: Acute respiratory distress syndrome.

Fig. 3:

Many factors—including physiological, clinical, radiological, and biological—are considered to identify ARDS subphenotypes. Several physiological parameters can be considered to categorize patients with ARDS, including PaO2/FiO2, dead space fraction, driving pressure, and ventilatory ratio. There is a positive correlation between illness severity and mortality, according to both the Berlin and global definitions, both of which use PaO2/FiO2 as the illness severity criterion.[4,77] One notable drawback of PaO2/FiO2 is its significant dependence on ventilator settings, particularly positive end-expiratory pressure, which may swiftly transfer one subset of patients to another.[78,79] In a recent study, investigators also distinguished recruitable and non-recruitable phenotypes using CT imaging, respiratory mechanics, and gas exchange.[80] These phenotypes are distinguished by their notably different reactions to standardized recruitment protocols.[80] The efficacy of using other physiological parameters (e.g., airway driving pressure and transpulmonary pressure) to guide intervention classification has yet to be fully elucidated.[[81], [82], [83]]

Clinical phenotypes (including pneumonia/non-pulmonary sepsis/trauma, direct/indirect, bacteria/virus/fungal/other, early/late stage, temporary/persistent, and acute kidney injury) act as an important framework for ARDS management and prognosis[79,84]; this indicates differences in incidence, risk strategy, and mortality in patients under different ARDS pathogenesis types. The main drawback of clinical phenotypes is that they make it difficult to classify patients because they have unique physiologies and respond differently to treatments. While ARDS is a clinical diagnosis, clinical characteristics may not be precise enough to differentiate among patients’ biological heterogeneity for matching targeted therapies to the most active, relevant pathways.[73]

Radiographic heterogeneity was reported in a study in which lung morphology was classified into focal and non-focal phenotypes.[85] The Lung Imaging for Ventilator Setting trial found no difference in 90-day mortality between standard and personalized ventilation strategies for focal or non-focal moderate-to-severe ARDS, but it did find a 21% misclassification at randomization.[86] Mortality was significantly higher among patients whose ventilator strategy was misaligned, and excluding the misaligned group from the whole patient group has a potential survival benefit. Effectively identifying and allocating patients to the correct phenotype are crucial for future clinical trials and precision medicine. Since plain chest radiographs are more readily available than CT, radiographic assessment of lung edema scoring can be used to quantify both the extent and density of alveolar edema; previous studies have found that radiographic assessment of lung edema score changes over time are associated with ARDS clinical outcome.[87,88]

With their lower chance of misclassification, biological markers are considered the most trustworthy for subphenotyping patients with ARDS. Several plasma biomarkers have been tested, including markers of inflammatory, endothelial injury, and coagulation disorder, all of which had prognostic value.[89,90] In addition, “hyperinflammatory” and “hypoinflammatory” subphenotypes were identified by the latent class analysis,[91] while “reactive” and “uninflamed” subphenotypes were identified using hierarchical clustering and canonical pathway analysis.[92,93] Three-variable (IL-8, bicarbonate, and protein C) and four-variable (addition of vasopressor) parsimonious models have been developed to improve efficacy,[94,95] though prospective validation will be needed.[96] Airspace sampling, such as bronchoalveolar lavage fluid[96] and heat moisture exchange filter fluid,[97] could also provide evidence of lung injury that plasma cannot, deepening our understanding of ARDS mechanisms. Omics technologies such as genomic, transcriptomic, proteomic, and metabolomic offer promising opportunities for pathway-specific interventions[96,[98], [99], [100], [101]]; however, these approaches are still in early development and not yet ready for patient use.[102]

Since ARDS develops rapidly, intervention should occur at clinical symptoms onset. Preventing unsafe exposure to immunomodulating drugs, like GCs, is critical,[103] highlighting that reliable identification of patient phenotype is a major hurdle for precision medicine clinical trials in critically ill populations.[104] Point-of-care clinical biomarker assays are needed to enable appropriate pre-intervention phenotyping.[105] ARDS heterogeneity includes severity, stage, etiology, clinical trial design, and population, all of which may be useful for distinguishing phenotypes for specific “treatable traits” beyond the current ARDS definition.[[106], [107], [108]] To better understand the important nodes of underlying physiological mechanisms, novel interventions of each subphenotype must be tested through preclinical research, translational clinical cohort studies, and randomized trials.[73] Well-designed clinical trials should also be designed to increase participant representativeness, including those from both resource-rich and resource-poor settings, to decrease trial population heterogeneity.[74]

GC Therapy in Non-COVID-19-Related ARDS

As GCs have been considered both standard and exploratory treatments for preventing the spread of inflammation and improving survival, previous studies have tested different regimens in terms of timing, dose, course, and withdrawal, thus laying the groundwork for GC therapy in ARDS.[109,110] A comparison of GCs is presented in Supplementary Box 2. Representative randomized controlled trials (RCTs) for ARDS and severe pneumonia are summarized in Table 2.Table 2 RCTs of ARDS.

