Acute Respiratory Distress Syndrome: Contemporary Management and Novel Approaches During COVID-19

George W. Williams, M.D.; Nathaniel K. Berg, B.S.; Alexander Reskallah, M.D.; Xiaoyi Yuan, Ph.D.; Holger K. Eltzschig, M.D., Ph.D.

Disclosures

Anesthesiology. 2021;134(2):270-282.

Abstract and Introduction

Introduction

Acute respiratory distress syndrome (ARDS) is defined as hypoxemia secondary to a rapid onset of noncardiogenic pulmonary edema.^[1] Etiologic risk factors for ARDS encompass both direct and indirect lung injuries including but not limited to pneumonia, sepsis, noncardiogenic shock, aspiration, trauma, contusion, transfusion, and inhalation injuries. Although clinical recognition and management of ARDS have improved significantly over the past 25 yr, it is still a leading cause of death in critically ill patients, with mortality rates consistently reported around 30 to 40%.^[2] An important factor in the high mortality rate in ARDS is that treatment is mainly focused on clinical management and no targeted therapies currently exist. Furthermore, ARDS management is often challenging as it commonly occurs in a clinical setting of multiple organ failure and can also lead to the development of nonpulmonary organ injury, such as acute kidney injury.^[3] Recently, the pandemic caused by coronavirus disease 2019 (COVID-19), which results from infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has led to a dramatic incidence in COVID-19–related ARDS. Thirty to forty percent of COVID-19 hospitalized patients develop ARDS, and it is associated with 70% of fatal cases.^[4,5] At the time of this writing (July 31, 2020), there are more than 4.5 million COVID-19 cases and 152,000 related deaths in the United States.^[6] Here, we describe select management strategies that have become foundations of ARDS clinical management and provide an update of emerging approaches for the treatment of ARDS related to COVID-19.

