Exploring pharmacological strategies in the management of ARDS: Efficacy, limitations, and future directions

Almuntashiri, Sultan

doi:10.2478/jccm-2025-0030

Figures & Tables

Beta-2 agonists in ARDS

Reference	Study design	Number of patients	Beta-agonists type and dose	Key findings
[14]	RCT	40 patients with ARDS Albuterol group (n=19) Placebo group (n=21)	IV albuterol infusions run at 0.075 ml/kg/h (15 μg/kg/h) for 7 days	↔ PaO₂/FiO₂ ratio at day 7 ↔ VFDs ↔ 28-day mortality ↔ Incidence of supraventricular arrhythmias
[15]	RCT	282 patients with ARDS Albuterol group (n=152) Placebo group (n=130)	Aerosolized albuterol (5 mg) q 4 hours for up to 10 days	↔ VFDs ↓ ICU free days in the albuterol group (13.5 vs 16.2; P=0.023) ↔ Mortality outcome at day 60 and at day 90 ↔ Organ failure free days ↔ Cardiac arrhythmias
[16]	RCT	326 patients with moderate to severe ARDS Albuterol group (n=162) Placebo group (n=164)	IV albuterol (15 μg/kg ideal bodyweight per hour) for up to 7 days	↑ 28-day mortality (34 vs 23%; P=0.03) ↓ VFDs (8.5 vs 11.1 days; P < 0.05) ↓ Organ failure free days (16.2 vs 18.5 days; P < 0.05) ↑ Incidence of cardiac arrhythmia (9 vs 2%; P < 0.05)

Appraisal of Key Clinical Studies of Pharmacologic Agents in ARDS

Reference	Drug Class	Study Design & Setting	Bias Risk	Evidence Strength
Steinberg et al. [5]	Corticosteroids	Multicenter RCT; persistent ARDS	Well-designed-blinded but late intervention	Moderate
Meduri et al. [6]	Corticosteroids	Multicenter RCT; early severe ARDS	Well-designed-blinded and early intervention; limited sample size	Moderate
Meduri et al. [7]	Corticosteroids	Multicenter RCT; prolonged ARDS	Blinded, limited sample size	Moderate
Villar et al. [8]	Corticosteroids	Multicenter, randomized, double-blind RCT	Strong methodological design with blinding	High
Tomazini et al. [9]	Corticosteroids	Multicenter, randomized, open-label controlled trial	Lack of blinding	Moderate
Papazian et al. [10]	NMBAs	Multicenter, randomized, double-blind RCT	Strong design with blinding and protocol standardization	High
Moss et al. [11]	NMBAs	Multicenter, randomized, open-label controlled trial	Lack of blinding; early termination for futility	Moderate
Forel et al. [12]	NMBAs	Multiple-center, prospective, controlled trial	Well-designed with blinding; limited by small sample size	Moderate
Gainnier et al. [13]	NMBAs	Multiple center, prospective, controlled trial	Strong blinding and randomization; small sample size	Moderate
Perkins et al. [14]	Beta-2 agonists	Single-center, randomized, double-blind placebo-controlled trial	Well-designed with blinding; small sample size limits generalizability	Moderate
Matthay et al. [15]	Beta-2 agonists	Multicenter, randomized, double-blind placebo-controlled trial	Strong design with adequate blinding; some heterogeneity in patient severity	Moderate
Gao Smith et al. [16]	Beta-2 agonists	Multicenter, randomized, double-blind, placebo-controlled trial	High-quality design with rigorous blinding; stopped early for safety concerns	Moderate