Table 2:Trial/author (year)	Design	Period	Participants	No. of patients (GCs/control)	Interventions	Duration (days)	Primary outcome (GCs vs. control)	Secondary outcomes	Others	
Burnard et al.[176] (1987)	Country: USA Multicenter (7 ICUs) Placebo-controlled Two parallel groups	June 1983–November 1985	ARDS	99 (50/49)	Methylprednisolone (bolus of 30 mg/kg for every 6 h for four doses)	1	No difference in mortality rate during 45-day follow-up (60% vs. 63%, P=0.74)	Lower reversal of chest radiograph and arterial blood gases were observed (9% vs. 56%, P < 0.018)	NA	
Meduri et al.[127] (1998)	Country: Memphis Multicenter (4 ICUs) Placebo-controlled Two parallel groups	October 1994–November 1996	Severe persistent ARDS	24 (16/8)	Methylprednisolone (bolus of 2 mg/kg followed by every 6 h: 2 mg/(kg·day) for 14 days, 1 mg/(kg·day) for 7 days, 0.5 mg/(kg·day) for 7 days, 0.25 mg/(kg·day) for 2 days, and 0.025 mg/(kg·day) for 2 days)	14	On day 10: Reduced LIS (1.7 vs. 3.0, P < 0.001) Improved PaO2: FiO2 (262 vs. 148, P < 0.001) ICU mortality: 0/16 (0%) vs. 5/8 (62%) (P=0.002) Hospital mortality: 2/16 (12%) vs. 5/8 (62%) (P=0.03)	Decreased MODS score (0.7 vs. 1.8, P <0.001) No increased rate of infections	Four patients in the control group crossed over because of failure to improve outcomes	
Confalonieri et al.[113] (2005)	Country: Italy Multicenter (6 ICUs) Placebo-controlled Two parallel groups	July 2000–March 2003	Severe CAP	48 (24/24)	Hydrocortisone (bolus of 200 mg followed by infusion of 240 mg/day at a rate of 10 mg/h)	7	On day 8: Improved PaO2: FiO2 ≥300 mmHg (16/23 vs. 5/23, P=0.0002) Reduced MODS score (0.3±0.5 vs. 1.0±0.9, P=0.003)	GCs treatment was associated with decreased CRP levels (18 mg/dL vs. 34 mg/dL, P=0.01), delayed septic shock (0% vs. 13%, P=0.001), reduced in-hospital stay and mortality (all P < 0.01) on day 8	NA	
ARDS Network/Steinberg et al.[112] (2006)	Country: USA Multicenter (25 ICUs) Placebo-controlled Two parallel groups	August 1997–November 2003	Persistent ARDS	180 (89/91)	Methylprednisolone (bolus of 2 mg/kg, followed by 0.5 mg/(kg·6 h) for 14 days, 0.5 mg/(kg·12 h) for 7 days, and tampered over 2–4 days)	23–25	No difference in 60-day mortality between groups (29.2% vs. 28.6%, P=1.0)	Improvement in MV-free days (P < 0.001), ICU-free days (P=0.02), and organ failure-free days (P < 0.001) at day 28 Higher rate of neuromuscular weakness (9 vs. 0, P=0.001)	Significantly increased rate of 60-day and 180-day mortality when GCs administered ≥14 days before the onset of ARDS More likely to be re-intubated after GCs treated (28% vs. 9%, P=0.006)	
Annane et al.[177] (2006)	Country: France Multicenter (19 ICUs) Placebo-controlled Post hoc analysis Two parallel groups	October 1995–February 1999	Septic shock-associated early ARDS	177 (85/92)	Hydrocortisone (50 mg/6 h) together with fludrocortisone (50 μg orally daily)	7	Decreased 28-day survival in non-responders (53% vs. 75%, HR=0.57, 95% CI: 0.36 to 0.89, P=0.013)	ICU mortality in non-responders (RR=0.73, 95% CI: 0.57 to 0.94, P=0.01) Hospital mortality in non-responders (RR=0.75, 95% CI: 0.59 to 0.96, P=0.016) No significant difference in adverse events (all P > 0.05)	Not all patients received lung-protective ventilation (mean tidal volume in all patients with ARDS >8 mL/kg)	
Meduri et al.[111] (2007)	Country: USA Multicenter (5 ICUs) Placebo-controlled Two parallel groups	April 1997–April 2002	Severe early ARDS (≤72 h)	91 (63/28)	Methylprednisolone (bolus of 1 mg/kg followed by 1 mg/(kg·day) continuous infusion for 14 days, 0.5 mg/(kg·day) for 7 days, 0.25 mg/(kg·day) for 4 days, and 0.125 mg/(kg·day) for 3 days)	28	On day 7: 2-fold reduction of a 1-point reduction in LIS (69.8% vs. 35.7%, P=0.002) and MODS scores (0.90±1.1 vs. 1.9±1.4; P=0.002) More patients breathing without assistance (54% vs. 25%; P=0.01)	Shorter length of ICU stay (7 days vs. 14.5 days; P=0.007) Lower rate of ICU mortality (20.6% vs. 42.9%; P=0.03) Fewer new infections (42.9% vs. 60.7%; P=0.002)	More received open-label methylprednisolone (7.9% vs. 35.7%; P=0.002)	
Meijvis et al.[178] (2011)	Country: Netherlands Multicenter (2 ICUs) Placebo-controlled Two parallel groups	November 2007–
September 2010	Severe CAP	304 (151/153)	DEX (5 mg daily)	4	Reduced length of hospital stay (6.5 days vs. 7.5 days, 95% CI: 0 to 2 days, P=0.048)	No difference in hospital mortality and 30-day mortality (all P > 0.05) Higher rate of hyperglycemia (67/151 [44%] vs. 35/153 [23%], P < 0.0001)	NA	
Tongyoo et al.[120] (2016)	Country: Thailand Single-center Placebo-controlled Two parallel groups	December 2010–
December 2014	Sepsis-associated ARDS	197 (98/99)	Hydrocortisone (200 mg/day in 4 bolus of 50 mg)	7	No difference in mortality at day 28 (22.5% vs. 27.3%, RR=0.82, 95% CI: 0.50 to 1.34, P=0.51)	Similar time to remove vital organ support (HR=0.74, 95% CI: 0.51 to 1.07, P=0.107)	Improvement in the PaO2: FiO2 (P=0.001) and LIS (P=0.01) Higher rate of hyperglycemia (80.6% vs. 67.7%, P=0.04)	
DEXA-ARDS/Villar et al.[123] (2020)	Country: Spain Multicenter (17 ICUs) Placebo-controlled Two parallel groups	March 2013–December 2018	Moderate-to-severe ARDS	277 (139/138)	DEX (20 mg/day bolus for 5 days followed by 10 mg/day for 5 days)	10	Longer MV-free days on day-28 (MD=4.8 days, 95% CI: 2.57 to 7.04, P < 0.0001)	Lower all-cause mortality on day-60 (between-group difference −15.3%, 95% CI: −25.9 to −4.9, P=0.0047)	Higher re-intubation rate with DEX compared with control (12 [8.6%] vs. 7 [5.1%])	
CoDEX trial/Angus et al.[179] (2020)	Country: Brazil Multicenter (41 ICUs) Placebo-controlled Two parallel groups	June 2020–July 2020	Moderate-to-severe ARDS	299 (151/148)	DEX (20 mg/day bolus for 5 days followed by 10 mg/day for 5 days or until discharge)	NA	Longer MV-free days on day-28 (MD=2.26 days, 95% CI: 0.2 to 4.38, P=0.04)	No difference in all-cause mortality, ICU-free days, and MV-free days at day-28	NA	
Gragueb‑Chatti et al.[155] (2021)	Country: France Multicenter (3 ICUs) Placebo-controlled Two parallel groups	March 10–29, 2020 and
August 2020–November 2020	COVID-19-related ARDS requiring invasive MV	151 (84/67)	DEX (6 mg/day for 10 days)	10	DEX did not significantly increase the incidence of VAP or BSI	DEX treatment was associated with more VFD at day-28	NA	
RECOVERY trial/Horby et al.[145] (2021)	Country: UK Multicenter (176 ICUs) Placebo-controlled Two parallel groups	March 2020–June 2020	COVID-19	6425 (2104/4321)	DEX (6 mg/day for 10 days)	10	Lower 28-day mortality among those who were receiving either invasive MV or oxygen alone at admission (aRR=0.83, 95% CI: 0.75 to 0.93, P < 0.001)	NA	DEX treatment showed no benefit and even harm among patients who did not require oxygen	
Moreno et al.[150] (2021)	Country: Spanish, Andorran, and Irish Multicenter (70 ICUs) Placebo-controlled Two parallel groups	February 2020–
September 2020	COVID-19-related ARDS requiring invasive MV	1835 (1117/781)	Methylprednisolone was used in 76.6% and DEX was used in 22.1% of patients. Mean duration of methylprednisolone and DEX treatment was 5 days and 10 days, respectively	NA	ICU mortality did not differ between groups (33.8% vs. 30.9%, P=0.28)	GCs treatment at ICU admission was associated with survival benefit (HR=0.53, 95% CI: 0.39 to 0.72) After the 17th day of admission, GCs treatment increased ICU mortality (long-term HR=1.68, 95% CI: 1.16 to 2.45)	Specific subgroups (age <60 years, severe ARDS) could benefit from GCs treatment	
Martinez-Guerra et al.[159] (2022)	Country: Mexico Single-center Placebo-controlled Two parallel groups	March 2020–September 2020	Severe COVID-19-related ARDS	1540 (688/852)	DEX (6 mg/day for 10 days) after June 17, 2020	NA	Reduced in-hospital mortality (18% vs. 31%, P < 0.01)	GCs treatment resulted in longer time before MV (5 days vs. 3 days, P < 0.01), and more HAP (20% vs. 10%, P < 0.01)	NA	
Lamouche‑Wilquin et al.[154] (2022)	Country: France Multicenter (15 ICUs) Placebo-controlled Two parallel groups	February 2020–December 2020	COVID-19-related ARDS	670 (369 early GCs/301 no early GCs)	DEX was used in 91% (336/369) of the early admitted patients, while methylprednisolone was used in 36% (19/53) beyond 24 h of admission	NA	The incidence of VAP was higher with early GCs treatment (HR=1.29, 95% CI: 1.05 to 1.58, P=0.016)	NA	VAP was associated with higher day-90 mortality, but early GCs treatment was not	
Reyes et al.[153] (2022)	Country: Latin, USA, and Europe Multicenter (84 ICUs) Placebo-controlled Two parallel groups	March 2020–January 2021	Severe COVID-19-related ARDS	3777 (2065/1712)	DEX dose and duration were determined by the attending physician	NA	Significant higher proportion of VAP was found (17.1% vs. 13.2%, P=0.014)	NA	DEX treatment was considered an adjusted risk factor of ICU-acquired respiratory infections	
Maskin et al.[180] (2022)	Country: Argentina Multicenter (4 ICUs) Dose-controlled Two parallel groups	June 2020–March 2021	COVID-19-related ARDS required invasive MV	98 (49 low-dose DEX/49 high-dose DEX)	DEX (6 mg/day for 10 days in low-dose group; 16 mg/day for 5 days followed by 8 mg/day for 5 days)	10	No difference in VFD ([0–14] day vs. [0–1] day, P=0.231) or mean duration of MV (19±18 days vs. 25±22 days, P=0.078) within 28 days after inclusion between groups	Higher cumulative hazard of successful discontinuation from MV in the high-dose group (HR=1.84, 95% CI: 1.31 to 2.5, P < 0.001)	NA	
Scaravilli et al.[181] (2022)	Country: Italy Multicenter (4 ICUs) Propensity-matched cohort study Two parallel groups	February 2020–December 2020	COVID-19-related ARDS requiring invasive MV	316 (158/158)	DEX (6 mg/day for 10 days)	10	Higher VAP incidence and risk for VAP	Mortality was similar between groups	VAP was associated with longer ICU and in-hospital LOS, and MV rate. VAP increased mortality (RR=1.64, 95% CI: 1.02 to 2.65, P=0.04)	
RECOVERY trial/RECOVERY Collaborative Group[148] (2023)	Country: UK, Asia, and Africa Multicenter (93 ICUs) Placebo-controlled Two parallel groups	May 2021–May 2022	COVID-19	1272 (659/613)	DEX (20 mg/day bolus for 5 days followed by 10 mg/day for 5 days or until discharge)	NA	Higher dose GCs result in higher day-28 mortality compared with usual care (123/659 [19%] vs. 75/613 [12%], RR=1.59, 95% CI: 1.12 to 2.10, P=0.0012)	NA	Higher dose DEX treatment resulted in an increase in hyperglycemia requiring an increased insulin dose	
ARDS: Acute respiratory distress syndrome; BSI: Blood stream infections; CAP: Community-associated pneumonia; CI: Confidence interval; COVID-19: Coronavirus disease 2019; CRP: C-reactive protein; DEX: Dexamethasone; FiO2: Fraction of inspired oxygen; GCs: Glucocorticoids; HAP: Hospital-acquired infections; HR: Hazard ratio; ICU: Intensive care unit; LIS: Lung injury scores; LOS: Length of stay; MD: Mean difference; MODS: Multiple organ dysfunction syndrome; MV: Mechanical ventilation; NA: Not available; PaO2: Partial pressure of oxygen in arterial blood; RCTs: Randomized controlled trials; RR: Risk ratio; VAP: Ventilator-associated pneumonia; VFD: Ventilator-free day.

Who benefits from GCs therapy?

Intervention stage

The first step is to identify patients who will benefit from GCs. The effects of a low-dose prolonged methylprednisolone regimen for severe early ARDS (≤72 h of symptom onset) were examined in a 2007 multicenter RCT (n=91), reported by Meduri et al.[111] Those receiving methylprednisolone had significantly: mitigated systemic inflammation, accompanied by lower C-reactive protein levels; improved pulmonary and extrapulmonary organ dysfunction, evidenced by lower lung injury and multiple organ dysfunction syndrome scores; and shortened mechanical ventilation (MV) duration and ICU length of stay (LOS). Unfortunately, studies have failed to demonstrate GC efficacy in late-stage ARDS. Although data from the ARDS Network demonstrated that GCs improved pulmonary function from 7 days to 14 days after ARDS diagnosis, the therapeutic effect did not persist when GCs were delivered after that window, based on significantly higher 60-day and 180-day mortality rates in subgroup analyses.[112] Early GC treatment in patients with severe community-acquired pneumonia prevented progression to septic shock (0% vs. 43%) and ARDS (0% vs. 17%),[113] while prolonged methylprednisolone treatment in early ARDS prevented progression to unresolving ARDS (8% vs. 36 %).[111] A meta-analysis of 8 RCTs and 10 cohort studies reported that patients with persistent ARDS appeared to benefit more if GCs were given within 14 days after symptom onset, further confirming the ARDS Network findings.[114]

Bacterial, viral, fungal, and other pathogenic infections

Notably, the effects of early initial GC administration did not persist in patients with influenza-induced ARDS. A retrospective analysis of the Recherche en Ventilation Artificielle-SRLF (REVA-SRLF) trial conducted during the A/H1N1 pandemic found that early initiation (within ≤3 days of initial MV) with moderate-dose GCs was associated with increased mortality.[115] Moreover, GC therapy was associated with an increased risk of myocardial and liver injury, shock, MV duration, and delayed viral airway clearance, consistent with studies in severe acute respiratory syndrome-associated coronavirus (i.e., severe acute respiratory syndrome coronavirus 2 and Middle East respiratory syndrome coronavirus).[116,117] Thus, routine GCs in patients with virus-induced ARDS should be used with caution, as it may be detrimental to multi-organ function.

