Acute Respiratory Distress Syndrome: Diffuse Alveolar Damage and Lung Protection

Introduction

Acute respiratory distress syndrome (ARDS) is an acute, diffuse inflammatory injury to the lung in which increased alveolar-capillary permeability allows protein-rich fluid to flood the alveoli. The result is non-cardiogenic pulmonary oedema, severe refractory hypoxaemia and profoundly reduced lung compliance.

It is a syndrome, not a disease - a stereotyped response of the lung to a wide range of insults. This is why the two priorities in management are treating whatever caused it and supporting the lung without adding further injury, rather than treating the ARDS itself.

The Berlin definition

1. Timing - onset within 1 week of a known clinical insult, or new or worsening respiratory symptoms
2. Imaging - bilateral opacities on chest radiograph or CT, not fully explained by effusions, lobar collapse or nodules
3. Origin of the oedema - respiratory failure not fully explained by cardiac failure or fluid overload, requiring objective assessment such as echocardiography if no risk factor for ARDS is present
4. Oxygenation - a reduced PaO2/FiO2 ratio measured with a PEEP or CPAP of at least 5 cmH2O

A newer global definition (2023) extends the criteria to include patients supported by high-flow nasal oxygen at 30 L/min or more, allows SpO2/FiO2 to be used where arterial gases are unavailable, and permits ultrasound for imaging - broadening the diagnosis to non-intubated patients and resource-limited settings, both of which the Berlin definition excluded.

Causes

Causes are conventionally divided by whether the insult reaches the lung through the airway or through the bloodstream, and the distinction has some bearing on the pattern of injury and the response to recruitment.

Pathophysiology

The histological correlate of ARDS is diffuse alveolar damage, which evolves through three overlapping phases.

1. Exudative phase (days 0 to 7) - injury to alveolar epithelium and capillary endothelium, with neutrophil influx, release of proteases and reactive oxygen species, and leakage of protein-rich fluid into the alveoli. Hyaline membranes form from precipitated plasma proteins and cellular debris, and surfactant is lost, causing widespread alveolar collapse.
2. Proliferative phase (days 7 to 21) - type II pneumocytes proliferate to repair the epithelium, fibroblasts migrate into the interstitium, and the exudate begins to organise. Many patients start to improve here.
3. Fibrotic phase (beyond 3 weeks) - in some patients, collagen deposition produces established fibrosis with cyst formation, prolonged ventilator dependence and lasting functional impairment.

Clinical features

ARDS typically develops 12 to 48 hours after the precipitating insult, and almost always within a week.

• Rapidly worsening breathlessness and marked tachypnoea
• Refractory hypoxaemia - saturations that fail to improve despite high-flow oxygen, which is the clinical signature of a large shunt
• Central cyanosis
• Widespread bilateral inspiratory crackles
• Use of accessory muscles, and later exhaustion
• Signs of the underlying cause - fever and hypotension in sepsis, abdominal pain in pancreatitis, injuries in trauma
• Absence of features of fluid overload - the JVP is not raised, there is no gallop rhythm, and there is no peripheral oedema unless independently present

Investigations

• Arterial blood gas - to calculate the PaO2/FiO2 ratio, and typically showing type 1 respiratory failure with a raised A-a gradient. Hypercapnia appears later, or is accepted deliberately during protective ventilation.
• Chest radiograph - bilateral infiltrates, usually within 24 hours of onset. Serial films track progression.
• CT thorax - shows the characteristic heterogeneous, gravity-dependent distribution with dense dependent consolidation and relatively spared anterior lung, which is the anatomical basis for proning
• Echocardiogram - to exclude a cardiac cause of the oedema, as the Berlin definition requires, and to assess right ventricular function which is frequently impaired
• BNP or NT-proBNP - a low level argues against a cardiac cause, though a raised level does not exclude ARDS
• Septic screen - blood cultures, sputum or tracheal aspirate, urine, and imaging directed at a suspected source
• Bronchoscopy with bronchoalveolar lavage - where the cause is unclear, to look for infection, haemorrhage or eosinophilic pneumonia
• Amylase or lipase, and a CT abdomen, where pancreatitis or an intra-abdominal source is possible
• FBC, U&Es, LFTs, clotting and lactate - to assess organ dysfunction, since ARDS rarely occurs in isolation

Management

There is no specific treatment for ARDS itself. Outcomes are determined by treating the cause promptly and by supporting the lung in a way that does not compound the injury. Management is in critical care.

