Aetiology

Respiratory acidosis (the consequence of prolonged hypercapnia) occurs because of acute, acute-on-chronic, or chronic derangements in the respiratory system that produce an imbalance between carbon dioxide production and elimination. In normal conditions, ventilation is regulated to maintain arterial partial pressure of carbon dioxide (PaCO₂) between 35 mmHg and 45 mmHg and arterial pH of 7.35 to 7.45.[1]

The elimination of carbon dioxide depends on alveolar ventilation (i.e., the volume of fresh gas that enters the alveoli with each inspiration).

  • Alveolar ventilation is the difference between total ventilation and physiological dead space ventilation, and is directly proportional to carbon dioxide elimination.

  • Physiological dead space is the volume of air that does not participate in exchange of carbon dioxide. It is the sum of the anatomical dead space (the conducting airways that do not participate in gas exchange) and alveolar dead space (areas of the lung with high ventilation to perfusion ratios [>1] due to ventilation/perfusion (V/Q) mismatching).[3][4]​​

On this physiological basis, causes and development of respiratory acidosis can be broadly categorised based on the following underlying pathological mechanisms:

  • Decrease in alveolar ventilation due to a decrease in total ventilation.

  • Decrease in alveolar ventilation due to an increase in dead space ventilation.

  • Increase in carbon dioxide production.

Decreased total ventilation

Respiratory acidosis may occur as a result of decreased alveolar ventilation as a consequence of decreased total ventilation (hypoventilation), underlying causes include:[5]

  • Decreased central respiratory drive:

    • drugs (sedatives, opiates, anesthetics),

    • central nervous system disease (CNS; e.g., stroke, trauma, encephalitis)

    • obesity hypoventilation syndrome

    • congenital diseases such as primary alveolar hypoventilation.

  • Altered neural transmission or myopathy:

    • Spinal cord injury

    • Amyotrophic lateral sclerosis (ALS)

    • Poliomyelitis

    • Guillain-Barre syndrome

    • Phrenic nerve injury

    • Muscular dystrophy

    • Polymyositis

  • Altered neuromuscular transmission:

    • Tetanus

    • Guillain-Barre syndrome

    • Organophosphate toxicity

    • Botulism

    • Myasthenia gravis

  • Chest wall deformities:

    • acute injury (e.g., flail chest, ruptured diaphragm),

    • congenital deformity (scoliosis, kyphosis, ankylosing spondylitis),

    • thoracoplasty

    • fibrothorax.

  • Upper airway disorders:

    • Upper airway obstruction (e.g., laryngospasm and angio-oedema).

  • Electrolyte disturbances (e.g., hypokalaemia, hypophosphataemia)

  • Endocrine disorders (e.g., hypothyroidism).

Increased dead space ventilation

Respiratory acidosis may be caused by a decrease in alveolar ventilation due to increase in dead space ventilation.[3]​ Rapid shallow breathing results in increased dead space ventilation, decreasing gas exchange, and, in turn, increased PCO2. Conditions associated with increased physiological dead space include:

  • Acute respiratory distress syndrome (ARDS)

  • Acute lung injury (ALI)

  • Advanced COPD

  • Pneumonia

  • Excessive oxygen therapy in COPD

  • Acute severe asthma

Increased carbon dioxide production

Causes that result in respiratory acidosis due to increased carbon dioxide production include:

  • High carbohydrate loads, which may be caused by:[6][7]

    • Total parenteral nutrition (TPN)

    • Overfeeding

  • Hypermetabolic states, which may be due to:[8]

    • Thyrotoxicosis

    • Catabolic states (e.g., sepsis, hypercortisolism)

    • Fever

While classifying aetiologies based on the underlying pathophysiology can be helpful, it is often challenging to apply this in a clinical setting because there is a wide range of conditions that can lead to respiratory acidosis and several mechanisms may contribute to the development of hypercapnia in some patients. From a clinician’s perspective, it is more practical to determine the acuity of the condition (acute, acute-on-chronic, or chronic) and approach the differential diagnosis from an organ-based perspective.

