Acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a severe inflammatory reaction of the lungs to pulmonary damage. While sepsis is the most common cause, a variety of systemic and pulmonary factors (e.g., pneumonia, aspiration) can lead to ARDS. Affected individuals initially present with acute-onset cyanosis, dyspnea, and tachypnea. The chief finding in ARDS is hypoxemic respiratory failure with decreased arterial oxygen pressure, which can progress to hypercapnic respiratory failure. Chest x-ray typically shows diffuse bilateral infiltrates. A defining laboratory feature of ARDS is a PaO₂/FiO₂ ratio ≤ 300 mm Hg. Management of ARDS is focused on maintaining adequate oxygenation, which often requires intubation and lung-protective mechanical ventilation. Moreover, any treatable causes of ARDS should be addressed. Even if adequate treatment is initiated, ARDS remains an acutely life-threatening disease with a high mortality rate. Most patients improve significantly in the weeks following the initial presentation, but some cases progress to pulmonary fibrosis, which prolongs hospital stays and delays the resolution of symptoms.

ARDS is a clinical syndrome of acute respiratory failure characterized by hypoxemia and bilateral pulmonary infiltrates that cannot be fully accounted for by heart failure or fluid overload. See the “Berlin criteria for ARDS” below. ^[1][2]

Systemic causes

• Sepsis (most common cause), e.g., secondary to trauma, infection or peritonitis ^[3]
• Trauma
• Shock
• Massive transfusion (See “TRALI” for details)
• Acute pancreatitis
• Hematopoietic stem cell transplantation
• Medication (e.g., salicylic acid, tricyclic antidepressants, bleomycin) ^[4]
• Recreational drug overdose (e.g., cocaine)

Primary damage to the lungs

• Pneumonia
• Aspiration
• Inhaled toxins
• Pulmonary contusion ^[5]
• Inhalation injury (e.g., inhalation of hyperbaric oxygen)
• Drowning incidents ^[6]
• Fat embolism (e.g., through blunt trauma)
• Amniotic fluid embolism (e.g., during labor)
• Lung transplantation

Sepsis is the most common cause of ARDS. ^[3]

• Tissue damage (pulmonary or extrapulmonary) → release of inflammatory mediators (e.g., interleukin-1) → inflammatory reaction → migration of neutrophils into alveoli → excessive release of neutrophilic mediators (e.g., cytokines, proteases, reactive oxygen species) → injury to alveolar capillaries and endothelial cells (diffuse alveolar damage, DAD) ; leading to:
  • Exudative phase: excess fluid in interstitium and on alveolar surface → pulmonary edema with normal pulmonary capillary wedge pressure (noncardiogenic pulmonary edema) → decreased lung compliance and respiratory distress
  • Hyaline membrane formation: exudation of neutrophils and protein-rich fluid into the alveolar space → formation of alveolar hyaline membranes → impaired gas exchange → hypoxemia
    • Hypoxemia → compensation through hyperventilation → respiratory alkalosis
    • Hypoxemia → chronic hypoxic pulmonary vasoconstriction → pulmonary hypertension and right-to-left pulmonary shunt (increased shunt fraction)
    • Damage to type I and type II pneumocytes → decrease in surfactant → alveolar collapse → intrapulmonary shunting
  • Organizing phase (late stage): proliferation of type II pneumocytes and infiltration of fibroblasts → progressive interstitial fibrosis

References:^[7]

• Acute dyspnea
• Tachypnea and tachycardia
• Cyanosis
• Diffuse crackles
• Fever, cough, and chest pain may also be present.

References:^[8]

Approach ^[2]

ARDS is a diagnosis of exclusion (see the Berlin criteria for ARDS). Consider ARDS in patients with rapid-onset respiratory failure and a potential trigger.

