Aetiology

Respiratory causes include:

  • Acute exacerbation of asthma

  • Pulmonary embolism: thrombosis of pulmonary arteries that can occur as a result of hypercoagulable states, such as those induced by pregnancy, oral contraceptive pill use, inherited protein deficiencies (e.g., protein C, protein S, antithrombin III, factor V Leiden deficiencies), and autoimmune conditions (e.g., antiphospholipid syndrome, systemic lupus erythematosus)

  • Pulmonary oedema

  • Acute respiratory distress syndrome, including from COVID-19 infection. Most deaths related to COVID-19 result from pulmonary viral infection with rapid development of acute respiratory failure. The pneumonia associated with COVID-19 is associated with severely hypoxic acute respiratory failure that often requires mechanical ventilatory support.[15]

  • Pneumonia (bacterial, viral, or combined)

  • Acute epiglottitis

  • Cardiogenic pulmonary oedema

  • Pulmonary trauma

  • Inhalation injury (with toxic fumes or gases including chlorine, smoke, carbon monoxide, hydrogen sulfide)

  • Upper/lower airway obstruction (e.g., foreign bodies, retropharyngeal abscess, epiglottitis, and swelling caused by acute allergy or anaphylaxis)

  • Pneumothorax

  • Chronic lung disease (e.g., COPD, cystic fibrosis, pulmonary fibrosis, chronic interstitial lung disease)

  • Bronchiectasis

  • Alveolar abnormalities (e.g., emphysema, Goodpasture's syndrome, granulomatosis with polyangiitis [formerly known as Wegener's granulomatosis])

  • Chest wall abnormalities (e.g., kyphoscoliosis)

  • Malignancy

  • Decompensated congestive cardiac failure

  • Collagen vascular disease

  • Aspiration of stomach contents or liquids.

Non-respiratory causes include:

  • Hypovolaemia (from haemorrhage or dehydration)

  • Shock (septic and cardiogenic)

  • Severe anaemia (e.g., due to gastrointestinal haemorrhage, haemorrhage secondary to vascular or solid organ trauma)

  • Drug overdose (opioid and sedative medicines)

  • Neuromuscular disorders (e.g., Guillain-Barre, myasthenia gravis, muscular dystrophy, motor neuron disease, poliomyelitis)

  • Central nervous system disorders (e.g., infection, stroke, infiltrating cancers, mass cancers, brainstem lesions)

  • Spinal disorders (e.g., upper spinal canal mass with cord compression, cervical spinal stenosis, cervical spinal cord injury)

  • Bony spinal deformity (e.g., kyphoscoliosis, ankylosing spondylitis)

  • Right-to-left cardiac shunting (e.g., cyanotic congenital heart disease)

  • Toxins (e.g., botulism)

  • Poisons (e.g., chlorine gas, carbon monoxide)

  • Near drowning.

Traumatic causes include:

  • Blood loss (hypovolaemia with decreased pulmonary perfusion)

  • Direct thoracic injury (rib fractures, flail chest, penetrating lung injuries, penetrating pulmonary vasculature injuries, diaphragmatic injury with loss of diaphragm muscle function, pulmonary contusion with oedema and bleeding into lung tissue)

  • Spinal injury

  • Head injury with haemorrhagic mass effect and direct brain injury

  • Pulmonary contusion with intraparenchymal haemorrhage

  • Traumatic pulmonary emboli of marrow fat and cell elements secondary to major fractures.

Pathophysiology

The respiratory system is responsible for oxygen and carbon dioxide exchange between the blood and the atmosphere. Respiratory failure occurs when this exchange fails and metabolic demands for oxygen and body system acid-base stabilisation are not maintained, creating a ventilation-perfusion mismatch.

Failure of oxygen exchange results in the development of severe hypoxaemia (both type I and type II respiratory failure) with cellular anoxia and tissue asphyxia. This can occur with all forms of lung disease, including:

  • Fluid filling of alveolar spaces

  • Collapse of alveolar spaces;

  • Re-distribution of blood flow from functioning alveolar units (shunting)

  • Loss of blood flow to alveolar tissue (e.g., pulmonary embolism);

  • Underlying loss of pulmonary tissue (e.g., emphysema, trauma, fibrosis); and

  • Thickening or fluid build-up at alveolar membranes that inhibits gas exchange (e.g., pneumonia).

Chronic hypoxia in patients with chronic respiratory failure stimulates increases in the number of circulating red blood cells (erythrocytosis).

Failure of carbon dioxide exchange results in hypercapnic respiratory failure (type II respiratory failure), causing increased carbon dioxide in arterial blood. Carbon dioxide accumulation leads to carbonic acid accumulation within the tissues, resulting in respiratory acidosis. Renal bicarbonate ion retention occurs to compensate for chronic respiratory acidosis.

Hypercapnic respiratory failure occurs with lung disorders that limit exchange of carbon dioxide from the blood to the atmosphere. These lung disorders include:

  • Poor ventilatory muscle function, as occurs with neuromuscular disorders (e.g., Guillain-Barre, drug over-dose);

  • Obstruction of airways and alveoli (e.g., asthma, COPD, pulmonary oedema);

  • Secretions in the small airways and alveoli (e.g., COPD, cystic fibrosis); and

  • Chest wall abnormalities (e.g., traumatic flail chest, kyphoscoliosis).

There are several factors that can trigger respiratory failure, including respiratory, non-respiratory, and traumatic factors.