An abrupt failure of ventilation, as occurs with CNS disease, drug-induced respiratory depression, or worsening of ventilation in patients with limited pulmonary reserve, such as in patients with exacerbation of COPD, results in elevated PaCO₂ levels (>45 mmHg), and there is a corresponding reduction in pH below 7.35. In contrast, patients who develop acute-on-chronic respiratory acidosis have elevated PaCO₂ levels (>45 mmHg), but their pH is higher than predicted by the elevated PaCO₂ level. In chronic respiratory acidosis, elevated PaCO₂ levels are associated with normal or near-normal pH (7.33 to 7.35) because of renal compensation.[9]

The development of respiratory acidosis is frequently accompanied by hypoxaemia. The calculation of the PAO2 - PaO2 (alveolar to arterial or A-a gradient) from a room air blood gas is helpful in distinguishing hypoventilation due to a decrease in total ventilation (A-a gradient is normal) from respiratory failure due to abnormal gas exchange from intrinsic lung disease (A-a gradient is widened). Of course, the normal A-a gradient (A-a gradient = age x 0.3) must be adjusted for age.[10]

Parenchymal lung disease

  • Both intrinsic lung disease and pulmonary vascular pathology can impair carbon dioxide excretion.

  • Common causes of hypercapnia are COPD and pneumonia.[11] Cardiogenic pulmonary oedema rarely causes hypercapnia, and it is a late complication of acute respiratory distress syndrome due to a combination of the use of positive end-expiratory pressure and increased dead space.

  • Acute lung injury is an uncommon but serious cause.

  • Additionally, it has been well established that excessive oxygen supplementation in chronic lung diseases, especially during acute COPD exacerbation, can result in worsening hypercapnia and poorer outcomes. However, the mechanism behind this phenomenon has been the focus of debate. It is likely multi-factorial, resulting from a combination of depression of the hypoxic respiratory drive, the Haldane effect, increased dead space ventilation, and absorption atelectasis.[12]

Airway obstruction

  • Often dramatic and acute, airway obstruction is a life-threatening emergency.

  • Causes include foreign body aspiration, laryngospasm, status asthmaticus, and angio-oedema.

  • Laryngospasm, status asthmaticus, and angio-oedema are uncommon causes of respiratory acidosis, except in the last stages when patients present with hypoxaemia or respiratory distress.

Central nervous system

  • CNS depression leads to alveolar hypoventilation by depression of the respiratory centre.

  • Often associated with altered mental status.

  • Common causes include intentional or accidental drug ingestion.

  • Serious causes include CNS infarction, haemorrhage, and infection.

Impaired chest wall mobility

  • Characterised by restriction of the normal chest wall excursion.

  • Pleural disease (effusion, empyema, pneumothorax, haemothorax, fibrothorax) may impair normal lung parenchymal expansion.

  • Common causes include obesity, pleural effusions, and empyema.

  • Serious causes include flail chest, pneumothorax, haemothorax, and empyema.

  • Skeletal diseases, such as kyphoscoliosis and ankylosing spondylitis, minimise normal chest expansion.

Neuromuscular disorders

  • Neuromuscular disorders can affect any component of the nerve-muscle complex.

  • Other neuromuscular abnormalities are typically present.

  • Common causes include electrolyte derangements (hypokalaemia and hypophosphataemia).

  • Serious causes include progressive neurological diseases (Guillain-Barre syndrome, amyotrophic lateral sclerosis), high cord trauma/lesion, organophosphate ingestion, tetanus, and botulism.

  • Systemic illnesses such as myasthenia gravis and hypothyroidism can be associated with hypoventilation, although hypothyroidism is an uncommon cause of respiratory acidosis, except in the last stages when patients present with hypoxaemia.

Overproduction of carbon dioxide

  • Systemic illnesses can lead to increased carbon dioxide production sufficient to overwhelm the normal respiratory system, but overproduction of carbon dioxide is a rare cause of respiratory acidosis.

  • Some causes are malignant hyperthermia, sepsis, heat exhaustion, thyrotoxicosis, and overfeeding with parenteral nutrition.

Other

  • Inadequate mechanical ventilation and insufflation of carbon dioxide into a body cavity (laparoscopic surgery) should be considered in the appropriate clinical setting.

  • The causes of respiratory acidosis associated with inadequate mechanical ventilation are diverse, and specific testing should focus on the history and examination findings.

  • Low tidal volume ventilation will commonly cause respiratory acidosis due to intentional hypoventilation as part of a lung-protective ventilation strategy.[13]

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