Preventive and rescue administration

Preventive GC administration has not been shown to prevent either the development of, or reverse, ARDS in patients with sepsis.[118] A meta-analysis of four studies assessing preventive GC treatment found a trend toward it increased odds of patients who developed ARDS, and increased mortality risk in those who subsequently developed ARDS.[119]

Can mortality be reduced after GC treatment?

Due to inconsistent study results, it remains uncertain whether GCs reduce mortality among patients with ARDS. Hydrocortisone administration improved pulmonary function but did not reduce 28-day mortality (hazard ratio [HR]=0.80, 95% confidence interval [CI]: 0.46 to 1.41) in early sepsis-associated ARDS (n=197).[120] A systemic review of 48 RCTs found that although GCs improved ventilator-free days (VFD) up to day 28 (mean difference=4.09, 95% CI: 1.74 to 6.44, low-certainty evidence) and might lower early all-cause mortality (risk ratio [RR]=0.77, 95% CI: 0.57 to 1.05; low-certainty evidence), they did not reduce late all-cause mortality (relative risk=0.99, 95% CI: 0.64 to 1.52; very low-certainty evidence).[121] The task force for the Critical Illness-Related Corticosteroid Insufficiency (CIRCI) guideline found that prolonged GC therapy was associated with increased VFD and ICU-free days and higher survival,[122] indicating that their therapeutic benefits outweighed potential risks. The DEX-ARDS RCT (n=277), conducted after publication of the CIRCI guidelines, found that early administration of dexamethasone (DEX) for 10 days resulted in reduced MV duration (between-group difference 4.8 days; 95% CI: 2.57 to 7.03) and all-cause mortality on day 60 (between-group difference 15.3%; 95% CI: −25.9 to 4.9%).[123]

How to determine an optimal therapeutic regimen?

GC therapy dose

Attention needs to be paid to GC dosage and use duration. From the mid-1950s to the 1980s, high-dose GCs were used to treat ARDS, with few survival benefits observed, especially from a short course of high-dose GCs. An observational study in which 105 patients with ARDS were allocated to high-dose or low-dose GCs (mean doses are 175 mg/day and 88.5 mg/day, respectively) according to their condition showed that except for a markedly decreased IL-18 and significant improvement in oxygenation among survivors, high-dose GC was related to higher 45-day mortality.[124] Kaplan–Meier analysis revealed that when the GC dosage was equal to 146.5 mg/day of methylprednisolone, it had the highest sensitivity and specificity for predicting death, indicating that high-dose GC was an independent risk factor for death. Collectively, high-dose GC therapy is not recommended for patients with either ARDS or sepsis according to current evidence.[125] In addition, a series of studies of patients with sepsis or septic shock showed no survival benefit, and potential harm in patients with normal (>9 g/dL) plasma cortisol.[126,127] Since the 1990s, physiologic steroid therapy (also known as a “supraphysiologic” or “stress” dose) in patients with ARDS and sepsis has been encouraging, including improved respiratory function, decreased lung and systemic inflammation, and survival benefits.[128,129] Most studies have used a protocol of ≤2 mg/(kg·day) with a gradual taper, but a more precise recommendation was made considering ARDS timing: methylprednisolone ≤1 mg/(kg·day) for early ARDS (≤72 h of onset) and 2 mg/(kg·day) for persistent/unresolving ARDS (≥5 days of onset), combined with a slow dosage reduction (9–12 days).[130] Although a null effect for low-dose steroid-based mortality efficacy in severe sepsis and septic shock could not be excluded, there appeared to be credible evidence for shock reversal efficacy; similarly, the beneficial effects of low-dose steroids were highly dependent on patient age and underlying risk factors.[131]

GC therapy duration

Previous clinical and experimental studies have demonstrated that GC exposure duration is critical to regulating cytokine production and that premature discontinuation leads to clinical deterioration (i.e., increased inflammatory markers and worsening multiple organ dysfunction).[132,133] In the ARDS Network, patients in the methylprednisolone group were able to breathe on their own sooner, but one-quarter of them resumed MV after rapid steroid discontinuation (28% vs. 9%). This result was probably attributable to the negative effects of GCs, such as neuromyopathy and shock recrudescence.[112] The potent anti-inflammatory effects of GCs were achieved at the expense of reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, with the risk of treatment-associated adrenal insufficiency in patients who are critically ill.[134]

Extended GC exposure restores GR quantity and function, resulting in lower inflammatory marker levels and higher functional surfactant levels.[130] A recent ARDS Network reanalysis reinforced that abruptly discontinuing GCs causes inflammatory rebound, which may explain the increased return to MV and mortality,[135] and that gradual tapering is essential to maintain inflammation resolution, restore tissue homeostasis, and suppress the HPA axis to forestall disease relapse because of inflammation rebound.[111,130] Hence, resuming GC administration should be considered if the patient's condition rapidly deteriorates after it is abruptly discontinued. With ongoing uncertainties, an individualized dosage regimen is required according to the underlying disease, organ function, and initial GC timing and options, rather than ARDS per se.[136]

Benefits and risks, as well as costs, must be balanced in treatment decision-making. We propose a tailored approach in which steroids are administered regularly to those most likely to benefit from them, avoided in patients at higher harm risk, and carefully evaluated on a case-by-case basis in those with intermediate risks/benefits.

GC Therapy in COVID-19-Related ARDS

COVID-19 has become the leading etiology of acute respiratory failure.[137,138] Severe acute respiratory syndrome coronavirus 2, the virus that causes COVID-19, attaches and internalizes along with the membrane-bound protein angiotensin converting enzyme (ACE-2) to cause intracellular damage.[139] Compared with non-COVID-19 ARDS, COVID-19-induced ARDS is characterized by reduced IL-6 expression,[140] lower total white cell count, and higher platelet count and fibrinogen.[141] DEX was reported to be therapeutic in severe COVID-19 by suppressing the IFN signal, expanding immunosuppressive immature neutrophils, and remodeling cellular interactions.[142] GCs also inhibit ROS generation in circulating T cells[143] and decrease CD4+ counts and human leukocyte antigen expression in circulating monocytes.[144]

The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial reported that DEX (6 mg/(kg·day) for 10 days) reduced 28-day mortality by one-third in patients undergoing invasive MV, and one-fifth in those who received oxygen supply, but did not benefit those who did not receive oxygen.[145] Several studies have demonstrated the positive effects of GCs on survival, without elevated risk of adverse events.[146,147] Although RECOVERY survival benefits results led to several recommendations regarding GC therapy in patients with severe COVID-19, controversial results remain. The latest RECOVERY trial (n=1272) reported significantly increased mortality risk in patients hospitalized with COVID-19 who require either no oxygen or simple oxygen with higher-dose GCs (DEX 20 mg/day for 5 days followed by 10 mg/day for 5 days or until discharge), compared with usual care which included low-dose GCs.[148] In the COVID-19 Dexamethasone (CoDEX) trial, in patients with moderate-to-severe COVID-19 (n=299), DEX administration led to no significant improvements in ICU mortality, ICU LOS, or MV duration.[149] A large retrospective cohort study of patients with COVID-19 with MV also identified a time-dependent effect for survival benefit, with a protective effect when GCs were administered within 2 weeks of diagnosis.[150] Recently, high-dose GCs (1 mg/kg methylprednisolone) treatment in patients with COVID-19 and non-resolving ARDS who had been treated with DEX as standard of care had higher 90-day mortality (adjusted HR=1.65, 95 % CI: 1.03–2.63).[151] The One Year Follow-ups of Patients Admitted to Spanish Intensive Care Units Due to COVID-19 (CIBERESUCICOVID) trial found a protective effect on 90-day mortality, even in specific subgroups (i.e., age ≥60 years, higher baseline severity, those who required MV at ICU admission).[152] A large, multicenter RCT (n=3777) found that treating patients with severe COVID-19 with DEX increased the incidence of ICU-acquired respiratory tract infections (17.1% vs. 13.2%), regardless of illness severity at ICU admission or duration of invasive MV.[153] Lamouche-Wilquin et al.[154] concluded that early GC treatment increased ventilator-associated pneumonia (VAP) rates, which were associated with higher 90-day mortality. However, Gragueb-Chatti et al.[155] reported that preventive DEX dose did not increase VAP occurrence or bispectral index monitoring, and even led to longer VFD at day 28 (9 [0–21] days vs. 0 [0–11] days). Whether GCs increase VAP incidence remains uncertain, yet clinicians should attend to high VAP rates in patients with COVID-19-related ARDS who are treated with GCs. These cumulative data emphasize that careful immune monitoring is needed. In conclusion, early GC initiation (≤7 days of symptom onset) should be avoided, and potential risks for nosocomial bacterial pneumonia and hyperglycemia should be considered.[156]

GCs Therapy Side Effects

Two key issues limit the use of GCs as therapeutic agents. First, high-dose and/or long-term GCs use can cause adverse effects, including infections, hyperglycemia, cardiovascular disease, muscle weakness, and gastrointestinal bleeding. Second, glucocorticoid resistance (GCR) and CIRCI are usually observed, but underestimated, in patients who are critically ill. Because these issues can be devastating, clinicians must evaluate the potential risks before making decisions regarding GC treatment for ARDS.

Infection

The increased risk of nosocomial infection in patients with ARDS from immunosuppression is a major concern. According to the ARDS Network,[112] the treated group had a lower probability of clinically diagnosed VAP, but it was difficult to determine how an undiscovered infection might affect the outcome due to the absence of infection surveillance. While several studies have found that GCs do not raise overall infection risk,[157,158] a meta-analysis showed a trend toward increased incidence of new infections with increasing GC doses.[119] In addition, conflicting results have been reported, including infection risk increases in cohort studies (RR=1.35, 95% CI: 0.99 to 1.84) and decreases in RCTs (RR=0.83, 95% CI: 0.65 to 1.06).[114] It is unclear whether this difference can be attributed to the strict patient selection and infection monitoring procedures in RCTs. Higher incidences of ICU-acquired infections (45.8% vs. 35.2%) and pneumonia (41.0% vs. 26.4%) have been linked to GC treatment for influenza-induced ARDS.[115] A higher rate of hospital-acquired infections (HAP) (20% vs. 10%), primarily HAP/VAP but not bloodstream infections, was found among COVID-19 patients with GCs treated compared with placebo.[159] The CIBERESUCICOVID trial (n=4226) reported an elevated incidence of both clinically diagnosed and microbiologically confirmed nosocomial bacterial pneumonia (odds ratio [OR]=1.29, 95 % CI: 1.01 to 1.65) and hyperglycemia (OR=2.17, 95 % CI: 1.35 to 3.48) in 3592 patients who received GCs.[152] Because early infection signs and symptoms can be masked by GCs, especially when insufficient infection surveillance measures are taken, infection rates vary. Future studies should define the timeframe for infection surveillance to more precisely define infection incidence in the context of clinical symptoms and etiological evidence, to provide prompt treatment.

