Acute Respiratory Distress Syndrome (ARDS)

Definition - Berlin Criteria (2012)

1. Onset within 1 week of a known clinical insult or new/worsening respiratory symptoms
2. Bilateral radiographic opacities - not fully explained by pleural effusions, atelectasis, or nodules
3. Respiratory failure not fully explained by cardiac failure or fluid overload (requires objective assessment, e.g., echocardiography, if no risk factor is present)
4. Hypoxemia with PaO2/FiO2 ≤ 300 mmHg on PEEP or CPAP ≥ 5 cm H2O

Severity Classification

• Fishman's Pulmonary Diseases and Disorders, p. 2480
• Sabiston Textbook of Surgery, p. 940

Etiology / Risk Factors

• Pneumonia (most common)
• Gastric aspiration
• Pulmonary contusion
• Inhalation injury, near-drowning

• Sepsis (most common indirect cause)
• Major trauma / multiple transfusions (TRALI)
• Severe pancreatitis
• Burns
• Shock / hypoperfusion
• Drug overdose
• Fishman's Pulmonary Diseases and Disorders, p. 2480

Pathophysiology

Three Phases of Diffuse Alveolar Damage (DAD)

• Widespread alveolar and interstitial edema, inflammation, hemorrhage
• Destruction of type I alveolar epithelial cells
• Hyaline membrane formation (precipitated plasma proteins + fibrin + necrotic debris) - the histologic hallmark of DAD
• Marked increase in pulmonary dead space fraction
• Minute ventilation typically doubles (~12 L/min)

• Reabsorption of edema fluid
• Fibrin deposition in alveoli and interstitium
• Proliferation of type II pneumocytes (cuboidal epithelium)
• Fibroblast infiltration; air-blood barrier thickening
• Disruption of pulmonary vascular bed

• Linked to prolonged mechanical ventilation
• Irreversible architectural remodeling
• Fishman's Pulmonary Diseases and Disorders, pp. 2479-2480

Key Mediators

• Neutrophil sequestration in alveolar/interstitial spaces - central to injury
• TNF-α, IL-6, IL-8 - proinflammatory cytokines driving neutrophil activation
• Phospholipase A2 - enzymatic degradation of surfactant, promoting alveolar collapse
• Reactive oxygen species (ROS)
• von Willebrand factor (VWF) antigen - elevated in ARDS edema fluid, correlates with poor outcomes
• Angiopoietin-2 - elevated levels in sepsis predict development of ALI

Clinical Features

• Acute onset of severe dyspnea and hypoxemia refractory to supplemental O2
• Tachypnea, tachycardia, cyanosis
• Diffuse bilateral crackles on auscultation
• CXR/CT: bilateral diffuse opacities ("whiteout"), often heterogeneous on CT (not truly diffuse)
• Reduced lung compliance (stiff lungs)
• Increased work of breathing
• The CT appearance shows a mix of consolidation, atelectasis, and relatively normal alveoli in a heterogeneous distribution - the "baby lung" concept (only the open alveoli receive tidal volume, greatly amplifying volutrauma risk)

Diagnosis

• Clinical: Berlin criteria above
• ABG: severe hypoxemia, often hypocapnia initially; metabolic acidosis may supervene
• CXR: bilateral infiltrates not explained by cardiomegaly or pleural effusion alone
• CT chest: more sensitive; shows heterogeneous infiltrates (gravity-dependent dense consolidation, non-dependent aeration)
• Echocardiography / BNP: to exclude cardiogenic pulmonary edema (the "non-cardiogenic" hallmark of ARDS)
• BAL: if needed to identify infectious etiology; reveals neutrophilia, elevated protein, inflammatory mediators

Management

1. Lung-Protective Mechanical Ventilation (cornerstone of therapy)

• Male: 50 + 2.3 × (height in inches - 60)
• Female: 45.5 + 2.3 × (height in inches - 60)

• Fishman's Pulmonary Diseases and Disorders, pp. 2499-2500
• Goldman-Cecil Medicine, p. 1066-1067

2. Prone Positioning

• One of the few interventions with proven mortality benefit in an RCT (PROSEVA trial, 2013)
• Indicated for moderate-severe ARDS (PaO2/FiO2 < 150)
• Should be initiated early in the course of ARDS
• Mechanism: redistributes lung perfusion toward better-ventilated dependent regions, recruits dorsal lung units, reduces ventral overinflation
• Requires experienced nursing staff; prone sessions typically 16+ hours/day
• Requires caution given risk of accidental extubation, line displacement
• Sabiston Textbook of Surgery, p. 940

3. PEEP Optimization

• PEEP recruits collapsed alveoli, reduces intrapulmonary shunt, and allows FiO2 reduction (limiting O2 toxicity)
• Titrated by FiO2/PEEP tables (ARDSNet), or increasingly guided by driving pressure or electrical impedance tomography (EIT)
• A 2024 systematic review (PMID 38512400) showed EIT-guided PEEP titration improves oxygenation and reduces driving pressure vs. ARDSNet tables

4. Sedation and Neuromuscular Blockade

• Deep sedation ensures ventilator synchrony and prevents patient-driven lung injury
• Neuromuscular blockade (NMB) with cisatracurium: early use (first 48h) in moderate-severe ARDS was evaluated in the ACURASYS and ROSE trials with conflicting results; not routinely recommended for all patients currently, but may be used for ventilator dyssynchrony or severe hypoxemia

5. Fluid Management

• Conservative fluid strategy (FACTT trial): achieving negative fluid balance reduces duration of mechanical ventilation and ICU stay without increasing renal failure
• Target dry intravascular volume once hemodynamic stability is achieved
• Diuresis helps reduce extrapulmonary edema

6. Adjunct Therapies (rescue, no proven mortality benefit)

• Sabiston Textbook of Surgery, p. 940

7. Extracorporeal Membrane Oxygenation (VV-ECMO)

• Reserved for refractory ARDS failing all conventional measures
• CESAR trial: reduced mortality for patients referred to ECMO centers
• EOLIA trial (2018): no statistically significant benefit (but stopped early; crossover complicated interpretation)
• 2024 network meta-analysis (PMID 38842731): VV-ECMO may reduce mortality in severe ARDS compared to supine ventilation; prone positioning should be tried first
• Should only be performed in high-volume, experienced centers

8. Treatment of Underlying Cause

• Antibiotics for sepsis/pneumonia
• Source control for abdominal sepsis
• Transfusion protocols for TRALI
• No therapy directly reverses diffuse alveolar damage - supportive ventilation buys time for spontaneous lung repair

Prognosis and Outcomes

• Overall mortality: 30-45% depending on severity and etiology
• Survivors frequently have impaired quality of life, with persistent pulmonary function deficits, neuromuscular weakness, and cognitive impairment (post-intensive care syndrome)
• Recovery: most survivors show gradual lung function improvement over 6-12 months; fibrotic phase (in a minority) may leave permanent restriction

Recent Evidence (2024-2025)

• [PMID 38842731] - Network meta-analysis (Intensive Care Med, Jul 2024): Prone positioning and VV-ECMO both reduce mortality vs. supine ventilation in severe ARDS; prone should be tried before ECMO
• [PMID 38512400] - Systematic review (Intensive Care Med, May 2024): EIT-guided PEEP titration outperforms ARDSNet table-based titration for oxygenation and driving pressure outcomes
• [PMID 41270941] - Systematic review (Respir Med, Dec 2025): Mechanical power (the energy per unit time transferred by ventilator to lung) is associated with ventilator-induced lung injury; monitoring mechanical power is an emerging metric alongside driving pressure