Acute Respiratory Distress Syndrome

Overview

Definition

Acute respiratory distress syndrome is a clinical syndrome (not a pathological diagnosis) characterized by a sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure.

The underlying mechanism of ARDS is diffuse alveolar damage (DAD):

• Also the histological correlate
• Indicates damage to the endothelial and alveolar epithelial cells
• Associated with inflammation and the development of hyaline membranes lining the inner alveolar walls

Acute respiratory distress syndrome is clinically diagnosed using the Berlin diagnostic criteria.

Epidemiology

• ARDS is the most common cause of non-cardiogenic pulmonary edema. 
• Approximately 190,000 cases of ARDS are reported in the United States each year.
• ≥ 20% of patients who are mechanically ventilated meet the criteria for ARDS
• Mortality rate: 27%–43%

Etiology

Acute respiratory distress syndrome results from clinical disorders that affect the lungs either directly or indirectly.

Direct lung injury:

• Bacterial pneumonia (e.g., Streptococcus pneumoniae)
• Viral pneumonia (e.g., influenza, COVID-19)
• Aspiration of gastric contents
• Pulmonary contusion
• Near-drowning incidents
• Toxic inhalation injury
• Lung transplant

Indirect lung injury:

• Sepsis (most common cause)
• Severe trauma: 
  • Multiple bone fractures
  • Flail chest
  • Head trauma
  • Burns
• Pancreatitis
• Multiple transfusions (transfusion-related acute lung injury (TRALI))
• Drug overdose
• Postcardiopulmonary bypass
• Hematopoietic stem cell transplant
• Fat embolism and amniotic fluid embolism

Risk of ARDS:

• Increases in a patient with multiple predisposing clinical conditions
• 25% in patients with severe trauma, which increases to 56% if there is associated sepsis
• Other risk factors:
  • Alcohol-abuse disorder
  • Cigarette smoking
  • Obesity

Pathophysiology

Acute respiratory distress syndrome begins with an initial injury to the pneumocytes and pulmonary endothelium, which starts a chain reaction of increasing inflammation and pulmonary damage that can have an uneven/patchy distribution.

Exudative phase

• Starts within 6–72 hours after an eliciting risk factor
• Progresses rapidly
• Lasts about 7 days
• Destruction of alveolar epithelial cells/type 1 pneumocytes (type 2 pneumocytes are more resistant to damage, but both are damaged) and capillary endothelial cells, producing numerous effects:
  • Damage to the alveolar capillary membrane → endothelial cell membranes become leaky → protein-rich fluid exits into the interstitial and alveolar spaces
  • Release of pro-inflammatory cytokines → leukocytes are recruited to the interstitia and alveoli
  • Inactivation of the surfactant (which helps keep alveoli open)
  • Fibrin precipitates, plasma proteins, necrotic debris, and dysfunctional surfactant form the “hyaline membranes” that line the inner alveolar walls (glassy/waxy appearance).
  • Loss of surfactant also results in a large increase in the surface tension of alveoli, leading to: 
    • Alveolar instability
    • Atelectasis
• Effects on lung function:
  • “Stiff lungs” → reduced lung compliance
  • Reduced diffusing capacity, shortness of breath, and hypoxemia
  • Intrapulmonary shunting results from alveolar microvascular occlusion.
  • Reduction of pulmonary arterial blood flow to the ventilated portions of the lung
  • Pulmonary dead space is increased, ultimately leading to hypercapnia in addition to hypoxemia.

Proliferative phase

• Usually lasts 7–21 days
• Many patients recover within 3–4 weeks after the initial lung injury.
• Beginning stage of lung repair and resolution of pathophysiological changes (reparative process)
• Alveolar epithelial cells begin proliferating along the alveolar basement membranes.
• New pulmonary surfactant is produced.