Hyperglycemia

Hyperglycemia is a common side effect of GCs and is evidenced by insulin resistance and impaired peripheral glucose uptake. Patients receiving GCs for pneumonia, sepsis, septic shock, or ARDS experience a marked rise in hyperglycemia, but not gastrointestinal bleeding, secondary infection, neuropsychiatric events, or cardiac events.[[160], [161], [162]] A group receiving methylprednisolone had a significantly higher incidence of hyperglycemia compared with a group receiving DEX.[163] Among patients with COVID-19, an episode of blood glucose concentration ≥180 mg/dL by post-admission day 3 occurred in 19% of patients in the DEX treatment group.[159] Because systemic GCs can increase hyperglycemia, their development may negate the benefits of GCs and impair prognosis in patients with COVID-19.[164] Hence, the appropriate GC therapy durations need to be determined, and intensive blood glucose monitoring is recommended.

Muscle weakness and neuromyopathy

Muscle weakness is commonly observed in patients with ARDS who received MV for >7 days. The ARDS Network showed conflicting results: a strong association between methylprednisolone and severe muscle weakness, and similar cases of neuromyopathy, between treated and placebo groups.[112] However, among patients with neuromyopathy, the treated group had a shorter median MV duration. Although 48-h continuous infusion of neuromuscular blocking agents did not raise the probability of ICU-acquired weakness,[165,166] the combination of GCs and neuromuscular blocking agents appeared to do so.[167] Increased blood glucose levels were considered to be associated with neuromuscular diseases.[168] GCs may protect against neuromyopathy in the intensive insulin therapy setting.[169] The links among GCs, ICU-acquired neuromuscular dysfunction, and clinical outcomes remain unclear. Comprehensive electrophysiologic monitoring techniques for neuromuscular function will be required.

GCR and CIRCI

Patients with ARDS and sepsis commonly progress to GCR, which can be acquired as a pathological host response to the ineffectiveness of endogenous GCs to modulate inflammation, endothelial function, and glucose metabolism,[170] or inherited via mutations in the NR3C1 gene.[171] Since patients with severe sepsis and septic shock have blunted adrenal functions, low-dose GCs as an adjuvant therapy have become the standard treatment.[172] To achieve a higher benefit-to-risk ratio, guidelines regarding optimal dosage must be followed, along with strict monitoring to prevent and manage side effects.[134] Current therapeutic GCs do all activate GR activity, raising the potential for adverse effects.[173] To improve the therapeutic balance, more work should be done to stimulate the anti-inflammatory functions of GCs rather than unneeded functions.[173] Increased GC dosing may help to alleviate GCR, though overdose is a known danger.

CIRCI was first described, in 2008, as relative adrenal insufficiency, which occurs when the adrenal cortex is already fully activated to create substantial quantities of cortisol, but not enough to handle the extreme stress of illness; it is also termed “starvation in plenty.”[174] None of the total dose, highest dose, or length of GC therapy are reliable indicators of HPA axis recovery.[175] Since the publication of the guidelines for the diagnosis and management of CIRCI in 2017, prolonged low-dose GCs therapy has been recommended for survival benefits in patients with septic shock who are unresponsive to fluid resuscitation and moderate to high-dose of vasopressor therapy, but not in those without septic shock.[134] Because the negative effects of GCs are often dose-dependent, dose reduction may be an option for reducing side effects.

Future Perspectives

ARDS is a heterogeneous syndrome with variable severity and underlying causes. To date, despite support therapies having been consistently proven beneficial, no specific pharmacotherapy agents have achieved concrete benefits. Clinical studies have demonstrated the potent anti-inflammatory and immunomodulatory effects of GCs in specific subgroups of ARDS. Nevertheless, overall mortality has not improved, especially following the COVID-19 pandemic. The complex interplay among efficacy, risk factors, and adverse events needs further consideration. Tailoring optimal treatment regimens by vigilantly monitoring the initial timeframe, dose, duration, drug selection, and tapering of GCs is of prime importance for improving outcomes in patients with ARDS. In the future, GC therapy in ARDS should be tailored according to personalized physiology and biology, as we move toward an era of precision medicine in critical illness. Global-scale collaboration—among academics, industry, regulatory agencies, sponsors, and patients—may help to reveal the benefits and potential risks of GC therapies in patients with ARDS.

Appendix Supplementary Materials

Image, application 1

Author Contributions

Yuanrui Zhao: Writing – original draft, Writing – review & editing. Zhun Yao: Visualization. Song Xu: Writing – review & editing. Lan Yao: Writing – review & editing. Zhui Yu: Conceptualization, Writing – review & editing.

Acknowledgments

Liping Lu helped to review the article. The graphical figures were created with Biorender.com.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethics Statement

Not applicable.

Conflict of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data Availability

Data availability is not applicable to this study as no new data were created or analyzed in this study.

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jointm.2024.02.002.
==== Refs
References