Corticosteroid in ARDS

Reference	Study design	Number of patients	Corticosteroid type and dose	Key findings
[5]	RCT	180 patients with ARDS Methylprednisolone (n=89) Placebo (n=91)	Methylprednisolone 2 mg/kg Followed by 0.5 mg/kg q 6 h for 14 days Followed by 0.5 mg/kg q 12 h for 7 days, and then tapering the dose over 2 or 4 days	↑ VFDs (11.2 vs 6.8 days; P<0.001) at day 28 ↑ ICU free days (8.9 vs 6.2 days; P=0.02) at day 28 ↑ VFDs (159 vs 149 days; P=0.04) at day 180 ↔ ICU free days at day 180 ↔ 60- or180-day mortality
[6]	RCT	91 patients with severe early ARDS Methylprednisolone (n = 63) Placebo (n = 28)	Methylprednisolone infusion (1 mg/kg/d) for up to 28 days	↑ VFDs (16.5 vs 8.7 days; P=0.001) at day 28 ↑ PaO₂/FiO₂ ratio (256 vs 179; P = 0.006) on day 7 ↓ Length of ICU stay (7 vs 14.5 days; P = 0.007) at day 28 ↓ ICU mortality (20.6 vs 42.9%; P = 0.03) at day 28 ↔ Length of hospital stay at day 28
[31]	RCT	216 patients with COVID-19 induced-ARDS Dexamethasone group (n=111) Methylprednisolone (n=105)	IV dexamethasone 6 mg daily for 7 to 10 days Methylprednisolone 250 – 500 mg daily for 3 days followed by oral prednisone 50 mg daily for 14 days	↓ Mortality (7.4 vs 36.9 %; P< 0.0001) at day 30 for methylprednisolone than dexamethasone ↑ Recovery time (3 vs 6 days; P < 0.0001) for methylprednisolone than dexamethasone
[7]	RCT	24 patients with severe ARDS Methylprednisolone (n=16) Placebo (n=8)	Methylprednisolone 2 mg/kg per day → taper over 32 days Loading: 2 mg/kg IV once Days 1–14: 2 mg/kg/day Days 15–21: 1 mg/kg/day Days 22–28: 0.5 mg/kg/day Days 29–30: 0.25 mg/kg/day Days 31–32: 0.125 mg/kg/day	↓ Mechanical ventilation duration (11.5 vs 23 days; P = 0.001) ↓ ICU mortality (0 vs 62%; P=0.002) ↓ Hospital mortality (12 vs 62%; P=0.03) ↓ Lung injury score (LIS) (1.7 vs 3.0; P<0.001) ↑ PaO₂/FiO₂ ratio (262 vs 148; P<0.001) ↑ Successful extubation (7 vs 0; P=0.05) ↑ Organ failure free days (16 vs 6 days; P =0.005)
[32]	RCT	81 Mechanically ventilated patients at high risk for ARDS Methylprednisolone (n=39) Placebo (n= 42)	Methylprednisolone 30 mg/kg, q 6 hours for 48 hours	↔ Oxygen requirements ↔ Days of intensive care ↑ Incidence of infection rate (P < 0.05)