Fibrotic phase

• Inflammatory exudates are converted into variable quantities of alveolar duct and interstitial fibrosis.
• Intimal fibrosis of pulmonary vessels leads to progressive vascular occlusion and pulmonary hypertension.
• Emphysema-like changes develop in some patients, consequently requiring supplemental oxygen.

Clinical Presentation

Vitals

• Tachypnea
• Tachycardia
• Fever may/may not be present
• Hypoxemia despite supplemental oxygen

Physical exam

• Diffuse rales/crackles
• Labored breathing
• Dyspnea
• Cyanosis

Exam findings not consistent with ARDS

• Cardiac exam:
  • S3 or S4 gallop
  • New or changed murmur
• Jugular venous distension (JVD)
• Lower extremity pitting edema

Diagnosis

Berlin diagnostic criteria of ARDS

• Acute onset (within 1 week)
• Diffuse bilateral infiltrates on chest X-ray
• No evidence of left heart failure or fluid overload
• Partial pressure of O₂/fraction of inspired O₂ (PaO₂/FiO₂) < 300 mm Hg: 
  • Mild ARDS: 201–300 mm Hg
  • Moderate ARDS: 101–200 mm Hg
  • Severe ARDS: ≤ 100 mm Hg

Laboratory tests

• BNP levels < 100 pg/mL favors ARDS (higher levels neither confirm heart failure nor exclude ARDS).
• Arterial blood gas (ABG):
  • Hypoxemia
  • Acute respiratory alkalosis
• Alveolar-arterial (A-a) gradient widening:
  • A-a gradient measures the difference between alveolar oxygen concentration and arterial oxygen.
  • Calculated using the following factors: age, atmospheric pressure, FiO₂, arterial O₂ and CO₂ in blood gas

Imaging

• Chest X-ray:
  • ARDS: bilateral pulmonary infiltrates
  • Findings more consistent with cardiogenic pulmonary edema:
    • Pulmonary venous congestion
    • Cardiomegaly
    • Pleural effusion
  • Finding more consistent with pneumonia: consolidation
• CT scan:
  • Not necessary, but gives more pulmonary details
  • ARDS: widespread patchy airspace opacities that are more apparent in the dependent lung zones
  • ARDS excluded by the following findings:
    • Pericardial effusion
    • Cardiomegaly
    • Pleural effusion
    • Cavitation
• Lung ultrasound:
  • B lines with smooth pleural morphology are suggestive of cardiogenic pulmonary edema.
  • B lines with uneven pleural line may indicate ARDS.
• Echocardiography:
  • Helps distinguish cardiac dysfunction if the clinical presentation is unclear
  • Findings more consistent with a cardiogenic cause:
    • Reduced left ventricular ejection fraction 
    • Elevated right-side filling pressure 
    • Severe aortic or mitral valve dysfunction

Additional tests

• Certain tests are conducted to evaluate the suspected etiology and/or rule out other conditions:
  • ECG and cardiac enzymes in acute coronary syndrome
  • Lipase in pancreatitis
  • Microbiological studies (e.g., cultures) in sepsis/infectious etiology
• Non-pulmonary imaging in cases of trauma (brain and spine imaging) or abdominal etiology, such as peritonitis or pancreatitis (abdominal CT)
• Bronchoscopy:
  • If etiology is unclear 
  • Specimens can be obtained for cytological and biochemical evaluation.
• Right heart catheterization:
  • Not performed routinely 
  • Helps in determining fluid status
  • Pulmonary-artery capillary wedge pressure:
    • Normal left ventricular (LV) function implies a non-cardiogenic cause.
    • High pulmonary-artery capillary wedge pressure (≥ 18 mm Hg) implies a cardiogenic cause.
• Lung biopsy:
  • Invasive and rarely needed
  • Performed if it will guide therapeutic management