Respiratory factors

  • Acute pulmonary vascular occlusion can result in ventilation-perfusion mismatch and respiratory failure due to insufficient blood flow to functioning alveoli. Massive pulmonary artery embolisation may cause high right-sided after-load pressures leading to cardiac dysfunction and inability of the heart to circulate adequate blood volume.

  • Pneumothorax can lead to respiratory failure if there is not enough lung reserve to compensate for the collapsed lung or lung segment. This would typically occur in the setting of pre-existing pulmonary dysfunction. Bilateral pneumothorax can cause catastrophic respiratory failure and rapid cardiac arrest.

  • Fluid or blood accumulation in the pleural space (pleural effusion) may lead to compression of pulmonary tissues and loss of pulmonary function, causing respiratory failure. Pleural effusions can occur secondary to infection, malignancy, trauma, cardiac failure, and collagen vascular disease, as well as many other conditions.

  • Destruction or infiltration of alveoli reduces the surface area available for gas exchange. Emphysema causes alveolar destruction, and the bullae that are formed occupy intra-thoracic space without contributing to gas exchange. Respiratory failure results from acute or eventual loss of the baseline number of alveolar units. Infiltration or filling of alveoli with fluid is a frequent cause of acute respiratory failure. Conditions that cause alveolar filling include pneumonia, pulmonary oedema, and pulmonary haemorrhage. Alveolar haemorrhage can occur with Goodpasture's syndrome, granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), and trauma. Fluid-filling of alveoli leads to the inability of these alveoli to provide gas exchange with the blood. Acute respiratory distress syndrome resulting from trauma, hypo-perfusion, or direct insult is a form of alveolar infiltration and injury.

  • Acute upper airway obstruction (e.g., from foreign body aspiration, acute epiglottitis, anatomical abnormalities, anaphylaxis) can inhibit air flow into the lungs and cause respiratory failure. Lower airway obstruction (e.g., from asthma, COPD, cystic fibrosis) is more common and involves constriction or mucous blockage of intermediate-size bronchioles.

  • Pulmonary embolus can occur as a result of hypercoagulability from clotting cascade diseases or abnormalities.

  • Exposure to toxic fumes can lead to damage of the upper airway, lower airway, or alveoli. Industrial gases such as chlorine are an example. The most common inhalation injury is smoke inhalation, where particulate matter and gases intermix and can cause upper airway and lower airway inflammation resulting in respiratory failure. Toxic gases such as carbon monoxide and hydrogen sulfide are exchanged in the lungs, yet result in asphyxia by inhibiting the ability of the blood to effectively extract oxygen from the lungs, as well as causing cellular metabolic damage (cellular asphyxia).

Non-respiratory factors

  • Poor perfusion of the brain, heart, and lungs (e.g., from haemorrhagic hypovolaemia, dehydration hypovolaemia, septic shock, cardiogenic shock, severe anaemia) can result in respiratory failure by reducing blood oxygenation and depressing central nervous system (CNS) respiratory centres.

  • Ventilation with pulmonary gas exchange is dependent on diaphragm and chest wall muscle functioning. Neurological disorders inhibiting respiratory muscle function limit ventilation and can cause respiratory failure. Examples include Guillain-Barre syndrome and myasthenia gravis. Muscular dystrophy results in muscle function abnormalities that limit ventilation and can result in respiratory failure.

  • Opioid and sedative medicines decrease respiratory drive in the CNS, with resulting limited ventilatory effort.

  • Injuries, disease, or insult of the CNS can result in loss of respiratory drive and secondary respiratory failure. Examples include infiltrating and mass cancers of the CNS, head injury with haemorrhagic mass effect, direct brain injury, infections, primary CNS disorders, and stroke.

Traumatic factors

  • Direct thoracic injury may result in a number of abnormalities that can lead to respiratory failure.

  • Direct brain injury can result in loss of respiratory drive.

  • Spinal injury can result in loss of peripheral nerve function and inability to ventilate due to inadequate respiratory muscle function.

Classification

Acute respiratory failure

Acute respiratory failure is a life-threatening acute impairment of oxygenation or carbon dioxide (CO₂) elimination. Respiratory failure may occur because of impaired gas exchange, decreased ventilation, or both. The level of oxygen in the blood becomes dangerously low or the level of carbon dioxide becomes dangerously high. Hypoxaemia occurs over a period of hours to days (less than 7 days). Acute respiratory failure can develop quickly and may require emergency treatment.[2]

Chronic respiratory failure

Chronic respiratory failure is a life-threatening chronic impairment of oxygenation or CO₂ elimination. Hypoxaemia occurs over a period of weeks to months (more than 7 days). Chronic respiratory failure develops more slowly and lasts longer than acute respiratory failure.[3]

Hypoxaemic respiratory failure

Acute respiratory failure that causes a low level of oxygen in the blood without a high level of carbon dioxide. Also known as type I respiratory failure.[4] This occurs when the PaO₂ is <8 kPa (<60 mmHg). The PaO₂ of patients with chronic lung disease can be as low as 6.7 kPa (50 mmHg) normally, and in these patients respiratory failure is defined as a 10% decrease in baseline arterial oxygen measurements.[5]

Hypercapnic respiratory failure

Acute respiratory failure that causes a high level of carbon dioxide in the blood. Also known as type II respiratory failure.[6] This occurs when there is hypoxia (PaO₂ is <8 kPa [<60 mmHg]) associated with a PaCO₂ that is >6.7 kPa (>50 mmHg).[5]

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