What is the definition of acute respiratory distress syndrome (ARDS), including its severity categories by PaO₂/FiO₂ ratio and its classification into direct (pulmonary) and indirect (extrapulmonary) types?

Definition of Acute Respiratory Distress Syndrome (ARDS)

ARDS is an acute inflammatory syndrome characterized by non-cardiogenic pulmonary edema with bilateral opacities on imaging, developing within 1 week of a known clinical insult, and classified by severity using the PaO₂/FiO₂ ratio measured at minimum PEEP of 5 cmH₂O. 1

Core Diagnostic Criteria (Berlin Definition)

ARDS diagnosis requires all four of the following components:

1. Timing Requirement

• Acute onset within 1 week of a known clinical insult or new/worsening respiratory symptoms 2, 1
• This temporal criterion distinguishes ARDS from chronic or subacute lung processes 1

2. Imaging Findings

• Bilateral opacities on chest radiograph or CT scan 3, 1
• Opacities cannot be fully explained by pleural effusions, lobar/lung collapse, or nodules 2, 1
• Critical pitfall: Standard chest radiographs correlate poorly with hypoxemia severity; infiltrates may appear asymmetric or patchy rather than diffuse, potentially causing misclassification 2

3. Origin of Edema

• Respiratory failure not fully explained by cardiac failure or fluid overload 3, 1
• When no clear ARDS risk factor exists, objective assessment (echocardiography) is mandatory to exclude hydrostatic pulmonary edema 2, 1
• Critical pitfall: Misattribution of cardiogenic pulmonary edema to ARDS leads to incorrect diagnosis and inappropriate management 1

4. Oxygenation Impairment

• Must be measured with minimum PEEP of 5 cmH₂O (10 cmH₂O for severe ARDS) 3, 1
• Critical pitfall: Calculating PaO₂/FiO₂ ratio without adequate PEEP leads to inaccurate severity staging 2

Severity Categories by PaO₂/FiO₂ Ratio

The Berlin definition stratifies ARDS into three severity levels with distinct mortality implications:

Mild ARDS

• PaO₂/FiO₂ ratio: 201–300 mmHg 3, 1
• Requires PEEP or CPAP ≥5 cmH₂O 3, 1

Moderate ARDS

• PaO₂/FiO₂ ratio: 101–200 mmHg 3, 1
• Requires PEEP ≥5 cmH₂O 3, 1

Severe ARDS

• PaO₂/FiO₂ ratio ≤100 mmHg 3, 1
• Requires PEEP ≥10 cmH₂O 3
• Associated with highest mortality (30-40% in-hospital mortality overall) 2
• Represents 20-30% of ARDS cases 4

The Berlin definition demonstrates significantly better predictive validity for mortality compared to the prior American-European Consensus Conference definition. 1, 5

Classification by Etiology: Direct vs. Indirect ARDS

ARDS can be triggered by two distinct pathophysiologic mechanisms, though specifying the exact trigger is not required for diagnosis: 2

Direct (Pulmonary) ARDS

• Results from direct injury to the alveolar epithelium 2
• Common causes include:
  • Pneumonia (bacterial, viral, fungal)
  • Aspiration of gastric contents
  • Pulmonary contusion
  • Inhalation injury
  • Near-drowning

Indirect (Extrapulmonary) ARDS

• Results from systemic inflammatory response affecting the pulmonary vascular endothelium 2
• Common causes include:
  • Sepsis (most common)
  • Non-thoracic trauma
  • Acute pancreatitis
  • Massive transfusion
  • Drug overdose

Important note: Even among patients meeting identical diagnostic criteria, there is wide variation in respiratory mechanics, dead-space ventilation, and ventilatory requirements, reflecting substantial physiological heterogeneity 2

Pathophysiologic Features

Understanding the underlying pathophysiology helps distinguish ARDS from mimicking conditions:

• Inflammatory injury: Leukocyte infiltration and local immune activation damage alveolar endothelial and epithelial cells 2
• Increased vascular permeability: Alveolar-capillary barrier disruption leads to protein-rich pulmonary edema 2, 6
• Loss of aerated lung tissue: Acute pulmonary edema reduces normally aerated lung regions 2
• Surfactant depletion: Creates extensive intrapulmonary shunting and profound hypoxemia 2
• Histologic progression: Diffuse alveolar damage evolves through exudative, fibroproliferative, and fibrotic phases with hyaline membrane formation 2

Conditions That Mimic ARDS

Critical pitfall: The following conditions can present identically to ARDS but require specific alternative treatments: 2

• Diffuse interstitial lung diseases
• Widespread pulmonary infections (e.g., Pneumocystis jirovecii pneumonia)
• Drug-induced lung injury
• Cardiogenic pulmonary edema (must be actively excluded)

Clinical Implications of ARDS Heterogeneity

ARDS encompasses wide variation across etiological, physiological, and biological domains, with no single criterion required for diagnosis, contributing to substantial patient-level heterogeneity. 2, 1

• This intrinsic heterogeneity has been a major factor in repeated failure of therapeutic trials 2, 1
• Interventions targeting specific pathophysiological mechanisms may only benefit selected subgroups 2
• Death most often results from multiorgan failure and unresolved sepsis rather than isolated respiratory failure 2