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Table 1. Summarized Results of Select Large-scale Intervention Trials Aimed at Improving Outcomes in Patients with Acute Respiratory Distress Syndrome
Clinical Intervention	Trial Name	Study Groups	Outcomes
Small tidal volumes	The 2000 Acute Respiratory Distress Syndrome Network trial (ARMA)⁹	Low tidal volume (6 ml/kg of predicted body weight) or Traditional tidal volume (12 ml/kg of predicted body weight)	Reduction in 180-day mortality 31.0% vs. 39.8% (P = 0.007)
PEEP	Higher vs. Lower PEEP (ALVEOLI)¹⁵	Low PEEP or High PEEP (inspiratory plateau pressure of 28–30)	No change in death before discharge 24.9% vs. 27.5% (P = 0.48)
Prone positioning	Proning Severe ARDS Patients (PROSEVA) trial²⁰	Supine position or Prone position (at least 16 h/day)	Reduction in 28-day mortality 16.0% vs. 32.8% (P < 0.001)
Steroids	Late Steroid Rescue Study (LaSRS)²⁷	In patients 7–28 days after onset of ARDS: Placebo or Methylprednisolone	No change in 60-day mortality 28.6% vs. 29.2% and Increased mortality in patients receiving methylprednisolone at least 14 days after ARDS diagnosis
	Dexamethasone Treatment for the Acute Respiratory Distress Syndrome (DEXA-ARDS)²⁸	Standard of care or Dexamethasone	Increase in ventilator-free days 12.3 vs. 7.5 days (P < 0.0001) and Reduction in all-cause mortality at day 60 21% vs. 36%
Conservative oxygenation	Normal Oxygenation Versus Hyperoxia in the Intensive Care Unit (ICU) (OXYGEN-ICU) trial³²	Conventional oxygen: PaO₂ up to 150 mmHg or SaO₂ up to 97 to 100% or Conservative oxygen: PaO₂ 70 to 100 mmHg or SaO₂ of 94 to 98%	Reduction in ICU mortality 11.6% vs. 20.2% (P = 0.01)
	Intensive Care Unit Randomized Trial Comparing Two Approaches to Oxygen Therapy (ICU-ROX)⁷⁵	Usual oxygen therapy: no upper limit to FIO₂ or SaO₂ or Conservative oxygen therapy: SaO₂ between 90 and 97%	No change in ventilator-free days 21.3 vs. 22.1 days and No change in 180-day mortality 35.7% vs. 34.5%
	Liberal or Conservative Oxygen Therapy for ARDS (LOCO2)³³	Liberal oxygenation: target PaO₂ 90–105 mmHg; SaO₂ > 96% or Conservative oxygenation: target PaO₂ 55–70 mmHg; SaO₂ 88–92%	Increased mortality in conservative oxygen group 34.3% vs. 26.5%
Extracorporeal membrane oxygenation	Conventional Ventilatory Support vs. ECMO for Severe Adult Respiratory Failure (CESAR)³⁵	Conventional management or Extracorporeal membrane oxygenation	Increased survival without severe disability at 6 months 63% vs. 47%
	Rescue Lung Injury in Severe ARDS (EOLIA)³⁶	Early extracorporeal membrane oxygenation or Conventional mechanical ventilation with extracorporeal membrane oxygenation as a rescue therapy	Non–statistically significant reduction in mortality 35% vs. 46% (P = 0.09)
Fluid restriction	Fluids and Catheters Treatment Trial (FACTT)³⁷	Liberal fluids (CVP 10–14) or Conservative fluids (CVP < 4)	No change in all-cause mortality at 60 days 25.5% vs. 28.4% (P = 0.30)
Early neuromuscular blockade	ARDS et Curarisation Systematique (ACURASYS)³⁸	Patients first sedated to a Ramsay sedation score of 6, then given: Placebo or Cisatracurium	Adjusted hazard ratio for death at 90 days of 0.68 in NM blockade group (P = 0.04)
	Reevaluation of Systemic Early Neuromuscular Blockade (ROSE)³⁹	Usual care: lightly sedated or Early neuromuscular blockade: deep sedation and cisatracurium	No change in 90-day mortality 42.5% vs. 42.8%
Statin treatment	Simvastatin in the Acute Respiratory Distress Syndrome (HARP-2)⁴⁷	Placebo or Simvastatin for maximum 28 days	No significant change in ventilator-free days 12.6 vs. 11.5 days or 28-day mortality 22% vs. 26.8%
	Statins for Acutely Injured Lungs from Sepsis (SAILS)⁴⁹	Placebo or Rosuvastatin for maximum 28 days	No change in 60-day mortality 28.5% vs. 24.9% and Fewer days free of renal or hepatic failure
Vitamins, nutrition, and supplements	Early vs. Delayed Enteral Nutrition (EDEN)⁴⁰	Trophic enteral feeding: 10–20 kcal/h or Full enteral feeding: 25–30 kcal/kg per day of nonprotein calories and 1.2 to 1.6 g/kg per day of protein	No change in ventilator-free days 14.9 vs. 15 days and No change in 60-day mortality 23.2% vs. 22.2%
	Omega Nutrition Supplement Trial (Omega)⁴⁸	Enteral supplementation of omega-3 fatty acids, γ-linolenic acid, and antioxidants or An isocaloric control	Reduction in ventilator-free days 14.0 vs. 17.2 days and Non-statistically significant increase in mortality 26.6% vs. 16.3% (P = 0.054)
	Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury (CITRIS-ALI)⁷⁶	Matched placebo (5% dextrose in water) or Vitamin C 50 mg/kg total body weight every 6 h for 96 h	No change in Sequential Organ Failure Assessment (SOFA) score 3 vs. 3.5
	Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET)⁷⁷	Placebo or Vitamin D3	No difference in 90-day mortality 23.5% vs. 20.6% (P = 0.26)
β₂-Agonist	Albuterol for the Treatment of ALI (ALTA)⁴¹	Aerosolized albuterol (5 mg) or Placebo (aerosolized saline)	No difference in ventilator-free days 14.4 vs. 16.6 and No difference in mortality before hospital discharge 23% vs. 17.7%
Antifungals	Ketoconazole for ALI/ARDS (KARMA)⁴⁶	Ketoconazole, 400 mg/day or Placebo	No difference in in-hospital mortality 34.1% vs. 35.2%
Lisofylline	Lisofylline for ALI/ARDS (LARMA)⁴⁵	Lisofylline (3 mg/kg with a maximum dose of 300 mg) or Placebo	No difference in mortality 31.9% vs. 24.7% (P = 0.215)

ARDS, acute respiratory distress syndrome; CVP, central venous pressure; FiO₂, fractional inspired oxygen tension; ICU, intensive care unit; PEEP, positive end-expiratory pressure; SaO₂, arterial oxygen saturation.