[29]	Cohort	20 postoperative ARDS patients Placebo (n=8) Methylprednisolone (n=12)	Loading dose 2 mg/kg followed by 2 mg/kg/day IV daily q 6 hours and then changed to a single oral dose or discontinued	↓ Mortality (8.3 vs 87.5%; P= 0.001) ↑ PaO₂/FiO₂ ratio on day 4 (P < 0.05)
[36]	RCT	99 ARDS patients Methylprednisolone (n=50) Placebo (n=49)	Methylprednisolone (30 mg/kg q 6 hours for 24 hours)	↔ Mortality at 45 days
[30]	Secondary analysis of RCT	745 ARDS patients No corticosteroids (n=506) Corticosteroids (n=239)	IV or PO corticosteroids (e.g. methylprednisolone /dexamethasone/prednisone/hydrocortisone) Doses: 20 mg methylprednisolone / 3.75 mg dexamethasone/ 25 mg prednisone/ 100 mg hydrocortisone daily	↔ Mortality
[8]	RCT	277 patients with moderate-to-severe ARDS Dexamethasone group (n=139) Control group (n=138)	Dexamethasone IV 20 mg once daily for 5 days and then reduced to 10 mg daily from day 6 to day 10	↑ VFDs (12.3 vs 7.5 days; P<0.0001) at 28 days ↑ PaO₂/FiO₂ (P < 0.05) on day 6 ↓ Mortality at 60 days (21% vs 36%, P = 0.0047) ↓ SOFA score on day 3 (P < 0.05) ↔ Adverse events
[9]	RCT	299 patients with COVID-19–associated with moderate to severe ARDS Dexamethasone (n =151) or Control (n = 148)	Dexamethasone IV 20 mg once daily for 5 days and then reduced to 10 mg for additional 5 days or until ICU discharge	↑ VFDs (6.6 vs 4 days; P = 0.04) at 28 days ↓ SOFA (6.1 vs 7.5; P = 0.004) at 7 days ↔ Mortality at 28 days ↔ ICU-free days at 28 days
[25]	RCT	106 patients with mild to moderate COVID-19-related ARDS Methylprednisolone (n=36), Dexamethasone (n=35), Hydrocortisone (n=35)	Dexamethasone IV 6 mg once daily for 10 days Methylprednisolone IV 16 mg BID for 10 days Hydrocortisone IV 50 mg TID for 10 days	↔ VFDs ↔ PaO₂/FiO₂ ratio ↔ ICU stays ↔ Hospital stays ↔ 28-day mortality ↔ Adverse events
[26]	RCT	98 patients with COVID-19-related ARDS High dexamethasone groups (n=49) Low dexamethasone groups (n=49)	16 mg of dexamethasone IV daily for 5 days followed by 8 mg for 5 days or 6 mg of dexamethasone IV daily for 10 days.	↔ VFD between high- and low-dose dexamethasone groups at 28 days ↑ Successful extubation on high dose group (P < 0.05) ↔ Adverse events
[37]	RCT	197 patients with sepsis related ARDS Hydrocortisone (n = 98) Placebo (n = 99)	Hydrocortisone IV 50 mg q 6 h daily for 7 days	↑ PaO₂/FiO₂ (319.1 vs 266.3; P = 0.001) ↔ Mechanical ventilation duration at day 28 ↔ Mortality at 28 days

