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 dyspnea, tachypnea, and cyanosis. 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 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. Glucocorticoids should be considered and 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 “Global definition of ARDS.” ^[1]

Systemic causes

• Sepsis (most common cause), e.g., secondary to trauma, infection, or peritonitis ^[2]
• Trauma
• Shock
• Massive transfusion (See “TRALI” for details)
• Acute pancreatitis
• Hematopoietic stem cell transplantation
• Medication (e.g., salicylic acid, tricyclic antidepressants, bleomycin) ^[3]
• Recreational drug overdose (e.g., cocaine)
• Major burns ^[4]

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. ^[2]

• 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: ^[7]
  • 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

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

Approach ^[4][8]

ARDS is a diagnosis of exclusion.

• Consider ARDS in patients with acute-onset respiratory failure and a potential trigger.
• Order chest x-ray to evaluate for bilateral infiltrates.
• Perform ABG analysis and calculate the PaO2/FiO2 ratio to confirm the diagnosis and assess severity.
• Consider additional testing (e.g., CT chest, echocardiography, and BNP) to:
  • Identify triggers
  • Rule out differential diagnoses
  • Assess for complications

Global definition of ARDS ^[1]

The Global definition of ARDS requires the presence of all of the following:

• Acute-onset respiratory failure
  • Within one week of a confirmed trigger (e.g., sepsis, pneumonia) and/or of worsening respiratory symptoms
  • Cannot be fully accounted for by heart failure or fluid overload
• Bilateral opacities on chest x-ray, CT, or ultrasound
  • Similar appearance to pulmonary edema
  • Findings cannot be fully attributed to pleural effusions, lobar or lung collapse, and/or nodules
• Hypoxemia
  • Measurements
    • PaO₂/FiO₂ ≤ 300 mm Hg (preferred)
    • SpO₂/FiO₂ ≤ 315 if SpO₂ is ≤ 97% (alternative if ABG is not available)
  • Severity categories (intubated ARDS only)
    • Mild ARDS: PaO₂/FiO₂ 201–300 mm Hg and/or SpO₂/FiO₂ 235–315
    • Moderate ARDS: PaO₂/FiO₂ 101–200 mm Hg and/or SpO₂/FiO₂ 148–235
    • Severe ARDS: PaO₂/FiO₂ ≤ 100 mm Hg and/or SpO₂/FiO₂ ≤ 148
• Respiratory support required
  • Intubated ARDS
  • Nonintubated ARDS
    • NIPPV or CPAP with ≥ 5 cm H₂O PEEP ^[1]
    • High-flow nasal cannula oxygen therapy (HFNC) with a flow of ≥ 30 L/minute

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

In resource-limited settings, ARDS may be diagnosed in patients who are not currently receiving respiratory support but meet the other three criteria. ^[1]

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 ^[9][10]

• 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 ^[9][10][11]

• 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 ^[1][11]

• 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 ^[11]

• Arterial blood gas
  • Hypoxemic respiratory failure (↓ PaO₂) and, initially, respiratory alkalosis (↑ pH)
    • PaO₂/FiO₂ ≤ 300 mm Hg
    • 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 ^[10]
    • D-dimer: to evaluate for pulmonary embolism (in patients with low to moderate pretest probability of PE)
    • Troponin: to evaluate for cardiac ischemia
  • Complications; see also:
    • Diagnosis of AKI
    • Diagnosis of sepsis
    • Diagnosis of DIC

Additional diagnostic studies ^[11]

• ECG: Signs of STEMI, LVH, or cardiac arrhythmias may indicate CHF.
• Echocardiography: to exclude or assess the degree of heart failure ^[10]
• Bronchoscopy with bronchoalveolar lavage (BAL) ^[11]
  • 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. ^[10]
• Lung biopsy: consider in rare cases ^[11]
  • To evaluate the stage of lung fibrosis after a prolonged ARDS course and decide whether treatment with steroids may be indicated ^[11]
  • 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 ^[8]

• Admit all patients with ARDS to the ICU.
• Address hypoxemia.
  • See “Oxygen therapy” and “Airway management” for details.
  • Apply lung-protective ventilation in intubated ARDS.
• Identify and treat the underlying cause (e.g., pneumonia, pancreatitis, sepsis).
• Initiate glucocorticoids in patients with intubated ARDS and/or if the cause responds to glucocorticoids.
• Provide supportive care.
• Adjust therapy based on severity.
  • Moderate or severe ARDS: Use prone positioning and consider a high PEEP strategy.
  • Early severe ARDS: Consider neuromuscular blockers.
  • Severe ARDS not responding to therapeutic adjustments: Consider ECMO.

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 ^{[4][8][12][13]}

Oxygenation

Hypoxemia is a hallmark feature of ARDS and should be addressed immediately.