Management

Treatment

Almost all patients are managed in the ICU

• Correct the underlying causes:
  • Pneumonia
  • Pancreatitis
  • Trauma
  • Sepsis
• Fluid management is difficult:
  • Patients with sepsis require a large fluid volume to maintain their BP.
  • Fluid restriction helps reduce left atrial filling pressure and improves oxygenation.
  • For balance, diuretics can facilitate fluid restriction/removal
• Supplemental oxygen:
  • Most patients require a high FiO_2.
  • Delivered via high-flow nasal cannula, face mask, or by intubation (mechanical ventilation)
• Mechanical ventilation:
  • Almost all patients will require intubation and mechanical ventilation. 
  • Low tidal volumes (4–8 mL/kg of predicted body weight)
  • Plateau pressure < 30 cm H₂O
  • Positive end-expiratory pressure (PEEP):
    • 5–20 cm H₂O (start at minimum PEEP for given FiO₂)
    • Opens the collapsed alveoli
    • Minimizes FiO₂ and maximizes PaO₂
  • Prone position has shown benefit.
• ECMO:
  • Last resort or rescue therapy
  • An option if respiratory failure is potentially reversible
  • Most common complication: bleeding
• Pharmacological therapies:
  • Glucocorticoids: 
    • Given if the patient is with non-ARDS indications
    • Early (within 14 days) in the course of persistent and moderate-to-severe ARDS
    • COVID-19 ARDS 
  • Neuromuscular blockade to promote ventilator synchrony during paralysis: no improvement in mortality (in moderate-to-severe ARDS)
  • Pulmonary vasodilators (e.g., inhaled nitrous oxide) may be harmful and worsen renal function even if oxygenation is temporarily improved.

Prognosis

Acute respiratory distress syndrome is a serious condition that is usually associated with high mortality and morbidity.

Several risk factors have been identified that can estimate the prognosis in a patient with ARDS:

• Advanced age (higher mortality rate)
• Preexisting organ dysfunction from chronic diseases: 
  • Chronic liver disease
  • CKD
  • Immunosuppression
• Direct lung injuries result in twice the number of mortalities compared to indirect causes of lung injury.

The majority of patients recover most of their lung function, but will take months.

Long-term complications:

• Many patients will develop lung fibrosis, whereas some may require long-term mechanical ventilation and oxygen supply. 
• Others: cognitive dysfunction (in 30%–55%), psychiatric illness (e.g., depression), reduced exercise endurance with muscle weakness

Differential Diagnosis

• Cardiogenic pulmonary edema: a condition caused by excess fluid in the lungs, resulting from cardiac failure. Cardiogenic etiology is suggested by an S3 or S4 gallop, elevated jugular venous pressure, and lower extremity edema with typical chest X-ray findings (pulmonary venous congestion, cardiomegaly, pleural effusion, response to diuresis). Management of cardiogenic pulmonary edema involves diuresis.
• Diffuse alveolar hemorrhage: a condition resulting from injury to the arterioles, venules, or capillaries. Diffuse alveolar hemorrhage is associated with multiple diseases (e.g., Goodpasture syndrome). Hemoptysis is usually present. Diffuse alveolar hemorrhage may present with sudden-onset respiratory distress, like ARDS. Diagnosis is by chest CT and bronchoscopy with bronchoalveolar lavage (BAL), which shows fresh RBCs and hemosiderin-laden macrophages.
• Acute interstitial pneumonitis (Hamman-Rich syndrome): a fulminant form of diffuse lung injury that mimics ARDS. The onset of acute interstitial pneumonitis is acute, and the symptoms include fever, cough, and dyspnea. Acute interstitial pneumonitis may be a subset of idiopathic ARDS but without a known risk factor. Diagnosis is by lung biopsy, which shows diffuse damage to the alveoli.
• Acute exacerbation of idiopathic pulmonary fibrosis: a condition similar to ARDS that presents with diffuse alveolar damage and acute interstitial pneumonitis, but with a worse prognosis. Acute exacerbation of idiopathic pulmonary fibrosis can occur in patients with previously undiagnosed interstitial lung disease. Diagnosis is made by comparing previous radiographic and CT images, and by lung biopsy.