Acute Respiratory Distress Syndrome (ARDS) - Comprehensive Review

1. Definition and Classification (Berlin Criteria, 2012)

Severity Classification

• Fishman's Pulmonary Diseases and Disorders, p. 2492
• Current Surgical Therapy 14e, p. 3285

2. Epidemiology

• Estimated incidence in the US: ~78.9 per 100,000 person-years (for P:F ≤300)
• Approximately 190,600 cases per year in the United States
• Incidence increases dramatically with age: up to 306 per 100,000 for ages 75-84 years
• Overall mortality has improved with lung-protective ventilation but remains 30-40%
• Incidence may have declined over time, possibly due to implementation of protective ventilation strategies
• Fishman's Pulmonary Diseases and Disorders, p. 2492

3. Etiology and Risk Factors

• Pneumonia (bacterial, viral, fungal)
• Aspiration of gastric contents
• Pulmonary contusion
• Near-drowning
• Inhalation injury

• Sepsis (most common cause overall)
• Severe trauma with shock
• Multiple blood transfusions / TRALI
• Pancreatitis
• Drug overdose / toxic ingestions
• Burns

4. Pathophysiology

Phase 1: Exudative Phase (Days 0-7)

• Hours: Endothelial cell swelling, widened intercellular junctions, increased pinocytotic vesicles, basement membrane disruption
• Days 1-3: Interstitial and alveolar edema, capillary congestion, intra-alveolar hemorrhage
• Days 3-7: Hyaline membrane formation (condensed fibrin + plasma proteins), extensive type I pneumocyte necrosis, inflammatory cell infiltration
• Pathologic correlate: Diffuse alveolar damage (DAD) - found in ~45% of autopsied ARDS cases

Phase 2: Proliferative Phase (Days 7-14+)

• Marked interstitial and alveolar inflammation
• Type II pneumocyte proliferation (attempting to replace lost type I cells)
• Progressive interstitial fibrosis and disordered healing
• Surfactant dysfunction: increases alveolar surface tension → collapse → shunting → hypoxemia

Physiologic Consequences

1. Reduced FRC from atelectasis
2. Intrapulmonary shunting - deoxygenated blood bypasses flooded/collapsed alveoli
3. Decreased compliance - "stiff lung," low compliance of 20-30 mL/cmH2O (normal ~80-100)
4. "Baby lung" concept - aerated lung is heterogeneous and small; delivering standard tidal volumes (10-15 mL/kg) to this small open fraction causes alveolar overdistention and volutrauma

• Fishman's Pulmonary Diseases and Disorders, p. 2493
• Murray & Nadel's Textbook of Respiratory Medicine, p. 263

5. Clinical Features

• Acute onset of severe dyspnea and hypoxemia (refractory to supplemental O2)
• Bilateral infiltrates on CXR/CT (ground-glass opacification)
• CT shows heterogeneous consolidation - NOT uniformly diffuse as CXR suggests; most dense in dependent regions
• Decreased lung compliance
• Progressive respiratory failure requiring mechanical ventilation
• Elevated A-a gradient
• No clinical evidence of cardiogenic pulmonary edema

6. Ventilation Strategies

6.1 Lung-Protective Ventilation (ARDSNet Protocol)

• Low VT: 6 mL/kg predicted body weight (PBW) + Pplat ≤30 cmH2O
• Traditional VT: 12 mL/kg PBW + Pplat ≤50 cmH2O

• Murray & Nadel's Textbook of Respiratory Medicine, p. 3126
• Rosen's Emergency Medicine, p. 1237

6.2 PEEP Optimization

1. Recruits collapsed alveoli → improves oxygenation, reduces shunt
2. Prevents atelectrauma - cyclic opening/closing of alveoli during inspiration/expiration

• ARDSNet FiO2/PEEP tables: Low PEEP table (titrated to FiO2) is the standard first-line approach
• Esophageal balloon-guided PEEP: Uses esophageal pressure as a pleural pressure surrogate to optimize transpulmonary pressure. Improves oxygenation but one major RCT showed no mortality benefit over FiO2-guided PEEP
• High vs. low PEEP trials (ALVEOLI, LOV, EXPRESS): High PEEP improved oxygenation but did NOT reduce mortality in unselected ARDS

• Murray & Nadel's Textbook of Respiratory Medicine, p. 264

6.3 Driving Pressure

• Reflects distending pressure of the available lung
• DP = VT / respiratory system compliance (Crs)
• DP ≤14 cmH2O is the target; re-analysis of ARDS RCTs showed DP was the single strongest mechanical variable predicting 60-day mortality
• Limitation: DP underestimates transpulmonary pressure in patients with high chest wall elastance (e.g., obesity, ascites). For those patients, transpulmonary driving pressure (DP minus the esophageal pressure swing) is more accurate
• Murray & Nadel's Textbook of Respiratory Medicine, p. 264

6.4 Recruitment Maneuvers

• Sustained inflations at high pressure (e.g., 35-40 cmH2O for 30-40 seconds) to open collapsed alveoli
• Closing pressures are lower than opening pressures, so recruited alveoli stay open with adequate PEEP
• Useful for treating acute hypoxemia, but frequent/aggressive recruitment with high PEEP led to hemodynamic and respiratory complications in the ART trial (2017), which actually showed increased mortality with aggressive recruitment - so routine use is NOT recommended

6.5 Mode of Ventilation

• VC ventilation guarantees tidal volume delivery but pressure varies with compliance changes
• PC ventilation limits peak pressure but tidal volume varies; useful when limiting peak pressure is a priority
• No strong evidence favors one mode over the other; the key parameters (low VT, Pplat ≤30) apply regardless of mode