• Noninvasive: See “Oxygen therapy.”
  • Indications ^[14]
    • May be considered for hemodynamically stable, alert patients with easy to oxygenate, mild ARDS.
    • Preoxygenation prior to intubation
  • Methods: maximum supplemental oxygen by HFNC, NIPPV, or nonrebreather mask
• Invasive
  • Indications: respiratory failure or rapid deterioration
  • Methods: Endotracheal intubation (see “Airway management.”)
    • Rapid sequence intubation
    • Consider pre-oxygenation (see nonivasive methods).

Lung-protective ventilation ^[8][12]

All patients with intubated ARDS should be treated with lung-protective ventilation to decrease the risk of VILI. ^[12]

• General initial settings include:
  • Low tidal volume (V_t 4–8 mL/kg) using predicted body weight: prevents alveolar distention ^[8]
  • 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” in “Mechanical ventilation” for more information and specific parameter settings.

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

Glucocorticoids ^[8][15]

Glucocorticoids likely reduce mortality and the duration of mechanical ventilation in patients with ARDS.

• Optimal regimen is not established; consider:
  • Dexamethasone (off-label) until extubation ^[15][16]
  • OR methylprednisolone (off-label) ^[15]
• Indications
  • Intubated ARDS
  • A cause that responds to glucocorticoids; see also: ^[8]
    • Treatment of pneumonia
    • Management of hospitalized patients with COVID-19
    • Treatment of pneumocystis pneumonia
• Precaution: may be harmful if initiated after > 2 weeks of mechanical ventilation

Supportive care

• Conservative fluid management
• Consider furosemide for volume overload.
• VTE prophylaxis
• Optimize nutrition.
• Consider stress ulcer prophylaxis.

Moderate to severe ARDS ^{[8][14][17][18]}

Prone positioning ^[19][20][21]

Prone positioning should be initiated promptly after stabilization.

• Effects
  • Reduces V/Q mismatch from dependent atelectasis
  • Increases lung compliance
• Indications ^[18]
  • P/F ratio < 150 mm Hg
  • Pulmonary edema
• Absolute contraindication: unstable spinal fracture
• Relative contraindications include: ^[14]
  • 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. ^[21]

High PEEP ^[8]

• Methods
  • Oxygenation-based PEEP titration
  • Plateau pressure-based PEEP titration
  • Titration to maximal compliance
• Effects
  • Lung recruitment maneuver: increases the surface area of lung available for gas exchange ^[8]
  • Improves oxygenation and is thought to reduce mortality

FiO₂/PEEP titration

Neuromuscular blockers ^[8]

• Consider within the first 48 hours for patients with a PaO₂/FiO₂ ratio < 150 mm Hg (i.e., early severe ARDS). ^[8][18]
• Optimal agent not established; cisatracurium may be considered.
• See “Muscle relaxants” for agents and dosages.

Severe ARDS with persistent hypoxemia ^[8][14]

The following interventions should only be considered in consultation with a specialist and if standard therapy is unsuccessful.

• Consider alternative ventilator settings (e.g., mode, parameters, or overall strategy): See “Mechanical ventilation.”
• Consider ECMO in patients with early ARDS (< 7 days) and: ^[18][25]
  • Very severe hypoxemia (PaO₂/FiO₂ < 80 mm Hg) or hypercapnia (pH < 7.25 and PaCO₂ ≥ 60 mm Hg) despite optimal management (e.g., high PEEP, neuromuscular blockers, prone positioning)
  • AND/OR if the plateau pressure becomes dangerously high (e.g., > 30 cm H₂O)
• Use a monitoring tool (e.g., Murray score) to identify patients at risk for requiring ECMO, enabling transfer to an ECMO unit before deterioration. ^[25]

All patients with ARDS ^[12]

• 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. ^[27]
• If there are signs of airway compromise: See airway management.
  • Basic airway maneuvers
  • If insufficient: Perform RSI.
• Start lung-protective ventilation strategy. ^[12][28][29]
• Ensure euvolemia.
• Initiate glucocorticoids in patients with intubated ARDS and/or if the cause responds to glucocorticoids. ^[8]
• Hemodynamic monitoring
• Monitor mechanical ventilation: capnography, pressure monitoring, and ABG checks.
• Reassess ventilation settings and strategy as needed. ^[18]
• 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

• Use prone positioning for > 12 hours/day. ^[12]
• Consider using a high PEEP strategy (e.g., see “High PEEP/FiO₂ strategy”). ^[8]
• Consider neuromuscular blockers: Initiate within 48 hours of presentation. ^[8][30]

Severe ARDS with persistent hypoxemia

• Consider ECMO in very severe hypoxemia or hypercapnia. ^[8]
• 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%. ^[31]

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