1 Meyer N.J. Gattinoni L. Calfee C.S. Acute respiratory distress syndrome Lancet 398 10300 2021 622 637 10.1016/s0140-6736(21)00439-6 34217425
2 Definition A.R.D.S. Ranieri V.M. Rubenfeld G.D. Thompson B.T. Ferguson N.D. Caldwell E. Acute respiratory distress syndrome: the Berlin Definition JAMA 307 23 2012 2526 2533 10.1001/jama.2012.5669 22797452
3 Gorman E.A. O'Kane C.M. McAuley D.F. Acute respiratory distress syndrome in adults: diagnosis, outcomes, long-term sequelae, and management Lancet 400 10358 2022 1157 1170 10.1016/s0140-6736(22)01439-8 36070788
4 Matthay M.A. Arabi Y. Arroliga A.C. Bernard G. Bersten A.D. Brochard L.J. A new global definition of acute respiratory distress syndrome Am J Respir Crit Care Med 209 1 2023 37 47 10.1164/rccm.202303-0558WS
5 van der Ven F.L.I.M. Valk C.M.A. Blok S. Brouwer M.G. Go D.M. Lokhorst A. Broadening the Berlin definition of ARDS to patients receiving high-flow nasal oxygen: an observational study in patients with acute hypoxemic respiratory failure due to COVID-19 Ann Intensive Care 13 1 2023 64 10.1186/s13613-023-01161-6 37452196
6 Sjoding M.W. Dickson R.P. Iwashyna T.J. Gay S.E. Valley T.S. Racial bias in pulse oximetry measurement N Engl J Med 383 25 2020 2477 2478 10.1056/NEJMc2029240 33326721
7 Fawzy A. Wu T.D. Wang K. Robinson M.L. Farha J. Bradke A. Racial and ethnic discrepancy in pulse oximetry and delayed identification of treatment eligibility among patients with COVID-19 JAMA Intern Med 182 7 2022 730 738 10.1001/jamainternmed.2022.1906 35639368
8 Ranieri V.M. Rubenfeld G. Slutsky A.S. Rethinking acute respiratory distress syndrome after COVID-19: if a "better" definition is the answer, what is the question? Am J Respir Crit Care Med 207 3 2023 255 260 10.1164/rccm.202206-1048CP 36150099
9 Bellani G. Laffey J.G. Pham T. Fan E. Brochard L. Esteban A. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries JAMA 315 8 2016 788 800 10.1001/jama.2016.0291 26903337
10 Kwizera A. Kabatooro D. Atumanya P. Tumukunde J. Kalungi J. Mwanje A.K. Respiratory support techniques for COVID-19-related ARDS in a Sub-Saharan African country: a multicenter observational study Chest 164 2 2023 369 380 10.1016/j.chest.2023.01.039 36773933
11 Standiford T.J. Ward P.A. Therapeutic targeting of acute lung injury and acute respiratory distress syndrome Transl Res 167 1 2016 183 191 10.1016/j.trsl.2015.04.015 26003524
12 Jonas A.M. Raj R. Vaping-related acute parenchymal lung injury: a systematic review Chest 158 4 2020 1555 1565 10.1016/j.chest.2020.03.085 32442559
13 Attaway A.H. Scheraga R.G. Bhimraj A. Biehl M. Hatipoğlu U. Severe COVID-19 pneumonia: pathogenesis and clinical management BMJ 372 2021 n436 10.1136/bmj.n436 33692022
14 Thompson B.T. Chambers R.C. Liu K.D. Acute respiratory distress syndrome N Engl J Med 377 6 2017 562 572 10.1056/NEJMra1608077 28792873
15 Laffey J.G. Madotto F. Bellani G. Pham T. Fan E. Brochard L. Geo-economic variations in epidemiology, patterns of care, and outcomes in patients with acute respiratory distress syndrome: insights from the LUNG SAFE prospective cohort study Lancet Respir Med 5 8 2017 627 638 10.1016/s2213-2600(17)30213-8 28624388
16 Matthay M.A. Zemans R.L. Zimmerman G.A. Arabi Y.M. Beitler J.R. Mercat A. Acute respiratory distress syndrome Nat Rev Dis Primers 5 1 2019 18 10.1038/s41572-019-0069-0 30872586
17 Group I.C.C.T. Acute lung injury and the acute respiratory distress syndrome in Ireland: a prospective audit of epidemiology and management Crit Care 12 1 2008 R30 10.1186/cc6808 18312626
18 Bos L.D.J. Ware L.B. Acute respiratory distress syndrome: causes, pathophysiology, and phenotypes Lancet 400 10358 2022 1145 1156 10.1016/s0140-6736(22)01485-4 36070787
19 Matthay M.A. Ware L.B. Zimmerman G.A. The acute respiratory distress syndrome J Clin Invest 122 8 2012 2731 2740 10.1172/jci60331 22850883
20 Williams A.E. Chambers R.C. The mercurial nature of neutrophils: still an enigma in ARDS? Am J Physiol Lung Cell Mol Physiol 306 3 2014 L217 L230 10.1152/ajplung.00311.2013 24318116
21 Zemans R.L. Matthay M.A. What drives neutrophils to the alveoli in ARDS? Thorax 72 1 2017 1 3 10.1136/thoraxjnl-2016-209170 27974631
22 Ballabh P. Kumari J. Krauss A.N. Shin J.J. Jain A. Auld P.A. Soluble E-selectin, soluble l-selectin and soluble ICAM-1 in bronchopulmonary dysplasia, and changes with dexamethasone Pediatrics 111 3 2003 461 468 10.1542/peds.111.3.461 12612222
23 Dagenais A. Fréchette R. Yamagata Y. Yamagata T. Carmel J.F. Clermont M.E. Downregulation of ENaC activity and expression by TNF-alpha in alveolar epithelial cells Am J Physiol Lung Cell Mol Physiol 286 2 2004 L301 L311 10.1152/ajplung.00326.2002 14514522
24 Eaton D.C. Helms M.N. Koval M. Bao H.F. Jain L. The contribution of epithelial sodium channels to alveolar function in health and disease Annu Rev Physiol 71 2009 403 423 10.1146/annurev.physiol.010908.163250 18831683
25 Short K.R. Kasper J. van der Aa S. Andeweg A.C. Zaaraoui-Boutahar F. Goeijenbier M. Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions Eur Respir J 47 3 2016 954 966 10.1183/13993003.01282-2015 26743480
26 McCubbrey A.L. Curtis J.L. Efferocytosis and lung disease Chest 143 6 2013 1750 1757 10.1378/chest.12-2413 23732585
27 Chen X. Tang J. Shuai W. Meng J. Feng J. Han Z. Macrophage polarization and its role in the pathogenesis of acute lung injury/acute respiratory distress syndrome Inflamm Res 69 9 2020 883 895 10.1007/s00011-020-01378-2 32647933
28 Short K.R. Kroeze E.J.B.V. Fouchier R.A.M. Kuiken T. Pathogenesis of influenza-induced acute respiratory distress syndrome Lancet Infect Dis 14 1 2014 57 69 10.1016/s1473-3099(13)70286-x 24239327
29 Matthay M.A. Resolution of pulmonary edema. Thirty years of progress Am J Respir Crit Care Med 189 11 2014 1301 1308 10.1164/rccm.201403-0535OE 24881936
30 Grégoire M. Uhel F. Lesouhaitier M. Gacouin A. Guirriec M. Mourcin F. Impaired efferocytosis and neutrophil extracellular trap clearance by macrophages in ARDS Eur Respir J 52 2 2018 1702590 10.1183/13993003.02590-2017
31 Scott B.N.V. Kubes P. Death to the neutrophil! A resolution for acute respiratory distress syndrome? Eur Respir J 52 2 2018 1801274 10.1183/13993003.01274-2018
32 Diwanji N. Bergmann A. Basement membrane damage by ROS- and JNK-mediated Mmp2 activation drives macrophage recruitment to overgrown tissue Nat Commun 11 1 2020 3631 10.1038/s41467-020-17399-8 32686670
33 Qadir N. SY Chang Pharmacologic treatments for acute respiratory distress syndrome Crit Care Clin 37 4 2021 877 893 10.1016/j.ccc.2021.05.009 34548139
34 Kadmiel M. Cidlowski J.A. Glucocorticoid receptor signaling in health and disease Trends Pharmacol Sci 34 9 2013 518 530 10.1016/j.tips.2013.07.003 23953592
35 Berrebi D. Bruscoli S. Cohen N. Foussat A. Migliorati G. Bouchet-Delbos L. Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10 Blood 101 2 2003 729 738 10.1182/blood-2002-02-0538 12393603
36 Ayroldi E. Riccardi C. Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action FASEB J 23 11 2009 3649 3658 10.1096/fj.09-134684 19567371
37 Abraham S.M. Lawrence T. Kleiman A. Warden P. Medghalchi M. Tuckermann J. Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1 J Exp Med 203 8 2006 1883 1889 10.1084/jem.20060336 16880258
38 Hammer M. Mages J. Dietrich H. Servatius A. Howells N. Cato A.C. Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock J Exp Med 203 1 2006 15 20 10.1084/jem.20051753 16380512
39 Minghetti L. Nicolini A. Polazzi E. Greco A. Perretti M. Parente L. Down-regulation of microglial cyclo-oxygenase-2 and inducible nitric oxide synthase expression by lipocortin 1 Br J Pharmacol 126 6 1999 1307 1314 10.1038/sj.bjp.0702423 10217523
40 Wu C.C. Croxtall J.D. Perretti M. Bryant C.E. Thiemermann C. Flower R.J. Lipocortin 1 mediates the inhibition by dexamethasone of the induction by endotoxin of nitric oxide synthase in the rat Proc Natl Acad Sci U S A 92 8 1995 3473 3477 10.1073/pnas.92.8.3473 7536934
41 Perretti M. Croxtall J.D. Wheller S.K. Goulding N.J. Hannon R. Flower R.J. Mobilizing lipocortin 1 in adherent human leukocytes downregulates their transmigration Nat Med 2 11 1996 1259 1262 10.1038/nm1196-1259 8898757
42 Lim H.Y. Müller N. Herold M.J. van den Brandt J. Reichardt H.M. Glucocorticoids exert opposing effects on macrophage function dependent on their concentration Immunology 122 1 2007 47 53 10.1111/j.1365-2567.2007.02611.x 17451463
43 Saraiva M. O'Garra A The regulation of IL-10 production by immune cells Nat Rev Immunol 10 3 2010 170 181 10.1038/nri2711 20154735
44 Vettorazzi S. Bode C. Dejager L. Frappart L. Shelest E. Klaßen C. Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1 Nat Commun 6 2015 7796 10.1038/ncomms8796 26183376
45 Ehrchen J.M. Roth J. Barczyk-Kahlert K. More than suppression: glucocorticoid action on monocytes and macrophages Front Immunol 10 2019 2028 10.3389/fimmu.2019.02028 31507614
46 Perretti M. Ahluwalia A. The microcirculation and inflammation: site of action for glucocorticoids Microcirculation 7 3 2000 147 161 10.1111/j.1549-8719.2000.tb00117.x 10901495
47 Baschant U. Tuckermann J. The role of the glucocorticoid receptor in inflammation and immunity J Steroid Biochem Mol Biol 120 2–3 2010 69 75 10.1016/j.jsbmb.2010.03.058 20346397
48 Morgan D.J. Davis D.M. Distinct effects of dexamethasone on human natural killer cell responses dependent on cytokines Front Immunol 8 2017 432 10.3389/fimmu.2017.00432 28450865
49 Franco L.M. Gadkari M. Howe K.N. Sun J. Kardava L. Kumar P. Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses J Exp Med 216 2 2019 384 406 10.1084/jem.20180595 30674564
50 Taves M.D. Ashwell J.D. Glucocorticoids in T cell development, differentiation and function Nat Rev Immunol 21 4 2021 233 243 10.1038/s41577-020-00464-0 33149283
