Acute Respiratory Distress Syndrome (ARDS)

Acute respiratory distress syndrome (ARDS) is a non-cardiogenic pulmonary oedema and diffuse lung inflammation syndrome that often complicates critical illness.

The diagnosis of ARDS is based on fulfilling three criteria:

• Acute onset (within 1 week)
• Bilateral opacities on chest x-ray
• PaO₂/FiO₂ ratio (arterial to inspired oxygen) of ≤300 on positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) ≥5 cm H₂O

Overall, 10% to 15% of patients admitted to the intensive care unit meet the criteria for acute respiratory distress syndrome (ARDS), with an increased incidence among mechanically ventilated patients.

Severity	PaO2/FiO2 Ratio	PEEP Requirement
Mild	200 mmHg < PaO2/FiO2 ≤ 300 mmHg	with PEEP or CPAP ≥ 5 cmH2O
Moderate	100 mmHg < PaO2/FiO2 ≤ 200 mmHg	with PEEP ≥ 5 cmH2O
Severe	PaO2/FiO2 ≤ 100 mmHg	with PEEP ≥ 5 cmH2O

Many different conditions can lead to ARDS, although sepsis is the most common cause, usually with a pulmonary origin (e.g. pneumonia). Other conditions associated with ARDS include:

The pathophysiology of ARDS is complex and incompletely understood.

Early in the development of ARDS, the primary pathological finding is diffuse alveolar damage. This leads to injury to the alveolar-capillary membrane, made up of type I and type II alveolar pneumocytes and capillary endothelial cells.

The alveolar air spaces are subsequently flooded with:

• Proteinaceous oedema fluid
• Inflammatory cells (neutrophils and activated alveolar macrophages)
• Inflammatory mediators, including proinflammatory cytokines, lipid mediators, and oxidants

Epithelial injury may be severe, with necrosis and sloughing of the type I cells exposing the basement membrane. Fibrin deposition occurs along the denuded basement membrane, resulting in the hyaline membranes that are characteristic of diffuse alveolar damage. Injury to type II cells and alveolar flooding contribute to surfactant dysfunction.

The early phase of ARDS manifests clinically as acute hypoxaemic respiratory failure with an increased alveolar-arterial oxygen gradient and poorly compliant lungs. Concomitant multiple organ failure may occur, particularly if the underlying cause of ARDS is sepsis. Right ventricular dysfunction is also common and is associated with worse outcomes.

After the acute onset of alveolar flooding and inflammation, some patients have rapid resolution and return to normal lung histology and function. In other patients, this early exudative inflammatory phase progresses to a fibroproliferative phase. This phase is characterised by continued respiratory failure, high minute ventilation, and poorly compliant lungs.

History

• Symptoms that suggest ARDS include the acute onset of shortness of breath and hypoxaemia leading to acute respiratory failure, and cough with expectoration of frothy pulmonary oedema.
• The history should be directed at determining whether there is an underlying condition associated with ARDS (e.g., sepsis) or features that might suggest an alternative diagnosis (e.g., pulmonary oedema secondary to heart failure).

Examination

• Physical examination findings that support the diagnosis of ARDS are acute hypoxic respiratory failure requiring high levels of oxygen and/or positive end-expiratory pressure (PEEP) to maintain an oxygen saturation >90%. Both peak inspiratory pressure and end-inspiratory plateau pressure are also increased.
• Lung examination may reveal basilar or diffuse rales.
• Particular attention should be put on identifying the source of infection if sepsis is suspected to be the underlying cause of ARDS.

• Arterial blood gas:
  • Arterial blood gas analysis should be performed for calculation of the partial pressure of oxygen, arterial (PaO₂)/inspired oxygen ratio (FiO2).
• Chest x-ray:
  • A chest x-ray should be performed to look for bilateral infiltrates that are consistent with pulmonary oedema and not fully explained by atelectasis or pulmonary effusions.
• Further tests to exclude heart failure:
  • Brain natriuretic peptide (BNP) levels should be considered if heart failure is a potential cause in patients with bilateral infiltrates on radiography. BNP levels <100 nanograms/L make heart failure unlikely, whereas BNP levels >500 nanograms/L make it likely.
  • An echocardiogram should be ordered if heart failure is still a possible diagnosis after BNP levels are available, particularly if there are no risk factors for ARDS present.
  • If the BNP and echocardiogram are inconclusive, insertion of a pulmonary artery catheter (to estimate left ventricular end-diastolic pressure) may be helpful to differentiate heart failure from ARDS.
• Further tests to look for underlying cause:
  • Blood, sputum, and urine cultures should be performed to investigate for the presence of sepsis. Viral testing should be considered in the appropriate clinical setting (e.g., influenza, SARS-CoV-2).
  • Bronchoalveolar lavage (BAL) or endotracheal aspiration for Gram stain and cultures are also recommended in patients with ARDS due to suspected pneumonia and those without a defined predisposing condition. However, bronchoscopy should be avoided in patients with suspected SARS-CoV-2 (COVID-19)-related ARDS due to high risk of provider exposure during aerosolising procedures. BAL can also be helpful for identifying other causes of acute respiratory failure with bilateral radiographic infiltrates that mimic ARDS, such as diffuse alveolar haemorrhage or acute eosinophilic pneumonia.
  • The best diagnostic test is an open lung biopsy. This is not routinely performed in critically ill patients because of the high risk of morbidity and mortality but it can be helpful in the setting of continued diagnostic uncertainty.
  • Serum lipase and amylase tests should be requested in patients with suspected acute pancreatitis.
  • Computed tomography (CT) scanning of the thorax is not routinely required to diagnose or manage ARDS. It is more sensitive than a plain chest x-ray and may be helpful in some cases for diagnosing pneumonia or underlying lung disease.

