Acute Respiratory Distress Syndrome (ARDS)

Pathophysiology and Management

DEFINITION AND DIAGNOSIS (Berlin Criteria 2012)

• Onset: Within 1 week of a known clinical insult or new/worsening respiratory symptoms
• Chest imaging: Bilateral opacities not fully explained by effusions, lobar collapse, or nodules
• Origin of edema: Not primarily from cardiac failure or fluid overload

2024 Global Definition Update: The new global definition (Matthay MA et al., AJRCCM 2024) allows SpO₂/FiO₂ ≤315 mmHg as a substitute for P/F ratio, and permits diagnosis in non-intubated patients on high-flow nasal oxygen (≥30 L/min) or NIV/CPAP. This broadens ARDS recognition to resource-limited settings.

CAUSES (ARDS Risk Factors)

Patient with Fever + Breathlessness + Hypoxia → Think ARDS

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

• Sepsis (most common overall cause - 40%)
• Severe trauma / non-thoracic
• Multiple blood transfusions (TRALI)
• Pancreatitis
• Burns
• Drug overdose
• Cardiopulmonary bypass

Clinical pearl: In a patient with fever + breathlessness + hypoxia, the triad points to either sepsis-induced ARDS or infectious pneumonia-induced ARDS as the most likely cause.

PATHOPHYSIOLOGY

Phase 1: Exudative Phase (Days 1-7)

1. Endothelial injury: Activated neutrophils release proteases, reactive oxygen species (ROS), and pro-inflammatory cytokines (IL-1, IL-6, IL-8, TNF-α) that damage capillary endothelial cells and widen intercellular junctions.
2. Epithelial injury: Type I pneumocytes (which cover ~95% of alveolar surface) are destroyed. This denudes the alveolar basement membrane.
3. Protein-rich edema floods alveoli: Loss of the tight epithelial barrier allows protein-rich fluid to pour into alveolar spaces. Condensed plasma proteins + cellular debris + dysfunctional surfactant = hyaline membrane formation.
4. Surfactant dysfunction: Surfactant is washed out and inactivated. Loss of surfactant causes alveolar collapse (atelectasis). This raises surface tension and further worsens compliance.
5. Neutrophil influx: Massive neutrophil recruitment into the interstitium and alveoli. Neutrophils release elastase, collagenase, and more ROS, amplifying injury.
6. Pulmonary vascular injury: Microthrombi form in pulmonary vasculature; vascular obliteration causes pulmonary hypertension.

• V/Q mismatch and intrapulmonary shunting → refractory hypoxemia (fails to correct with supplemental O₂ alone)
• Reduced lung compliance (stiff lungs = increased work of breathing)
• Increased dead space → hypercapnia in severe cases
• Right-to-left shunting dominates

Phase 2: Proliferative Phase (Days 7-14)

• Type II pneumocytes proliferate along denuded alveolar basement membranes - they synthesize new surfactant and differentiate into Type I cells
• Hyaline membranes begin to be reorganized
• Shift from neutrophil-predominant to lymphocyte-predominant infiltrate
• Fibroblast and myofibroblast proliferation begins
• Collagen deposition starts (elevated BAL N-terminal procollagen peptide III detectable as early as 24h)
• Many patients begin improving in this phase

Phase 3: Fibrotic Phase (>14-21 days, some patients)

• Alveolar and interstitial fibrosis replaces the inflammatory exudate
• Emphysema-like changes with large bullae form
• Intimal fibroproliferation in microcirculation → progressive pulmonary hypertension
• Increased pneumothorax risk (poor compliance + bullae)
• Associated with significantly increased mortality

Diffuse Alveolar Damage (DAD) is the pathologic hallmark - but found on autopsy in only ~45-50% of clinical ARDS cases, confirming pathologic heterogeneity.

MANAGEMENT

A. Treat the Underlying Cause

• Cultures + broad-spectrum antibiotics for suspected sepsis/pneumonia
• Source control (drain abscess, manage peritonitis)
• Treat aspiration, pancreatitis, etc.

