Acute Respiratory Distress Syndrome (ARDS) - Complete Answer for MD Exams

Definition

Severity Classification (Berlin)

Etiology / Risk Factors

Direct (Pulmonary) Causes

• Pneumonia (most common - bacterial, viral, fungal)
• Aspiration of gastric contents
• Pulmonary contusion
• Near-drowning
• Inhalation injury / toxic gas exposure
• Reperfusion injury post lung transplant

Indirect (Extrapulmonary) Causes

• Sepsis (most common overall cause - accounts for ~40% of cases)
• Severe pancreatitis
• Major trauma / polytrauma
• Burns
• Massive blood transfusions (TRALI - Transfusion-Related Acute Lung Injury)
• Hemorrhagic shock / hypotension
• Drug overdose (heroin, salicylates, barbiturates)
• Fat embolism

Pathophysiology

Phase 1: Exudative Phase (Day 0-7)

1. Triggering event activates alveolar macrophages and circulating neutrophils
2. Neutrophils marginate in pulmonary capillaries and transmigrate into alveolar spaces
3. Release of proteases, reactive oxygen species (ROS), cytokines (TNF-α, IL-1β, IL-6, IL-8) causes endothelial and epithelial injury
4. Loss of alveolar-capillary barrier integrity → protein-rich fluid leaks into alveolar spaces (noncardiogenic pulmonary edema)
5. Type II pneumocyte injury → reduced surfactant production → alveolar collapse
6. Hyaline membrane formation - fibrin-rich exudate lines alveolar walls
7. Pathologists call this constellation Diffuse Alveolar Damage (DAD)

Phase 2: Proliferative Phase (Day 7-21)

• Type II pneumocytes proliferate to restore epithelium
• Fibroblast influx begins
• Clinical improvement in some patients, or progression to fibrosis in others

Phase 3: Fibrotic Phase (After Day 21)

• Disordered repair with collagen deposition
• Dense fibrosis replaces normal lung architecture
• Reduced lung compliance persists
• Only occurs in a subset of patients

Physiological Consequences

• Decreased FRC (functional residual capacity) due to alveolar flooding and collapse
• Intrapulmonary shunting (blood passes non-ventilated alveoli without oxygenation)
• Dead space ventilation increases (ventilated but non-perfused units)
• Decreased lung compliance - the lung becomes "stiff"
• Pulmonary hypertension from hypoxic vasoconstriction + microvascular thrombosis
• Severe refractory hypoxemia (does NOT respond to supplemental O2 alone)

Clinical Features

Symptoms and Signs

• Acute onset dyspnea (typically within hours to 2-3 days of inciting event)
• Tachypnea, tachycardia
• Severe hypoxemia - cyanosis, SpO2 not improving despite high-flow O2
• Bilateral coarse crackles on auscultation
• Agitation, restlessness (due to hypoxia)
• Features of underlying cause (fever in sepsis/pneumonia, abdominal pain in pancreatitis, etc.)

ABG Findings

• Severe hypoxemia: PaO2 markedly reduced
• Initially: respiratory alkalosis (hyperventilation)
• Later: respiratory acidosis + metabolic acidosis (if shock coexists)
• PaO2/FiO2 ratio < 300 (defining criterion)

Investigations

Chest X-Ray / CT

• Bilateral, diffuse "white-out" / ground-glass opacities affecting all lung zones
• Opacities NOT explained by pleural effusion, cardiomegaly, or atelectasis alone
• CT chest: Heterogeneous consolidation - dependent consolidation + non-dependent ground glass = "baby lung" distribution
• No cardiomegaly (unlike cardiogenic pulmonary edema)

ABG (mandatory)

• Calculate PaO2/FiO2 ratio to classify severity
• Serial ABGs to monitor response to ventilation

Echocardiography / BNP

• To rule out cardiogenic pulmonary edema (differentiating ARDS from heart failure)
• PCWP ≤ 18 mm Hg (if Swan-Ganz catheter placed) - but not routinely required now

Other

• CBC, CRP, procalcitonin (infection workup)
• Blood cultures, BAL/sputum culture
• LFTs, amylase/lipase (pancreatitis)
• Coagulation screen (DIC)

Management

1. Treatment of Underlying Cause

• Antibiotics for sepsis / pneumonia
• Source control for sepsis
• Treat pancreatitis, trauma, etc.