The goals of treatment in patients with ARDS are supportive care and a protective strategy of lung ventilation using low tidal volumes to limit end inspiratory plateau pressure.

Oxygenation and ventilation

• Although the original low tidal volume trial by the ARDS Network targeted an oxygen saturation between 88% and 95%, two subsequent clinical trials suggest that higher oxygenation targets may be associated with better clinical outcomes. Based on these findings, it seems prudent to target an oxygen saturation of ≥92%.
• Occasionally patients can be managed with non-invasive ventilation, but the failure rate is high and the majority will require endotracheal intubation and mechanical ventilation. Ventilator-associated lung injury may be limited by the use of a low tidal volume, plateau-pressure-limited protective ventilatory strategy. This therapy has been shown to reduce mortality.
• A tidal volume of 4-8 mL/kg predicted body weight should be used to maintain an inspiratory plateau pressure <30 cm H₂O. Predicted body weight for men is calculated as 50 + 0.91 × (height [cm] - 152.4), and for women is 45.5 + 0.91 × (height [cm] - 152.4). If the plateau pressure is >30 cm H₂O, then tidal volume should be lowered to 5 mL/kg or as low as 4 mL/kg, if needed.
• Positive end-expiratory pressure (PEEP) and FiO₂ should be titrated using established PEEP titration tables. The available data suggest that higher levels of PEEP are safe and may improve oxygenation in some patients. Mortality is reduced in patients who respond with improved oxygenation.
• Respiratory acidosis, a common complication of low tidal volume ventilation, is treated by increasing the respiratory rate. Although it is not known what level of respiratory acidosis is harmful in patients with ARDS, permissive hypercapnia is often tolerated due to low tidal volume ventilation. However, severe hypercapnia is independently associated with higher intensive care unit (ICU) mortality. Normocapnia often cannot be achieved (and should not be a goal). Clinical guidelines recommend that an arterial pH of 7.30 to 7.45 is maintained, but studies suggest patients who undergo permissive hypercapnia can tolerate a blood pH as low as 7.15. Bicarbonate infusions may be administered when the pH falls below 7.15.

Prone positioning

• Prone positioning can improve oxygenation in patients with ARDS and has been shown to reduce mortality in patients with severe ARDS (PaO₂/FiO₂ <150).

Conservative intravenous fluid management

• The patient's fluid balance should be maintained as slightly negative or neutral (providing the patient is not in shock). A central line is recommended to measure the central venous pressure (CVP), with regular assessments of fluid status. The goal is to keep the CVP < 4 cm H₂O.

Antimicrobials

• In patients who have an infectious cause for ARDS (e.g., pneumonia or sepsis), the prompt initiation of antimicrobials is important. Empirical antibiotics targeted at the suspected underlying infection should be used as soon as possible after obtaining appropriate cultures including blood, sputum, and urine cultures. Antivirals or antifungals may be appropriate in patients with suspected or confirmed viral or fungal infections. Once culture results are available, the antimicrobial regimen can be tailored for the identified organism. There is no evidence to support the use of antibiotics in patients who have ARDS without infection.

Supportive care

• Standard supportive care of critically ill patients includes prevention of deep vein thrombosis, blood glucose control, prophylaxis against stress-induced gastrointestinal bleeding, haemodynamic support to maintain a mean arterial pressure >60 mmHg, and transfusion of packed red blood cells in patients with haemoglobin <70 g/L. Nutrition should be provided enterally where possible.

Refractory hypoxaemia

• In patients with refractory hypoxaemia despite an FiO₂ of 1.0 and high levels of PEEP, rescue therapies for oxygenation should be considered:
  • Neuromuscular paralysis
  • Inhaled nitric oxide and inhaled prostacyclin
  • Extracorporeal membrane oxygenation
  • High-frequency oscillatory ventilation