51 Liberman A.C. Druker J. Perone M.J. Arzt E. Glucocorticoids in the regulation of transcription factors that control cytokine synthesis Cytokine Growth Factor Rev 18 1–2 2007 45 56 10.1016/j.cytogfr.2007.01.005 17336577
52 Li C.C. Munitic I. Mittelstadt P.R. Castro E. Ashwell J.D. Suppression of dendritic cell-derived IL-12 by endogenous glucocorticoids is protective in LPS-induced sepsis PLoS Biol 13 10 2015 e1002269 10.1371/journal.pbio.1002269
53 Oh K.S. Patel H. Gottschalk R.A. Lee W.S. Baek S. Fraser I.D.C. Anti-inflammatory chromatinscape suggests alternative mechanisms of glucocorticoid receptor action Immunity 47 2 2017 10.1016/j.immuni.2017.07.012 298.e–309.e
54 Banuelos J. Shin S. Cao Y. Bochner B.S. Morales-Nebreda L. Budinger G.R. BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis Allergy 71 5 2016 640 650 10.1111/all.12840 26752231
55 de Castro Kroner J. Knoke K. Kofler D.M. Steiger J. Fabri M. Glucocorticoids promote intrinsic human T(H)17 differentiation J Allergy Clin Immunol 142 5 2018 10.1016/j.jaci.2018.07.019 1669.e–73.e
56 Busillo J.M. Cidlowski J.A. The five Rs of glucocorticoid action during inflammation: ready, reinforce, repress, resolve, and restore Trends Endocrinol Metab 24 3 2013 109 119 10.1016/j.tem.2012.11.005 23312823
57 Busillo J.M. Azzam K.M. Cidlowski J.A. Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome J Biol Chem 286 44 2011 38703 38713 10.1074/jbc.M111.275370 21940629
58 Filep J.G. Delalandre A. Payette Y. Földes-Filep E. Glucocorticoid receptor regulates expression of l-selectin and CD11/CD18 on human neutrophils Circulation 96 1 1997 295 301 10.1161/01.cir.96.1.295 9236448
59 Cronstein B.N. Kimmel S.C. Levin R.I. Martiniuk F. Weissmann G. A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1 Proc Natl Acad Sci U S A 89 21 1992 9991 9995 10.1073/pnas.89.21.9991 1279685
60 Tuckermann J.P. Kleiman A. McPherson K.G. Reichardt H.M. Molecular mechanisms of glucocorticoids in the control of inflammation and lymphocyte apoptosis Crit Rev Clin Lab Sci 42 1 2005 71 104 10.1080/10408360590888983 15697171
61 Masferrer J.L. Seibert K. Zweifel B. Needleman P. Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme Proc Natl Acad Sci U S A 89 9 1992 3917 3921 10.1073/pnas.89.9.3917 1570314
62 Amratia D.A. Viola H. Ioachimescu O.C. Glucocorticoid therapy in respiratory illness: bench to bedside J Investig Med 70 8 2022 1662 1680 10.1136/jim-2021-002161
63 Sugimoto M.A. Vago J.P. Teixeira M.M. Sousa L.P. Annexin A1 and the resolution of inflammation: modulation of neutrophil recruitment, apoptosis, and clearance J Immunol Res 2016 2016 8239258 10.1155/2016/8239258
64 Miyata M. Lee J.Y. Susuki-Miyata S. Wang W.Y. Xu H. Kai H. Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M Nat Commun 6 2015 6062 10.1038/ncomms7062 25585690
65 Marik P.E. Meduri G.U. Rocco P.R. Annane D. Glucocorticoid treatment in acute lung injury and acute respiratory distress syndrome Crit Care Clin 27 3 2011 589 607 10.1016/j.ccc.2011.05.007 21742218
66 Ehrchen J. Steinmüller L. Barczyk K. Tenbrock K. Nacken W. Eisenacher M. Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes Blood 109 3 2007 1265 1274 10.1182/blood-2006-02-001115 17018861
67 Yin S. Ding M. Fan L. Yu X. Liang Z. Wu L. Inhibition of inflammation and regulation of AQPs/ENaCs/Na(+)-K(+)-ATPase mediated alveolar fluid transport by total flavonoids extracted from Nervilia fordii in lipopolysaccharide-induced acute lung injury Front Pharmacol 12 2021 603863 10.3389/fphar.2021.603863
68 Panettieri R.A. Schaafsma D. Amrani Y. Koziol-White C. Ostrom R. Tliba O. Non-genomic effects of glucocorticoids: an updated view Trends Pharmacol Sci 40 1 2019 38 49 10.1016/j.tips.2018.11.002 30497693
69 Meduri G.U. The role of the host defence response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment Eur Respir J 9 12 1996 2650 2670 10.1183/09031936.96.09122650 8980983
70 Meduri G.U. Tolley E.A. Chinn A. Stentz F. Postlethwaite A. Procollagen types I and III aminoterminal propeptide levels during acute respiratory distress syndrome and in response to methylprednisolone treatment Am J Respir Crit Care Med 158 5 Pt 1 1998 1432 1441 10.1164/ajrccm.158.5.9801107 9817690
71 van Zaane B. Nur E. Squizzato A. Gerdes V.E. Büller H.R. Dekkers O.M. Systematic review on the effect of glucocorticoid use on procoagulant, anti-coagulant and fibrinolytic factors J Thromb Haemost 8 11 2010 2483 2493 10.1111/j.1538-7836.2010.04034.x 20735729
72 Ayroldi E. Zollo O. Bastianelli A. Marchetti C. Agostini M. Di Virgilio R. GILZ mediates the antiproliferative activity of glucocorticoids by negative regulation of Ras signaling J Clin Invest 117 6 2007 1605 1615 10.1172/jci30724 17492054
73 Beitler J.R. Thompson B.T. Baron R.M. Bastarache J.A. Denlinger L.C. Esserman L. Advancing precision medicine for acute respiratory distress syndrome Lancet Respir Med 10 1 2022 107 120 10.1016/s2213-2600(21)00157-0 34310901
74 Wick K.D. Aggarwal N.R. Curley M.A.Q. Fowler A.A. 3rd Jaber S. Kostrubiec M. Opportunities for improved clinical trial designs in acute respiratory distress syndrome Lancet Respir Med 10 9 2022 916 924 10.1016/s2213-2600(22)00294-6 36057279
75 Prescott H.C. Calfee C.S. Thompson B.T. Angus D.C. Liu V.X. Toward smarter lumping and smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design Am J Respir Crit Care Med 194 2 2016 147 155 10.1164/rccm.201512-2544CP 27244481
76 Ware L.B. Matthay M.A. Mebazaa A. Designing an ARDS trial for 2020 and beyond: focus on enrichment strategies Intensive Care Med 46 12 2020 2153 2156 10.1007/s00134-020-06232-x 33136196
77 Ferguson N.D. Fan E. Camporota L. Antonelli M. Anzueto A. Beale R. The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material Intensive Care Med 38 10 2012 1573 1582 10.1007/s00134-012-2682-1 22926653
78 Beitler J.R. Sarge T. Banner-Goodspeed V.M. Gong M.N. Cook D. Novack V. Effect of titrating positive end-expiratory pressure (PEEP) with an esophageal pressure-guided strategy vs an empirical high PEEP-FiO2 strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome: a randomized clinical trial JAMA 321 9 2019 846 857 10.1001/jama.2019.0555 30776290
79 Wilson J.G. Calfee C.S. ARDS subphenotypes: understanding a heterogeneous syndrome Crit Care 24 1 2020 102 10.1186/s13054-020-2778-x 32204722
80 Wendel Garcia P.D. Caccioppola A. Coppola S. Pozzi T. Ciabattoni A. Cenci S. Latent class analysis to predict intensive care outcomes in acute respiratory distress syndrome: a proposal of two pulmonary phenotypes Crit Care 25 1 2021 154 10.1186/s13054-021-03578-6 33888134
81 Amato M.B. Meade M.O. Slutsky A.S. Brochard L. Costa E.L. Schoenfeld D.A. Driving pressure and survival in the acute respiratory distress syndrome N Engl J Med 372 8 2015 747 755 10.1056/NEJMsa1410639 25693014
82 Beitler J.R. Majumdar R. Hubmayr R.D. Malhotra A. Thompson B.T. Owens R.L. Volume delivered during recruitment maneuver predicts lung stress in acute respiratory distress syndrome Crit Care Med 44 1 2016 91 99 10.1097/ccm.0000000000001355 26474111
83 Tonelli R. Grasso S. Cortegiani A. Ball L. Castaniere I. Tabbì L. Physiological effects of lung-protective ventilation in patients with lung fibrosis and usual interstitial pneumonia pattern versus primary ARDS: a matched-control study Crit Care 27 1 2023 398 10.1186/s13054-023-04682-5 37853480
84 Matthay M.A. Arabi Y.M. Siegel E.R. Ware L.B. Bos L.D.J. Sinha P. Phenotypes and personalized medicine in the acute respiratory distress syndrome Intensive Care Med 46 12 2020 2136 2152 10.1007/s00134-020-06296-9 33206201
85 Constantin J.M. Grasso S. Chanques G. Aufort S. Futier E. Sebbane M. Lung morphology predicts response to recruitment maneuver in patients with acute respiratory distress syndrome Crit Care Med 38 4 2010 1108 1117 10.1097/CCM.0b013e3181d451ec 20154600
86 Constantin J.M. Jabaudon M. Lefrant J.Y. Jaber S. Quenot J.P. Langeron O. Personalised mechanical ventilation tailored to lung morphology versus low positive end-expiratory pressure for patients with acute respiratory distress syndrome in France (the LIVE study): a multicentre, single-blind, randomised controlled trial Lancet Respir Med 7 10 2019 870 880 10.1016/s2213-2600(19)30138-9 31399381
87 Warren M.A. Zhao Z. Koyama T. Bastarache J.A. Shaver C.M. Semler M.W. Severity scoring of lung oedema on the chest radiograph is associated with clinical outcomes in ARDS Thorax 73 9 2018 840 846 10.1136/thoraxjnl-2017-211280 29903755
88 Jabaudon M. Audard J. Pereira B. Jaber S. Lefrant J.Y. Blondonnet R. Early changes over time in the radiographic assessment of lung edema score are associated with survival in ARDS Chest 158 6 2020 2394 2403 10.1016/j.chest.2020.06.070 32659235
89 Rosenberger C.M. Wick K.D. Zhuo H. Wu N. Chen Y. Kapadia S.B. Early plasma angiopoietin-2 is prognostic for ARDS and mortality among critically ill patients with sepsis Crit Care 27 1 2023 234 10.1186/s13054-023-04525-3 37312169
90 Redaelli S. von Wedel D. Fosset M. Suleiman A. Chen G. Alingrin J. Inflammatory subphenotypes in patients at risk of ARDS: evidence from the LIPS-A trial Intensive Care Med 49 12 2023 1499 1507 10.1007/s00134-023-07244-z 37906258
91 Calfee C.S. Delucchi K. Parsons P.E. Thompson B.T. Ware L.B. Matthay M.A. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials Lancet Respir Med 2 8 2014 611 620 10.1016/s2213-2600(14)70097-9 24853585
92 Bos L.D.J. Scicluna B.P. Ong D.S.Y. Cremer O. van der Poll T. Schultz M.J. Understanding heterogeneity in biologic phenotypes of acute respiratory distress syndrome by leukocyte expression profiles Am J Respir Crit Care Med 200 1 2019 42 50 10.1164/rccm.201809-1808OC 30645145
93 Bos L.D. Schouten L.R. van Vught L.A. Wiewel M.A. Ong D.S.Y. Cremer O. Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis Thorax 72 10 2017 876 883 10.1136/thoraxjnl-2016-209719 28450529