• Order chest x-ray to evaluate for characteristic findings (bilateral infiltrates).
• Perform an ABG and calculate the P/F ratio (the ratio of arterial oxygen partial pressure, as measured by arterial blood gas, to fractional inspired oxygen administered to the patient)
• Consider additional testing in order to:
  • Identify triggers
  • Rule out differential diagnoses
  • Assess potential complications

Berlin criteria for ARDS

The Berlin criteria are the criteria most commonly used to define ARDS. All four of the following conditions must be met: ^[1][2]

• Acute onset: respiratory failure within one week of a known predisposing factor (e.g., sepsis, pneumonia) or worsening respiratory symptoms
• Bilateral opacities (on chest x-ray or CT)
  • Similar appearance to pulmonary edema
  • Not sufficiently explained by pleural effusions, lobar or lung collapse, or nodules
• Hypoxemia: PaO₂/FiO₂ ≤ 300 mm Hg (measured with a minimum of 5 cm H₂O PEEP) ^[9]
  • Mild ARDS: PaO₂/FiO₂ = 201–300 mm Hg
  • Moderate ARDS: PaO₂/FiO₂ = 101–200 mm Hg
  • Severe ARDS: PaO₂/FiO₂ ≤ 100 mm Hg
• Respiratory failure cannot be fully accounted for by heart failure or fluid overload.

ARDS diagnostic criteria include: Abnormal x-ray, Respiratory failure < 1 week after a known or suspected trigger, Decreased PaO₂/FiO₂, Should exclude CHF or fluid overload as a potential cause of respiratory distress.

Imaging

Chest x-ray is usually sufficient for diagnosis. However, distinguishing between ARDS and CHF can be challenging. In these cases, correlation with other tests (e.g., CT chest, lung ultrasound, echocardiogram) may be useful.

Chest x-ray ^[10][11]

• Indications: all patients suspected of having ARDS
• Acute findings (1–7 days)
  • Often normal in the first 24 hours
  • Diffuse bilateral symmetrical infiltrates
  • In severe cases: bilateral attenuations that make the lung appear white on x-ray (“white lung”)
  • Air bronchograms may be visible.
• Intermediate (8–14 days) to late (> 15 days) findings
  • Typical course: Acute features remain stable, then resolve.
  • Fibrotic course: Reticular opacities begin to appear and may become permanent.
• Findings supportive of ARDS rather than CHF
  • Predominantly peripheral opacities
  • Small or absent pleural effusions
  • No cardiomegaly or septal lines

CT chest without contrast ^[10][11][12]

• Indications: may be used if chest x-ray findings are insufficient or to further investigate for underlying causes or complications
• Acute findings (1–7 days)
  • Symmetrical ground-glass opacities are the most important finding.
  • Gravity-dependent density gradient
    • The lungs may appear normal in nondependent regions.
    • Dense consolidation in dependent regions
  • Bronchial dilatation may be visible.
  • Additional findings may include small pleural effusions, air bronchograms (see “Chest x-ray” above).
• Intermediate (8–14 days) to late (> 15 days) findings: a phase of stability is followed either by resolution or progressive development of fibrosis
  • Mixed findings may be seen.
  • Potential long-term persistence of ground-glass opacities
  • Cysts and bullae may develop.

Lung ultrasound ^[12]

• Indications: may be helpful in differentiating between cardiogenic pulmonary edema and ARDS
• Key findings
  • Bilateral B pattern
  • C pattern (consolidation)
  • Abnormal pleural line (thickening, irregular pattern, and/or alterations in lung sliding)

Laboratory studies ^[12]

• Arterial blood gas
  • Hypoxemic respiratory failure (↓ PaO₂) and, initially, respiratory alkalosis (↑ pH)
    • PaO₂/FiO₂ ≤ 300 mm Hg (see “Definition” above)
    • Increased A-a gradient
  • With disease progression, hypercapnic respiratory failure (↑ PaCO₂; ↓ pH) may develop due to respiratory exhaustion.
• Additional laboratory studies to consider
  • Underlying causes/triggers
    • CBC: leukocytosis in sepsis or pneumonia
    • Lipase: elevated in pancreatitis
    • Blood cultures: to identify bacteremia
    • Sputum gram stain and culture: to identify bacterial pneumonia
    • Advanced tests: urine antigen testing, serologic tests (see “Diagnostics” in pneumonia)
  • Differential diagnoses
    • BNP: to evaluate for heart failure ^[11]
    • D-dimer: to evaluate for pulmonary embolism
    • Troponin: to evaluate for cardiac ischemia
  • Complications: See diagnostics in acute kidney injury, sepsis, and DIC.