2. Lung-Protective Mechanical Ventilation (CORNERSTONE of management)

• Used to keep collapsed alveoli open ("open lung strategy")
• Minimum PEEP = 5 cm H2O (per Berlin definition)
• Higher PEEP titrated based on PEEP/FiO2 tables (ARDSNet) or esophageal pressure-guided titration

3. Prone Positioning

• Strong evidence: >12-16 hours/day prone position reduces mortality in moderate-severe ARDS (PaO2/FiO2 <150)
• Mechanism: redistributes ventilation/perfusion more evenly, recruits dorsal atelectatic regions, reduces ventilator-induced lung injury
• Landmark trial: PROSEVA trial (2013) - 28-day mortality 16% vs 32.8% with prone positioning
• Used early in the course of ARDS

4. Neuromuscular Blockade (NMB)

• Cisatracurium infusion for 48 hours in severe ARDS (PaO2/FiO2 < 150)
• Reduces ventilator asynchrony and inflammatory biomarkers
• ACURASYS trial showed mortality benefit - though debated by ROSE trial
• Current practice: use deep sedation; NMB reserved for refractory cases

5. Conservative Fluid Management

• Conservative fluid strategy (keeping patients euvolemic or slightly negative fluid balance) improves lung function vs. liberal strategy
• FACTT trial: Conservative fluid management → more ventilator-free days
• Diuresis to reduce pulmonary edema where feasible

6. ECMO (Extracorporeal Membrane Oxygenation)

• Reserved for severe refractory ARDS failing all conventional therapy
• Venovenous ECMO (VV-ECMO) allows lung rest
• CESAR trial: Benefit shown with transfer to ECMO center
• EOLIA trial (2018): No significant mortality benefit (stopped early); benefit remains debated
• Indications: PaO2/FiO2 < 80 despite optimized therapy

7. Corticosteroids

• Controversial - no consensus on routine use
• May be considered in unresolving ARDS after 7-14 days (fibroproliferative phase)
• Recent 2024-2026 meta-analyses (PMID: 39165240; PMID: 41325621) suggest possible mortality reduction but increased infection risk - benefit is debated
• Dexamethasone (6 mg/day or 20 mg/day tapering regimen) used in some centers
• NOT routinely recommended

8. Adjunct Therapies (Improve Oxygenation, No Proven Mortality Benefit)

• Inhaled nitric oxide (iNO): Improves V/Q matching and oxygenation transiently; does NOT reduce mortality
• Inhaled epoprostenol: Similar to iNO; improves oxygenation only
• High-frequency oscillatory ventilation (HFOV): No mortality benefit (OSCILLATE, OSCAR trials)
• Recruitment maneuvers: Transient oxygenation improvement; no mortality benefit (ART trial)

Complications

Prognosis

• Overall mortality: 30-45% (varies by severity and underlying cause)
• Most deaths are due to MODS/sepsis rather than refractory hypoxemia alone
• Survivors may have long-term morbidity: reduced exercise tolerance, pulmonary fibrosis, neurocognitive deficits, ICU-acquired weakness
• Mortality by severity (Berlin):
  • Mild ARDS: ~27%
  • Moderate ARDS: ~32%
  • Severe ARDS: ~45%

Differential Diagnosis

Summary Mnemonics

• Bilateral infiltrates
• Onset within 1 week
• Respiratory failure NOT cardiac
• Oxygenation PaO2/FiO2 <300 + PEEP ≥5

• Low tidal volume (6 ml/kg)
• Optimize PEEP
• Wean FiO2
• Prone positioning
• Restrict fluids
• Origin - treat underlying cause
• NMBs if refractory
• ECMO last resort