7. Adjunctive Therapies

7.1 Prone Positioning

• Homogenizes ventilation from dorsal to ventral (reduces V/Q mismatch)
• Redistributes atelectasis away from dependent zones
• Reduces the dorsal-to-ventral transpulmonary pressure gradient
• Decreases VILI by making ventilation distribution more uniform

• Prone ≥16 hours/day vs. supine
• 28-day mortality: 16% (prone) vs. 32.8% (supine) - dramatic mortality benefit
• All patients received low VT ventilation; most received NMB and vasopressors

• Minimum 16 consecutive hours prone per session
• Neuromuscular blockade to facilitate proning and prevent patient dislodgement
• Meticulous attention to: endotracheal tube, central lines, arterial lines, eye pressure (retinal ischemia risk), pressure ulcers on nose, ears, face
• Absolute contraindications: Spinal instability or unstable fractures
• Not contraindications (though challenging): Vasopressors, renal replacement therapy, obesity
• Fishman's Pulmonary Diseases and Disorders, p. 2500
• Washington Manual of Medical Therapeutics, p. 290

7.2 Neuromuscular Blockade (NMB)

• Severe ventilator dyssynchrony
• High respiratory drive contributing to VILI
• Reverse triggering
• Murray & Nadel's Textbook of Respiratory Medicine, p. 3159

7.3 Conservative Fluid Management

• FACTT Trial (ARDSNet): In patients without shock, a conservative fluid strategy (targeting lower CVP/PAOP) reduced duration of mechanical ventilation compared to liberal strategy
• No mortality difference, but more ventilator-free days
• Goal: Minimize pulmonary edema while maintaining adequate organ perfusion
• Not applicable to patients in shock (who require resuscitation)

7.4 Corticosteroids

• Theoretical benefit: Anti-inflammatory in exudative phase; anti-fibrotic in proliferative phase
• Evidence is mixed overall
• COVID-19 ARDS (special case): A meta-analysis of 7 trials (n=1703 critically ill COVID-19 patients) showed glucocorticoids reduced 28-day mortality vs. standard care/placebo
• For non-COVID ARDS, routine corticosteroid use remains controversial and is not a standard recommendation outside of specific underlying etiologies (e.g., organizing pneumonia)
• Washington Manual of Medical Therapeutics, p. 290

7.5 Extracorporeal Membrane Oxygenation (VV-ECMO)

• Mechanical ventilation with high settings (FiO2 >0.9, Pplat >30 cmH2O) for ≥7 days
• CNS hemorrhage
• Severe immunosuppression (ANC <400/mm3)
• Nonrecoverable condition
• Current Surgical Therapy 14e, p. 3289

7.6 Inhaled Vasodilators (Inhaled NO, Prostacyclins)

• Improve V/Q matching by selectively vasodilating ventilated lung units
• Improve oxygenation transiently but no proven mortality benefit
• May be used as a bridge to other rescue therapies

8. Ventilator-Induced Lung Injury (VILI) - Key Mechanisms

9. Summary: Ventilation Strategy Quick Reference

ARDS Lung-Protective Ventilation (Mode: Volume-Controlled AC)
─────────────────────────────────────────────────────
VT:         6 mL/kg PREDICTED body weight
Pplat:      ≤30 cmH2O
Driving P:  ≤14 cmH2O
RR:         Start 14-20/min; increase for hypercapnia (max 35/min)
PEEP:       FiO2/PEEP table (ARDSNet); titrate to oxygenation
FiO2:       Lowest needed to maintain SpO2 88-95%
I:E ratio:  1:2 (adjust for dyssynchrony / iPEEP)
Permissive hypercapnia: Accept PaCO2 up to 50-60+ mmHg if pH >7.20

RESCUE THERAPIES (for P:F <150 despite the above):
  1. Prone positioning ≥16h/day (strongest evidence: 50% ↓ mortality)
  2. Inhaled NO / prostacyclins (oxygenation bridge)
  3. Recruitment maneuver (use cautiously; avoid routine use)
  4. VV-ECMO at experienced center

10. Complications

• Barotrauma (pneumothorax, pneumomediastinum)
• Ventilator-associated pneumonia (VAP)
• Pulmonary hypertension and cor pulmonale
• Multiorgan dysfunction (biotrauma-mediated)
• Post-ARDS pulmonary fibrosis
• ICU-acquired weakness (especially with prolonged NMB)
• Psychological sequelae (PTSD, depression, cognitive impairment)

• Fishman's Pulmonary Diseases and Disorders (Chapter 141)
• Murray & Nadel's Textbook of Respiratory Medicine (Chapters 11, 31, 134)
• Rosen's Emergency Medicine (Chapter 2)
• Washington Manual of Medical Therapeutics (Chapter 8)
• Current Surgical Therapy 14e (Chapter 16)
• ARMA Trial: ARDS Network. N Engl J Med. 2000;342:1301-1308
• PROSEVA Trial: Guérin et al. N Engl J Med. 2013;368:2159-2168
• Berlin Definition: Ranieri VM et al. JAMA. 2012;307:2526-2532

Recent Evidence Alert: A 2026 systematic review (PMID: 42153811) confirmed mechanical power is associated with mortality in mechanically ventilated patients, supporting efforts to minimize all components of VILI energy delivery. A 2026 systematic review on ARDS complications (PMID: 41906154) is now available in Critical Care.