Respiratory failure – pathophysiology, and clinical features

01Definition and overview

The respiratory system has two parts, either of which can fail: the gas-exchanging organ (the airways, alveoli and pulmonary circulation) and the ventilatory pump (the respiratory centre, nerves, muscles and chest wall). Respiratory failure is present when gas exchange is impaired enough to cause hypoxaemia, with or without hypercapnia. In practice that is a PaO2 below 8 kPa (60 mmHg) on air at sea level, and in type 2 a PaCO2 that is raised (above about 6 kPa, 45 mmHg); the PaO2 is usually low on air, but can be normal once the patient is on oxygen.

Respiratory failure is acute when it develops over hours or days and the pH is disturbed, and chronic when it develops over weeks, months or years, and the kidneys have compensated. Acute failure can be superimposed on chronic failure, as in a COPD exacerbation. A patient can also have both types at once: a PaO2 that is low for two reasons, and a PaCO2 that is high.

02Etiology and pathophysiology

Why the PaO2 falls

Five mechanisms lower the arterial oxygen. The alveolar–arterial (A–a) gradient, the gap between the oxygen the alveoli should supply and the oxygen in the arterial blood, separates hypoventilation and a low inspired oxygen, where it is normal, from the other three mechanisms, where it is wide.

Most hypoxaemia in disease of the lung is V/Q mismatch, with shunt in the worst cases. Shunt is the reason a patient with a flooded lung can stay hypoxic on a mask delivering 60 per cent oxygen.

Why the PaCO2 rises

The PaCO2 rises when alveolar ventilation falls below what is needed to remove the carbon dioxide the body makes. Alveolar ventilation is the breaths a minute multiplied by the volume of each breath that reaches the alveoli (the tidal volume less the dead space). The pump can fail at any level:

• Drive: sedatives and opioids, brainstem stroke, central sleep apnoea, and severe hypothyroidism.
• Nerves and muscles: high cervical spinal cord injury, motor neurone disease, Guillain–Barré syndrome, myasthenia gravis, muscular dystrophies, and the critical illness neuromyopathy of long stays in intensive care.
• Chest wall and pleura: kyphoscoliosis, flail chest, and severe obesity (obesity hypoventilation).
• Airways: COPD and severe asthma, where the work of breathing is greater than the muscles can sustain, and obstructive sleep apnoea.
• Lungs with a large dead space: emphysema, and the end of an exhausting illness, where tired muscles take shallow breaths.

The rise in PaCO2 acidifies the blood. When it is acute, the pH falls a great deal; when it is chronic, the kidneys retain bicarbonate over several days and bring the pH back close to normal. Patients with chronic hypercapnia and a high bicarbonate then suffer severe acidosis only when something tips them further, an infection or extra oxygen.

Acute respiratory distress syndrome

ARDS is the lung's reaction to a direct injury (pneumonia, aspiration, inhalation, contusion) or an indirect one (sepsis, severe trauma with transfusion, pancreatitis). Inflammation makes the alveolar–capillary barrier leak, flooding the alveoli with protein-rich fluid that is not from heart failure, and surfactant is lost, so the lungs are stiff and collapse. The result is shunt and severe type 1 failure. The Berlin definition asks for onset within a week of an insult, bilateral opacities on imaging, failure not explained by the heart, and a PaO2/FiO2 ratio of 300 mmHg or less on a positive end-expiratory pressure (PEEP) of 5 cmH₂O or more, graded mild, moderate and severe at 200 and 100 mmHg. The 2024 global definition keeps the same core (onset within a week, bilateral opacities on X-ray, CT or ultrasound, not fully explained by heart failure or fluid overload) but also counts patients on high-flow nasal oxygen at 30 L/min or more, or on CPAP or non-invasive ventilation, which the Berlin definition could not, and accepts the SpO₂/FiO₂ ratio (315 or less) where there is no blood gas, as in settings with few resources. Ventilated patients are still graded at 200 and 100 mmHg.

03Clinical features

Hypoxaemia and hypercapnia produce different pictures, and many patients show both.

The signs of respiratory distress are the use of accessory muscles, indrawing of the intercostal spaces, fast breathing, sweating, inability to speak in sentences, an unwillingness to lie flat, and, late and dangerous, agitation, drowsiness and exhaustion. Asynchronous or paradoxical movement of the chest and abdomen shows that the diaphragm is failing.

Central cyanosis appears when more than about 5 g/dL of haemoglobin is deoxygenated, so it is a late sign in a patient who is anaemic, and may be seen in polycythaemia without much hypoxia. A silent chest in an asthmatic and a normal respiratory rate in an exhausted patient are danger signs, not reassurance.

04Diagnosis and management

Diagnosis

An arterial blood gas is the key test: it gives the PaO2 and PaCO2, the pH and the bicarbonate, and shows whether the failure is acute, chronic or acute on chronic. The normal values on air are a pH of 7.35 to 7.45, a PaO2 of 10.6 to 13.3 kPa (80 to 100 mmHg), a PaCO2 of 4.8 to 6.1 kPa (36 to 46 mmHg) and a bicarbonate of 22 to 26 mmol/L. Pulse oximetry follows trends and is a good guide to oxygen, but it does not tell the PaCO2, it can be falsely high in carbon monoxide poisoning, and it is unreliable in poor perfusion.

Then look for the cause: chest X-ray, ECG, blood tests including a count, electrolytes and infection markers, spirometry, and for neuromuscular disease, the vital capacity and maximal respiratory pressures, since the oxygen saturation, the respiratory rate and the tidal volume change late. The PaO2/FiO2 ratio grades severity in ARDS.

