A. The components of the extrapulmonary compartment are the (a) central nervous system (CNS), (b) peripheral nervous system, (c) respiratory muscles, (d) chest wall, (e) pleura, and (f) upper airway.

B. Extrapulmonary compartment impairment causes hypoventilation; the resultant respiratory failure is always hypercapnic.

C. Hypercapnic respiratory failure is due to extrapulmonary causes in up to 17% of cases.

A. Extrapulmonary disorders lead to hypercapnic respiratory failure from a decrease in normal force generation (CNS dysfunction, peripheral nervous system abnormalities, chest wall, pleural disorders, or respiratory muscle dysfunction) or an increase in impedance to bulk flow ventilation (upper airway obstruction).

B. Any condition that impairs respiratory muscle function can result in decreased force generation; if impairment is severe enough, alveolar ventilation may be compromised and PaCO₂ increased.

C. CNS depressants (narcotics, barbiturates), metabolic abnormalities (hypothyroidism, starvation, metabolic alkalosis), CNS structural lesions, primary alveolar hypoventilation, and central sleep apnea cause either a decrease in central respiratory drive from loss of sensitivity to PaCO₂ and pH changes or as a result of a peripheral chemoreceptor loss of sensitivity to hypoxia.

D. Disruption of impulse transmission from the respiratory center in the brainstem to the respiratory muscles may result in respiratory failure. The innervation of the inspiratory respiratory muscles may be involved as part of a generalized process, such as in Guillain-Barré syndrome (GBS), myasthenia gravis, amyotrophic lateral sclerosis (ALS), neuromuscular junction blockade, or as an isolated abnormality with variable affects to the respiratory system depending on the level of the injury, such as in phrenic nerve palsy and spinal cord trauma or lesions.

E. Peripheral nervous system dysfunction that causes hypercapnic respiratory failure is always associated with a reduced vital capacity (usually <50% of predicted value) and markedly decreased maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) at the mouth (usually to <30% of predicted). A few examples of this include ALS, poliomyelitis, GBS, paralytic shellfish poisoning, diphtheria, tick paralysis, myasthenia
gravis, Eaton-Lambert syndrome, critical illness polyneuropathy, botulism, and organophosphate poisoning.

F. Certain systemic myopathies feature prominent respiratory muscle involvement, such as muscular dystrophies, myotonic disorders, inflammatory and endocrine myopathies, and electrolyte disturbances (hypophosphatemia, hypermagnesemia/hypomagnesemia, hypokalemia, hypercalcemia).