Additional diagnostic studies ^[12]

• ECG: Signs of STEMI, LVH, or cardiac arrhythmias may indicate CHF.
• Echocardiography: to exclude or assess the degree of heart failure ^[11]
• Bronchoscopy with bronchoalveolar lavage (BAL) ^[12]
  • Useful for infections that are hard to diagnose, inflammatory disease (e.g., vasculitis), and cancer
  • BAL samples can be tested with Giemsa/Gram staining as well as specialized cultures for intracellular bacteria, viruses, and fungi.
• Right heart catheterization
  • To exclude CHF in the absence of any risk factors
  • PCWP > 18 mm Hg is considered to confirm the presence of cardiac insufficiency. ^[11]
• Lung biopsy: consider in rare cases ^[12]
  • To evaluate the stage of lung fibrosis after a prolonged ARDS course and decide whether treatment with steroids may be indicated ^[12]
  • Indicated if other studies (e.g., BAL, blood cultures) are inconclusive

• Cardiogenic pulmonary edema
• Acute exacerbations of interstitial lung diseases
• Transfusion-related acute lung injury (TRALI)
• Transfusion-associated circulatory overload (TACO)
• See also differential diagnoses of dyspnea.

The differential diagnoses listed here are not exhaustive.

Approach

• Consult ICU early, i.e., as soon as respiratory failure due to ARDS is suspected.
• Address hypoxemia (see “Oxygen therapy” and “Airway management” for details).
• Apply lung-protective ventilation strategies.
• Augment therapy as needed based on severity (see the Berlin criteria for ARDS).
  • Moderate-severe ARDS: Apply prone positioning, lung recruitment maneuvers; consider neuromuscular blockade.
  • Severe ARDS refractory to therapy: Consider indications for ECMO based on the Murray score.
• Identify and treat the underlying cause (e.g., pneumonia, pancreatitis, sepsis).

ARDS is a life-threatening condition that usually requires early lung-protective ventilation (i.e., with low tidal volumes and low plateau pressures) to prevent further lung damage.

All patients with ARDS ^{[2][9][13][14][15][16]}

The foundation of management in all patients with ARDS consists of treating hypoxemia, lung-protective ventilation (to minimize further lung damage), treatment of the underlying cause, and supportive care.

• Oxygenation: Hypoxemia is a hallmark feature of ARDS and should be addressed immediately.
  • Noninvasive methods: See oxygen therapy
    • Indications ^[17]
      • Consider for hemodynamically stable, alert patients with easy to oxygenate, mild ARDS.
      • Pre-oxygenation prior to intubation
    • Methods: Maximum supplemental oxygen by nonrebreather mask or NIPPV ^[18][19]
  • Invasive methods
    • Indications: respiratory failure or rapid deterioration
    • Methods: Endotracheal intubation (see airway management)
      • Rapid sequence intubation
      • Consider pre-oxygenation with NIPPV or HFNC. ^[17]
• Lung-protective ventilation: All patients with ARDS should be treated with lung-protective ventilation to decrease the risk of VILI. ; ^[9]
  • General initial settings include:
    • Low tidal volume (V_t 6–8 mL/kg) : prevents alveolar distention
    • Low plateau pressure (P_Plat ≤ 30 cm H₂O): prevents barotrauma
    • PEEP > 5 cm H₂O: allows for alveolar recruitment
  • Allow for permissive hypercapnia
  • PEEP and FiO₂ can be adjusted to recruit collapsed alveoli and improve oxygenation.
    • Oxygenation goal: PaO₂ 55–80 mm Hg or SpO₂ 88–95%
    • Avoid oxygen toxicity: use lowest FiO₂ possible
  • See lung-protective ventilation strategy for more information and specific parameter settings.
  • See also “Intensive care” in “COVID-19.”
• Supportive care
  • Conservative fluid management
  • Consider furosemide for volume overload.
  • VTE prophylaxis
  • Optimize nutrition.
  • Consider stress ulcer prophylaxis
• Identify and treat the underlying cause: See “Etiology”.
• Disposition: Admit all patients with ARDS to the ICU.

A low tidal volume and low plateau pressure are the principles of lung-protective ventilation.