Treat the cause

• Antibiotics within one hour and source control in sepsis - drainage of collections, removal of infected lines, surgery where needed
• Antivirals where indicated, and treatment of the specific precipitant - pancreatitis, trauma, transfusion reaction
• Stop the causative drug in drug-induced injury

Lung-protective ventilation

The ARDSNet trial compared tidal volumes of 6 ml/kg with 12 ml/kg of predicted body weight and found an absolute mortality reduction of around 9% with the lower volume.² This remains the single most important therapeutic advance in ARDS.

• Tidal volume 6 ml/kg predicted body weight - calculated from height and sex, not actual weight, because lung size relates to height
• Plateau pressure below 30 cmH2O, and driving pressure (plateau minus PEEP) ideally below 15 cmH2O
• PEEP titrated to recruit collapsed alveoli and prevent cyclical collapse, with higher levels used in moderate to severe disease
• Permissive hypercapnia - accepting a raised PaCO2 and a pH down to around 7.20 in exchange for lower volumes and pressures. The CO2 matters less than the lung.
• Target oxygenation of PaO2 8 to 10.7 kPa or SpO2 88 to 95% - aiming for normal values requires damaging pressures and oxygen concentrations for no benefit

Additional strategies in moderate to severe disease

• Prone positioning - for at least 12 to 16 hours a day in severe ARDS with a PaO2/FiO2 ratio below 20 kPa (150 mmHg). The PROSEVA trial showed a large mortality reduction. Proning improves the match of ventilation to perfusion, recruits dorsal lung and reduces compression by the heart and abdomen. It is labour-intensive and carries risks of tube displacement, pressure injury and line dislodgement, so it needs a trained team.
• Conservative fluid strategy - after resuscitation, a restrictive approach shortens ventilation and ICU stay, though without a clear mortality benefit. Balance against organ perfusion.
• Neuromuscular blockade - a short early infusion may help in severe ARDS with ventilator dyssynchrony, though the evidence became less certain after the ROSE trial and it is no longer routine
• Corticosteroids - dexamethasone improves outcomes in moderate to severe ARDS in some trials and is established in COVID-19-related respiratory failure. Practice varies and it should be a consultant-level decision.
• Extracorporeal membrane oxygenation (ECMO) - for refractory hypoxaemia or uncontrollable hypercapnia despite optimal ventilation. Delivered in designated centres, with early referral far preferable to late.
• Inhaled nitric oxide or prostacyclin - improve oxygenation transiently but do not improve mortality, so they are used as a rescue bridge rather than as treatment
• Recruitment manoeuvres - used cautiously, since aggressive recruitment with high pressures caused harm in one large trial

General supportive care

• Sedation minimisation with daily sedation holds, and analgesia-first strategies
• Venous thromboembolism prophylaxis and stress ulcer prophylaxis
• Early enteral nutrition
• Glycaemic control, and management of acute kidney injury including renal replacement therapy
• Head-up positioning and oral care to reduce ventilator-associated pneumonia
• Early mobilisation and physiotherapy once stable, to limit ICU-acquired weakness
• Communication with family, and realistic discussion of prognosis and ceilings of care

Complications

• Ventilator-induced lung injury - volutrauma, barotrauma and atelectrauma
• Pneumothorax and pneumomediastinum - a sudden deterioration in a ventilated ARDS patient is a pneumothorax until proven otherwise, and may be under tension
• Ventilator-associated pneumonia
• Multi-organ failure - the usual cause of death, rather than hypoxaemia itself
• Right ventricular failure (acute cor pulmonale) - from raised pulmonary vascular resistance and high intrathoracic pressures
• Pulmonary fibrosis in survivors of the fibrotic phase, with persistently reduced transfer factor
• ICU-acquired weakness - critical illness polyneuropathy and myopathy, causing prolonged physical disability
• Delirium
• Venous thromboembolism
• Post-intensive care syndrome - persistent physical, cognitive and psychological impairment, with anxiety, depression and post-traumatic stress disorder affecting a substantial proportion of survivors and their families

Red flags

Prognosis

Overall mortality is around 35 to 45%, rising with severity from roughly 27% in mild to 45% in severe disease. Death is usually from the underlying illness and multi-organ failure rather than from hypoxaemia itself, which is why source control matters more than any ventilator setting.

Adverse prognostic factors are older age, greater severity of hypoxaemia, sepsis as the cause, higher organ failure scores, and immunosuppression.

Recovery in survivors is prolonged and incomplete more often than is generally appreciated. Lung function usually returns close to normal within 6 to 12 months, with a mildly reduced transfer factor being the commonest residual abnormality. The lasting problems are largely extrapulmonary: muscle weakness, fatigue, reduced exercise capacity, cognitive impairment, anxiety, depression and post-traumatic stress disorder persist for years in a substantial proportion, and many patients do not return to their previous employment. Structured follow-up after critical illness, physical rehabilitation and psychological support are therefore part of the treatment of ARDS, not an afterthought to it.