Oxygen

Oxygen is given to a target, written on the chart: 94 to 98 per cent for most patients and 88 to 92 per cent for those at risk of hypercapnia (COPD, obesity hypoventilation, chest wall deformity, neuromuscular disease, cystic fibrosis, bronchiectasis with fixed airflow obstruction, and a previous hypercapnic episode). A critically ill patient starts at 94 to 98 per cent until the blood gas is known, and the target is lowered only if the PaCO2 is raised. Devices differ in what they can promise:

• Nasal cannulae and simple masks give a variable concentration, about 24 to 55 per cent, that depends on the patient's breathing.
• A mask with a reservoir bag gives high concentrations in emergencies.
• A Venturi (fixed-performance) mask gives a set concentration, such as 24 or 28 per cent, and is the choice for patients at risk of hypercapnia.
• High-flow nasal oxygen gives warmed and humidified gas at high flow, is well tolerated and slightly splints the airway. It is used in acute hypoxaemic failure, where a large trial found it at least as good as non-invasive ventilation.

Ventilatory support

1. 1

   CPAP

   Continuous positive airway pressure re-expands collapsed alveoli and lowers the work of breathing. It is used in cardiogenic pulmonary oedema, in obstructive sleep apnoea, and after surgery.
2. 2

   Non-invasive ventilation (NIV)

   Bilevel positive pressure through a tight mask, in a patient who is awake, cooperative and able to protect the airway. It is the treatment for acute hypercapnic failure, a pH below 7.35 with a PaCO2 above 6.5 kPa that persists after an hour of optimal medical treatment, in COPD, chest wall disease, neuromuscular disease and obesity hypoventilation. Compared with standard care, it roughly halves the mortality and cuts the need for intubation by about two-thirds in COPD exacerbations.
3. 3

   Invasive ventilation

   Through an endotracheal tube, for severe distress that persists on maximal treatment (breathing rate above about 40, inability to speak, exhaustion), falling consciousness, a rising PaCO2 or a PaO2 below 8 kPa despite oxygen, and when the airway cannot be protected. In neuromuscular disease the vital capacity is followed, since the saturation changes late: critical care is called when it falls below about 20 mL/kg or is falling fast, and ventilation is started by about 10 to 15 mL/kg, earlier with bulbar weakness, a rising PaCO2 or exhaustion.
4. 4

   Severe ARDS

   Prone positioning, for 16 hours or more a day and started early, when the PaO2/FiO2 ratio stays below 150 mmHg on a PEEP of at least 5 cmH₂O; it lowers mortality and is part of standard care. Neuromuscular blockade for a short while and extracorporeal membrane oxygenation (ECMO) in specialised centres are options for selected patients, and guidelines differ on whether blockade should be routine.

Lung-protective ventilation is the standard in ARDS and is used in nearly all ventilated patients: a tidal volume of 6 mL/kg of predicted body weight, which comes from the height and sex (4 to 8), plateau pressures below 30 cmH₂O, PEEP, and acceptance of a mildly raised PaCO2 (permissive hypercapnia) so as not to overdistend the lung. Low tidal volumes improved survival in ARDS. Inhaled nitric oxide has not been shown to improve survival, and high-frequency oscillation is not used, since a trial suggested it may do harm. Corticosteroids were long thought not to help, but a randomised trial of early dexamethasone lowered mortality, and they are now conditionally suggested in ARDS. Fluid is restricted when blood pressure allows.

Treat the cause: antibiotics for pneumonia, diuretics for pulmonary oedema, anticoagulation for embolism, bronchodilators and steroids for obstructive disease, drainage of a pleural collection, and naloxone for opioid overdose.

Chronic failure is managed with long-term oxygen for hypoxaemia, and home non-invasive ventilation, usually at night, for chronic hypercapnia from neuromuscular disease, chest wall disease, obesity hypoventilation and, selectively, COPD that stays hypercapnic after an admission.

05Epidemiology

Acute respiratory failure is a leading reason for admission to critical care, and COPD is its commonest cause of the hypercapnic type. About one admission in ten to a critical care unit meets the Berlin definition of ARDS, and pneumonia and non-pulmonary sepsis are its commonest risk factors; in older series up to about 40 per cent of patients with the sepsis syndrome developed it.

Chronic hypercapnic failure is increasing with the rise in obesity: obesity hypoventilation is a growing reason for home ventilation, and with COPD, motor neurone disease and the muscular dystrophies it makes up most of the patients on long-term ventilation.

06Prognosis

The outcome depends mainly on the cause, the patient's age and other illnesses, and how many organs fail. A patient with a reversible type 2 failure from a COPD exacerbation, ventilated early, has a good chance of leaving hospital; the outlook is worse in the elderly with severe underlying disease or with a very low pH. Non-invasive ventilation lowers the death rate.

In ARDS, mortality grows with severity: about 27, 32 and 45 per cent in mild, moderate and severe disease in the Berlin cohort. Hospital mortality was about 35 to 46 per cent across the grades in recent international data, and ARDS is still under-recognised and under-treated. It has fallen from about 60 per cent as lung-protective ventilation and general care improved, and it is highest when the cause is intra-abdominal sepsis. Most deaths come from multiple organ failure rather than from failure of gas exchange alone. Survivors often have lasting weakness, tiredness and reduced exercise capacity for months or years, and some a lasting psychological burden.

Chronic hypercapnic failure that needs home ventilation is a marker of advanced disease; survival depends on the cause and is poorest in COPD with frequent admissions, while patients with obesity hypoventilation or a stable neuromuscular disease can do well for years on night-time ventilation.