Neuromuscular blocking agents in ARDS

Reference	Study design	Number of patients	NMBAs type and dose	Key findings
[10]	RCT	339 patients with moderate to severe ARDS Cisatracurium (n=177) Placebo (n=162)	15 mg of cisatracurium followed by a continuous infusion of 37.5 mg/hour for 48 hours	↓ Hazard ratio of mortality. HR= 0.68 (95% CI, 0.48 to 0.98; P = 0.04) ↓ Mortality (23.7 vs 33.3 %; P=0.05) at 28-day ↓ Mortality (30.8% vs 44.6%, P=0.04) in patients with baseline PaO₂/FiO₂ <120 mm Hg ↔ Mortality at 90-day ↑ VFDs (10.6 vs 8.5 days; P=0.04) at 28 days ↑ VFDs (53.1 vs 44.6 days; P=0.03) at 90 days ↑ ICU free days (47.7 vs 39.5; P=0.03) at 90 days ↔ ICU free days at 28 days
[11]	RCT	1006 patients with moderate-severe ARDS Cisatracurium group (n=501) Control group (n=505)	15 mg of cisatracurium followed by a continuous infusion of 37.5 mg/hour for 48 hours	↔ 90 days mortality ↔ Hospital death at 28 days ↔ VFDs at 28 days ↔ ICU free days at 28 days ↔ Hospital free days at 28 days ↑ Cardiovascular adverse events (14 vs 4 events; P=0.02)
[12]	RCT	36 patients with moderate-severe ARDS Cisatracurium (n = 18) Placebo (n = 18)	A bolus dose of cisatracurium 0.2 mg/kg was followed by a continuous infusion at an initial rate of 5 μg/kg/min for 48 hr	↔ Mechanical ventilation duration ↔ VFDs at 28 days ↔ ICU mortality ↑ PaO₂/FiO₂ ratio (P < 0.001)
[13]	RCT	56 patients with moderate-severe ARDS Cisatracurium (n=28) Placebo (n=28)	50 mg bolus of cisatracurium followed by a continuous infusion at an initial rate of 5 μg/kg/min for 48 hr	↑ PaO₂/FiO₂ ratios (P < 0.05) ↔ ICU mortality ↔ VFDs at day 28 ↔ VFDs at day 60
[47]	Retrospective cohort study	172 patients with moderate-severe ARDS Control (n = 86) Cisatracurium (n = 86)	NA	↓ Length of ICU stay (9.37 vs 14.67 days; P <0.01) ↓ Duration of ventilation (6.40 vs 12.38 days; P <0.01) ↔ Length of hospital stay ↔ Mortality outcomes at 28-day, 90-day, or 1-year
[44]	Retrospective cohort study	58 patients with moderate-severe ARDS Cisatracurium (n=29) Vecuronium (n=29)	The treatment duration was around three days (74.2 vs 69.6 hr) in cisatracurium and vecuronium, respectively The average daily dose 123.7 vs 63 mg/day in cisatracurium and vecuronium, respectively The hourly infusion rate 7.9 vs 4.4 mg/hr in cisatracurium and vecuronium, respectively	↔ Ventilator days ↔ ICU mortality ↔ Hospital mortality ↔ Length of ICU stay ↔ Hospital length of stay ↔ PaO₂/FiO₂ ratio after 48 hours
[43]	Retrospective cohort study	3802 patients with ARDS or at risk for ARDS Cisatracurium (n=1,901) Vecuronium (n=1,901)	Continuous infusion of NMBA for at least 2 days. The exact dose is not available.	↔ Mortality outcome ↔ Hospital length of stay ↓ Ventilator days (P = 0.005) in patients treated with cisatracurium ↓ ICU length of stay (P = 0.028) in patients treated with cisatracurium
[45]	Retrospective cohort study	76 patients with severe ARDS Atracurium (n=18) Cisatracurium (n=58)	The treatment duration (2.5 vs 2.6 days) in atracurium and cisatracurium, respectively The treatment dose (1.9 vs 2.5 μg/kg/min) in atracurium and cisatracurium, respectively	↔ PaO₂/FiO₂ at 72 hr ↔ VFDs at day 28 ↔ ICU length or stay ↔ Hospital length of stay ↔ Hospital mortality
[46]	Retrospective cohort study	225 patients with ARDS Atracurium (n = 75) Cisatracurium (n = 150)	Atracurium 4 µg/kg/min, titrated by 0.5 µg/kg/min q 15 minutes to a maximum dose of 20 µg/kg/min for at least 12 hr Cisatracurium 1 µg/kg/min, titrated by 0.5 µg/kg/min q 15 minutes to a maximum dose of 10 µg/kg/min for at least 12 hr	↑ PaO₂/FiO₂ ratio (68.6 vs 54.6; P= 0.011) for atracurium than cisatracurium at 24 hours, ↑ PaO₂/FiO₂ ratio (52.3 vs 41.3; P=0.014) for atracurium than cisatracurium at 72 hours ↔ PaO₂/FiO₂ ratio at 48 hours ↔ ICU length of stay ↔ Hospital length of stay ↔ Duration of mechanical ventilation ↑ Hospital mortality (58.7 vs 36 %; P=0.001) in atracurium than cisatracurium

Exploring pharmacological strategies in the management of ARDS: Efficacy, limitations, and future directions

Figures & Tables

Fig. 1.

Beta-2 agonists in ARDS

Appraisal of Key Clinical Studies of Pharmacologic Agents in ARDS

Corticosteroid in ARDS

Neuromuscular blocking agents in ARDS

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