94 Sinha P. Delucchi K.L. McAuley D.F. O'Kane C.M. Matthay M.A. Calfee C.S. Development and validation of parsimonious algorithms to classify acute respiratory distress syndrome phenotypes: a secondary analysis of randomised controlled trials Lancet Respir Med 8 3 2020 247 257 10.1016/s2213-2600(19)30369-8 31948926
95 Bihari S. Bersten A. Paul E. McGuinness S. Dixon D. Sinha P. Acute respiratory distress syndrome phenotypes with distinct clinical outcomes in PHARLAP trial cohort Crit Care Resusc 23 2 2021 163 170 10.51893/2021.2.oa3 38045528
96 Battaglini D. Al-Husinat L. Normando A.G. Leme A.P. Franchini K. Morales M. Personalized medicine using omics approaches in acute respiratory distress syndrome to identify biological phenotypes Respir Res 23 1 2022 318 10.1186/s12931-022-02233-0 36403043
97 Bastarache J.A. McNeil J.B. Plosa E.J. Sucre J.S. Kerchberger V.E. Habegger L.E. Standardization of methods for sampling the distal airspace in mechanically ventilated patients using heat moisture exchange filter fluid Am J Physiol Lung Cell Mol Physiol 320 5 2021 L785 L790 10.1152/ajplung.00595.2020 33655765
98 Metwaly S. Côté A. Donnelly S.J. Banoei M.M. Lee C.H. Andonegui G. ARDS metabolic fingerprints: characterization, benchmarking, and potential mechanistic interpretation Am J Physiol Lung Cell Mol Physiol 321 1 2021 L79 L90 10.1152/ajplung.00077.2021 33949201
99 Martin T.R. Zemans R.L. Ware L.B. Schmidt E.P. Riches D.W.H. Bastarache L. New insights into clinical and mechanistic heterogeneity of the acute respiratory distress syndrome: summary of the Aspen Lung Conference 2021 Am J Respir Cell Mol Biol 67 3 2022 284 308 10.1165/rcmb.2022-0089WS 35679511
100 Diray-Arce J. Fourati S. Doni Jayavelu N. Patel R. Maguire C. Chang A.C. Multi-omic longitudinal study reveals immune correlates of clinical course among hospitalized COVID-19 patients Cell Rep Med 4 6 2023 101079 10.1016/j.xcrm.2023.101079
101 Neyton L.P.A. Langelier C.R. Calfee C.S. Metagenomic sequencing in the ICU for precision diagnosis of critical infectious illnesses Crit Care 27 1 2023 90 10.1186/s13054-023-04365-1 36941644
102 Neyton L. Calfee C.S. Metabolic signatures of ARDS and ARDS heterogeneity Am J Physiol Lung Cell Mol Physiol 321 6 2021 L1067 L1068 10.1152/ajplung.00218.2021 34668417
103 Wick K.D. McAuley D.F. Levitt J.E. Beitler J.R. Annane D. Riviello E.D. Promises and challenges of personalized medicine to guide ARDS therapy Crit Care 25 1 2021 404 10.1186/s13054-021-03822-z 34814925
104 Hendrickson C.M. Calfee C.S. A new frontier in ARDS trials: phenotyping before randomisation Lancet Respir Med 7 10 2019 830 831 10.1016/s2213-2600(19)30175-4 31399380
105 Shah F.A. Meyer N.J. Angus D.C. Awdish R. Azoulay É. Calfee C.S. A research agenda for precision medicine in sepsis and acute respiratory distress syndrome: an Official American Thoracic Society Research Statement Am J Respir Crit Care Med 204 8 2021 891 901 10.1164/rccm.202108-1908ST 34652268
106 Reddy K. Calfee C.S. McAuley D.F. Acute respiratory distress syndrome subphenotypes beyond the syndrome: a step toward treatable traits? Am J Respir Crit Care Med 203 12 2021 1449 1451 10.1164/rccm.202101-0218ED 33565943
107 Maslove D.M. Tang B. Shankar-Hari M. Lawler P.R. Angus D.C. Baillie J.K. Redefining critical illness Nat Med 28 6 2022 1141 1148 10.1038/s41591-022-01843-x 35715504
108 Sinha P. Kerchberger V.E. Willmore A. Chambers J. Zhuo H. Abbott J. Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials Lancet Respir Med 11 11 2023 965 974 10.1016/s2213-2600(23)00237-0 37633303
109 Meduri G.U. Annane D. Confalonieri M. Chrousos G.P. Rochwerg B. Busby A. Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS Intensive Care Med 46 12 2020 2284 2296 10.1007/s00134-020-06289-8 33150472
110 Wagner C. Griesel M. Mikolajewska A. Mueller A. Nothacker M. Kley K. Systemic corticosteroids for the treatment of COVID-19 Cochrane Database Syst Rev 8 8 2021 10.1002/14651858.Cd014963 Cd014963
111 Meduri G. Golden E. Freire A.X. Taylor E. Zaman M. Carson S.J. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial Chest 131 4 2007 954 963 10.1378/chest.06-2100 17426195
112 Steinberg K.P. Hudson L.D. Goodman R.B. Hough C.L. Lanken P.N. Hyzy R. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome N Engl J Med 354 16 2006 1671 1684 10.1056/NEJMoa051693 16625008
113 Confalonieri M. Urbino R. Potena A. Piattella M. Parigi P. Puccio G. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study Am J Respir Crit Care Med 171 3 2005 242 248 10.1164/rccm.200406-808OC 15557131
114 Ruan S. Lin H. Huang C. Kuo P.H. Wu H.D. Yu C.J. Exploring the heterogeneity of effects of corticosteroids on acute respiratory distress syndrome: a systematic review and meta-analysis Crit Care 18 2 2014 R63 10.1186/cc13819 24708846
115 Brun-Buisson C. Richard J. Mercat A. Thiébaut A.C. Brochard L. REVA-SRLF A/H1N1v 2009 Registry Group Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome Am J Respir Crit Care Med 183 9 2011 1200 1206 10.1164/rccm.201101-0135OC 21471082
116 Liu J. Zhang S. Dong X. Li Z. Xu Q. Feng H. Corticosteroid treatment in severe COVID-19 patients with acute respiratory distress syndrome J Clin Invest 130 12 2020 6417 6428 10.1172/jci140617 33141117
117 Arabi Y.M. Mandourah Y. Al-Hameed F. Sindi A.A. Almekhlafi G.A. Hussein M.A. Corticosteroid therapy for critically ill patients with middle east respiratory syndrome Am J Respir Crit Care Med 197 6 2018 757 767 10.1164/rccm.201706-1172OC 29161116
118 Bone R.C. Fisher C.J. Jr. Clemmer T.P. Slotman G.J. Metz C.A. Early methylprednisolone treatment for septic syndrome and the adult respiratory distress syndrome Chest 92 6 1987 1032 1036 10.1378/chest.92.6.1032 3315478
119 Peter J.V. John P. Graham P.L. Moran J.L. George I.A. Bersten A. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis BMJ 336 7651 2008 1006 1009 10.1136/bmj.39537.939039.BE 18434379
120 Tongyoo S. Permpikul C. Mongkolpun W. Vattanavanit V. Udompanturak S. Kocak M. Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial Crit Care 20 1 2016 329 10.1186/s13054-016-1511-2 27741949
121 Lewis S.R. Pritchard M.W. Thomas C.M. Smith A.F. Pharmacological agents for adults with acute respiratory distress syndrome Cochrane Database Syst Rev 7 7 2019 CD004477 10.1002/14651858.CD004477.pub3
122 Meduri G.U. Bridges L. Shih M.C. Marik P.E. Siemieniuk R.A.C. Kocak M. Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature Intensive Care Med 42 5 2016 829 840 10.1007/s00134-015-4095-4 26508525
123 Villar J. Ferrando C. Martínez D. Ambrós A. Muñoz T. Soler J.A. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial Lancet Respir Med 8 3 2020 267 276 10.1016/s2213-2600(19)30417-5 32043986
124 Yang J.W. Jiang P. Wang W.W. Wen Z.M. Mao B. Lu H.W. The controversy about the effects of different doses of corticosteroid treatment on clinical outcomes for acute respiratory distress syndrome patients: an observational study Front Pharmacol 12 2021 722537 10.3389/fphar.2021.722537
125 Tasaka S. Ohshimo S. Takeuchi M. Yasuda H. Ichikado K. Tsushima K. ARDS clinical practice guideline 2021 J Intensive Care 10 1 2022 32 10.1186/s40560-022-00615-6 35799288
126 Veterans Administration Systemic Sepsis Cooperative Study Group Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis N Engl J Med 317 11 1987 659 665 10.1056/nejm198709103171102 2888017
127 Meduri G.U. Headley A.S. Golden E. Carson S.J. Umberger R.A. Kelso T. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial JAMA 280 2 1998 159 165 10.1001/jama.280.2.159 9669790
128 Balk R.A. Steroids for septic shock: back from the dead? (Pro) Chest 123 5 Suppl 2003 10.1378/chest.123.5_suppl.490s 490s–9s
129 Tang B.M. Craig J.C. Eslick G.D. Seppelt I. McLean A.S. Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis Crit Care Med 37 5 2009 1594 1603 10.1097/CCM.0b013e31819fb507 19325471
130 Meduri G.U. Annane D. Chrousos G.P. Marik P.E. Sinclair S.E. Activation and regulation of systemic inflammation in ARDS: rationale for prolonged glucocorticoid therapy Chest 136 6 2009 1631 1643 10.1378/chest.08-2408 19801579
131 Moran J.L. Graham P.L. Rockliff S. Bersten A.D. Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective Crit Care 14 4 2010 R134 10.1186/cc9182 20626892
132 Keh D. Boehnke T. Weber-Cartens S. Schulz C. Ahlers O. Bercker S. Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study Am J Respir Crit Care Med 167 4 2003 512 520 10.1164/rccm.200205-446OC 12426230
133 Jantz M.A. Sahn S.A. Corticosteroids in acute respiratory failure Am J Respir Crit Care Med 160 4 1999 1079 1100 10.1164/ajrccm.160.4.9901075 10508792
134 Annane D. Pastores S.M. Rochwerg B. Arlt W. Balk R.A. Beishuizen A. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): society of critical care medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017 Intensive Care Med 43 12 2017 1751 1763 10.1007/s00134-017-4919-5 28940011
135 Meduri G. Bridges L. Siemieniuk R. Kocak M. An exploratory reanalysis of the randomized trial on efficacy of corticosteroids as rescue therapy for the late phase of acute respiratory distress syndrome Crit Care Med 46 6 2018 884 891 10.1097/ccm.0000000000003021 29432350
136 Hensley M.K. Sjoding M.W. Prescott H.C. COUNTERPOINT: should corticosteroids be routine treatment in early ARDS? No Chest 159 1 2021 29 33 10.1016/j.chest.2020.07.059 33422201
137 COVID-ICU Group on behalf of the REVA Network and the COVID-ICU Investigators Clinical characteristics and day-90 outcomes of 4244 critically ill adults with COVID-19: a prospective cohort study Intensive Care Med 47 1 2021 60 73 10.1007/s00134-020-06294-x 33211135
138 Grasselli G. Greco M. Zanella A. Albano G. Antonelli M. Bellani G. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy JAMA Intern Med 180 10 2020 1345 1355 10.1001/jamainternmed.2020.3539 32667669