Moderate to severe ARDS ^[13][14][20]

Prone positioning ^[21][22][23]

Prone positioning should be initiated promptly after stabilization. ^[20]

• Effects
  • Reduces V/Q mismatch from dependent atelectasis
  • Increases lung compliance
• Indications ^[14]
  • P/F ratio < 150 mm Hg
  • Pulmonary edema
• Absolute contraindication: unstable spinal fracture
• Relative contraindications include: ^[20]
  • Hemodynamic instability
  • Severe trauma, recent sternotomy, other unstable fractures
  • ↑ ICP
  • Massive hemoptysis
• Duration: typically done for at least 12–16 hours/day
• Complications include:
  • ET tube displacement or obstruction
  • Abnormal vital signs: ↓ SpO₂, ↓ HR, ↓ BP
  • Hemoptysis
  • Pressure injuries
  • Other: facial edema, ocular injury , venous stasis

An unstable spinal fracture is the only absolute contraindication to prone positioning. ^[23]

Lung recruitment maneuvers ^[14][24]

• Definition: a series of treatment measures that increase the surface area of lung available for gas exchange
• Methods
  • Sustained inflation techniques (e.g., increasing airway pressure to 30–40 cm H₂O for 30–40 seconds followed by a decrease in PEEP)
  • Incremental PEEP increase: See ARDSnet protocol.

Other considerations

• Neuromuscular blockade ^{[9][14][28][29]}
  • Consider within the first 48 hours for patients with P/F ratio < 150 mm Hg and/or severe patient-ventilator dyssynchrony. ^[14]
  • See “muscle relaxants” for agents and doses.
• Corticosteroids: Consider in early ARDS. ^[2]
  • Methylprednisolone
  • Budesonide ^[30][31]

Severe ARDS with persistent hypoxemia (rescue therapy) ^[2][9][20]

The following interventions should only be considered with expert consultation and when guideline-recommended treatments have failed.

• Consider alternative ventilator settings (e.g., mode, parameters, or overall strategy): See mechanical ventilation.
• Consider experimental therapies (e.g., inhaled vasodilators such as nitric oxide or prostacyclin). ^[28][32][33]
• ECMO: method of supporting the O2/CO2 exchange through the use of artificial lung membranes ^[34]
  • Consider ECMO in the following patients: ^[14]
    • PaO₂/FiO₂ < 80 mmHg despite optimal management (e.g., high PEEP, neuromuscular-blocking agents, prone positioning)
    • AND/OR if the plateau pressure becomes dangerously high (e.g., P_Plat > 30 cm H₂O)
  • The Murray score for ARDS can also be used to identify patients who may benefit from ECMO. ^[34]
    • Murray score 2–3 and/or P/F ratio < 150 mm Hg (with FiO₂ > 90%): Consider transfer to ECMO center.
    • Murray score 3–4 and/or P/F ratio < 100 mm Hg (with FiO₂ > 90%) despite optimal care: ECMO is indicated

All patients with ARDS ^[9]

• Perform ABCDE survey.
• Call for help early: Consult ICU and/or rapid response team.
• Optimize oxygenation.
• Quantify hypoxemia: Use the P/F ratio to evaluate ARDS severity. ^[1]
• If there are signs of airway compromise: See airway management.
  • Basic airway maneuvers
  • If insufficient: Perform RSI.
• Start lung-protective ventilation strategy. ^[9][36][37]
• Ensure euvolemia.
• Hemodynamic monitoring
• Monitor mechanical ventilation: capnography, pressure monitoring, and ABG checks.
• Reassess ventilation settings and strategy as needed. ^[14]
• Supportive care: See adjunctive care of ventilated patients for pain management and sedation.
• Identify and treat the underlying cause.
• ICU admission

Moderate or severe ARDS

• Consider prone positioning for > 12–16 hours/day. ^[9]
• Use incremental FiO₂-PEEP combinations based on ARDSnet protocol.
• Consider lung recruitment maneuvers.
• Consider neuromuscular blockade: Start in the first 48 hours. ^[29]

Severe ARDS with persistent hypoxemia

• Consider ECMO based on the Murray score for ARDS.
• Expert consultation is required for further ventilator adjustment or experimental therapies.

• Disease course
  • Most patients begin to improve after the first 1–3 weeks and symptoms usually resolve fully.
  • Some develop interstitial pulmonary fibrosis with prolonged ventilator dependence and restrictive lung disease.
• In patients with simultaneous multiorgan failure, the mortality rate is 30–50%. ^[38]

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