Diseases that reduce minute ventilation or increase dead space fall into four major categories: parenchymal lung and chest wall disease, sleep disordered breathing, neuromuscular disease, and respiratory drive disorders (Fig. 264-1B). The clinical manifestations of hypoventilation syndromes are nonspecific (Table 264-1) and vary depending on the severity of hypoventilation, the rate at which hypercapnia develops, the degree of compensation for respiratory acidosis, and the underlying disorder. Patients with parenchymal lung or chest wall disease typically present with shortness of breath and diminished exercise tolerance. Episodes of increased dyspnea and sputum production are hallmarks of obstructive lung diseases, such as chronic obstructive pulmonary disease (COPD), whereas progressive dyspnea and cough are common in interstitial lung diseases. Excessive daytime somnolence, poor quality sleep, and snoring are common among patients with sleep-disordered breathing. Sleep disturbance and orthopnea are also described in neuromuscular disorders. As neuromuscular weakness progresses, the respiratory muscles, including the diaphragm, are placed at a mechanical disadvantage in the supine position due to the upward movement of the abdominal contents. New-onset orthopnea is frequently a sign of reduced respiratory muscle force generation. More commonly, however, extremity weakness or bulbar symptoms develop prior to sleep disturbance in neuromuscular diseases, such as amyotrophic lateral sclerosis (ALS) or muscular dystrophy. Patients with respiratory drive disorders do not have symptoms distinguishable from other causes of chronic hypoventilation.
The clinical course of patients with chronic hypoventilation from neuromuscular or chest wall disease follows a characteristic sequence: An asymptomatic stage where daytime PaO2 and PaCO2 are normal, followed by nocturnal hypoventilation, initially during rapid eye movement (REM) sleep and later in non-REM sleep. Finally, if vital capacity drops further, daytime hypercapnia develops. Symptoms can develop at any point along this time course and often depend on the pace of respiratory muscle functional decline. Regardless of cause, the hallmark of all alveolar hypoventilation syndromes is an increase in alveolar PCO2 (PACO2) and, therefore, in PaCO2. The resulting respiratory acidosis eventually leads to a compensatory increase in plasma bicarbonate concentration. The increase in PACO2 results in an obligatory decrease in PAO2, often resulting in hypoxemia. If severe, the hypoxemia manifests clinically as cyanosis and can stimulate erythropoiesis, thereby inducing secondary erythrocytosis. The combination of chronic hypoxemia and hypercapnia may also induce pulmonary vasoconstriction, leading eventually to pulmonary hypertension, right-ventricular hypertrophy, and right heart failure.