139 Lamers M.M. Haagmans B.L. SARS-CoV-2 pathogenesis Nat Rev Microbiol 20 5 2022 270 284 10.1038/s41579-022-00713-0 35354968
140 Bain W. Yang H. Shah F.A. Suber T. Drohan C. Al-Yousif N. COVID-19 versus Non-COVID-19 acute respiratory distress syndrome: comparison of demographics, physiologic parameters, inflammatory biomarkers, and clinical outcomes Ann Am Thorac Soc 18 7 2021 1202 1210 10.1513/AnnalsATS.202008-1026OC 33544045
141 Sjoding M.W. Admon A.J. Saha A.K. Kay S.G. Brown C.A. Co I. Comparing clinical features and outcomes in mechanically ventilated patients with COVID-19 and acute respiratory distress syndrome Ann Am Thorac Soc 18 11 2021 1876 1885 10.1513/AnnalsATS.202008-1076OC 33577740
142 Sinha S. Rosin N.L. Arora R. Labit E. Jaffer A. Cao L. Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19 Nat Med 28 1 2022 201 211 10.1038/s41591-021-01576-3 34782790
143 Siska P.J. Decking S.M. Babl N. Matos C. Bruss C. Singer K. Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone J Clin Invest 131 22 2021 e148225 10.1172/jci148225
144 Cour M. Simon M. Argaud L. Monneret G. Venet F. Effects of dexamethasone on immune dysfunction and ventilator-associated pneumonia in COVID-19 acute respiratory distress syndrome: an observational study J Intensive Care 9 1 2021 64 10.1186/s40560-021-00580-6 34663481
145 RECOVERY CollaborativeHorby P. Lim W.S. Emberson J.R. Mafham M. Bell J.L. Dexamethasone in hospitalized patients with COVID-19 N Engl J Med 384 8 2021 693 704 10.1056/NEJMoa2021436 32678530
146 Chaudhuri D. Sasaki K. Karkar A. Sharif S. Lewis K. Mammen M.J. Corticosteroids in COVID-19 and non-COVID-19 ARDS: a systematic review and meta-analysis Intensive Care Med 47 5 2021 521 537 10.1007/s00134-021-06394-2 33876268
147 Mourad A. Thibault D. Holland T.L. Yang S. Young A.R. Arnold Egloff S.A. Dexamethasone for inpatients with COVID-19 in a national cohort JAMA Netw Open 6 4 2023 e238516 10.1001/jamanetworkopen.2023.8516
148 RECOVERY Collaborative Group Higher dose corticosteroids in patients admitted to hospital with COVID-19 who are hypoxic but not requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial Lancet 401 10387 2023 1499 1507 10.1016/s0140-6736(23)00510-x 37060915
149 Tomazini B.M. Maia I.S. Cavalcanti A.B. Berwanger O. Rosa R.G. Veiga V.C. 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 324 13 2020 1307 1316 10.1001/jama.2020.17021 32876695
150 Moreno G. Carbonell R. Martin-Loeches I. Solé-Violán J. Correig I Fraga E. Gómez J. Corticosteroid treatment and mortality in mechanically ventilated COVID-19-associated acute respiratory distress syndrome (ARDS) patients: a multicentre cohort study Ann Intensive Care 11 1 2021 159 10.1186/s13613-021-00951-0 34825976
151 Lopinto J. Arrestier R. Peiffer B. Gaillet A. Voiriot G. Urbina T. High-dose steroids for nonresolving acute respiratory distress syndrome in critically ill COVID-19 patients treated with dexamethasone: a multicenter cohort study Crit Care Med 51 10 2023 1306 1317 10.1097/ccm.0000000000005930 37199534
152 Torres A. Motos A. Cillóniz C. Ceccato A. Fernández-Barat L. Gabarrús A. Major candidate variables to guide personalised treatment with steroids in critically ill patients with COVID-19: CIBERESUCICOVID study Intensive Care Med 48 7 2022 850 864 10.1007/s00134-022-06726-w 35727348
153 Reyes L.F. Rodriguez A. Bastidas A. Parra-Tanoux D. Fuentes Y.V. García-Gallo E. Dexamethasone as risk-factor for ICU-acquired respiratory tract infections in severe COVID-19 J Critical Care 69 2022 154014 10.1016/j.jcrc.2022.154014
154 Lamouche-Wilquin P. Souchard J. Pere M. Raymond M. Asfar P. Darreau C. Early steroids and ventilator-associated pneumonia in COVID-19-related ARDS Crit Care 26 1 2022 233 10.1186/s13054-022-04097-8 35918776
155 Gragueb-Chatti I. Lopez A. Hamidi D. Guervilly C. Loundou A. Daviet F. Impact of dexamethasone on the incidence of ventilator-associated pneumonia and blood stream infections in COVID-19 patients requiring invasive mechanical ventilation: a multicenter retrospective study Ann Intensive Care 11 1 2021 87 10.1186/s13613-021-00876-8 34057642
156 Chalmers J.D. Crichton M.L. Goeminne P.C. Cao B. Humbert M. Shteinberg M. Management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline Eur Respir J 57 4 2021 2100048 10.1183/13993003.00048-2021
157 Venkatesh B. Finfer S. Cohen J. Rajbhandari D. Arabi Y. Bellomo R. Adjunctive glucocorticoid therapy in patients with septic shock N Engl J Med 378 9 2018 797 808 10.1056/NEJMoa1705835 29347874
158 Annane D. Renault A. Brun-Buisson C. Megarbane B. Quenot J.P. Siami S. Hydrocortisone plus fludrocortisone for adults with septic shock N Engl J Med 378 9 2018 809 818 10.1056/NEJMoa1705716 29490185
159 Martinez-Guerra B.A. Gonzalez-Lara M.F. Roman-Montes C.M. Tamez-Torres K.M. Dardón-Fierro F.E. Rajme-Lopez S. Outcomes of patients with severe and critical COVID-19 treated with dexamethasone: a prospective cohort study Emerg Microbes Infect 11 1 2022 50 59 10.1080/22221751.2021.2011619 34839785
160 Fang F. Zhang Y. Tang J. Lunsford L.D. Li T. Tang R. Association of corticosteroid treatment with outcomes in adult patients with sepsis: a systematic review and meta-analysis JAMA Intern Med 179 2 2019 213 223 10.1001/jamainternmed.2018.5849 30575845
161 Chang X. Li S. Fu Y. Dang H. Liu C. Safety and efficacy of corticosteroids in ARDS patients: a systematic review and meta-analysis of RCT data Respir Res 23 1 2022 301 10.1186/s12931-022-02186-4 36333729
162 Rygård S.L. Butler E. Granholm A. Møller M.H. Cohen J. Finfer S. Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis Intensive Care Med 44 7 2018 1003 1016 10.1007/s00134-018-5197-6 29761216
163 Torres A. Sibila O. Ferrer M. Polverino E. Menendez R. Mensa J. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial JAMA 313 7 2015 677 686 10.1001/jama.2015.88 25688779
164 Sardu C. D'Onofrio N. Balestrieri M.L. Barbieri M. Rizzo M.R. Messina V. Outcomes in patients with hyperglycemia affected by COVID-19: can we do more on glycemic control? Diabetes Care 43 7 2020 1408 1415 10.2337/dc20-0723 32430456
165 Alhazzani W. Alshahrani M. Jaeschke R. Forel J.M. Papazian L. Sevransky J. Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials Crit Care 17 2 2013 R43 10.1186/cc12557 23497608
166 National Heart, Lung, and Blood Institute PETAL Clinical Trials NetworkMoss M. Huang D.T. Brower R.G. Ferguson N.D. Ginde A.A. Early neuromuscular blockade in the acute respiratory distress syndrome N Engl J Med 380 21 2019 1997 2008 10.1056/NEJMoa1901686 31112383
167 Behbehani N.A. Al-Mane F. D'yachkova Y. Paré P. FitzGerald J.M Myopathy following mechanical ventilation for acute severe asthma: the role of muscle relaxants and corticosteroids Chest 115 6 1999 1627 1631 10.1378/chest.115.6.1627 10378560
168 Stevens R.D. Dowdy D.W. Michaels R.K. Mendez-Tellez P.A. Pronovost P.J. Needham D.M. Neuromuscular dysfunction acquired in critical illness: a systematic review Intensive Care Med 33 11 2007 1876 1891 10.1007/s00134-007-0772-2 17639340
169 Hermans G. Wilmer A. Meersseman W. Milants I. Wouters P.J. Bobbaers H. Impact of intensive insulin therapy on neuromuscular complications and ventilator dependency in the medical intensive care unit Am J Respir Crit Care Med 175 5 2007 480 489 10.1164/rccm.200605-665OC 17138955
170 Dendoncker K. Libert C. Glucocorticoid resistance as a major drive in sepsis pathology Cytokine Growth Factor Rev 35 2017 85 96 10.1016/j.cytogfr.2017.04.002 28479044
171 Nicolaides N.C. Charmandari E. Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes Hormones 16 2 2017 124 138 10.14310/horm.2002.1728 28742501
172 Annane D. Pastores S.M. Arlt W. Balk R.A. Beishuizen A. Briegel J. Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a multispecialty task force of the society of critical care medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM) Crit Care Med 45 12 2017 2089 2098 10.1097/ccm.0000000000002724 28938251
173 Buttgereit F. Bijlsma J.W.J. Strehl C. Will we ever have better glucocorticoids? Clin Immunol 186 2018 64 66 10.1016/j.clim.2017.07.023 28757452
174 Meduri G.U. Kanangat S. Glucocorticoid treatment of sepsis and acute respiratory distress syndrome: time for a critical reappraisal Crit Care Med 26 4 1998 630 633 10.1097/00003246-199804000-00003 9559593
175 Dinsen S. Baslund B. Klose M. Rasmussen A.K. Friis-Hansen L. Hilsted L. Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself Eur J Intern Med 24 8 2013 714 720 10.1016/j.ejim.2013.05.014 23806261
176 Bernard G.R. Luce J.M. Sprung C.L. Rinaldo J.E. Tate R.M. Sibbald W.J. High-dose corticosteroids in patients with the adult respiratory distress syndrome N Engl J Med 317 25 1987 1565 1570 10.1056/nejm198712173172504 3317054
177 Annane D. Sébille V. Bellissant E. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome Crit Care Med 34 1 2006 22 30 10.1097/01.ccm.0000194723.78632.62 16374152
178 Meijvis S.C. Hardeman H. Remmelts H.H. Heijligenberg R. Rijkers G.T. van Velzen-Blad H. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial Lancet 377 9782 2011 2023 2030 10.1016/s0140-6736(11)60607-7 21636122
179 Angus D.C. Derde L. Al-Beidh F. Annane D. Arabi Y. Beane A. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial JAMA 324 13 2020 1317 1329 10.1001/jama.2020.17022 32876697
180 Maskin L.P. Bonelli I. Olarte G.L. Palizas F. Jr. Velo A.E. Lurbet M.F. 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 37 4 2022 491 499 10.1177/08850666211066799 34898320
181 Scaravilli V. Guzzardella A. Madotto F. Beltrama V. Muscatello A. Bellani G. Impact of dexamethasone on the incidence of ventilator-associated pneumonia in mechanically ventilated COVID-19 patients: a propensity-matched cohort study Crit Care 26 1 2022 176 10.1186/s13054-022-04049-2 35698155