B. Lung-Protective Ventilation (ARDSNet Protocol) - Grade A evidence

• Tidal volume (TV): 6 mL/kg of predicted body weight (not actual)
• Plateau pressure: ≤30 cmH₂O
• Driving pressure (Pplat - PEEP): Target <15 cmH₂O - associated with improved survival
• PEEP: Titrated to maintain alveolar recruitment - use the ARDSNet high-PEEP/FiO₂ table
• FiO₂: Minimum needed to achieve SpO₂ 92-96% (avoid hyperoxia)
• Rate: Can increase up to 35 breaths/min to allow permissive hypercapnia

C. Prone Positioning - Grade B evidence (mortality benefit in severe ARDS)

• Indicated when P/F ratio <150 mmHg despite lung-protective ventilation
• Recommendation: ≥16 hours/day prone sessions (PROSEVA trial: Guerin et al., NEJM 2013)
• Mechanism: Redistributes alveolar edema, recruits dorsal lung segments, reduces V/Q mismatch, decreases atelectrauma
• Mortality benefit: ~50% reduction in 28-day mortality in severe ARDS

D. Fluid Management - Conservative strategy (Grade B)

• ARDS patients: Use a conservative fluid strategy to minimize further pulmonary edema
• Target: Lowest left atrial filling pressure compatible with adequate organ perfusion
• FACTT trial: Conservative fluids = more ventilator-free days (no survival difference, but improved lung function)
• Use vasopressors for shock rather than fluid loading once euvolemia is achieved

E. PEEP Optimization

• Adequate PEEP keeps alveoli open at end-expiration (prevents atelectrauma)
• Higher PEEP may worsen hemodynamics (reduces venous return)
• No single optimal PEEP strategy proven; ARDSNet PEEP/FiO₂ tables are widely used
• "Open lung" approach: Recruit with higher PEEP, but LOCO2/ART trials showed high-PEEP recruitment maneuvers may increase mortality - so routine aggressive recruitment is no longer recommended

F. Neuromuscular Blockade (NMB) - Grade C (selective use)

• Cisatracurium infusion (48h) in severe ARDS (P/F <150) was shown to reduce mortality in the ACURASYS trial
• However, the larger ROSE trial (NEJM 2019) showed NO mortality benefit from routine early NMB
• Current recommendation: Use NMB for patient-ventilator dyssynchrony or severe refractory hypoxemia - not routinely

G. Extracorporeal Membrane Oxygenation (ECMO) - Grade B (select patients)

• Indicated for severe refractory ARDS (P/F <80 despite optimized ventilation + prone)
• Veno-venous (VV) ECMO: Provides gas exchange while resting injured lungs
• CESAR trial and EOLIA trial showed potential benefit in severe ARDS at expert centers
• Allows "ultra-protective" ventilation (TV 3-4 mL/kg)

H. Glucocorticoids - Grade D (not routinely recommended)

• Multiple trials failed to show consistent mortality benefit
• Current evidence does NOT support routine glucocorticoids in ARDS
• Exception: Low-dose hydrocortisone 200 mg/24h may be considered in:
  • Septic shock refractory to vasopressors
  • Severe CAP with ARDS
• 2024 meta-analysis (Soumare et al., Ann Intern Med 2026, PMID 41325621): Confirms corticosteroids in pneumonia + ARDS may reduce mortality but increase infection risk - careful patient selection required

I. Other Therapies (NOT proven to improve survival)

J. Supportive ICU Care (General Principles)

• VTE prophylaxis: LMWH + sequential compression devices
• GI prophylaxis: PPI or H2-blocker
• Enteral nutrition: Early (within 24-48h) via nasogastric tube - preferred over parenteral
• Glucose control: Target 140-180 mg/dL (avoid tight control)
• Sedation: Minimize (daily sedation interruption); avoid prolonged deep sedation
• Head-of-bed elevation: 30-45° to reduce aspiration
• Infection surveillance: Regular cultures, early de-escalation of antibiotics
• Delirium prevention: Minimize benzodiazepines, early mobilization

SUMMARY TABLE: Evidence-Based ARDS Therapies

OUTCOMES

• Mortality has fallen from >60% (1980s) to <40% currently
• Most survivors recover near-normal lung function by 6-12 months
• However, significant long-term morbidity remains:
  • ICU-acquired weakness (myopathy/axonopathy from proteolysis)
  • Cognitive impairment (attention, memory, processing speed)
  • PTSD and mood disorders
  • Reduced 6-minute walk distance for years post-discharge